Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=2)[C:34](O)=[O:35])=[N:7][N:6]=1)([CH3:3])[CH3:2].C1C[N:41]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:40]C1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=2)[C:34]([NH:41][CH3:40])=[O:35])=[N:7][N:6]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C(=O)O)c3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cncc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of 5-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)nicotinic acid (500 mg, 0.967 mmol) in DMF (10 mL) was added PyBOP (755 mg, 1.45 mmol), HOBt (196 mg, 1.45 mmol) and DIPEA (0.50 mL, 2.9 mmol). Methylamine hydrochloride (77.7 mg, 1.160 mmol) was added and the reaction was stirred for 2 h under Ar at RT. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried. The crude product was purified with basic alumina chromatography (eluting with EtOAc) to give 5-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylnicotinamide (150 mg, 29%). MS (ESI, pos. ion) m/z: 531.2 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([O:14][CH3:15])=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl.[OH-].[Na+]>O1CCCC1>[F:13][C:11]1[CH:12]=[C:7]([B:20]([OH:21])[OH:19])[C:8]([O:14][CH3:15])=[N:9][CH:10]=1
Reactant: COc1ncc(F)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(F)cc1B(O)O
Temperature: -100 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 20 mL, 32 mmol) was slowly added (0.4 mL/min) to a solution of 3-bromo-5-fluoro-2-methoxypyridine (6.0 g, 29.12 mmol) and triisopropylborate (8.4 mL, 36.62 mmol) in dry tetrahydrofuran (70 mL) at −100° C. under argon atmosphere. The reaction mixture was stirred at −100° C. for 2 hours and afterwards the temperature was allowed to warm up slowly overnight to ambient temperature before being cooled down to 0° C. Aqueous hydrochloric acid (1N solution, 120 mL) was slowly added and the mixture was stirred at 0° C. for 1 hour. A solution of sodium hydroxide (32% in water) was then added until pH was around 6 and the resulting mixture was extracted with diethyl ether (×3). The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound (3.28 g, 66%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:18]=[CH:19][C:20]=1[CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:28](=[O:29])[CH:27]([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[C:15]([F:14])[CH:16]=2)[CH3:31])=[CH:6][CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Reactant: NCc1ccc(C(F)(F)F)nc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1ccc(C(F)(F)F)nc1Cl)c1ccc(CNS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 61.3 %

Procedure:
To a stirred solution of (2-chloro-6-(trifluoromethyl)pyridin-3-yl)methanamine (2.9 g, 13.8 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (3.8 g, 13.8 mmol) in tetrahydrofuran (100 mL) were added 1-hydroxybenzotriazol (1.89 mL, 13.8 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.4 g, 13.8 mmol) and N-ethyldiisopropylamine (7 mL, 41.4 mmol) to gave an suspension. After addition of N,N-dimethylformamide (1 mL) the reaction mixture was stirred for 36 h at room temperature. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: cyclohexane/ethyl acetate 1:2) to afford N-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (3.96 g, 61%).
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:33][C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (100 mg) was dissolved in DMF (2 mL), 2-bromoacetophenone (52 mg) was added, and potassium carbonate (36 mg) was further added. The reaction solution was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After the solution was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was recrystallized from IPE to obtain 69 mg of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH3:14])[C:11]([NH:15][CH:16]=[O:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1Cl>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH3:14])[C:11]([NH:15][CH:16]=[O:17])=[N:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Product: CC1CN(c2cccc(Cl)c2)N=C1NC=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 3.0 g. amount of the preceding product is dissolved in 10 ml. of a mixture of formic acid and acetic anhydride (Example 15). The mixture is allowed to remain at room temperature for 3 hours, then is poured into ice water to separate a partial gum and solid. This material is collected, dissolved in dichloromethane and filtered through a short column of a hydrous magnesium silicate. The effluent is concentrated while adding hexane to separate 3.1 g. of the product of the Example as light yellow crystals, m.p. 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1/[CH:4]=[CH:5]/[C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=2[S:8][CH:7]=1.O.O.Cl[Sn]Cl.Cl.[NH4+].[OH-].C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[NH2:20][C:17]1[CH:18]=[CH:19][C:2]([CH3:1])=[C:3]([CH:16]=1)/[CH:4]=[CH:5]/[C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=2[S:8][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1/C=C/c1csc2c(N)ncnc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(N)cc1/C=C/c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
(E)-7-(2-methyl-5-nitrostyryl)thieno[3,2-d]pyrimidine-4-amine (0.3 g, 0.96 mmol) was dissolved in ethyl acetate (5 mL) and then SnCl2.2H2O (1 g, 4.81 mmol) and conc. HCl (0.5 mL) were added thereto, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed NH4OH solution was added thereto to pH 5. Then, anhydrous Na2CO3 was added thereto to pH 7. The reaction mixture was filtered with Celite and washed with ethyl acetate several times. The filtrate was concentrated under reduced pressure to obtain the title compound (260 mg, 84% yield) without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.Cl.CN.C1C[N:32]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:31]C1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:32][CH3:31])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (860 mg, 2.37 mmol) and methylamine hydrochloride salt (0.34 g, 4.75 mmol) in 10 mL of DMF was added PyBOP (1300 mg, 2.49 mmol) and TEA (1.13 mL, 8.3 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as an offwhite powder (165 mg, yield 19%). MS calcd for (C16H18BN3O5S): 375.1. MS found (ESI negative): (M−H)−=374.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.87 (s, 1H), 9.17 (bs, 1H), 7.93 (d, J=4.8 Hz, 1H), 7.41 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H)), 6.35 (d, J=8.8, 2 Hz, 1H), 4.87 (s, 2H), 3.77 (s, 2H), 2.63 (d, J=4.4 Hz, 3H).
