Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:26]1[CH2:31][CH:30]2[CH:28]([C:29]2([C:33]2[CH:38]=[CH:37][CH:36]=[C:35](I)[CH:34]=2)[CH3:32])[C:27]1=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([Sn](CCCC)(CCCC)[C:46]1[N:47]=[CH:48][N:49]([C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:50]=1)CCC>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([N:26]1[CH2:31][CH:30]2[CH:28]([C:29]2([CH3:32])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:50]3[N:49]([C:51]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[CH:48]=[N:47][CH:46]=3)[CH:34]=2)[C:27]1=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.2 %

Procedure:
To tris(dibenzylideneacetone)dipalladium (0) (8.7 mg, 9.5 μmol) in tetrahydrofuran (2.5 ml) at room temperature was added triphenylarsine (12 mg, 39.2 μmol). After 10 min, a solution of 3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 67, 0.15 g, 3.8 mmol) in tetrahydrofuran (2.5 ml) was added. A minute later, 4-(tributylstannyl)-1-triphenylmethyl-1H-imidazole (Preparation 73, 0.332 g, 0.55 mmol) in tetrahydrofuran (3 ml) was added. The reaction mixture was stirred at room temperature for 30 min and then refluxed for 3.5 h. The cooled reaction mixture was concentrated in vacuo and chromatographed on silica gel eluting with hexane:ethyl acetate (1:1 then 0:1) to give the title compound (55 mg, 25%).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.S(Cl)([Cl:12])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH:1]1([C:7]([Cl:12])=[O:9])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)C1CC=CCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CC=CCC1
Yield: 84.4 %

Procedure:
An acid chloride was prepared as follows: anhydrous 3-cyclohexenecarboxylic acid (50 g, 0.4 mol) was placed in a 500 mL round-bottom flask and a few drops of N,N-dimethylformamide was added as a catalyst. To this was added dropwise thionyl chloride (58.4 mL, 0.8 mol), diluted with anhydrous toluene (50 mL), at room temperature and the reaction mixture was refluxed for 4 hours. The final product was fractionally distilled to yield 48.8 grams of 3-cyclohexenecarboxylic acid chloride at a yield of 85%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:14][CH2:15][CH2:16][CH2:17]Br)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[C:29]([F:32])[C:30]=1[OH:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[Si:7]([O:14][CH2:15][CH2:16][CH2:17][O:31][C:30]1[C:29]([F:32])=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[Cl:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCOC(=O)c1cc(F)c(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)c(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c1
Temperature: 50 °C

Procedure:
Potassium carbonate and 3-(tert-butyldimethylsilyloxy)propyl bromide were added to a DMF solution of ethyl 3-chloro-5-fluoro-4-hydroxybenzoate, and the mixture was stirred at 50° C. to obtain ethyl 4-[3-(tert-butyldimethylsilyloxy)propoxy]-3-chloro-5-fluorobenzoate.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.Cl[C:18]1[N:23]=[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.C(O)CCC>CO>[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:18]2[N:23]=[C:22]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH:21]=[CH:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1nccc(N2CCc3ccccc32)n1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1, 219 mg, 0.77 mmol) in methanol (2 ml) was added to a solution of 2-chloro-4-(indolin-1-yl)pyrimidine (Method 3, 200 mg, 0.86 mmol) in ii-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica (1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (201 mg, 61%). NMR: 2.19 (s, 6H), 2.21-2.3 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.25 (m, 2H), 3.8-4.1 (m, 5H), 5.75 (m, 1H), 6.2 (m, 2H), 6.8-6.9 (m, 3H), 7.0-7.1 (m, 1H), 7.15-7.25 (m, 1H), 7.5-7.6 (m, 2H), 8.05-8.1 (m, 1H), 8.3-8.4 (m, 1H), 8.95 (s, 1H); MS (MH+): 406.5.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=O.B.C1(N(CCCBr)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:8]1([N:7]([CH2:17][CH2:16][CH2:15][Cl:14])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)CCCl
Agent: B
Agent: BrCCCN(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: ClCCCN(c1ccccc1)c1ccccc1

