Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S)C.[H-].[Na+].[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23]C)[CH:16]=2)=[CH:9][N:8]=1>CN(C)C=O>[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([OH:23])[CH:16]=2)=[CH:9][N:8]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: COc1cc(O)cc(Cc2cnc(N)nc2N)c1
Temperature: 25 °C

Procedure:
A solution of 32.2 g. of ethylmercaptan in 310 ml. of dimethylformamide was added dropwise with cooling and nitrogen gasification to a suspension of 25 g. of 50% sodium hydride in 310 ml. of dimethylformamide. The mixture was subsequently treated with a solution of 27 g. of 2,4-diamino-5-(3,5-dimethoxybenzyl)pyrimidine in 310 ml. of dimethylformamide, stirred at 100° C. for 17 hours, cooled down to room temperature and concentrated under a high vacuum. The residue, dissolved in a small amount of water, was filtered, the filtrate was extracted three times with 50 ml. of benzene each time and the aqueous phase was adjusted to pH 4-5 with concentrated hydrochloric acid while cooling with ice-water. Subsequently, it was brought to pH 9 with concentrated ammonia and the precipitated product, 23.3 g. of α-(2,4-diamino-5-pyrimidyl)-5-methoxy-m-cresol of melting point 254°-255° C. (from methanol) was isolated.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][CH2:22][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:31][CH:30]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)N(CCCOc1ccc(C#N)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCOc1ccc(C#N)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
1.56 g of tert-butyl 1-benzyl-4-piperidinyl[3-(4-cyanophenoxy)propyl]carbamate was dissolved in 20 ml of methanol, and then, 0.30 g of 5% palladium-carbon was added to the solution, followed by stirring under a hydrogen atmosphere at room temperature under an atmospheric pressure for 18 hours. After completion of the reaction, the catalyst was removed, and the solvent was then removed under a reduced pressure to obtain 1.05 g of tert-butyl 3-(4-cyanophenoxy)propyl(4-piperidinyl)carbamate.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[C:27]#[CH:28]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:26](=[O:29])[C:27]#[CH:28])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propynoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-propynoyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]3[NH:20][C:21]([C:23]4[C:27]([NH:28][C:29](=[O:38])[C:30]5[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=5[F:37])=[CH:26][NH:25][N:24]=4)=[N:22][C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[C:29]([NH:28][C:27]1[C:23]([C:21]2[NH:20][C:19]3[CH:39]=[CH:40][C:16]([O:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:17][C:18]=3[N:22]=2)=[N:24][NH:25][CH:26]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c[nH]nc1-c1nc2cc(OCC3CCNCC3)ccc2[nH]1)c1c(F)cccc1F
Yield: 41.1 %

Procedure:
4-{2-[4-(2,6-Difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazol-5-yloxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (0.024 g, 0.043 mmol) (prepared in a manner analogous to Example 130) was treated with 1:1 TFA:DCM (2 ml) for 20 min. The solution was reduced in vacuo and azeotroped with toluene (×3). Purification by preparative LC/MS gave 2,6-difluoro-N-{3-[5-(piperidin-4-ylmethoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide as a white solid (8 mg, 41%). (LC/MS: Rt 1.99, [M+H]+ 453.06).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[CH:31]=[CH:30][C:17]([CH2:18][O:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[CH:31]=[CH:30][C:17]([CH2:18][O:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (2 ml) in dry dichloromethane (50 ml) was added dropwise dry dimethyl sulfoxide (3.4 ml) at -60° C. and the resulting mixture was stirred for 10 minutes. To the mixture was added a solution of N-p-nitrobenzyloxycarbonyl-4-hydroxymethylpiperidine (5.88 g) in dry dichloromethane (40 ml) at the same temperature. After stirring for 15 minutes, triethylamine (14 ml) was added to the mixture. The reaction mixture was stirred at -60° C. for 5 minutes and at room temperature for 30 minutes, and diluted with dichloromethane. The reaction mixture was washed successively with water, dilute hydrochloric acid and again water, dried over anhydrous sodium sulfate and evaporated to give N-p-nitrobenzyloxycarbonyl-4-formylpiperidine.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>C(O)(C)C>[C:1]1([C:7]2[N:16]=[C:15]([N:22]3[CH2:23][CH2:24][CH2:25][CH:20]([CH2:19][OH:18])[CH2:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: OCC1CCCNC1
Solvent: CC(C)O
Product: OCC1CCCN(c2nc(-c3ccccc3)nc3ccccc23)C1
Yield: 50.1 %

