Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][O:26][C:21]2=[CH:20][C:7]=1[CH2:8][N:9]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].NN.C(O)C>ClCCl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][O:26][C:21]2=[CH:20][C:7]=1[CH2:8][NH2:9])[CH3:2]
Reactant: CCOCOc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OCO2
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CCOCOc1cc2c(cc1CN)OCO2

Procedure:
N-(2-Ethoxymethoxy-4,5-methylenedioxybenzyl)phthalimide (1.70 g, 4.77 mmol) was treated with 0.5 mL (16 mmol) hydrazine in 90 mL refluxing ethanol for three hr. The reaction mixture was cooled and the phthalhydrazide was removed by filtration and washed three times with ethyl ether. The organic solutions were combined and evaporated to dryness on a rotary evaporator to yield a residue, which was taken up in dichloromethane. The organic solution was washed three times with 10% sodium hydroxide and the combined aqueous solutions were back-extracted with dichloromethane two times. The combined organic solutions were washed with brine and dried over sodium sulfate/potassium carbonate. Evaporation of the solvent gave of 2-ethoxymethoxy-4,5-methylenedioxybenzylamine as a slightly yellow liquid (0.98 g, 92% yield) that solidified upon standing. IR: 3298 cm-1. 1HNMR (200 MHz): δ 6.77 (1H, s); 6.75 (1H, s); 5.91 (2H, s); 5.18 (2H, s); 3.74 (2H, q, J=7.1 Hz); 3.73 (2H, s); 1.45 (2H, br s); and 1.24 ppm 3H, t,J=7.1 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:53])=[C:9]([CH2:11][O:12][C:13]2[CH:52]=[CH:51][C:16]([CH2:17][N:18]3[CH:22]=[C:21](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:30]CC4C=CC(OCC5N=C(C6OC=CC=6)OC=5C)=CC=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.C(O)C>[C].[Pd].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:53])=[C:9]([CH2:11][O:12][C:13]2[CH:52]=[CH:51][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([OH:30])=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 55.9 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-yl]propenoate (12.5 g), 5% palladium-carbon (20.0 g), ethanol (200 ml), and tetrahydrofuran (200 ml) was stirred under a hydrogen atmosphere at room temperature for 7 hours. After removal of the catalyst by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration, and ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-hydroxy-1H-pyrazol-4-yl]propionate (4.40 g, yield: 56%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 145–146° C.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CC(C)=O>[CH:10]1([NH:16][C:17]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCCCC(=N)N
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)NC1CCCCC1

Procedure:
Following a procedure similar to that described in Example 23 but using 8.4 g. sodium in 1100 ml. dry acetone, 50 g. valeramidine hydrochloride, and 46.4 g. cyclohexyl isocyanate in 300 ml. dry acetone there was obtained, after recrystallization from isopropyl alcohol 58.4 g. 1-cyclohexyl-3-(pentanimidoyl)urea hydrochloride; m.p. 146°-148°C.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CCN(CC)CC.[CH2:27]=[C:28]=[O:29]>C(Cl)Cl>[C:28]([O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:29])[CH3:27]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: C=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (13 mg, 0.05 mmol) in anhydrous CH2Cl2 (1 ml) is cooled in an ice-bath and treated withtriethylamine (Et3N) (7 μl, 0.05 mmol). Ketene is passed through the resulting solution for 10 mins. The solvent and excess ketene are removed in vacuo to leave crude benzyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:35]([O:37]C)=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O.CO.O1CCCC1>[C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:11]([C:35]([OH:37])=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Yield: 95.3 %

