Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[N:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:13]=[N:14][C:6]=12.[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][C:28]=1[O:36][CH3:37])[CH3:25]>CN1C(=O)CCC1>[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH:33][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]3[N:12]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])[CH:13]=[N:14][C:6]=23)=[CH:29][C:28]=1[O:36][CH3:37])[CH3:25]
Reactant: CCOc1ccc(CCN)cc1OC
Reactant: Cc1cc(C)c(-n2cnc3c(NCCCl)cc(C)nc32)c(C)c1
Solvent: CN1CCCC1=O
Product: CCOc1ccc(CCNCCNc2cc(C)nc3c2ncn3-c2c(C)cc(C)cc2C)cc1OC

Procedure:
Heat a solution of (2-chloroethyl)[5-methyl-3-(2,4,6,-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-amine (0.030 g, 0.09 mmol) and 4-ethoxy-3-methoxy phenethylamine (0.10 g, 0.55 mmol) in dry NMP (2 mL) at 110° C. for 16 h. Pour the cooled mixture onto water (20 mL) and extract twice with EtOAc (20 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% MeOH in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a solid.
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[CH:14]=[CH:15][C:16]([N+:24]([O-:26])=[O:25])=[C:17]([C:20]([O:22][CH3:23])=[O:21])[C:18]=2[CH:19]=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[N+:24]([C:16]1[CH:15]=[CH:14][C:13]2[N:12]3[CH2:8][CH2:9][CH2:10][C:11]3=[CH:19][C:18]=2[C:17]=1[C:20]([O:22][CH3:23])=[O:21])([O-:26])=[O:25]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCOS(C)(=O)=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])ccc2c1cc1n2CCC1
Yield: 95.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.096 g) was added to a solution of methyl 2-(3-methanesulfonyloxypropyl)-5-nitro-1H-indole-4-carboxylate (Intermediate 20, 0.460 g) in DMF (12 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.320 g) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=1)[CH:16]=[O:17]
Reactant: Oc1cnc(C(F)(F)F)nc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 130 °C
Yield: 83.4 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidin-5-ol (1.5 g, 9.14 mmol) and 3,4-difluorobenzaldehyde (1.299 g, 9.14 mmol) in DMF (18 mL), was added K2CO3 (1.642 g, 11.88 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.18 g, 7.62 mmol, 83% yield) as a brown oil. LCMS: rt=3.08 min, [M+H+]=287
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C@H:18]3[C@H:22]([C:23]4[C:33]5=[C:34]6[C:29](=[CH:30][CH:31]=[CH:32]5)[CH2:28][CH2:27][CH2:26][N:25]6[CH:24]=4)[C:21](=[O:35])[NH:20][C:19]3=[O:36])=[CH:14][NH:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:23]1([C@H:22]2[C@H:18]([C:13]3[C:12]4[C:16](=[CH:17][C:9]([OH:8])=[CH:10][CH:11]=4)[NH:15][CH:14]=3)[C:19](=[O:36])[NH:20][C:21]2=[O:35])[C:33]2=[C:34]3[C:29](=[CH:30][CH:31]=[CH:32]2)[CH2:28][CH2:27][CH2:26][N:25]3[CH:24]=1
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2cc(O)ccc12
Yield: 28.9 %

Procedure:
The (rac)-trans-3-[6-(benzyloxy)-1H-indol-3-yl]-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrolidine-2,5-dione (500 mg, 1.05 mmol) and 10% Pd/C (10 mg) were stirred under 1 atmosphere of hydrogen in methanol (200 mL) at room temperature for 24 hours. The reaction mixture was filtered through a bed of Celite and the filtrate evaporated to dryness. The residue was purified by silica gel chromatography, eluting with 1-7% methanol in dichloromethane to afford to yield (rac)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(6-hydroxy-1H-indol-3-yl)pyrrolidine-2,5-dione (117 mg, 28%) as an off-white solid. Mp: 167-170° C.; 1H NMR (DMSO-d6) 400 MHz δ: 11.50 (bs, 1H), 10.62 (s, 1H), 7.32 (s, 1H), 7.13-7.17 (m, 3H), 6.83-6.89 (m, 2H), 6.71 (d, J=1.9 Hz, 1H), 6.48-6.52 (m, 1H), 4.46 (d, J=6.6 Hz, 1H), 4.37 (d, J=6.6 Hz, 1H), 4.01 (s, 2H), 2.89 (s, 2H), 2.09 (s, 2H); LCMS [M+H]: 386.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C1C(=O)N([I:27])C(=O)C1>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([I:27])=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2[nH]c(I)nc2n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 5.7 %