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23]C(=O)OC(C)(C)C)[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:23][C@@H:9]([CH2:8][C@H:5]1[CH2:4][CH2:3][C@@H:2]([F:1])[CH2:7][CH2:6]1)[CH2:10][N:11]([CH3:12])[C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@@H](N)C[C@H]1CC[C@@H](F)CC1)C(=O)OCc1ccccc1

Procedure:
A solution of tert-butyl (S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (550 mg, 1.3 mmol) in TFA/CH2Cl2 (20 mL, v/v 20%) was stirred for 1 h at rt, quenched with satd aq NaHCO3 until no further gas evolution was visible and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and condensed under reduced pressure to obtain benzyl (S)-2-amino-3-(cis-4-fluorocyclohexyl)propylmethylcarbamate (400 mg, yield 95%). 1H NMR (CDCl3, 400 MHz) δ 1.42(m, 4 H), 1.64(m, 4 H), 2.98(d, 3 H), 3.21(m, 1 H), 3.50(m, 1 H), 3.90(m, 1 H), 5.13(d, 2 H), 7.33(m, 5 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.[H-].CN(C)CCCN=C=NCC.[C:32]([C:34]1[CH:66]=[CH:65][CH:64]=[CH:63][C:35]=1[O:36][C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[NH:41]C(C3C=CC=CN=3)=[N:43][C:39]=2[CH:38]=1)#[N:33]>C(OCC)(=O)C.CN1CCCC1=O>[C:32]([C:34]1[CH:66]=[CH:65][CH:64]=[CH:63][C:35]=1[O:36][C:37]1[C:51]([O:52][C:53]2[CH:54]=[CH:55][C:56]([S:59]([CH3:62])(=[O:60])=[O:61])=[CH:57][CH:58]=2)=[CH:50][C:40]2[NH:41][C:7]([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:43][C:39]=2[CH:38]=1)#[N:33]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C#N)cc1
Reactant: O=C(O)c1cccnn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [H-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cccnn4)nc3cc2Oc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.3 mg of pyridazine-3-carboxylic acid, 15 mg of 1-hydroxybenzotriazole and 15 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydride were added in order to an N-methylpyrrolidone (0.3 ml) solution of 15 mg of 4-(2-cyano-phenoxy)-5-(4-methanesulfonyl-phenoxy)-benzene-1,2-diamine obtained in Example 17, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, and washed with saturated sodium bicarbonate solution, and the solvent was evaporated away under reduced pressure. The resulting residue was dissolved in 0.2 ml of N-methylpyrrolidone, and 5 mg of ytterbium trifluoromethanesulfonate was added to it, and the reaction liquid was stirred overnight at 140° C. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was evaporated away under reduced pressure to obtain the entitled compound as a brown solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10]>CCO>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COc1cccc(/C(C#N)=C\c2ccc(C)c(C)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C(C#N)Cc2ccc(C)c(C)c2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
NaBH4 (1.8 g, 47 mmol) was added slowly to the solution of (2E)-3-(3,4-dimethylphenyl)-2-(3-methoxyphenyl)acrylonitrile (6.17 g, 23.5 mmol) in EtOH (100 mL) under argon. The mixture was stirred at 70° C. for 16 h. The solution was cooled to room temperature and quenched with water. The reaction mixture was diluted with 100 mL water and acidified with 6M HCl (aq.). After extraction with ether (3×100 mL), the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to get 3-(3,4-dimethylphenyl)-2-(3-methoxyphenyl)propanenitrile as a white solid (6 g, 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH:20]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])([CH3:22])[CH3:21]>O>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:23]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:20]([CH3:22])[CH3:21])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)NCCCCO
Solvent: O
Product: CC(C)N(CCCCO)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 56.5 %

Procedure:
30 g of 2-chloro-5,6-diphenylpyrazine and 131.22 g of 4-(isopropylamino)-1-butanol were mixed and then heated with stirring at 190° C. for 10 hours. The reaction solution was air-cooled, poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain 22.96 g of the desired compound as a colorless crystal having a melting point of 102 to 103° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]([F:26])([F:25])[F:24])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:25][C:23]([F:24])([F:26])[CH2:22][N:7]1[C:6]([CH2:4][OH:3])=[CH:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 1 a], 2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol as colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(=O)C>C(#N)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:1][C:3]2[CH:7]=[CH:6][N:5]([C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cccnc1-n1ccc(C=O)n1
