Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]2[C:15]3[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:33]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1)Nc1cc(C(F)(F)F)ccc1F
Yield: 42 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a white solid (30 mg, 42%).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:34](#[N:37])[CH:35]=C>>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:35][C:34]#[N:37])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: C=CC#N
Agent: Cl
Product: CCCCc1nnc(OC2CCN(CCC#N)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine (Example 14, 0.244 mmol, 100 mg) and acrylonitrile (1 mL) may be stirred at room temperature for 20 h. The organic solvent may be removed in vacuo, and the residue may be purified by column chromatography on silica gel using 1-2% of MeOH in DCM to provide 3-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-propionitrile.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[C:5]([O:14][CH3:15])=[C:6]([C:10]([Cl:13])=[CH:11][CH:12]=1)[C:7](Cl)=[O:8]>C(Cl)(Cl)Cl>[Cl:3][C:4]1[C:5]([O:14][CH3:15])=[C:6]([C:10]([Cl:13])=[CH:11][CH:12]=1)[C:7]([NH:1][NH2:2])=[O:8]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: NN
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)ccc(Cl)c1C(=O)NN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.22 mol. hydrazine in 100 ml. chloroform at -10° C. was added 0.1 mol. of 3,6-dichloro-2-methoxybenzoyl chloride. The mixture was stirred at ambient temperature for 2 hours, filtered, and the filtrate evaporated in vacuo. The residue was crystallized from methanol and water, then recrystallized from chloroform and hexane to obtain the titled product, m.p. 144°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccc(Br)cc2)n[nH]1
Product: Clc1ccc(-c2ccc(Br)cc2)nn1

Procedure:
A mixture of 20.0 g. of 6-(p-bromophenyl)-3(2H)-pyridazinone (prepared as described in Example 1) in 100 ml. of phosphorus oxychloride is heated at reflux temperature for 41/2 hours. The excess phosphorus oxychloride is removed under reduced pressure and the residue is stirred with water-cracked ice to decompose the remaining phosphorus oxychloride. The product is recovered by filtration and recrystallized from dilute dimethylformamide yielding tan crystals, m.p. 201°-203° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=2)[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: C[C@@H](N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 92 %

Procedure:
The example 14 was prepared form the reaction of piperazino derivative 2 and 4-nitrobenzoyl chloride by following the similar procedure described for the example 12. After column purification the product was obtained as brown prisms in 92% yield.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:10]=[CH:11][C:12](=[S:15])[NH:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>>[CH3:22][S:15][C:12]1[CH:11]=[CH:10][C:9]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])=[CH:14][N:13]=1
Reactant: O=S(c1ccccc1)c1ccc(=S)[nH]c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(S(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-(phenylsulfinyl)pyridine-2-thione (2.21 g., .01 moles) in 25 ml. of 2.5N sodium hydroxide is treated with 1.6 g. of dimethyl sulfate. After stirring at room temperature for 3 hours, the reaction mixture is extracted with methylene chloride. The extracts are washed with water, dried and evaporated in vacuo to yield 2-(methylthio)-5-(phenylsulfinyl)pyridine.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:18][N:16]1[CH:17]=[C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)[CH:14]=[N:15]1
Reactant: Cc1oc(-c2cnn(C)c2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2cnn(C)c2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A mixture of 4-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-1-methyl-1H-pyrazole (1.0 g), methyl 4-aminobenzoate (0.9 g), sodium carbonate (0.6 g) and sodium iodide (1.1 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 55% ethyl acetate/hexane) to give the title compound (0.5 g, 39%) as an amorphous compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O.C([O-])(=O)C>CN(C=O)C>[CH2:26]([O:25][C:23]([CH2:22][N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])=[O:24])[CH3:27]
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
Methyl 3-hydroxy-2-(4-nitro-benzenesulfonylamino)-propionate (4.0 g, 13.1 mmol) and potassium carbonate anhydride (5.45 g, 39.4 mmol) were suspended in DMF (25 mL), and ethyl bromoacetate (2.91 mL, 26.3 mmol) was added dropwise at 0° C. After stirring for 4 hours, 50 mL of distilled water and 100 mL of acetate were introduced and stirred to separate layers. The supernatant was washed with 50 mL of a 5% Na2S2O3 aqueous solution, 50 mL of a 1N HCl aqueous solution, 50 mL of a saturated NaHCO3 aqueous solution, and 100 mL of distilled water, and it was dried and concentrated under reduced pressure. The mixture was separated with hexane and ethylacetate (2:1) in a silica gel column to obtain a yellow oil (4.43 g, 86.5).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6](=[O:18])[CH2:5][CH2:4][NH:3]1.I[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[CH3:1][C@@H:2]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6](=[O:18])[CH2:5][CH2:4][N:3]1[C:24]1[CH:25]=[CH:20][CH:21]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1
Product: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1c1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared from (R)-2-methyl-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (Example 39E) and 1-iodo-3-trifluoromethoxy-benzene in analogy to example 33. MS: 414.4 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[CH2:32]([O:34]C1C=CC=CC=1N1CCNCC1)[CH3:33]>>[CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[O:34][CH2:32][CH3:33])[CH2:19][CH2:20]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCOc1ccccc1N1CCNCC1
Product: CCOc1ccccc1N1CCN(CCn2c(CC)nc3ccccc3c2=O)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2-ethoxyphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[OH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:39]2[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]2)[CH:7]=1)=[O:9]
Reactant: OCCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(N3CCN(CCO)CC3)c2)c1)c1ccnc(N2CCOCC2)c1
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(2-hydroxyethyl)piperazine to give the title compound in 62% yield; NMR Spectrum: (DMSOd6) 2.45 (m, 8H), 3.53 (m, 8H), 3.71 (m, 4H), 4.4 (t, 1H), 7.07 (t, 2H), 7.25 (d, 2H), 7.54 (d, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.26 (t, 2H), 10.19 (s, 1H), 10.47 (s, 1H): Mass Spectrum: M+H+ 566.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][OH:24]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][C:27]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(F)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(CO)ccc1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-4-fluorobenzyl alcohol (Oakwood), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:11]=[CH:10][NH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[CH:11]=[CH:10][N:9]([S:35]([C:33]3[CH:32]=[CH:31][C:22]4[N:23]([CH2:24][CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)[C:19]([C:15]([CH3:18])([CH3:14])[CH2:16][CH3:17])=[N:20][C:21]=4[CH:34]=3)(=[O:37])=[O:36])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(NC1CC1)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC4CC4)c3)ccc2n1CC1CCOCC1
Yield: 83.3 %

