Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC=CC=1.[NH2:28][C:29]1[C:37]([CH3:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:30]=1[C:31](O)=[O:32]>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:31](=[O:32])[C:30]3[CH:34]=[C:35]([Cl:39])[CH:36]=[C:37]([CH3:38])[C:29]=3[N:28]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 10, Step D) (3.02 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 6 Step A) (1.86 g, 10 mmol) and pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with more acetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes at a temperature of −5 to 0° C. The reaction mixture was stirred 15 minutes more at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a light yellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/ pH 3 water) showed a major peak corresponding to the title compound and having 95.7% of total chromatogram peak area.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:6]2.[H-].[Na+].CN(C)C=O.[CH3:26][O:27][CH2:28]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:26][O:27][CH2:28][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[N+:11]([O-:13])=[O:12])[CH:4]=[C:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2c(C)ccc([N+](=O)[O-])c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc([N+](=O)[O-])c2n1COC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of ethyl 4-methyl-7-nitro-1H-indole-2-carboxylate (7.0 g), 60% sodium hydride (1.35 g) and N,N-dimethylformamide (40 ml) was stirred at room temperature for 30 min. This solution was ice-cooled, and a solution of chloromethyl methyl ether (2.6 ml) in tetrahydrofuran (15 ml) was added dropwise. The mixture was stirred at for 4 hr, and the reaction solution was diluted with ethyl acetate, washed with saturated brine, aqueous citric acid solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-1:5) to give the title compound (5.6 g, yield 68%) as pale-yellow needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(F)cc1F
Product: COc1ccc(/C(C#N)=C/c2ccc(F)cc2F)cc1OC
Yield: 31.2 %

Procedure:
2,4-Difluorobenzaldehyde (142 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (94 mg, yield: 31%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH:11]=2)[CH2:6][CH2:5]1.[C:26](OC(=O)C)(=O)[CH3:27].N1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C>[CH2:34]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH:11]=2)[CH2:6][CH2:5]1)[C:35]1[CH:27]=[CH:26][CH:38]=[CH:37][CH:36]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: Cc1nc(Nc2ncc(C(=O)O)s2)cc(N2CCN(CCO)CC2)n1
Agent: CN(C)c1ccncc1
Product: Cc1nc(Nc2ncc(C(=O)O)s2)cc(N2CCN(CCOCc3ccccc3)CC2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 7) (30 g, 0.082 mol), pyridine (300 mL) and DMAP (0.3 g) were mixed in a four-necked flask, and acetic anhydride was added by droplet when the temperature was controlled at 30° C. After adding, it was heated up to 50° C. and reacted overnight in thermal insulation. After reaction it was cooled down to room temperature and grew the grain overnight. After air pump filtration, the cake was rinsed by suitable amount of methylene dichloride. Then the cake was taken up and put into methylene dichloride (150 mL) and stirred for 30 min at room temperature. After air pump filtration the cake was dried to constant weight by blast at 60° C. to give light yellow to off-white solid target Compound 17 (Pg is acetyl) (24 g, yield: 71.7%).
Reaction SMILES: C([S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(C)(C)C.O.C(SC1C=CC(N)=CC=1)(C)(C)C.[C:28](Cl)(Cl)=[O:29]>[Fe].C1C=CC=CC=1.C(O)(=O)C>[SH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:28]=[O:29])=[CH:8][CH:7]=1
Reactant: CC(C)(C)Sc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Agent: [Fe]
Agent: CC(C)(C)Sc1ccc(N)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C=Nc1ccc(S)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(t-butylmercapto)nitrobenzene (52.8 g., 0.25 mol) and iron powder (150 g.) in 1 l. of water there was added 1 ml. of acetic acid. The reaction mixture was stirred 18 hours at 90° C. and filtered. Both the residue and filtrate were extracted several times with methylene dichloride, and the combined dried methylene dichloride extracts were concentrated at reduced pressure to give 18.2 g. of a brown oil. This is a 40% weight yield of 4-(t-butylmercapto)aniline. To this oil in 100 ml. of benzene there was then added dropwise 158 g. of a 12.5% benzene solution of phosgene (0.2 mol) with cooling. The reaction mixture was stirred for 1 hour at 10° C., overnight at room temperature and then at reflux temperature for 7 hours. After standing overnight the reaction mixture was filtered, the filtrate concentrated at reduced pressure, then vacuum-distilled. Two product fractions were collected as
Reaction SMILES: [C:1]([CH:4]([CH3:31])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=[C:9]2[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][CH3:30])([OH:3])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:30][O:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[CH2:18][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][CH:4]([CH3:31])[C:1]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:3])[CH:7]=2)[N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCNC1
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)O)ccc21
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)N3CCCC3)ccc21

