Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[CH:22]=[CH:23][C:24](O)=[O:25].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]([NH:1][C@H:2]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=2)[CH3:3])=[O:25])[CH:27]=[CH:28][CH:29]=1
Reactant: C[C@H](N)c1cccc(NCc2cccnc2)c1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1cccc(Cl)c1)c1cccc(NCc2cccnc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
A mixture of (s)-[3-(1-amino-ethyl)-phenyl]-pyridin-3-ylmethyl-amine (0.2 mmol), 3-chlorocinnamic acid (0.2 mmol), EDACeHCl (0.4 mmol), DMAP (0.2 mmol), triethylamine (0.6 mmol) in dichloromethane (4 mL) was stirred at 5 room temperature for 12 h. The reaction mixture was purified by flash chromatography eluting with 5% methnol in ethyl acetate to provide the desired title compound (51 mg) as a solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C@H:18]2[C@H:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:21][N:20]([C:30]([N:32]3[CH2:37][CH2:36]S[CH2:34][CH2:33]3)=[O:31])[CH2:19]2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:42][S:43]([O-:46])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O.[K+].[K+].[K+].[K+].[K+].OS([O-])=O.[Na+].C([O-])(O)=O.[Na+]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C@H:18]2[C@H:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:21][N:20]([C:30]([N:32]3[CH2:37][CH2:36][S:43](=[O:46])(=[O:42])[CH2:34][CH2:33]3)=[O:31])[CH2:19]2)[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:8]=1
Reactant: O=S(=O)([O-])O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)N2CCSCC2)C[C@H]1c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)N2CCS(=O)(=O)CC2)C[C@H]1c1ccc(F)cc1
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a stirred solution of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-1-(thiomorpholine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (0.20 g, 0.33 mmol, described herein above) in MeOH (2 ml) at RT, was added potassium monopersulfate triple salt (0.30 g, 0.49 mmol). Stirring was continued an additional 3 hours, then a solution of NaHSO3 (40%) was added, the ph was adjusted to 9 with an aqueous solution of NaHCO3, and finally the product was extracted with Et2O. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 185 mg (88%) of the title compound as_white foam.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][NH:48]1>CN(C)C=O>[CH3:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][N:48]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCCCN1CCCOc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and (RS) 2-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.N1CCOCC1>C(O)C.CO.[C].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: O=[N+]([O-])c1cc(/C=C\c2ccccc2)ccc1Cl
Agent: [Rh]
Solvent: CO
Solvent: CCO
Solvent: C1COCCN1
Product: Nc1cc(CCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a suspension of 4-chloro-3-nitrobenzaldehyde (1 g) and benzyltriphenylphosphonium bromide (2.34 g) in toluene (35 mL) was added sodium hydride (55%, 0.28 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with methylene chloride. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 2-chloro-5-((Z)-2-phenylvinyl)-1-nitrobenzene (0.79 g). The obtained 2-chloro-5-((Z)-2-phenyl -vinyl)-1-nitrobenzene (0.16 g) was dissolved in ethanol (6 mL) -methanol (2 mL). To the solution was added 5% rhodium-carbon powder (20 mg) and morpholine (5 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (87 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[O:18][C:17](=[O:19])[CH2:16][C@@H:15]([CH:20]=[CH2:21])[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.C(#[N:31])C>>[NH2:31][N:2]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[O:18][C:17](=[O:19])[CH2:16][C@@H:15]([CH:20]=[CH2:21])[CH2:14]2)=[CH:5][CH:4]=1
Reactant: C=C[C@@H]1CC(=O)O[C@H](CCCCc2ccc(C#N)cc2)C1
Reactant: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1CC(=O)O[C@H](CCCCc2ccc(C=NN)cc2)C1

Procedure:
The title compound was prepared from the product of step C (1.00 g, 3.53 mmol) in a manner similar to example 1 step G with a modification in the purification. The residue was dissolved in acetonitrile and TFA (402 mg, 3.53 mmol) was added. The solvent was evaporated under reduced pressure and the residue redissolved in a minimal amount of acetonitrile. Addition of Et2O caused the precipitation of the crude product which was filtered and washed with Et2O. The material was briefly suspended in ice water, filtered, washed with ice water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1O)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:28])=O.[Na+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1[Cl:28])=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2cccc(F)c2)c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
4-(3-Fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (15) (60 g, 0.17 mol) was dissolved in 600 mL anhydrous DMF under a blanket of argon and cooled to −30° C. Oxalyl chloride (40.7 mL, 0.47 mol) was then added very slowly (producing a large volume of gas), with the reaction vessel open to the atmosphere. The solution was then heated to 75° C. for 2 hours. The solution was cooled to room temperature and poured into a solution of 150 g. NaCl in 6 L ice water without stirring. The mixture was allowed to sit without stirring for 15 minutes, and was then stirred vigorously for 1 minute with a spatula. The precipitated solid product was collected by vacuum filtration to yield 55 g (87% yield) of 7-chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.34 (q, J=7.2 Hz, 2H), 5.45 (s, 2H), 7.06-7.17 (m, 3H), 7.37 (m, 1H), 7.49 (d, J=5.6 Hz, 1H), 8.20 (d, J=5.6 Hz, 1H) ppm; EIMS m/z 366 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[CH:6]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[O:34][C:35]([CH2:38]Br)=[CH:36][CH:37]=1)=[O:32])[CH3:29]>>[CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[CH:6]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:38][C:35]4[O:34][C:33]([C:31]([O:30][CH2:28][CH3:29])=[O:32])=[CH:37][CH:36]=4)[CH:23]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1ccc(CBr)o1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C(C)C)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of step (vi) (1 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807)(0.65 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 20% ethyl acetate in toluene. Yield 0.375 g.
Reaction SMILES: C([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C)=O.[CH3:17][Mg]I>>[C:16]1([CH:11]=[CH:3][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:17]=1
Reactant: C[Mg]I
Reactant: CC(C=O)(c1ccccc1)c1ccccc1
Product: C(=Cc1ccccc1)c1ccccc1