Procedure:
Following the same procedure in Example 29, using N-cyclopropyl-1H-pyrrole-3-carboxamide (49 mg, 0.33 mmol) (see the step B in example 32 for preparation), sodium hydride (110 mg, 60%, 2.75 mmol) and 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (354 mg, 0.92 mmol) in THF (10 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to give 137 mg (83%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.50-0.57 (m, 2 H), 0.69-0.75 (m, 2 H), 0.78 (t, J=7.42 Hz, 3 H), 1.42-1.56 (m, 4 H), 1.60 (s, 6 H), 1.95 (q, J=7.62 Hz, 2 H), 2.21-2.37 (m, 1 H), 2.67-2.75 (m, 1 H), 3.23-3.35 (m, 2 H), 3.84-3.93 (m, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 6.65 (dd, J=3.32, 1.76 Hz, 1 H), 7.28 (dd, J=3.32, 2.15 Hz, 1 H), 7.77-7.84 (m, 1 H), 7.90-8.01 (m, 2 H), 8.26 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=499.0; Anal. Calcd for C26H34N4O4S+1.2 TFA (635.48): C, 53.68; H, 5.58; N, 8.82. Found: C, 53.65; H, 5.61; N, 8.56.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COC(=O)C(CC1C=CC=CC=1)[C:11]1[C:19]2[C:14](=[C:15]([CH2:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:20]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([CH:32]([CH2:33][C:34]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[CH2:31][OH:30])=[CH:11]2)[CH3:21]
Reactant: C1CCOC1
Reactant: CCc1cccc2c(C(Cc3ccccc3)C(=O)OC)c[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1cccc2cc(C(CO)Cc3ccccc3)[nH]c12
Temperature: 0 °C
Yield: 96 %

Procedure:
To a stirred suspension of lithium aluminum hydride (0.702 g, 18.5 mmol) in 80 mL of anhydrous tetrahydrofuran under nitrogen at 0° C. was slowly added (about 1.5 hours) a solution of 7-ethyl-α-(phenylmethyl)-1H-indole-3-acetic acid methyl ester (prepared in Step 2) (5.17 g, 16.8 mmol) in 30 mL of anhydrous tetrahydrofuran. The resulting dark red mixture was heated under reflux for 2 hours. It was cooled to 0° C., and quenched by the dropwise addition of 40 mL of water. The precipitated aluminum salts were removed by filtration and washed with ether. The layers of the filtrate were separated, and the aqueous layer was washed with ether. The combined ether layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give the desired alcohol as a brown oil (4.51 g, 96%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)=[N:7][C:2]([NH:18][C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)=[N:3][CH:4]=1
Reactant: OCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(O)c1
Product: OCc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2Cl)c1
Yield: 85 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using {3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}methanol and 3-aminophenol as the starting materials in 85% yield. LCMS for C17H16ClN4O2 (M+H)+: m/z=343.1.
Reaction SMILES: [Si](C([O:17][CH:18]([Si](C(C)(C)C)(C)C)[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)C1C=C(Cl)C=C(Cl)C=1)(C(C)(C)C)(C)C.C([Li])CCC.[Cl:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1.Cl>CCCCCC.O1CCCC1>[Cl:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([Cl:26])[C:22]=1[C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([Cl:39])=[CH:41][CH:42]=1)[CH2:18][OH:17]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)C(OC(c1cc(Cl)cc(Cl)c1)[Si](C)(C)C(C)(C)C)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CO)cc1Cl