Procedure:
3-(N,N-diphenylamino)-1-chloropropane is prepared by the reaction of diphenylamine with 3-chloropropionyl chloride, followed by reduction with borane in tetrahydrofuran, by a procedure analogous to the preparation of 3-[N,N-diphenylamino]-1-bromopropane in Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[S:15]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[CH3:20])=[CH:19][CH:18]=3)=[O:7])[C:9]=2[CH:17]=[CH:16]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cc1

Procedure:
As described for Example 1, 4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (0.001 ml) is reacted with 2-methylbenzoyl chloride in dichloromethane to give the product. Crystallization from ethyl acetate-hexane gives crystals, m.p. 181°-182° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[C:8]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][C@:17]([CH2:22][OH:23])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1.CCN(CC)CC>CC(C)=O>[CH3:6][N:5]([CH3:7])[C:3]([CH2:2][O:20][C:18](=[O:19])[C@@:17]([CH2:22][OH:23])([CH3:21])[CH2:16][C@H:15]([NH2:24])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
2-Chloro-N,N-dimethylacetamide (40 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid dimethylcarbamoylmethyl ester.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:4])=[O:3].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(N(CC)CC)C>O1CCCC1>[Cl:21][CH2:20][CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[CH2:14][CH2:13]1
Reactant: ClCCCBr
Reactant: CS(=O)(=O)Oc1ccc2c(c1)CCNCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2c(c1)CCN(CCCCl)CC2
Yield: 52.6 %

Procedure:
A mixture of 7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (1.75 g, 7.3 mmol), 1-bromo-3-chloropropane (0.80 ml, 8.1 mmol) and triethylamine (3 ml, 21.5 mmol) in anhydrous tetrahydrofuran (25 ml) was heated at reflux for 5 h. The mixture was cooled, evaporated in vacuo and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml) and the combined organics washed with brine (150 ml), dried (Na2SO4) and evaporated in vacuo. Purification by chromatography on silica gel using 10-70% ethyl acetate in hexane gradient elution gave the title compound as a pale orange oil (1.22 g, 53%).
Reaction SMILES: [CH3:1][I:2].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]=3[CH3:24])[N:11]=2)[CH2:6][CH2:5]1>CC(C)=O>[I-:2].[CH3:3][N+:4]1([CH3:1])[CH2:9][CH2:8][CH:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]=3[CH3:24])[N:11]=2)[CH2:6][CH2:5]1
Reactant: CI
Reactant: Cc1[nH]c2ccccc2c1-c1noc(C2CCN(C)CC2)n1
Solvent: CC(C)=O
Product: Cc1[nH]c2ccccc2c1-c1noc(C2CC[N+](C)(C)CC2)n1
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
Methyl iodide (200 mg) was added to a stirred solution of 1-methyl-4-[3-(methylindol-3-yl)-1,2,4-oxadiazol-5-yl]piperidine (300 mg) in anhydrous acetone (20 ml) at room temperature. After stirring at room temperature for two hours the precipitate was isolated by filtration and dried to afford the title compound (300 mg) mp 246° C.; Found C, 49.00; H, 5.30; N, 12.51 C18H23N4OI requires C, 49.32; H, 5.29; N, 12.78%; δH (360 MHz, DMSO) 2.25-2.35 (4 H, m, 2×CH2), 3.14 (3 H, s, NMe), 3.18 (3 H s NMe), 3.41 (1 H, m, CH), 3.48-3.56 (4 H, m, 2×CH2N), 3.90 (3 H, s, NMe), 7.22-7.33 (2 H, m, H-5, H-6), 7.58 (1 H, d, J=7, H-7), 8.05 (l H, d, J=7, H-4), 8.12 (1 H, s, H-2); M/Z (no M+), 199(90), 140(100), 96(90).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=2[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: C1CNCCNC1
Reactant: COc1cc2nc(CCl)n(C)c2c(OC)c1OC
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5n4C)CC3)n(C)c2c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-5,6,7-trimethoxybenzimidazole (39 mg) and homopiperazine (7 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][CH:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([NH2:25])[C:18]=2[O:17]1.[NH:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:35]=O)[C:29]=2[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[C:29](=[C:30]([CH2:35][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:25][C:24]5[C:18]6[O:17][CH:16]([CH3:15])[CH2:20][C:19]=6[CH:21]=[CH:22][CH:23]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC1Cc2cccc(N)c2O1
Product: CC1Cc2cccc(Nc3ccc4c(NCc5cccc6[nH]ccc56)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=421.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2,3-dihydro-2-methyl-7-benzofuranamine (CAS 26210-74-2) and indole-4-carbaldehyde as described in example 26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)[N:9]=1.C(O)(C(F)(F)F)=[O:34].[OH-].[K+].OO>O.C(O)C.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:14][C:11]([C:12]([NH2:13])=[O:34])=[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)[N:9]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCc1ccc(F)c(F)c1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 95 °C

