Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([NH2:36])[CH:32]=1.O>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:36][C:33]3[CH:32]=[C:31]([CH3:30])[NH:35][N:34]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 40 °C
Yield: 28.8 %

Procedure:
To a solution of compound 12 (84 mg, 0.30 mmol) in DMF (3 mL) at room temperature were added DIPEA (0.103 mL, 0.6 mmol) and 5-methyl-1H-pyrazol-3-amine (88 mg, 0.9 mmol). The reaction mixture was heated at 40° C. overnight. Water was added, and the yellow precipitate was collected by filtration and washed with water. The solid was purified by silica gel chromatography eluting with DCM/MeOH to give compound 1 (30 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.54 (s, 1H), 7.40 (m, 2H), 7.68 (t, 1H), 7.9-7.7 (m, 2H), 8.08 (m, 2H), 8.74 (d, 1H), 10.66 (s, 1H), 12.20 (s, 1H); LC-MS (ESI) m/z: 348 (M+H)+.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:10]=1[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:37]([CH2:44][C:45](=O)[CH3:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C>O1CCCC1>[CH3:7][O:8][C:9]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:10]=1[CH:11]=[C:45]([CH3:46])[CH2:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)CCc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C=C(C)CCc2ccccc2)c1

Procedure:
A solution of n-butyl lithium (29 ml. of 2.2 M) is added dropwise to 2,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g.) in tetrahydrofuran (200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone (9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude 1-(2,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene as an oil. It is purified by chromatography on silica gel and elution with benzene.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]O)(=[O:14])[CH:12]=[CH2:13].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>ClCCl>[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CC(=O)OCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOC(=O)c1ccc(O)cc1
Reaction time: 4 h
Yield: 5.2 %

Procedure:
2000 g of dichloromethane, 40.0 g of 4-hydroxybenzoic acid, 39.6 g of 4-hydroxybutyl acrylate and 0.05 g of methoquinone were charged into a separable flask of the same type as used in Reference Example 1, and then a liquid mixture consisting of 54.0 g of N,N'-dicyclohexylcarbodiimide, 5.9 g of dimethylaminopyridine and 60 g of dichloromethane was dropwise added thereto at room temperature over 4 hours, while replacing the flask inside gas with a nitrogen gas. After the same treatment as in Reference Example 1, 3.8 g of p-hydroxybenzoyloxybutyl acrylate of the following chemical formula was obtained (yield: 5%): ##STR14##
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cccnc2)cc1F
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: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cccnc2)cc1F
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 7 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.6 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].C(#N)C>ClCCl>[CH3:32][S:29]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(C3=CCNCC3)cnc12
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15 %

Procedure:
To a solution of 3-[1-(1,2,3,6-tetrahydro-pyridin-4-yl)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino]-propan-1-ol as prepared in example 27 (50.0 mg; 0.132 mmol; 1 eq) in anhydrous dichloromethane (660 μL) are successively added N,N′-dimethylaminopyridine (16.1 mg; 0.132 mmol; 1 eq) and mesyl chloride (10.3 μL; 0.132 mmol; 1 eq). The solution is allowed to stir at room temperature for 17 hours after which period the reaction is almost complete. The reaction mixture is concentrated under vacuum and the resulting residue is taken-up with ethyl acetate (10 mL). The organic solution is washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. Two successive column chromatography on silica gel (eluent column 1: ethyl acetate/methanol/triethylamine 8:2:0.2; eluent column 2: dichloromethane/methanol 95:5) and one column chromatography on reversed-phase (C18, acetonitrile) affords the title compound as a white solid (9 mg; 0.020 mmol; 15%)
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])(=[O:41])=[O:40])[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])(=[O:40])=[O:41])[CH2:35][CH2:34]1
Reactant: CCCCCCCCS(=O)(=O)N1CCN(c2cc(F)c(OC)cc2F)CC1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: CCCCCCCCS(=O)(=O)N1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 87.4 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-(2,5-difluoro-4-methoxyphenyl)-1-(octylsulfonyl)piperazine (300 mg). The resulting crude product was purified on TLC (developer, hexane: ethyl acetate=11:5) to provide 4-(2,5-difluoro-4-hydroxyphenyl)-1-(octylsulfonyl)piperazine (253 mg).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[CH3:12][C:13]1[C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:21])[O:15][N:14]=1>ClCCl.C([O-])(O)=O.[Na+].C1(C)C=CC=CC=1>[CH3:11][O:10][N:9]([CH3:8])[C:18]([C:17]1[C:13]([CH3:12])=[N:14][O:15][C:16]=1[CH3:21])=[O:19]
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1c(C)noc1C
Temperature: 25 °C
Yield: 98.9 %