Procedure:
The procedure of Example 42 was followed using the product from Example 41 (280 mg, 0.526 mmol), lithium hydroxide (55 mg, 1.32 mmol) in water (0.4 ml), methanol (1 ml) and tetrahydrofuran (1 ml) to give 260 mg (95%) of the product.
Reaction SMILES: CO.[OH-].[Na+].C[O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:30])=[CH:24][CH:23]=1)=[O:8].Cl>O>[F:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:12]3[C:11]4[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=4)[N:15]=[CH:14][CH:13]=3)=[CH:23][CH:24]=2)=[O:30])=[CH:37][CH:36]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
After adding methanol (9 ml) and 2N aqueous sodium hydroxide (3 ml) to methyl-4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinoline carboxylate (300 mg, 0.65 mmol), the mixture was stirred at room temperature for 2 hours and then at 60° C. for 20 minutes. The reaction solution was cooled to room temperature and 1N hydrochloric acid was added for neutralization, after which methanol (6 ml) and water (6 ml) were added, the mixture was stirred overnight, and the precipitated light brown crystals were filtered out and dried under reduced pressure to obtain the title compound (227 mg, 0.51 mmol, 78.0%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:21][C:22]([CH3:24])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH:22]([CH3:24])[CH3:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication 88/08424, 2.0 g) is dissolved in 35 ml of methanol and acetone (0.48 g) is added. The reaction is cooled to 0° and acetic acid (to pH 4.0) is added. The reaction is stirred 15 min at 0° and then sodium cyanoborohydride (0.50 g) is added. The reaction is allowed to warm slowly to 20°-25° and followed by TLC until completion. Additional acetic acid, sodium cyanoborohydride and acetone are sometimes necessary to force the reaction to completion. The reaction is diluted with chloroform (100 ml), washed with saturated aqueous sodium bicarbonate (50 ml), saline (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (75 g silica gel, 4:1 hexane/ethyl acetate) affords the title compound, NMR (300 MHz, CDCl3) 7.67, 6.91, 4.15, 3.57, 3.00, 1.48 and 1.23 δ.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH2:5]O.C(N(S(F)(F)[F:23])CC)C>ClCCl>[F:23][CH2:5][CH:4]([NH:3][O:2][CH3:1])[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16]
Reactant: CCN(CC)S(F)(F)F
Reactant: CONC(CO)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: CONC(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a stirred thick suspension of 2-methoxyamino-3-(2,4,6-trichloro-phenyl)-propan-1-ol (1.0 g; 3.5 mmol) in dichloromethane (7.0 ml) at −16° C. under nitrogen was added dropwise a solution of diethylaminosulfur trifluoride (0.46 ml; 3.5 mmol) in dichloromethane (2.0 ml). During addition temperature rose to −12° C. The mixture turned to a brown orange solution which was allowed to warm at 20° C. and was stirred for 2 h. The organic solution was washed with saturated hydrogen carbonate solution (gas release), 1N hydrochloric acid, brine and dried over sodium sulfate. The solvent was removed in vacuo. The crude material was subject to flash column chromatography (eluant: cyclohexan/ethyl acetate 95:5) to afford 0.43 g (43% of theory) of N-[1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-O-methyl-hydroxylamine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:5]([CH2:7][C:8]([O:10]CC)=O)=O.[Cl-].[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH2+:31][NH2:32])[CH3:30])=[CH:25][CH:24]=1)=[O:22])[CH3:19]>CC(O)=O>[Cl:16][C:14]1[CH:13]=[C:4]([C:5]2[CH2:7][C:8](=[O:10])[N:31]([CH:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])=[CH:24][CH:25]=3)[CH3:30])[N:32]=2)[CH:3]=[C:2]([Cl:1])[CH:15]=1
Reactant: CCOC(=O)c1ccc(C(C)[NH2+]N)cc1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(C(C)N2N=C(c3cc(Cl)cc(Cl)c3)CC2=O)cc1

Procedure:
A solution of ethyl (3,5-dichlorobenzoyl)acetate (3.0 g, 11.5 mmol) and {1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinium chloride (2.55 g, 10.4 mmol) was refluxed in HOAc (80 ml) for 4 hr. The solvent was removed under reduced pressure, and the residue taken up with ethyl acetate, washed with sat. NaHCO3 2×, brine, and dried over Na2SO4. Flash column chromatography (SiO2, 0-5% ethyl acetate in DCM gradient) gave ethyl 4-{1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoate as a white solid. TLC (5% ethyl acetate-DCM) Rf 0.43. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.78 (d, J=7.0 Hz, 3H); 3.55 (d, J=22.6 Hz, 1H); 3.60 (d, J=22.6 Hz, 1H); 4.36 (q, J=7.1 Hz, 2H); 5.57 (q, J=7.0 Hz, 1H); 7.39 (t, J=1.9 Hz, 1H); 7.50 (d, J=8.4 Hz, 2H). 7.52 (d, J=1.9 Hz, 2H); 8.02 (d, J=8.4 Hz, 2H). MS C20H18Cl2N2O3 Cald: 404.07; Obsd (M+1): 405.20.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][P:22]([O:34][CH2:35][CH3:36])([CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])[C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:2].CO>[Pd].ClCCl.CO.C(O)(=O)C>[CH2:1]([N:3]([CH2:21][P:22]([O:34][CH2:35][CH3:36])([CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])[C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CN(CC)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(CCCCc1ccccc1)CN(CC)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1.5 h