Procedure:
A mixture containing 12.3 g (0.05 mole) of 2-phenyl-4-chloroquinazoline, 5.75 g (0.05 mole) 3-(hydroxymethyl) piperidine and 200 ml isopropanol was refluxed for 11/2 hrs. The resulting reaction mixture was filtered after standing at room temperature for 11/2 hrs. The white crystalline solid obtained from the filtration was recrystallized with methanol and water to give 8.0 g of the title compound, m.p. 116°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[C:25]1([CH2:31][CH2:32][C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C(CCc1ccccc1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 29.2 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.16 mmol) obtained in Example 1, (3), and 3-phenylpropionyl chloride (28 μL, 0.19 mmol), the title compound (21 mg, yield 29%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:8]=2[N:9]([CH2:17][CH2:18]3)[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.C(O)C.C1COCC1.[BH4-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]2[CH2:17][CH2:18][C:19]3=[CH:20][CH:21]=[CH:22][C:7]1=[C:8]23
Reactant: c1coc(C2=Nc3ccccc3N3CCc4cccc2c43)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: c1coc(C2Nc3ccccc3N3CCc4cccc2c43)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
An ice cold solution of 8.88 g of 1,2-dihydro-6-furylindolo[1,7-ab][1,5]benzodiazepine (HCl salt) in 100 ml 3:1 absolute ethanol-THF is treated portionwise with 2.5 g NaBH4 added at such a rate as to minimize foaming. After stirring for 1.5 hours at 0° C., water is added dropwise and the product is partitioned in CH2Cl2 -water. The aqueous phase is extracted with CH2Cl2 and the combined organic portions are washed with brine, dried over K2CO3, and concentrated to an oil which solidifies upon standing to yield 6-furyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 141°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH:12]([N:15]=[C:16]=[O:17])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:16]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:17])([CH3:14])[CH3:13]
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6v (98% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and iso-propyl isocyanate as a white solid. IR(CHCl3) 3294, 1712, 1533 cm−1; 1H-NMR (CDCl3) δ1.29 (d, J=6.8 Hz, 6H), 4.12 (hep, J=6.8 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 8.65 (br s, 1H); ESIMS m/e 271 and 273 (M++1, 35Cl and 37Cl).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2].I[CH3:12]>C1COCC1>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH2:8][CH3:9])([CH3:12])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)CC
Reactant: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC)CC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (1.13 mL, 8.05 mmol) was dissolved in THF (1 ml) under nitrogen. The mixture was cooled to −78° C. and n-Buli (3.08 mL, 7.7 mmol) was added dropwise to form LDA. A solution of 2-ethyl-butyric acid ethyl ester (0.57 mL, 3.5 mmol) in THF (2 ml) was added dropwise to this solution. The resulting mixture was stirred at −78° C. under nitrogen for 30 minutes before iodomethane (0.5 mL, 8.05 mmol) was added dropwise and the mixture was first stirred for 1 hour at −78° C., and then 30 minutes at 0° C., and finally 30 minutes at room temperature. The reaction mixture was quenched with H2O (5 ml). The mixture was extracted twice with Et2O (5 ml), washed with 2M HCl (5 ml) then dried over MgSO4.
Reaction SMILES: BrC(Br)C.[Mg].Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:46])[C:30]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=3)([CH3:35])[CH2:31][S:32]2)=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[Si:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:29]2([OH:46])[C:28]3[C:33](=[CH:34][C:25]([O:24][CH2:23][O:22][CH3:21])=[CH:26][CH:27]=3)[S:32][CH2:31][C:30]2([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=2)[CH3:35])=[CH:8][CH:9]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2=O)cc1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2(O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
Under argon atmosphere dibromoethane (0.11 ml, 1.28 mmol) was added dropwise to tetrahydrofuran suspension (5 ml) of magnesium turning (224 mg, 9.33 mmol) and the mixture was stirred for 10 minutes at 60° C. At the same temperature, tetrahydrofuran solution (5 ml) of p-bromo-t-butyldimethylsilyloxybenzene (2.30 g, 8.01 mmol) was added dropwise thereto and the mixture was heated under refluxing for 1.5 hours. To the resulting solution was added dropwise tetrahydrofuran solution (5 ml) of 7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methylthiochroman-4-one (1.00 g, 2.67 mmol) and the mixture was heated under refluxing for 3 hours. After adding saturated aqueous ammonium chloride solution, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified with silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 1.29 g (yield: 83%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:32])([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH:29]1([CH2:28][C:20]([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([CH3:32])[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:31][CH2:30]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)C(C)(N)CC1CC1
Product: CC(C)(C)OC(=O)C(C)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and tert-butyl 2-amino-3-cyclopropyl-2-methyl-propanoate (example 186b) as starting materials and isolated (105 mg, 31%); MS (ESI, m/z): 443.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)=O>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:1]=[CH:8]/[C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=1
Reactant: Cc1ccccn1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(/C=C/c2ccccn2)cc1
Yield: 37 %