Procedure:
Using a similar procedure to that described in Example 49, part g, except starting from methyl 4-[5-(2-carboxypropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate, and using pyrrolidine instead of pentylamine, methyl 3-methoxy-4-[5-(2-methyl-3-pyrrolidino-3-oxopropyl)-1-propylindol-3-ylmethyl]benzoate was obtained (60%) as a colorless glass; partial NMR (250 MHz, DMSO-d6): 0.78(t, 3H, CH2CH3), 0.98(d, 3H, CH(CH3)), 1.4-1.8 (complex m, 6H), 2.6(m, 1H), 2.83(m, 4H), 3.3(complex m, 2H), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[H][H].[CH2:12]([OH:18])[CH2:13][O:14][CH2:15][CH2:16]O>[Pd]>[NH2:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH:9][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:18])[N:1]=1
Reactant: OCCOCCO
Reactant: Nc1nc(N)nc(N)n1
Reactant: [H][H]
Agent: [Pd]
Product: Nc1nc(N)nc(NCCOCCO)n1
Reaction time: 2 h
Yield: 13.5 %

Procedure:
In a stainless steel autoclave of an inner volume of 100 ml, 1.26 g (10 mmol) of melamine, 250 mg of 5% Pd—C catalyst, and 30 ml of diethylene glycol were charged. After the inside of the reaction system was sufficiently substituted with nitrogen gas, 10 kg/cm2 of hydrogen gas was introduced under pressure at normal temperature. Then, the temperature was elevated while stirring, and after the temperature reached 260° C., the reaction was carried out at the same temperature for further 2 hours. After cooling, the reaction mixture was taken out and quantitative analysis of the reaction product was performed under the above analytical conditions. As a result, the reaction conversion rate of the starting material melamine was 21.5% and it was confirmed that there was produced only 13.5% of 2,4-diamino-6-(5-hydroxy-3-oxapentylamino)-1,3,5-triazine as the product, and an obvious decrease in activity as compared with the mixed catalyst systems was confirmed.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[ClH:1].[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1ccn2c(=O)c(CCCl)c(C)nc2c1
Solvent: Cc1ccccc1
Product: Cc1ccn2c(=O)c(CCN3CCN(c4cccc(Cl)c4)CC3)c(C)nc2c1
Product: Cl
Yield: 46.2 %

Procedure:
A mixture of 2.4 g of 3-(2-chloroethyl)-2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 5.9 g of 1-(m-chlorophenyl)piperazine and 25 ml of toluene was refluxed for 30 hours. After completion of the reaction, the rection mixture was then treated in the same manner as in Example 4, and the obtained crude crystals were recrystallized from a mixture of methanol and ethanol to give 2.2 g of the desired compound as pale yellow plates, m.p. 272° - 274°C (decomp.).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[C:18]2[S:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1O