Procedure:
659 μl (8.15 mmol) of pyridine are added to a suspension of 343.07 mg (3.45 mmol) of N,O-dimethylhydroxylamine hydrochloride in 10 mL of dichloromethane. The mixture is stirred at room temperature until fully dissolved. A solution of 526.32 mg (3.13 mmol) of 3,5-dimethylisoxazole-4-carbonyl chloride in 5 mL of dichloromethane is then added. After stirring for 1 hour at room temperature, the reaction mixture is taken up in saturated aqueous NaHCO3 solution and stirred for a few minutes, and the phases are separated by settling. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue obtained is taken up in toluene and evaporated, the operation being repeated a second time. 570 mg of N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide are then obtained, corresponding to the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([O:19]C)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+].O.CCOC(C)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1C
Temperature: 60 °C
Yield: 74.9 %

Procedure:
The product from step 1 (470 mg, 1.6 mmol, 1.0 equiv) was dissolved in MeOH (10 mL) and 2.5 M NaOH (2.5 mL) was added. The mixture was heated to 60° C. for three hours. When the reaction had cooled to room temperature, water and EtOAc were added. The phases were separated, and the aqueous layer was adjusted to pH 7 with 6N HCl. The aqueous phase was extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated to dryness. The residue was azeotroped with hexanes to provide 335 mg (75%) of the title compound as a foamy white solid. MS (ES+) m/e 280 [M+H]+.
Reaction SMILES: [Ca:1].C(=O)([O-])[O-:3].[Ca+2].[O-:7][Si:8]([O-:11])([O-:10])[O-:9].[Ca+2].[Ca+2]>O>[O-:7][Si:8]([O-:11])([O-:10])[O-:9].[Ca+2:1].[Ca+2:1].[OH-:3].[Ca+2:1].[OH-:3]
Reactant: O=C([O-])[O-]
Reactant: [Ca]
Agent: [Ca+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: O
Product: [OH-]

Procedure:
Table 7 is directed to the valuation of synthetic calcium and magnesium silicates versus the limestone or calcium carbonate fillers currently utilized in the trade. In this regard, "Micro-Cel®" is the registered trade name of the Celite Corporation of Lompoc, Calif. The "Micro-Cel®" products comprise of synthetic, hydrous, calcium silicates produced by the hydro-thermal reaction of diatomite, hydrated lime, and water. According to the Celite Corporation, the different grades of "Micro-Cel®" have the following typical physical and chemical properties:
Reaction SMILES: [Cl:1][CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3].CC1C2C(C)(C)C(C2)CC=1>>[Cl:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3].[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3]
Reactant: CC(Cl)NC(=O)Cl
Agent: CC1=CCC2CC1C2(C)C
Product: C=CN=C=O
Product: CC(Cl)N=C=O
Yield: 23 %