Procedure:
A stirred solution of 1,3-di-N-butyl xanthine (100 mg, 3.39 mmol) in anhydrous DMF (3 ml) was treated with NIS (94 mg, 3.75 mmol) and left to stir at rt. under nitrogen for 23 hours. The mixture was partitioned between sat. Na2SO3(aq) solution and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The product was purified by passing down an SPE (Si, 5 g) cartridge eluting with EtOAc/cyclohexane mixtures. The product fraction was concentrated to afford the title compound as a white solid (75 mg, 51%); NMR; δH (400 MHz, d6-DMSO) (app.td, 6H, J=7.5 and 4 Hz), 1.21-1.34 (m, 4H), 1.45-1.54 (m, 2H), 1.56-1.66 (m, 2H), 3.84 (t, 2H, J=7.5 Hz), 3.93 (t, 2H, J=7.5 Hz), 14.10 (s, 1H); m/z 391.3[MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[F:19])[CH:5]=[CH:4][N:3]=1>[Ni].CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([F:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reaction time: 4 h
Yield: 78.3 %

Procedure:
In a Parr Shaker flask was combined 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (11.68 g, 40.8 mmol) and MeOH (200 ml) under argon. Raney Ni (50% wet, 0.955 g, 8.15 mmol) was added. The argon atmosphere was removed and replaced with hydrogen (10-20 psi) and the reaction mixture shaken under hydrogen for 4 hours. The completed reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to dryness to provide 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (8.2 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.28 (d, J=5.9 Hz, 1H), 7.25 (dd, J=11.2, 7.5 Hz, 1H), 7.02 (dd, J=2.2 Hz, 1H), 6.95 (dd, J=5.8, 2.0 Hz, 1H), 6.74 (dd, J=12.3, 8.3 Hz, 1H), 5.57 (s, 2H); MS (ESI): m/z 257.0 [M+H]+
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[O:32]1[CH2:34][C@@H:33]1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.Cl([O-])(=O)(=O)=O.[Li+]>CC#N>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:34][C@H:33]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[OH:32])[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: c1cncc([C@H]2CO2)c1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NC[C@@H](O)c2cccnc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (124 mg, 0.28 mmol), (S)-3-oxiranyl-pyridine (34 mg, 0.28 mmol) and lithium perchlorate (60 mg, 0.56 mmol) in CH3CN was heated to 100° C. in a sealed tube and stirred for 1 h. The reaction mixture was concentrated and diluted with ethyl acetate. The solution was then treated with 1M Na2CO3 and the organic phase was separated. The aqueous phase was re-extracted with ethyl acetate (×2). The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.05 CH2Cl2:MeOH:NH4OH as an eluent to afford 15 mg of the title compound as an off-white solid (10%), m/z 562.7 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=3[CH:3]=2)=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazin-3-one and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 2. Melting Point: 123-126° C. (diethylether)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: COCCOCCOCCOCCOCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCOCCOC(=O)OCCl

Procedure:
In a manner similar to the method described in Example 3, chloromethyl chloroformate (Aldrich) was reacted with 2,5,8,11,14,17-hexaoxanonadecan-19-ol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give chloromethyl 2,5,8,11,14,17-hexaoxanonadecan-19-yl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), chiral-3-oxo-2,4,7,10,13-pentaoxatetradecyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C46H58Cl2F2N3O13: [(M+H)+]: 968, found: 968.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>>[C:14]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(C)C(=O)Cl
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c[nH]c2c1

Procedure:
Methyl 3-isobutyrylindole-6-carboxylate (618 mg) was prepared from methyl indole-6-carboxylate (500 mg) and isobutyryl chloride (0.84 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:53](Cl)(OC1C=CC=CC=1)[O:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(OCC)(=O)C.O>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:53]([O:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(Oc3ccccc3)nc12
Reaction time: 5 h
Yield: 11 %

Procedure:
To a mixture of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (140 mg) and sodium carbonate (14 mg) in ethyl acetate (1.5 ml) was added dropwise a solution of 1,1-dichloro-1,1-diphenoxymethane (67 mg) in ethyl acetate (1 ml) in water bath and the mixture was stirred at same temperature for 5 hours. The reaction mixture was evaporated in vacuo and dissolved in chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-phenoxy-1H-benzimidazol-4-yl)carbonylaminobenzamide (18 mg).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCc1c[nH]c2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (3.29 g, 21.0 mmole) and pyridine (1.74 g, 22.0 mmole) were added to a solution of tryptamine (3.2 g, 20.0 mmole) in CH2Cl2 and stirred for 24 h at room temperature. Working up was performed by extracting the batch successively with water, with 1M HCl and with 1M NaOH. The organic phase was dried with Na2SO4 and evaporated. The product was obtained as a colorless solid (m.p. 44-46° C.) in a yield of 5.58 g (100%).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[C:6]1([C:12](=[O:14])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1>>[C:6]1([C:12]([OH:14])([CH2:4][CH3:5])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: CC(=O)C1=CCCCC1
Reactant: CC[Zn]CC
Product: CCC(C)(O)C1=CCCCC1
Yield: 56 %

Procedure:
Diethylzinc addition to 1-(1-cyclohexenyl)-ethanone (1.04 mL, 8.05 mmol) was performed according to general procedure A using 2 mol % of Compound B enantiomer (88 mg). The product was purified by column chromatography (hexanes/EtOAc: 96/4) to give 697.1 mg of 9 (56% yield, 96% ee) of a colorless oil: [60 ]D 20=+5.9 (c 3.0, MeOH). [Published [α]D 20=+0.7 (c 3.0, MeOH, 51% ee)].
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:12][CH2:13][CH:14]([NH:17][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]2
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC1CCC2(CCc3ccccc3C2)CC1
Temperature: 0 °C