Procedure:
React t-Butyldimethylsilyl-3,5-dichlorobenzyl ether (858.A1) (1 mole) with n-Butyllithium 1.6M solution in hexane followed by 4-Chlorobenzoyl chloride, (1.01 mole), in Tetrahydrofuran, while cold and treat the intermediate with aqueous Hydrochloric acid to give 3,5-dichloro-4-(4-chlorobenzoyl)benzyl alcohol (858.B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:6][CH:7]=1.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:21][C:4]1[C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(Cl)cc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(Cl)cc2N)C1
Yield: 92.9 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(5-chloro-3-nitropyridin-2-ylamino)pyrrolidine-1-carboxylate (802 mg, 2.34 mmol) in MeOH (25 mL) and water (25 mL) were added iron dust (2.00 g, 35 mmol) and NH4Cl (1.25 g, 2.4 mmol). The mixture was heated at reflux for 6 h and filtered through Celite, washing with EtOAc. The filtrate was concentrated and the residue was dissolved in CH2Cl2 (150 mL) and 1 M aq NaOH (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined CH2Cl2 layer was washed with brine (50 mL), dried over Na2SO4 and concentrated to leave (R)-tert-butyl 3-(3-amino-5-chloropyridin-2-ylamino)pyrrolidine-1-carboxylate (680 mg, 93%) as a black solid. LC-MS Method 1 tR=1.28 min, m/z=313, 257.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)=O)(C)(C)C.Br[C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]1([S:32]([N:29]2[C:26]3=[N:27][CH:28]=[C:23]([C:11]4[CH:12]=[N:8][NH:9][CH:10]=4)[CH:24]=[C:25]3[CH:31]=[CH:30]2)(=[O:34])=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cn[nH]c3)cnc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a degassed (sparging with argon for 5 minutes), stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.31 g, 4.45 mmol) and 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.97 mmol) in dioxane (12.0 ml) was added Pd(Ph3P)4 (0.171 g, 0.148 mmol), followed by a degassed aqueous solution of sodium carbonate (4.45 ml, 8.90 mmol). The reaction mixture was stirred under nitrogen at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and saturated aqueous ammonium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 1-(phenylsulfonyl)-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as a yellow solid. LRMS (ESI) calculated for C16H12N4O2S [M+H]+, 325.1; found 325.0.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:33]1([S:39]([NH:2][CH:3]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:4]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[O:5])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
3,5-Dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (1.0 g) was suspended in tetrahydrofuran (10 ml). Triethylamine (0.38 ml) was added and the solution was stirred for 15 mins. Benzenesulphonyl chloride (0.35 ml) was added and the solution was stirred at room temperature for 1 hour. Work-up as for Example 14 gave a solid which was recrystallised from ethanol to yield the title compound, 0.85 g, m.p. 114°-116° C. 1H NMR (360 MHz, CDCl3) δ7.98 (1H, s), 7.72 (2H, d, J=7 Hz), 7.54-7.30 (5H, m), 7.17 (1H, t, J=7 Hz), 7.06 (1H, t. J=7 Hz), 6.94 (1H, s), 6.89 (1H, s), 6.62 (2H, s), 5.17 (1H, d, J=9.2 Hz), 4.68 (2H, ABq, J=11.9 Hz), 4.33 (1H, m), 3.27 (2H, m), 2.27 (6H, s).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])=[C:2]=[S:3].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[NH2:22].C(O)(=O)C>C(O)C>[SH:3][C:2]1[N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])[C:14](=[O:13])[C:15]2[C:16](=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:22]=1
Reactant: COc1ccccc1N=C=S
Reactant: COC(=O)c1ccc(C)cc1N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1-n1c(S)nc2cc(C)ccc2c1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
1-Isothiocyanato-2-methoxy-benzene (0.76 mL, 5.45 mmol) was added to a solution of 2-amino-4-methyl-benzoic acid methyl ester (900 mg, 5.45 mmol) and acetic acid (1.5 mL) in ethanol (10 mL), and heated at reflux for 16 hr. The reaction mixture was cooled to room temperature and diluted with ethanol. The precipitated solid was filtered, washed with ethanol and dried to afford 2-mercapto-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (1.0 g, 62%) as white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1.C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]2[C:22]([CH:33]([CH3:34])[CH3:35])=[CH:23][C:24]([CH:30]([CH3:31])[CH3:32])=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)c(C(C)C)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(N)cc2C(C)C)c(C(C)C)c1
Reaction time: 21 h
Yield: 89.5 %

Procedure:
22.0 g of [(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-4-nitro-phenyl ester and 6 g of Raney nickel were mixed in 110 mL tetrahydrofuran under 50 psi of hydrogen. After 21 hours, the reaction was filtered and concentrated to give an orange oil which was dissolved in ethyl acetate, filtered through a pad of silica, and concentrated to give an oily solid. Recrystallization from 53 diethyl ether/hexanes gave 18.60 g (89%) of the title compound as a cream colored solid; mp 153-155° C.