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 2-(3-formyl-1H-pyrazol-1-yl)nicotinate (400 mg, 1.631 mmol) and morpholine (220 μl, 2.53 mmol) in acetonitrile (25 mL) NaCNBH4 (130 mg, 2.069 mmol) was added, and the pH adjusted to 5-6 by adding glacial acetic acid (110 μL, 1.922 mmol). The mixture was stirred at room temperature for 1 h, another portion of NaCNBH4 (30 mg, 0.477 mmol) added and stirred for 2 hrs. For work up the mixture was concentrated, dissolved in 100 mL of dichloromethane, washed subsequently with water and brine, dried (MgSO4), filtered off and concentrated to give 710 mg of the crude title product. Purification by chromatography over silica gel (CH2Cl2/3%-5% methanol) and concentration yielded 518 mg of the title compound as clear oil; ESI-MS [M+H]+: 317.20.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:22])=[O:21]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CN(CCC#Cc1ccccn1)S(=O)(=O)c1ccccc1Cl
Yield: 35.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-chlorobenzene-1-sulfonyl chloride (79 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 37 mg of 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brown oil (Yield: 35%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=2)[NH:18][CH:17]=1.[CH3:29]I.O>CN(C)C=O>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1
Reactant: CI
Reactant: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(CC(N)=O)ccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (80% dispersion in oil) (0.14 g) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetamide (1.5 g) in dry dimethylformamide (10 ml). After stirring the red solution for 30 min, methyl iodide (0.41 ml) was added and the mixture was stirred for a further 16 h. Water (40 ml) was added, the solid collected by filtration and crystallised from propan-2-ol to give the title compound as a yellow powder (1.25 g), m.p. 200°-2° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[N:3]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[C:11]([CH3:22])[CH:10]=1.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([O:1][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[N:3]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([F:18])[F:19])=[C:11]([CH3:22])[CH:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(N2C(=O)N(C)CC2O)ccc1OC(F)(F)C(F)F
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(N2C(=O)N(C)CC2OCc2ccccc2)ccc1OC(F)(F)C(F)F
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
16.1 g (0.05 mol) of 4-hydroxy-1-methyl-3-[3-methyl-4-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazolidin-2-one are dissolved in 150 ml of acetonitrile, and 1.50 g of sodium hydride (80% strength in white oil) are added at 5° C. The mixture is stirred for 10 minutes at 5° C., and 6.40 g (0.05 mol) of benzyl chloride are subsequently added dropwise at 5° C. The mixture is stirred for 5 hours at 50°and poured into 400 ml of ice-water. The mixture is extracted twice with 100 ml of methylene chloride in each case, and the combined methylene chloride phases are washed with 100 ml of water and dried over sodium sulfate. After removing the solvent by distillation, 19.4 g (94% of theory) of 4-benzyloxy-1-methyl-3-[3-methyl-4-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazolidin-2-one are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][N:11]1[S:35]([CH3:38])(=[O:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:8][CH2:9][C@H:10]1[N:11]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12][C@H:13]([SH:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1COCc1ccccc1
Reaction time: 18 h
Yield: 75 %

Procedure:
9.07 g (20 mmol) of (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol and 9.5 ml (80 mmol) of benzylbromide were dissolved in 660 ml DMF, cooled to 0° C. and treated with 1.4 g (32 mmol) of 55% NaH over 15 min in 4 portions. The reaction was warmed up over night and treated with 4.75 ml (40 mmol) benzylbromide/700 mg (16 mmol) 55% NaH and 6 h later again with the same amount of benzylbromide/NaH. After further 16 h at room temperature the reaction was quenched with saturated NH4Cl solution/EtOAc (3×). The organic phase was washed with aqueous 10% NaCl soution, dried over Na2SO4 and evaporated to give 25 g crude product. Flash-chromatography on silica gel (Hexane/EtOAc 4:1 to 1:4) gave 6.43 g (59%) of (2S,4R)-2-benzyloxymethyl-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine, MS: 544 (MH+). 6.4 g (11.77 mmol) (2S,4R)-2-benzyloxymethyl-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine were dissolved in 170 ml TFA and treated at 0° C. with 18.75 ml (117.7 mmol) of triethylsilane. After 18 h at 0° C., the mixture was evaporated and purified by flash-chromatography on silica gel (Hexane/EtOAc 4:1 to 1:4) to give 2.66 g (72%) of (3R,5S)-5-benzyloxymethyl-1-methanesulfonyl-pyrrolidine-3-thiol, MS: 302 (MH+).