Procedure:
A mixture of 160 parts of 1-chloroethylcarbamyl chloride and 537 parts of α-pinene is heated from 24° to 105° C. in the course of 2 hours, whilst stirring, and the reaction mixture is subjected to fractional distillation. A total of 27.6 parts (23% of theory) of 1-chloroethyl isocyanate of boiling point 92° C./1,013 mbar and 34.6 parts of vinyl isocyanate of boiling point 38.5° C./1,013 mbar, is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].[Cl-].[Na+]>ClCCl.O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (60 g) and imidazole (12.9 g) in dichloromethane (300 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (31.4 g) in dichloromethane at 0° C. over a 30-minute period. After one hour, the reaction mixture was poured into a mixture of ethyl acetate (1 l), water (400 ml) and saturated aqueous sodium chloride (200 ml). The organic layer was separated, washed in turn with water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (1.2 l) eluting with a mixture of hexane and ethyl acetate (1:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-(tert-butyldimethylsilyloxy)methyl-4-methanesulfonyloxypyrrolidine (71 g).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>CS(C)=O>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: C1CNCCNC1
Solvent: O
Solvent: CS(C)=O
Product: c1cncc(-c2cc3c(-c4cccc(N5CCCNCC5)n4)n[nH]c3cn2)c1

Procedure:
Following the procedures of Example 143 and starting with 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and homopiperazine, 187 was obtained and lyophilized from water to afford 42 mg (78%). ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO)•9.58 (s, 1H), 9.44 (s, 1H), 9.36 (s, 2H), 9.31 (s, 1H), 9.11 (d, J=8.3 Hz, 1H), 8.99 (s, 1H), 8.94 (d, J=5.4 Hz, 1H), 8.23-8.15 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.12 (s, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.43 (d, J=21.5 Hz, 2H), 3.27-3.17 (m, 2H), 2.24 (s, 2H)
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl.Cl[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1>[O-]CC.[Na+]>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][S:1][CH2:2][CH2:3][OH:4])[CH:9]=1
Reactant: OCCS
Reactant: ClCc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: OCCSCc1cccnc1
Yield: 76.8 %

Procedure:
A stirred solution of sodium ethoxide (4.6 g of sodium in 100 ml ethanol) was treated with 2-mercaptoethanol (7.8 g, 0.1 mol) followed by 3-chloromethylpyridine hydrochloride (16.4 g, 0.1 mol). The mixture was then refluxed under argon for 3.5 hours, filtered and evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 3% methanol in ethyl acetate, to give 2-(3-pyridylmethylthio)ethanol (13 g), as a yellow oil;
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl.O>CO>[N+:9]([CH:12]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: 0 °C

Procedure:
Benzaldehyde (2, 52.35 g, 0.493 mol) and nitromethane (30.11 g, 0.493 mol) were dissolved in methanol (100 mL) in a two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel. NaOH (25.6 g, 0.641 mol) in ice/water (50 mL) was added dropwise to the solution keeping the temperature below 15° C. A fine slurry formed during the addition and methanol was added to allow stirring. After the addition the slurry was diluted with ice/water and the resulting clear solution was added dropwise to a solution of conc. HCl/H2O (200/300 mL); a yellow precipitate was formed during the addition. The precipitate was filtered on a buchner funnel, washed with water and crystallized from methanol obtaining pure 3 (58.78 g, 80%). Yellow needles. M.p. 57-58° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7].Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl.O>[CH3:39][Si:2]([CH3:38])([CH3:1])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([N:27]=[C:41]=[O:43])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N=C=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (from EXAMPLE 3.2B, 90 mg in a mixture of 1 mL chloroform and 1 mL water containing 47 mg calcium carbonate) at 0° C. was added 46 mg triphosgene and the mixture allowed to warm slowly to room temperature. After 2 hours, the reaction was quenched by the addition of 2N hydrochloric acid, extracted with methylene chloride and the organics dried over sodium sulfate to give the crude title compound (94 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]([CH2:14][C@@H:15]([NH2:17])[CH3:16])[C:13]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@@H:15]([NH:17][C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)N)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc2ccc3ccn(C[C@H](C)NC(=O)C(F)(F)F)c3c2c1
Yield: 58.5 %

