Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)(=[O:17])=[O:16])[C:11]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[C:10]([O:34][CH3:35])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:39][C:40]([O:42][CH3:43])=[O:41].C(Cl)Cl.CCOC(C)=O>CN(C=O)C>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]([O:34][CH3:35])[C:11]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)(=[O:17])=[O:16])[N:13]=2)[CH:3]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(O)c2)nc1OC
Reactant: COC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1cccc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.41 g of 5-methyl-pyridine-2-sulfonic acid [2-(3-hydroxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 1, were dissolved in DMF (30 ml) and treated with NaH (0.061 g of a 65% NaH suspension in oil) under ice cooling. The mixture was stirred for 1 h at RT, treated dropwise with 0.11 g of methyl chloroacetate and was stirred at RT for 20 h until the reaction was completed according to TLC analysis (CH2Cl2/EtOAc: 4/1). The mixture was partitioned between brine and EtOAc the organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/EtOAc: 7/1). Combination of the purified fractions and evacuation in vacuo afforded {3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenoxy}-acetic acid methyl ester as a light yellow crystalline solid. ISP mass spectrum, m/e 567.2 (M+1 calculated for C27H26N4O8S: 567).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:30])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([F:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11](=[O:30])[C:10]=1[C:8]#[N:7]
Reactant: O=C(NC1CCCCC1)c1c(O)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Yield: 50 %

Procedure:
A solution of Compound 43 (5.1 g, 12.36 mmol) in 20 ml neat phosphorus oxychloride was heated at 100° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 2.05 g (50%) of yellow solids. M.P. 236° C. 1H NMR (DMSO-d6): δ 5.54 (s, 2H), 7.14 (m, 2H), 7.33 (m, 2H), 7.59 (dd, J=4.0, 9.1 Hz, 1H), 7.72 (td, J=2.8, 7.9 Hz, 1H), 7.91 (dd, J=2.8, 8.9 Hz, 1H). EIMS m/z 331 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[N:9]([C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:8][CH2:7][CH2:6]1)([OH:3])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]([C:17](=[O:30])[C:18]3[CH:19]=[CH:20][C:21]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)[CH2:8][CH2:7][CH2:6][CH:5]([CH2:4][C:1]([N:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)=[O:3])[C:11]=2[CH:12]=1
Reactant: O=C(O)CC1CCCN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccc(Cl)cc21
Reactant: CN1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)CC2CCCN(C(=O)c3ccc(C4CCCCC4)cc3)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-carboxymethyl-7-chloro-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in dichloromethane (50 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.54 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. To the mixture are added with stirring N-methylpiperazine (0.24 ml) and triethylamine (0.46 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=40:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) as colorless amorphous.
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]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:22]1[CH:23]=[CH:24][C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccncc1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(Nc3ccncc3)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
4-Chloro-2-phenyl quinazoline, 1 equivalent, was treated with 1 equivalent 4-aminopyridine and 1 equivalent potassium carbonate in dimethylformamide (DMF), under reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to an oil. This crude material was dissolved in ethyl acetate and chromatographed using hexane:ethyl acetate:methanol 8:2:0.5 to obtain solid product. Electron impact mass spectroscopy (EIMS) gave a molecular ion corresponding to the calculated molecular weight of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:8])=[CH:5][N:4]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30]>>[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[CH:28]=[CH:27][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: CCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(CBr)nc1
Product: CCN1CCN(Cc2ccc(C(N)=O)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 5 with 1-ethylpiperazine (0.4 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(4-ethylpiperazin-1-yl)methylnicotinamide. MS (Q1) 512.2 (M)+
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[N:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.[H-].[Na+]>>[CH2:1]([C:5]1([CH2:5][CH2:1][CH2:2][CH3:3])[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=2)[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2cnccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCCC1(CCCC)Nc2ccncc2N1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
2-butyl-3-[(2'-tert-butoxycarbonylbiphen-4-yl)methyl]-2-butyl-3H-imidazo[4,5-c]pyridine was prepared according to the procedure described in Example 1, Part A from 2-butylimidazo[4,5-c]pyridine (220 mg, 1.25 mmol), tert-butyl 4'-bromomethylbiphenyl-2-carboxylate (414 mg, 1.19 mmol), and NaH (1.88 mmol).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:11]=[C:12](/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39])[CH:13]=[C:14]([F:35])[C:15]=1[C@@H:16]1[C:21]2[NH:22][C:23]3[C:28]([C:20]=2[CH2:19][C@@H:18]([CH3:29])[N:17]1[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=[CH:25][CH:24]=3>CC(C)=O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[C:38](/[CH:37]=[CH:36]/[C:12]1[CH:13]=[C:14]([F:35])[C:15]([C@@H:16]2[C:21]3[NH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[CH2:19][C@@H:18]([CH3:29])[NH+:17]2[CH2:30][C:31]([F:34])([CH3:32])[CH3:33])=[C:10]([F:9])[CH:11]=1)([OH:40])=[O:39].[C:1](/[CH:2]=[CH:3]/[C:4]1[CH:11]=[C:10]([F:9])[C:15]([C@@H:16]2[C:21]3[NH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[CH2:19][C@@H:18]([CH3:29])[NH+:17]2[CH2:30][C:31]([CH3:33])([F:34])[CH3:32])=[C:14]([F:35])[CH:13]=1)([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: C[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2c(F)cc(/C=C/C(=O)O)cc2F)N1CC(C)(C)F
Solvent: CC(C)=O
Product: C[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2c(F)cc(/C=C/C(=O)O)cc2F)[NH+]1CC(C)(C)F
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 110.3 %