Procedure:
To the product of Step D Example 129 (30.0 mg, 0.0516 mmol, material in the TFA salt form) was added 1,4-dioxane (4 mL), ethanol (0.5 mL), KOH (0.272 mg, 4.92 mmol), H2O (0.6 mL) and H2O2 (0.21 g). The reaction was heated to 95° C. for 22 hours. The solution was concentrated and the residue was dissolved in ethyl acetate before washing with water, drying (Na2SO4) and concentrating. The residue was purified by preparative thin layer chromatography (20 cm×20 cm, 1000 μm, silica gel) eluting with 10.5% ethyl acetate/dichloromethane affording the product. MS (electrospray) m/e 485.2 MH+ (Rt=4.2 min LC/MS).
Reaction SMILES: [F:1][C:2]([F:23])([CH:21]=[CH2:22])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20])[OH:4].[C:24](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH:21]1([C:2]([F:1])([F:23])[CH:3]([C:5]2[S:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH3:20])[OH:4])[CH2:24][CH2:22]1
Reactant: C=CC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 365 mg 2,2-Difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol in 10 ml pyridine were added 5 ml acetic acid anhydride. The ice bath was removed and the reaction mixture stirred at room temperature for one hour. The ice was added and the reaction mixture diluted by addition of 100 ml dichloromethane. The organic layer was separated and washed with 50 ml water, 1 M HCl, saturated NaHCO3 solution and brine. Then the organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting residue was dissolved in 30 ml diethyl ether (flask 1). 246 mg palladium, (II) acetate were added and the mixture cooled in an ice bath. In a second flask 4.0 g N-methyl-N-nitroso-p-toluenesulfonamide were suspended in 30 ml ethanol. An argon current was bubbled permanently through flask 2 and afterwards through flask 1. 2N NaOH was added dropwise to flask 2 until dissolution of N-methyl-N-nitroso-p-toluenesulfonamide, then the argon current was stopped. The reaction mixture (flask 1) was stirred at 0° C. for an additional hour. Then 10 ml acetic acid were added and the reaction mixture diluted by addition of 80 ml ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed in vacuo. The resulting residue was dissolved in 20 ml methanol, 1 ml sodium methylate solution (30%) were added and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was then neutralized by addition of acetic acid, the solvent was removed in vacuo and the residue purified by reversed phase HPLC to obtain 120 mg 2-Cyclopropyl-2,2-difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as lyophilisate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH2:22]([CH2:24][NH2:25])[OH:23]>CCOCCO.Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:25][CH2:24][CH2:22][OH:23])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: NCCO
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOCCO
Product: Nc1ccc(OS(=O)(=O)c2ccc(NCCO)cc2)cc1[N+](=O)[O-]