Procedure:
A solution of 1.5 g of (S)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine, 0.74 g of triethylamine and 1.04 g of ethyl trifluoroacetate in 100 ml of anhydrous methanol was stirred at room temperature for 27 hours. After the solvent had been drawn off in a vacuum, the residue was taken up with 100 ml of ahydrous dioxane, 1.56 g of DDQ were added and the mixture was boiled under reflux for 1.5 hours. Subsequently, the reaction mixture was concentrated in a vacuum and the residue was purified by column chromatography on silica gel (dichloromethane/acetone 4:1). 1.2 g (59%) of (S)-N-[2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethyl]-trifluoracetamide were obtained as a pale brown solid which was used in the next reaction without additional recrystallization.
Reaction SMILES: [H-].[Na+].[C:3]12([N:13]3[C:17]4[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:25])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1[S:37](Cl)(=[O:39])=[O:38].O>C1COCC1.CN(C=O)C>[C:3]12([N:13]3[C:17]4[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=[CH:21][C:16]=4[N:15]([S:37]([C:29]4[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=4[O:27][CH3:26])(=[O:38])=[O:39])[C:14]3=[O:25])[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: CCOc1ccc2[nH]c(=O)n(C34CC5CC(CC(C5)C3)C4)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(C13CC4CC(CC(C4)C1)C3)c(=O)n2S(=O)(=O)c1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.35 g of sodium hydride as a 60% dispersion in oil is added in portions to a suspension of 2.5 g of 3-(adamant-1-yl)-5-ethoxy-1,3-dihydro-2H-benzimidazol-2-one in 10 ml of THF and 20 ml of DMF and the mixture is stirred for 30 minutes at RT. 2.2 g of 2-methoxy-4-nitrobenzenesulfonyl chloride are then added and the formation of a yellow precipitate is observed. The reaction mixture is poured into iced water and the precipitate obtained is filtered off and washed with water, with 95° EtOH and with ether to give 3.8 g of the expected product. M.p.=231° C.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[CH2:17]([C:21]1[S:30][C:29]2[NH:28][C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[N:25]=[C:24]([N:35]3[CH2:40][CH2:39][NH:38][C@@H:37]([CH2:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:36]3)[C:23]=2[N:22]=1)[CH2:18][CH2:19][CH3:20]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[NH3:22].[CH2:17]([C:21]1[S:30][C:29]2[NH:28][C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[N:25]=[C:24]([N:35]3[CH2:40][CH2:39][N:38]([CH3:1])[C@@H:37]([CH2:41][CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:36]3)[C:23]=2[N:22]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2)C1
Product: N
Reaction time: 5 h

Procedure:
Add sodium triacetoxyborohydride and aqueous formaldehyde (37%w/w, to a solution of (S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.50 g, 1.1 mmol) in dichloroethane (12 mL) and stir. After 5 hours, dilute with a saturated aqueous solution of sodium bicarbonate, and separate the layers. Extract the aqueous layer with dichloromethane (3×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to an oil (0.24 g). Purify the oil by flash chromatography, eluting with a gradient of a 5% solution of 2M ammonia in methanol, in dichloromethane (0–100% over 30 minutes), and then with a 5% solution of 2M ammonia in methanol, in dichloromethane to give the title compound (0.19 g): Mass spectrum (APCI+, m/e): 460 (M+1); 1H NMR (300 MHz, CDCl3), δ (ppm): 7.39–7.11 (m, 5H), 7.11–6.95 (m, 2H), 6.94–6.81 (m, 1H), 6.69–6.57 (m, 1H), 5.01 (s, 1H), 4.40–3.93 (br. m, 1H), 3.34–3.16 (m, 1H), 3.08–2.92 (m, 1H), 2.93–2.40 (m, 7H), 2.40–2.23 (m, 4H), 2.06–1.51 (m, 4H), 1.38 (d, 2H, J=7.1 Hz), 0.90 (t, 3H, J=7.1 Hz).