Procedure:
A mixture of vanillin (30.4 g, 0.2 mol), rhodanine (26.6 g, 0.2 mol), anhydrous sodium acetate (41 g, 0.5 mol) and glacial acetic acid was stirred and heated at reflux for one and one-half hours. The cooled reaction mixture was added to water (1200 mL) and the yellow-orange solid that separated was collected, washed with water and air dried; yield 46 g.
Reaction SMILES: N1CCCCC1.[CH3:7][N:8]([CH2:10][CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:21](=[O:51])[C@H:22]([NH:33]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:12]1)[CH3:9]>CO>[NH2:33][C@H:22]([CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[C:21]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH:11]([CH2:10][N:8]([CH3:9])[CH3:7])[CH2:12]1)=[O:51]
Reactant: CN(C)CC1Cc2ccccc2N(C(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)OCC2c3ccccc3-c3ccccc32)C1
Solvent: CO
Solvent: C1CCNCC1
Product: CN(C)CC1Cc2ccccc2N(C(=O)[C@H](N)Cc2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
Piperidine (0.66 ml) was added to a methanol (10 ml) solution of 3-(R,S)-(N,N-dimethylamino)methyl-1-[2-(R)-(9-fluorenylmethoxy)carbonylamino-3-(indol-3-yl)propanoyl]-1,2,3,4-tetrahydroquinoline (0.797 g) at room temperature. The reaction mixture was stirred at room temperature for 18 hours, then concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/methanol=10/1) to obtain the entitled compound (0.382 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].N[C:14](N)=[O:15]>C(OCC)C>[CH3:11][C:9]1([CH3:10])[O:12][C:14](=[O:15])[NH:1][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: NC(N)=O
Reactant: Cc1cccc(C(C)(C)O)c1N
Solvent: CCOCC
Product: Cc1cccc2c1NC(=O)OC2(C)C
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 2.88 g of 2-(2-amino-3-methylphenyl)propan-2-ol and 2.14 g of urea is stirred in a sealed vessel at 150° C. over 6 hours. The reaction mixture is cooled to room temperature, admixed with diethyl ether, clarified by filtration and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.22 (1:2 EtOAc-heptane); Rt=3.46.
Reaction SMILES: F[C:2]1[N:3]=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:8][C:5]1[N:4]=[N:3][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:23])([F:24])[F:9])[CH:12]=3)[CH2:22][CH2:21]2)=[CH:7][CH:6]=1
Reactant: Fc1ccc(F)nn1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 2.7 parts of 3,6-difluoropyridazine, 4.6 parts of 1-[3-(trifluoromethyl)phenyl]piperazine, 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred overnight at 60° C. The reaction mixture was poured 1nto water. The product was filtered off, washed with water and crystallized from 2-propanol, yielding 3 parts (46%) of 3-fluoro-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp. 131.5° C. (compound 24).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[C:24](O)=[O:25]>>[F:18][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=[C:21]([C:20]([F:35])([F:19])[F:34])[CH:22]=1
Reactant: Cc1ccccc1-c1ccncc1NCC(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-(4-o-tolyl-pyridin-3-yl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 68 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (34%). MS (ESI): m/z=490.11 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][C:5]=1[O:21][CH3:22].[OH-].[Li+].Cl.O>C1COCC1.CO>[CH3:22][O:21][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH:8]=[C:9]([CH3:10])[C:4]=1[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of 0.325 g (1.00 mmol) of 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 20 ml of THF/MeOH (1:1) was added 2.50 ml (2.50 mmol) of lithium hydroxide solution (1 molar in water) drop by drop and the reaction mixture was then heated up to reflux. After 8 hours, it was poured into crashed ice and acidified with HCl/H2O (1N) to pH 3.0 and then extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.24 g (77%) of the title compound as light yellow solid. MS: 310.0 (M−H−).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)[CH:10]([CH2:18][OH:19])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[CH2:18][OH:19])[CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(CO)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@H]1CNCC[C@H]1N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (373 mg, 1.25 mmol) in anhydrous DCM (10 mL) was slowly added a solution of diisobutylaluminum hydride in hexanes (1M, 3.8 mL, 3.8 mmol) at −70° C. The reaction mixture was allowed to warm to −10° C. over 90 min, then stirred at RT for 15 min. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (188 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[C:5]([F:34])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)(=[O:23])=[O:24])([CH3:20])[CH2:9][O:10][C@@:11]([C:12]#[N:14])([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:5]([F:34])=[CH:4][CH:3]=1
Reactant: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
A suspension of (R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (8.43 g, 14.70 mmol) and triethylamine (5.12 ml, 36.8 mmol) in 85 ml DCM was cooled to 0-5° C. Trifluoroacetic anhydride (2.49 ml, 17.64 mmol) was added dropwise over 30 min. Additional triethylamine (1.54 ml, 11.07 mmol) and trifluoroacetic anhydride (0.75 ml, 5.29 mmol) were added to complete the reaction. The reaction mixture was quenched by addition of 14 ml aqueous ammonia (25%) and 14 ml water. The emulsion was stirred for 15 min, more water and DCM were added and the layers were separated. The organic layer was dried with MgSO4H2O, filtered and evaporated. Purification by column chromatography on a silica gel (hexanes/10-25% EtOAc) gave 8.09 g of the title compound as a yellow resin.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:19][CH2:18][C:17]([S:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:7][C:8]=2[CH:13]=1)(=[O:16])=[O:15])([CH3:20])[CH3:21])(=[O:37])=[O:36]
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CO)ccc2n1CC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)COS(C)(=O)=O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-1-ol (Step H, 356 mg, 0.94 mmol) in dichloromethane (8 mL) were added triethylamine (157 μL, 1.13 mmol) and methanesulfonyl chloride (87 μL, 1.13 mmol) at 0° C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (30 mL×3). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude title compound (411 mg) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.[CH3:23]CN(CC)CC.[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1C(Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[CH2:23][C:39]1[CH:38]=[CH:37][CH:33]=[C:32]([O:31][CH3:30])[CH:40]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cccc(CC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.300 g, 1.02 mmol), Et3N (0.15 mL, 1.1 mmol), 2-methoxybenzoyl chloride (0.17 g, 1.02 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (5.0 mL), sodium cyanoborohydride (0.47 g, 7.5 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([CH2:11][S:12][CH3:13])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)c(F)cc1Br
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1c(N)c(Br)cc(F)c1F

Procedure:
To a solution of 2-bromo-4,5-difluoroaniline (100 g) and dimethyl sulfide (49 ml) in anhydrous dichloromethane (1.2 liter) is added gradually N-chlorosuccinimide (90 g) at below 15° C., and thereafter is further added in portions triethylamine (93 ml) at 15° C. After the addition, the mixture is refluxed for 7 hours. After cooling, 10% aqueous sodium hydroxide (one liter) is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=1:2). The product is recrystallized from n-hexane to give 6-bromo-3,4-difluoro-2-methylthiomethylaniline (52 g) as a white crystal, m.p. 60°-61° C.