Procedure:
To an ice cooled solution of the free base prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C) in 12 ml. of pyridine, 1 ml. of ethyl chloroformate is added. The mixture is allowed to stand in the cold for about 5 hours and then poured into ice water. The solid that precipitates is collected on a filter and recrystallized from methylene chloride: benzene to give ethyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene] -4-carbamate [I(c)].
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[ClH:5].Cl.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:22])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:7].[ClH:5].[CH3:1][NH:2][C:3](=[SH:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:24][CH:23]=2)[CH2:14][CH2:15]1)[OH:4]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 64.4 %

Procedure:
The procedure described in Example 2 was followed, using 0.4 g of methyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin- 1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.75 g (32% of theory) of N-methyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 240°-243° C.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1>O>[Cl:11][C:12]1[C:13]2[N:14]([C:18]([CH:3]=[O:4])=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(-c2cn3cccc(Cl)c3n2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc(-c2nc3c(Cl)cccn3c2C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
N,N-Dimethylformamide (30 mL) was cooled to 0° C. and treated with phosphorous oxychloride (1.08 mL, 11.6 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 10 minutes. To this was added 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine (2.0 g, 7.75 mmol) and the resulting solution was stirred for 48 hours. Water was added to the reaction. The solids were then filtered and azeoptroped with methanol to give 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (2.2 g, 99%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](F)=[N:11][CH:12]=1)[CH3:2].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(COc1ccc(F)nc1)OCC
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OCC
Temperature: 170 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
5-(2,2-diethoxyethoxy)-2-fluoropyridine (502 mg, 2.19 mmol) and potassium tert-butoxide (279 mg, 2.49 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (240 mg, 1.00 mmol), and stirred at 170° C. for 15 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled to room temperature, then water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:3) to obtain 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (292 mg, yield: 65%) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](N)[CH2:12][CH2:13]C>>[CH2:9]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10])[CH2:11][CH2:12][CH3:13]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: CCCCN
Product: CCCCn1ccc(=O)c(O)c1C

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4-pyridinone was employed, starting with butylamine (5.3 g). No precipitate was observed after concentration. Recrystallization from ethanol and diethyl ether resulted in a white powder (4.5 g). Proton NMR (D20): 7.84 (d, 1H), 6.80 (d, 1H), 4.15 (q, 2H), 2.39 (s, 3H), 1.61 (m, 2H), 1.16 (m, 2H), 0.72 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:27]1([CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][C:37]([OH:43])=[CH:38][CH:39]=3)[O:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:43][C:37]2[CH:36]=[C:35]3[C:40]([CH2:41][CH2:42][CH:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:34]3)=[CH:39][CH:38]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)OC(c1ccccc1)CC2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OC(c2ccccc2)CC3)nc1

Procedure:
5-Nitro-2-(2-phenylchroman-7-yloxy)pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 115 mg of 2-phenylchroman-7-ol. The product was purified on preparative TLC-plate covered with silica gel using toluene-ethyl acetate (15:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.46-7.32 (m, 5H), 7.22 (d, 1H, J 9.1 Hz), 7.20 (d, 1H, J 8.9 Hz), 6.72 (dd, 1H, J 8.9, 2.3 Hz), 6.72 (d, 1H, J 2.3 Hz), 5.16 (dd, 1H, J 10.1, 2.1 Hz), 2.97 (ddd, 1H, J −16.7, 11.3, 5.9 Hz), 2.77 (ddd, 1H, J −16.7, 8.1, 4.5 Hz), 2.20 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.Cl>CO>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)N1CCN(c2ccc(N)cc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
1-tert-Butyl-4-(4-nitro-phenyl)-piperazine (348 mg, 1.32 mmol) is dissolved in MeOH (10 mL) and tin (II) dichloride dihydrate (1.08 g, 4.79 mmol) is added. The mixture is cooled using a water bath and conc. HCl is added (3 mL). The reaction is stirred at 40° C. overnight. After removing the methanol, the resultant solution is basified using conc. NaOH (pH 11). The water phase is extracted with diethyl ether (3×) and the organic layers combined, dried over MgSO4, filtered, concentrated in vacuo to afford the title compound (308 mg, 99%) which is used in the next step without further purification. LCMS: Rt 2.16 min (87%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=C[C:9]=1[NH2:10])([O-])=O.[CH3:12][OH:13]>[Pd]>[OH:13][C:12]1[C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Product: Nc1cccc(O)c1N
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-nitro-4-aminophenol (4.6 g, 30 mmol) in methanol is added 500 mg of Pd/C. A hydrogenation reaction is performed at room temperature for 2 hours and then terminated. The Pd/C is removed by filtration to obtain 4.1 g of 3-hydroxy-o-phenylenediamine, with a yield of 95%.