Procedure:
A solution of maleic acid (1.31 g, 11.29 mmol) in acetone (15 ml) was stirred under nitrogen. A solution of (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (Example 1) (5.00 g, 11.3 mmol) in acetone (25 ml) was added to the maleic acid solution to give a yellow solution. The reaction vessel was covered in foil to protect from light and purged with a stream of nitrogen gas overnight until the solvent evaporated. A solid was obtained which was dried in vacuo for 2 hours to give the title compound as a cream solid (6.23 g, 98%). 1H NMR (500 MHz, DMSO, 27° C.) 0.95-1.34 (9H, m), 2.24-2.45 (1H, m), 2.54-2.66 (1H, m), 2.8-2.99 (2H, m), 3.52 (1H, s), 5.22 (1H, s), 6.26 (2H, s), 6.67 (1H, d), 6.89-7.07 (2H, m), 7.19 (1H, d), 7.39-7.51 (3H, n), 7.55 (1H, d), 10.59 (1H, s). An XRPD trace of this maleate salt is shown in FIG. 8 and a DSC trace shown in FIG. 9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N(CC)CC)C.[CH3:20][N:21]=[C:22]=[O:23]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:22](=[O:23])[NH:21][CH3:20])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: CN=C=O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N1C(=O)C(=O)c2cc(F)ccc21
Yield: 74.5 %

Procedure:
A mixture of 5-fluoroisatin (9.9 g), triethylamine (1 ml) and dimethylformamide (30 ml) is stirred under ice-cooling, and thereto is added dropwise methyl isocyanate (3 g) at the same temperature. The mixture is stirred at room temperature for 30 minutes, and the precipitates are taken by filtration to give 5-fluoro-1-methylcarbamoylisatin (8.7 g). M.p. 230°-232° C.
Reaction SMILES: [Br:1][C:2]1[C:12](C)=[CH:11]C(OCC(C)=O)=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH3:24].[CH3:25]O.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:31]2[O:30][CH:29]=[C:28]([CH3:25])[C:27]=2[C:12]=1[CH3:11]
Reactant: C1CCOC1
Reactant: CO
Reactant: CC(=O)COc1cc(C)c(Br)c(C)c1Cc1ccc(C(C)C)cc1
Product: Cc1c(Br)c(C)c2c(C)coc2c1Cc1ccc(C(C)C)cc1
Yield: 84 %

Procedure:
Using 1-(4-bromo-1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone obtained in Reference Example 189, the title compound was synthesized in the same manner as in Reference Example 143. Yield 84%. Melting point: 76-77° C. (methanol-THF).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([C@@H:24](O)[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.CCCCCC>ClCCl>[Br:1][C@@H:24]([C:16]1[CH:15]=[C:14]([C:13]([F:28])([F:27])[F:12])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1)[CH3:25]
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CSC
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57.5 %