Procedure:
2-Methylpyridine (5.7 g) and methyl 4-formylbenzenecarboxylate (10 g) were processed in the same manner as in Production Example 16-1 to obtain the entitled compound (5.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:23])[C:9]([OH:22])([C:14]1[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=1)[C:10]([F:13])([F:12])[F:11].Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:23])[C:9]([OH:22])([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=1)[C:10]([F:12])([F:11])[F:13]
Reactant: COc1ccc(C(O)(C(C)c2ccc(-c3ccc(CC#N)cc3)cc2Cl)C(F)(F)F)cn1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(c1ccc(-c2ccc(CC#N)cc2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
To a solution of {3′-chloro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-yl}-acetonitrile (87 mg) in dioxane (2.8 ml) was added conc. aqueous HCl (0.31 ml). The mixture was stirred at 100° C. for 1.5 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic phase was concentrated to dryness and the product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (59 mg) as a colorless solid. MS (m/e)=447.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:40])=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (84.6 mg, 0.20 mmol) and 4-isocyanato-benzoic acid methyl ester (Aldrich, 53.1 mg, 0.30 mmol) in CH2Cl2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac 4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (89.7 mg, 74.7%) which was used in the next step without further purification.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[CH3:4][S:1]([O:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH2:6])=[CH:10][CH:11]=2)[CH2:16]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(c2ccc(N)cc2)C1
Yield: 106.3 %

Procedure:
40 ml (0.516 mol) of mesyl chloride was added dropwise at 5° C. to 83.3 g (0.4 mol) of N-(4-nitrophenly)-3-hydroxypyrrolidine (1) dissolved in 625 ml of anhydrous THF and 72.7 ml (0.6 mol) of triethylamine. The mixture was allowed to return to room temperature and was then poured onto ice. After filtering off the precipitate by suction and drying, 109 g of yellow powder (2) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1C=CC=C[C:16]=1Cl.C(Cl)C.[OH-].[Na+]>C(N(CC)CC)C>[CH2:15]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Clc1ccccc1Cl
Agent: CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CCn1c2ccccc2c2ccccc21
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A 0.5-liter autoclave equipped with a stirrer was charged with carbazole (82.0 g), o-dichlorobenzene (100 g), ethyl chloride (40.2 g), 48% sodium hydroxide (73.9 g) and triethylamine (5 g). After the atmosphere in the autoclave was replaced with nitrogen gas, the autoclave was heated to the reaction temperature of 100° C. and the reaction mixture was stirred at the same temperature for 9 hours, while keeping the temperature. After completion of the reaction, the mixture was cooled to 50° C., and was transferred into a separatory funnel. The autoclave was washed with o-dichlorobenzene and water. The washings were combined with the reaction mass, and the combined mixture was separated. The separated organic layer was washed with a 25% sulfuric acid solution to neutralize base traces, and the water layer was removed by separation to give 273.0 g of an o-dichlorobenzene solution of N-ethylcarbazole. The analysis of this solution by chromatography revealed that the content of N-ethylcarbazole was 34.9% and the yield thereof was 99.6%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[O:15]1[C:19]2[CH:20]=[CH:21][C:22](B(O)O)=[CH:23][C:18]=2[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:21]=[CH:20][C:19]2[O:15][CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc4c(c3)CCO4)cc12
Temperature: 130 °C
Yield: 21.9 %

Procedure:
To a solution of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), 2,3-dihydrobenzofuran-5-boronic acid (65.0 mg, 0.39 mmol) in EtOH (0.5 mL) and toluene (0.5 mL) was added 2N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol). The reaction mixture was degassed with N2 for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol) and degassed with N2 for another 5 minutes. The suspension was sealed in a pressure tube and heated to 130° C. for 1 hour. As the reaction progressed, the suspension became clear, turned to orange and then dark brown. The reaction mixture was diluted with EtOAc (5 mL) and water (5 mL), and filtered through a syringe filter. The aqueous layer was acidified to pH 5 by 1N HCl solution, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 8.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 9.0 to 10.0 min. Flow: 25 mL/min) to provide the title compound (24.8 mg, 22% yield). MS (ES+) 315.1 (M+H)+. Retention time=2.68 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1>CO.C(#N)C>[Cl:5][C:6]1[N:11]=[C:10]([NH:4][CH:1]([CH3:3])[CH3:2])[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: CC(C)N
Solvent: CO
Solvent: CC#N
Product: CC(C)Nc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of isopropylamine (0.10 mL, 1.20 mmol) in MeOH (2 mL) was added dropwise to a ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (104 mg, 0.40 mmol) in acetonitrile (2 mL). The mixture was stirred at rt overnight. The residue was purified by preparative HPLC to give the title compound as a dry film, 63 mg (56%).