Procedure:
A mixture of 1-[[ethyl[[ethoxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester (800 mg., 1.56 mmole), methanol (50 ml.), and 10% palladium on carbon catalyst (150 mg.) was hydrogenated on the Parr apparatus at 50 psi for 1.5 hours. The catalyst was removed by filtration (Celite bed) and the methanol stripped to give 600 mg. residue. This residue was passed through a pad of silica eluting with dichloromethane/methanol/acetic acid (100/5/5) to remove a polar impurity. After evaporation and azeotropic removal (toluene) of residual acetic acid, 550 mg. of 1-[[ethyl[[ethoxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline was obtained as an oil. Tlc (dichloromethane/methanol/acetic acid; 100:5:5) single spot at Rf =0.6.
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].Cl>C(#N)C>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1
Reactant: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2C)CC1

Procedure:
Preparation according to Example 1: 4-[2-methyl-3-(methylsulfonyl)phenyl]piperidine (0.41 g, 1.62 mmol), acetonitrile (40 ml), potassium carbonate (0.53 g, 4.8 mmol) and 1-iodopropane (0.127 ml, 1.62 mmol). Yield: 0.238 g (50%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 233-235° C. MS m/z (relative intensity, 70 eV) 295 (M+, 4), 267 (17), 266 (bp), 129 (13), 115 (14).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[S:22][C:23]([N+:26]([O-])=O)=[CH:24][CH:25]=2)=[O:20])=[N:2]1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:26][C:23]1[S:22][C:21]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:20])=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc([N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Temperature: 50 °C
Reaction time: 7 h
Yield: 52.3 %

Procedure:
Compound 51 (1.5 g, 3.84 mmol), iron powder (4.3 g, 76.8 mmol) and ammonium chloride (616 mg, 11.52 mmol) were added with ethanol (10.0 mL) and water (10.0 mL) at room temperature, stirred at 50° C. for 7 hours and the reaction mixture was filtered through celite. The filtrate was extracted with ethyl acetate and the organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in a mixed solvent of chloroform/ethyl acetate to obtain Compound 56 (724 mg, 52%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([OH:18])[CH2:20]1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reactant: O[C@H]1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(I)cc2c(N2CCC[C@H](O)C2)c1S(C)(=O)=O
Yield: 54.4 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), (S)-(+)-3-hydroxypiperidine (119 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, the residue was extraced with dichloromethane and 10% Na2CO3, and then purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate, and the resulting white crystals were filtered off. One obtained 191 mg (54%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][NH:6][C:7](=[O:20])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH3:22]>CO>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:7]([NH:6][CH2:5][CH2:4][C:3]([NH2:22])=[O:2])=[O:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N
Reactant: COC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCC(N)=O
Reaction time: 48 h

Procedure:
A solution of 11 g of t-butyloxycarbonyl-L-prolyl-β-alanine methyl ester in 80 ml of methanol was saturated with ammonia gas at 0° C and stored for 2 days at room temperature. The solution was concentrated in vacuo and the residue crystallised from methanol/water. Yield: 9.8 g; melting point 175°-4 177° C; [α]D25 = -44.5° (c = 1 in dimethylformamide).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)CCC(=O)O
Product: CC(C)(C)CCC(=O)Cl
Yield: 83.2 %