Procedure:
Under an argon atmosphere, a suspension of N-bromosuccinimide (206 mg, 1.16 mmol) in anhydrous dichloromethane (3.8 mL) was added dropwise with dimethyl sulfide (105 μL, 1.40 mmol) under ice cooling over 3 minutes. The mixture was added dropwise with a solution of (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (200 mg, 0.78 mmol, >99.5% ee) in anhydrous dichloromethane (2 mL) at −20° C., and the mixture was stirred at room temperature for 9 hours. The reaction mixture was add with n-hexane, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent, n-hexane) to obtain 144 mg of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[O:13][CH2:12][CH2:11][C:10]=12)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cccc2c1CCO2
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 7.4 g. of N-isopropyl-2,3-dihydro-4-benzofuranamine in 200 ml. of glacial acetic acid, cooled to 15°± 5°C. is added 2.5 g. of sodium isocyanate. The mixture is stirred at room temperature for 15 hours and then concentrated in vacuo. The residue is treated with 150 ml. of 2N sodium hydroxide and then extracted with chloroform. The chloroform extract is dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oil of 1-isopropyl-1-(2,3-dihydro-4-benzofuranyl) urea.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])[CH:5]([CH3:7])[CH3:6].Cl.[OH2:14]>>[P:9]([CH2:8][NH:4][CH2:3][C:2]([OH:1])=[O:14])([OH:10])([OH:11])=[O:12].[CH:5]([N:4]([CH2:8][P:9]([OH:11])([OH:10])=[O:12])[CH2:3][C:2]([OH:14])=[O:1])([CH3:6])[CH3:7]
Reactant: CC(C)N(CCO)CP(=O)(O)O
Reactant: O
Agent: Cl
Product: CC(C)N(CC(=O)O)CP(=O)(O)O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 315 °C
Yield: 13 %
Yield: 52 %

Procedure:
In a 100 ml Monel autoclave were mixed 2.30 g (11.7 mmol) of N-(2-hydroxyethyl)-N-isopropylaminomethylphosphonic acid and 3.73 g (93.0 mmol) of dry, powdered NaOH. The reagents were mixed together well. The reaction vessel was flushed with N2, and the mixture was heated to 315° C. for three hours. During the heating period at 315° C. the internal pressure in the vessel rose from 5×105N/M2 to 1.3×106N/M2. At the end of the heating period the excess pressure that was generated was released and 8 ml of water were introduced. The temperature of the reaction was maintained at 300° C. for three hours while the internal pressure rose from 3.1×106N/M2 to 3.9×106N/M2. The vessel was then cooled to room temperature and the residual pressure was released. The reaction mixture was diluted with water and neutralized with 93 mmol of HCl. This solution was concentrated to dryness. The residue was taken up in conc. HCl and the precipitated NaCl was filtered off. The filtrate was concentrated and purified by ion exchange chromatography (Dowex 50×8-400), to yield 1.03 g (52.0%) of N-phosphonomethylglycine and 0.32 g (13.0%) of N-isopropyl-N-phosphonomethylglycine
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[C:7]([N+:10]([O-])=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].[Sn](Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:10][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[C:8]=1[OH:9]
Reactant: N#Cc1cccc([N+](=O)[O-])c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#Cc1cccc(N)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 272.1 %

Procedure:
A mixture of 6-cyano-2-nitrophenol(600 mg, 1.0 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in acetic acid(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(365 mg, 75%). 1H NMR (CD3OD): δ 6.92 (d, 1H), 6.85-6.69 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[C:16]=1[C:25]([OH:27])=O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:37]1([CH2:40][NH:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH2:39][CH2:38]1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(CC1C2C(=CC=CC=2)NC=1C(O)=O)C1N=NN(C)N=1.C(NCC)C>>[CH:37]1([CH2:40][N:41]([CH2:42][CH:43]2[CH2:45][CH2:44]2)[C:25]([C:16]2[N:17]([CH3:24])[C:18]3[C:23]([C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:35])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:27])[CH2:39][CH2:38]1
Reactant: C1CC1CNCC1CC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)O)n(C)c3ccccc23)n1
Agent: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)O)[nH]c3ccccc23)n1
Solvent: CCNCC
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)N(CC3CC3)CC3CC3)n(C)c3ccccc23)n1
Yield: 62 %