Procedure:
For example, vinylnaphthalene may be obtained by reacting formylnaphthalene with a Grignard reagent such as methyl magnesium iodide and then dehydrating the reaction product. Vinylphenylphenylethane may be obtained by reacting diphenylethane with acetyl chloride in the presence of a Friedel-Craft catalyst to produce acetylphenylphenylethane, reducing the thus produced product with sodium boron hydride and then dehydrating the thus reduced product. Isopropenylphenylphenylethane may be obtained by reacting formylphenylphenylethane with a Grignard reagent such as methyl magnesium iodide and then dehydrating the reaction product. 1,2-diphenylethylene may be obtained by reacting benzaldehyde with benzyl magnesium bromide and then dehydrating the reaction product; 1,2-diphenylpropene may likewise be obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:22][CH:21]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (30.0 mg, 0.133 mmol) using the same procedure employed for Example 2 (2), but with 4-methoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (13.2 mg, 27%) having the following characteristics.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[C:11]([CH2:28][NH:29][CH3:30])=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:14]=[CH:13]2>ClCCl>[CH3:8][O:9][C:10]1[C:11]([CH2:28][N:29]([CH3:30])[C:3](=[O:4])[O:5][C:11]([CH3:28])([CH3:12])[CH3:10])=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:14]=[CH:13]2
Reactant: CNCc1c(OC)ccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine (0.627 g, 1.9 mmol; Example 144) was dissolved in dichloromethane (25 ml) and boc-anhydride (0.62 g, 2.8 mmol) was added. The mixture was stirred for 2 hours, washed with brine, dried (MgSO4) and evaporated. The crude product was purified through a plug of silica using 5% MeOH in dichloromethane as the eluent. Yield 0.628 g (78%). White solid. MS (ESI+) for C22H26N2O5S m/z 375 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1C(=O)C2=CC=CC=C2C1=O.O.NN.O>CO>[Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH2:6]
Reactant: Cc1c(Cl)cccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cccc1CN
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
1.15 g of N-(3-chloro-2-methylbenzyl)phthalimide was dissolved in 20 mL of methanol, and 5 mL of hydrazine monohydrate was added thereto at room temperature. Thereafter, it was warmed to 80° C., followed by continuously reacting overnight. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 628 mg (yield 100%) of a title compound as a colorless clear oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc2ccccc2c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Nc1cccc(NC(=O)c2ccc3ccccc3c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of N-(3-nitrophenyl)-2-naphthalenecarboxamide (2.94 g), iron powder (3.0 g) and hydrochloric acid (35%, 9 ml) in ethanol (30 ml) was stirred at 80° C. for 2 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-(3-aminophenyl)-2-naphthalenecarboxamide (2.17 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:53]3[CH2:57][C:56](=[O:58])[NH:55][CH2:54]3)=O)=N2)C=CC=1F>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([N:53]3[CH2:57][C:56](=[O:58])[NH:55][CH2:54]3)=[O:27])[CH:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:28])[F:29])[CH:8]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 103A in analogy to the synthesis of the compound of Example 1. 26 mg (72% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[C:14]([CH2:15][CH:16]=[CH2:17])=[C:13]([OH:18])[CH:12]=[CH:11][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]>C(O)C.[Pd]>[OH:1][C:2]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([OH:18])[CH:12]=[CH:11][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: C=CCc1c(O)ccc(C(=O)N2CCCC2)c1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc(C(=O)N2CCCC2)c1O
Reaction time: 3 h
Yield: 86 %