Procedure:
15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 25 ml ethanolamine in 100 ml ethyl glycol in a round bottom flask. The reaction mixture was heated to reflux for 90 min and then cooled on ice. Reaction mixture was then diluted with 250 ml of 2N aqueous HCl, the compound precipitated and was filtered off with suction. The preciptate was the washed with water and dried, yielding 15.5 g of 2-amino-5-(4-[2-hydroxyethyl]aminophenylsulfonyloxy)nitrobenzene (melting point 180° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18][OH:19])=[CH:5]2>C(Cl)Cl.O>[CH3:13][S:14]([O:19][CH2:18][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)CCCn1c(CO)cc2cc(Cl)ccc21
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)CCCn1c(COS(C)(=O)=O)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [5-chloro-1-(3-methanesulfonyl-propyl)-1H-indol-2-yl]-methanol (0.60 g, 2.0 mmol) and TEA (0.60 g, 6 mmol) in 20 mL of DCM was added MsC1 (0.45 g, 4 mmol) in an ice bath. The reaction mixture was stirred at RT for 3 hours. The resulting mixture was diluted with 10 mL of water and then extracted with DCM (10 mL×3). The combined organic layers were dried over Na2SO4, and then concentrated in vacuo to afford the crude {5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl methanesulfonate which was used in the next step without any purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][C:46]#[CH:47])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][C:46]#[CH:47])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCn1cncc1CSc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: C#CCn1cncc1CS(=O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-(2-propin-1-yl)imidazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (639 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (356 mg) in dichloromethane (15 ml) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-(2-propin-1-yl)imidazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (451 mg) (Compound 443) as yellow amorphous.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[CH2:14][CH2:13]2)[CH2:2]1.[C:27]([OH:32])(=[O:31])[C:28]([NH2:30])=[O:29].CS(C)=[O:35]>>[C:27]([OH:32])(=[O:31])[C:28]([OH:35])=[O:29].[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([CH:15]3[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C@H:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[N:1]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])[CH2:2]4)[CH2:17][CH2:16]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: c1ccc2c(c1)NC[C@H]2CCN1CCC(c2ccc3[nH]ccc3c2)CC1
Reactant: CS(C)=O
Reactant: NC(=O)C(=O)O
Product: NC(=O)C(=O)N1C[C@@H](CCN2CCC(c3ccc4[nH]ccc4c3)CC2)c2ccccc21
Product: O=C(O)C(=O)O

Procedure:
from 5-{1-[(S)-2-(2,3-dihydro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-1H-indole and oxalamic acid. Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[CH3:31][O:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N)c3)cs2)c1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A solution (4 mL) of the crude compound (290 mg, 0.88 mmol) obtained in Example 26a in tetrahydrofuran was cooled in an ice bath, triethylamine (0.16 mL, 1.14 mmol) and methoxyacetylchloride (115 mg, 1.06 mmol) were added, and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=30/70-ethyl acetate) to give the title compound (339 mg, 96% in 2 steps) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.[N:47]([CH3:50])=[C:48]=[O:49]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][N:30]([C:48]([NH:47][CH3:50])=[O:49])[CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: Fc1cncc(Cn2cnc3ccc(-c4ccnc5[nH]c(C6CCNCC6)cc45)cc32)c1
Reactant: CN=C=O
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)N1CCC(c2cc3c(-c4ccc5ncn(Cc6cncc(F)c6)c5c4)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 12D trifluoroacetate salt (30.0 mg, 0.070 mmol) in N,N-dimethylformamide (0.3 mL) was added triethylamine (0.05 ml, 0.352 mmol) and isocyanatomethane (6.0 mg, 0.106 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and purified by reverse-phase HPLC (Phenomenex Luna C8 AXIA column, 100 Å) eluting with a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water with 10 mM ammonium acetate to afford the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 1.51-1.66 (m, 2 H) 1.87-1.98 (m, 2 H) 2.61 (d, J=4.58 Hz, 3 H) 2.74-2.91 (m, 3 H) 4.04 (m, 2 H) 5.66 (s, 2 H) 6.11 (s, 2 H) 7.10 (d, J=4.88 Hz, 1 H) 7.57 (dd, J=8.54, 1.53 Hz, 1 H) 7.61-7.68 (m, 1 H) 7.76-7.83 (m, 2 H) 8.16 (d, J=5.19 Hz, 1 H) 8.42 (s, 1 H) 8.47-8.52 (m, 2 H) 11.32 (s, 1 H). MS (ESI) m/e 484 (M+H)+.