Procedure:
3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-methyl-1H-indole-2-carboxylic acid (0.08 g, 0.156 mmol) and bis cyclopropylmethylamine (0.02 g, 0.156 mmol) were used to synthesize the title compound instead of using 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid and diethylamine in step (ii) of example 131 (0.05 g, yield: 62%).
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([OH:15])[CH2:12][CH2:13][CH3:14]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:11][CH2:12][CH2:13][CH3:14])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CCCCO
Product: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Reaction time: 0.5 h
Yield: 99 %

Procedure:
692 g (2.78 mol) of dibutyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 2000 g (27 mol) of 1-butanol (made by Wako, Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 126° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational stirring and heating were carried out for approximately 30 minutes at normal pressure, whereupon the liquid mixture boiled, and hence distilling off of a low boiling component began. This state was maintained for 8 hours, and then the purge valve was closed, and the pressure in the system was gradually reduced, and residual low boiling component was distilled off with the pressure in the system at from 76 to 54 kPa. Once low boiling component stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 952 g of reaction liquid was obtained in the flask. According to 119Sn—, 1H—, and 13C-NMR analysis results, the product 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane was obtained at a yield of 99% based on the dibutyltin oxide. The same procedure was carried out so as to produce 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane to be used in the following step B.
Reaction SMILES: [Cl:1][C:2]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][OH:9].[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37](O)[CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[ClH:1].[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:30])[F:31])[C:2]=2[Cl:1])[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Product: Cl
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of 3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propan-1-ol (0.60 g, 1.34 mmol) in toluene (4 mL) at RT was added 3-hydroxy-benzoic acid methyl ester (0.22 g, 1.45 mmol). The mixture was treated with polymer bound triphenylphosphine (0.82 g, 2.50 mmol, 3 mmol/g, Fluka Chemie) (0.71 g, 2.14 mmol, 3 mmol/g, Fluka Chemie). After 15 minutes of stirring, the mixture was treated with DIAD (0.33 mL, 1.67 mmol) and was stirred overnight at RT. The reaction mixture was filtered, concentrated and purified via preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to yield the title compound (0.25 g, 32%); MS (ES+) m/e 583 [M+H]+.
Reaction SMILES: [IH:1].[CH3:2][CH:3]([OH:12])[CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[C:6]1SC.O.[NH2:14][NH2:15]>CC(O)C>[IH:1].[NH:14]([C:6]1[N:5]([CH2:4][CH:3]([CH3:2])[OH:12])[CH2:9][CH2:8][N:7]=1)[NH2:15]
Reactant: CSC1=NCCN1CC(C)O
Reactant: NN
Agent: I
Solvent: CC(C)O
Solvent: O
Product: CC(O)CN1CCN=C1NN
Temperature: -10 °C

Procedure:
A solution of 30.2 g of α-methyl-2-(methylthio)-2-imidazoline-1-ethanol, hydroiodide, 5.2 ml of hydrazine hydrate and 200 ml of 2-propanol was refluxed for 4 hours, clarified and cooled at -10° C. The solid was collected, washed with 100 ml of cold 2-propanol, then 200 ml of ether and dried at 60° C. in vacuo, giving 26.0 g of the desired intermediate, mp 140°-142° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:7]=1[S:14](Cl)(=[O:16])=[O:15].O>O1CCCC1>[Br:5][C:6]1[C:7]2[S:14](=[O:15])(=[O:16])[N:4]([CH:1]([CH3:3])[CH3:2])[C:12](=[NH:13])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: N#Cc1cccc(Br)c1S(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1C(=N)c2cccc(Br)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
70 mg of isopropylamine is added at ambient temperature to a solution of 150 mg 2-bromo-6-cyano-benzenesulfonyl chloride in 5 ml of tetrahydrofuran. After stirring for 16 h at ambient temperature the mixture is poured into water and extracted with ethylacetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue with cyclohexane—ethyl acetate (2:1) affords 99 mg of 7-bromo-2-isopropyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-ylideneamine (P2.1).