Procedure:
1-[2,4-dihydroxy-3-(2-propenyl)benzoyl]pyrrolidine (750 mg) in 2 ml ethanol was hydrogenated at room temperature and 5 psi for three hours using 4% Pd/C as catalyst. The solvent was removed under vacuum and the residue was chromatographed on silica gel using 50/50 ethyl acetate/hexane as eluant to give the product (650 mg).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.CN([CH:18]=[O:19])C1C=CC=CC=1.C(Cl)(Cl)=O>>[CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[CH:6]1[C:7]([CH:18]=[O:19])=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1
Reactant: CN(C=O)c1ccccc1
Agent: O=C(Cl)Cl
Agent: c1ccc2c(c1)OCO2
Product: O=Cc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Into a mixture of 97.7 g (0.80 mole) of 1,2-methylenedioxybenzene and 108 g (0.80 mole) of N-methylformanilide was introduced 80.0 g (0.81 mole) of phosgene at 50° C. over a 1-hour period. Then, the reaction mixture was heated at 70° C. for 5 hours, poured into ice water, and allowed to stand for 1 hour. Thereafter, the resulting mixture was treated in the same manner as in Example 1 to obtain 48.0 g (0.393 mole) of 1,2-methylenedioxybenzene and 58.9 g (0.392 mole) of piperonal. The yield and selectivity of piperonal were 49.0% and 96.3%, respectively. The recoveries of N-methylaniline and N-methylformanilide were 64.2% and 2.3%, respectively.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8]O)[CH2:2]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:11][CH2:8][CH2:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: OCCCC1CCOC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCCCC1CCOC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
3-(Tetrahydro-3-furanyl)-1-propanol (1 g, 7.68 mmol) was dissolved in DMF (10 ml) and carbon tetrabromide (5.09 g, 15.36 mmol) added. The solution turned yellow. The solution was cooled to 0° C. and triphenylphosphine (4.03 g, 15.36 mmol) added dropwise as a solution in DMF (20 ml) (˜30 mins, temperature maintained <2° C. throughout). The reaction mixture was stirred at 0° C. for 1 hour before gradually allowing to warm to room temperature and stirred for a further 2 hours. The solvent was removed in vacuo. Attempted trituration of the resultant brown oil with either DCM or cyclohexane was unsuccessful. The solvent was removed and the oil diluted with DCM and was purified by chromatography on silica (100 g) using a 0-25% ethyl acetate-cyclohexane over 40 mins using a Flashmaster II. The appropriate fractions were combined and dried down to give the title compound as a yellow oil (0.676 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH3:22])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1.[Sn](Cl)Cl.[OH-].[Na+].O>CCO>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: COc1cc2c(N[C@H](C)c3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(N[C@H](C)c3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 55.5 %

Procedure:
To a suspension of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N—((R)-1-(pyridin-2-yl)ethyl)quinolin-4-amine (Intermediate 24) (1.05 g, 2.503 mmol) in EtOH (20 mL) was added tin(II) chloride (1.66 g, 8.76 mmol) and the mixture stirred at 40° C. for 2.5 h. The reaction mixture was basified to pH 12 using 2M aq. sodium hydroxide solution. Water (30 mL) was added and the aqueous suspension extracted with DCM (3×30 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated to dryness under a stream of nitrogen. The resulting residue was purified by chromatography (100 g column, 2M methanolic ammonia gradient) to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4—((R)-1-(pyridin-2-yl)ethyl)quinoline-3,4-diamine (543 mg, 1.39 mmol, 56% yield) as a dark brown gum.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CC(N(C)C)=O>[N:25]1([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C:11]3[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=3)=[C:4]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:3]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cc1cccc(-n2cnc3c(-c4cnc(N)nc4)nc(Cl)nc32)c1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-n2cnc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)c1
Temperature: 94 °C

Procedure:
To a solution of 5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine (0.182 mmolmmol) in dimethyl acetamide (4 ml) was added morpholine (0.4 mmol). The reaction mix was heated on an oil bath maintained at 94° C. for 12 h. The reaction was monitored for the absence of the give 5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine, by LC-MS. The crude material was directly loaded onto a preparative HPLC column and purified by chromatography to give the title compound. m/z: 389.2 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:37]([O:54][CH2:55][CH2:56]/[C:57](=[N:59]/O)/[NH2:58])([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Si:37]([O:54][CH2:55][CH2:56][C:57]1[N:59]=[C:6]([C:5]2[C:4]([CH3:11])=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[O:8][N:58]=1)([C:50]([CH3:53])([CH3:51])[CH3:52])([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: CC(C)(C)[Si](OCC/C(N)=N/O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)ccc1-c1nc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)no1
Temperature: 100 °C

Procedure:
6-Chloro-2-methylnicotinic acid (Example 425, Step 1) (150 mg, 0.87 mmol) trichloroacetonitrile (0.13 ml, 1.31 mmol) and solid supported triphenylphosphine on polystyrene (1.88 mmol/g, 1.5 g, 2.62 mmol) were taken up in tetrahydrofuran (10.9 ml). The mixture was heated in the microwave at 100° C. for 5 minutes and cooled to room temperature. (1Z)-3-{[tert-Butyl(diphenyl)silyl]oxy}-N′-hydroxypropanimidamide (329 mg, 0.96 mmol), THF (5 mL), and N-ethyl-N-isopropylpropan-2-amine (0.15 ml, 0.87 mmol) were added. The resulting mixture was heated in the microwave at 150° C. for 15 minutes, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified via silica gel chromatography (0-35% ethyl acetate in hexane) to afford the title compound.