Procedure:
4,4-Dimethylpentanoic acid (40 g; Chem Lett, (1980), 571) was treated at 20° for 16 h with thionyl chloride (40 g) and the mixture distilled under reduced pressure to yield 4,4-dimethylpentanoyl chloride (38 g) b.p. 52°-58° at 10 mm Hg; δ (CDCl3) 0.94 (9H, s, C(CH3)3 ; 1.66 (2H, t, J=9 Hz, CH2) and 2.88 (2H, t, J=9 Hz, CH2CO).
Reaction SMILES: [N:1]([C:4]1[C:5]2[N:6]([CH:20]=[CH:21][N:22]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]=1[C:10]#[N:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CO.O>[NH2:1][C:4]1[C:5]2[N:6]([CH:20]=[CH:21][N:22]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]=1[C:10]#[N:11]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of crude 8-azido-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (68 mg, 0.21 mmol) and triphenylphosphine (83.7 mg, 0.32 mmol) in MeOH (2.5 mL) was stirred and refluxed for 1 h. 2 M HCl in water (1 mL) was added and the reaction mixture was further refluxed for 1 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was dissolved in water. The aqueous solution was basified to pH 12 by the addition of 2 M NaOH in water. The resulting slurry was extracted with DCM (2×) and the combined organic fractions were dried over Na2SO4, filtered and evaporated. The remaining residue was dissolved in hot MeOH, then the solution was slowly cooled to RT and the formed precipitate was filtered and washed with cold MeOH to yield the title compound (32.5 mg, 0.11 mmol, 52%) as a brownish solid. MS: 303 [M+1]+; HPLC: AtRet=1.72.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:24]5[N:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=5)[CH2:19][CH2:18]4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(N2CCC(Oc3ccc4c(c3)CCN(C3CCC3)CC4)CC2)nc1
Temperature: 180 °C

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (60 mg, 0.2 mmol), 6-chloronicotinonitrile (31 mg, 0.22 mmol) and triethylamine (0.03 ml, 0.22 mmol) were dissolved in acetonitrile (2 ml) and heated to 180° C. in a microwave reactor for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with water, brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) to afford the title compound (E160); MS (ES+) m/e 403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(=O)c1ccc(OCC(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)c(Cl)c1
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (780 mg, clear colorless oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone (860 mg, 3.7 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[Cl:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]2[N:11]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:12]=[CH:13][C:5]=12
Reactant: Clc1c(I)cnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(I)cnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
NaH (0.960 g, 24.0 mmol, 60% dispersion in mineral oil) at 0° C. was added to 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (5.57 g, 20.0 mmol) in dimethylformamide (“DMF”; 40 mL) and stirred at 0° C. for 20 minutes. Benzenesulfonyl chloride (2.82 mL, 22.0 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Water (200 mL) was added and stirred for 10 minutes. The solid formed was collected by filtration, washed with ether, and dried to give 4-chloro-5-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (8.20 g, 98% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(C(C)C)C(C)C)C.[CH2:22]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([I:36])[CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C1COCC1.CCOCC>[CH2:22]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:2]=2[F:1])=[C:31]([I:36])[CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1I
Reactant: O=Cc1ccc(C(=O)Cl)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(C(=O)Nc2ccc(Cc3ccccc3)cc2I)c(F)c1
Reaction time: 0.5 h

Procedure:
To a slurry of 2-fluoro-4-formylbenzoyl chloride (1.5 mmol) in 5 mL THF was added N-ethyl-N-isopropylpropan-2-amine (0.39 mL, 2.2 mmol) and 4-benzyl-2-iodobenzenamine (0.41 g, 1.3 mmol). After 30 min, the reaction was treated with 1N HCl and Et2O. The organic layer was washed 1×1N HCl, 2×sat'd aq. NaHCO3, and 1× brine. The org. layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting material was purified by ISCO, 40 g, 0-20% EtOAc/hexanes to give N-(4-benzyl-2-iodophenyl)-2-fluoro-4-formylbenzamide as a white solid. MS (ESI) m/z: Calculated: 459.0; Observed: 457.9 (M−−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9](B3OCCCO3)[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.[C:23]([NH:26][C:27]1[N:28]([CH3:33])[N:29]=[CH:30][C:31]=1Br)(=[O:25])[CH3:24]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:31]3[CH:30]=[N:29][N:28]([CH3:33])[C:27]=3[NH:26][C:23](=[O:25])[CH3:24])[CH:8]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(B2OCCCO2)c1
Reactant: CC(=O)Nc1c(Br)cnn1C
Product: CC(=O)Nc1c(-c2cccc(-n3c(N)nc4ccccc43)c2)cnn1C

Procedure:
2-Amino-1-[3-(5-acetamido-1-methyl-4-pyrazolyl)phenyl]benzimidazole was prepared from 3-(2-amino-1-benzimidazolyl)-phenyl-1,3,2-dioxaborinane and 3-acetamido-4-bromo-2-methylpyrazole according to method A. mp 135°-137° C.