Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:49])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[N:15]([C:24](=[O:41])[CH2:25][NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=3)=[O:28])[CH:14]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+]>CO.O>[C:45]([O:44][C:42]([CH:14]1[CH2:13][CH:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:49])[CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:15]1[C:24](=[O:41])[CH2:25][NH:26][C:27](=[O:28])[NH:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[C:36]([OH:38])=[O:37])=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(S(=O)(=O)c3ccc(N(C)C)cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(S(=O)(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2F)cc1
Yield: 8.3 %

Procedure:
A The process is performed as described in Example 1A, but starting with 1.5 g of tert-butyl (2RS,4SR,5RS)-4-(4-dimethylaminophenyl)sulphonyl-1-{2-[3-(3-ethoxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-2-pyrrolidinecarboxylate and 0.12 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.12 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-4-(4-dimethylaminophenyl)sulphonyl-5-(2-fluorophenyl)-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.4; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (250 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 1.52 (s, 9H: C(CH3)3); 2.43 and 2.77 (2 mts, 1H each: CH2 at 3); 3.04 (s, 6H: N(CH3)2); 3.63 and 3.99 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 3.86 (mt, 1H: H4); 4.56 (broad t, J=8 Hz, 1H: H2); 5.71 (d, J=3 Hz, 1H: H5); 6.81 (d, J=8.5 Hz, 2H: H of the aromatic at 4 (H ortho to the N(CH3)2)); from 7.00 to 7.70 (mt, 6H: aromatic H); 7.68 (d, J=8.5 Hz, 2H: H of the aromatic at 4 (H meta to the N (CH3)2)); 7.80 (mt 1H: H of the aromatic at 5 (H6)); 8.00 (mt, 1H: aromatic H (H2: ortho to the COOH))].
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10](=[O:19])[CH2:9]1)=[O:6]>CO>[F:3][C:4]([F:20])([F:21])[C:5]([NH:7][C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C@@H:10]([OH:19])[CH2:9]1)=[O:6]
Reactant: COc1ccc2c(c1)C(NC(=O)C(F)(F)F)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Reaction time: 8 h

Procedure:
Sodium borohydride (20 mg, 0.51 mmol) was added to a solution of 2,2,2-trifluoro-N-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide (140 mg, 0.51 mmol) in anhydrous methanol (4 mL). After stirring overnight, the volatiles were removed in vacuo and the crude material purified by silica gel chromatography, eluting with 5% methanol in dichloromethane furnished as the first eluting isomer cis-2,2,2-trifluoro-N-(-3-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide; (60 mg, 0.22 mmol) 1H-NMR (300 MHz, CDCl3) δ 7.34 (d, 1H), 7.01-6.82 (m, 3H), 5.35 (m, 1H), 5.15 (m, 1H), 3.82 (s, 3H), 2.87 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:24]>C(Cl)Cl>[NH2:24][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CBr)c2F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (5.00 g, 12.24 mmol) in DCM (15 ml) was added dropwise to ammonia (7.0 M solution in MeOH) (69.9 ml, 490 mmol) and the mixture was stirred overnight at rt. The solvent was removed and the crude material was neutralized to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (4.22 g, 12.24 mmol, 100% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (d, 2H), 8.15 (s, 1H), 7.76 (d, 2H), 7.62-7.69 (m, 1H), 7.54-7.61 (m, 1H), 4.12 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][C:22]([OH:39])([CH3:38])[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:27]4[CH:26]=[N:25][N:24]([CH2:23][C:22]([OH:39])([CH3:38])[CH3:21])[CH:28]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)cn1

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similar to as described in Example 5 and triturated from water followed by methanol to give 100 mg of 10-bromo-9-fluoro-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol via similar to as described in Procedure E to afford 18.1 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 468 (M)+. 1H NMR (400 MHz, DMSO) δ 8.62 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 7.08-6.91 (m, 2H), 5.50 (s, 1H), 4.68 (s, 1H), 4.54-4.45 (m, 2H), 4.41-4.29 (m, 2H), 4.07 (s, 2H), 1.50 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.O>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 1-[4′-(trifluoromethyl)-4-biphenylyl]-1-pentanone (500 mg, 1.63 mmol) in THF (16 mL) and water (8 mL) under nitrogen at 0° C. (ice/water bath) was added sodium borohydride (74 mg, 1.96 mmol) portion-wise. After stirring the mixture for 1 hour at rt, the reaction was diluted with water (30 mL) and extracted into EtOAc (3×30 mL). The combined organic extract was separated, dried (MgSO4) and reduced under vacuum to afford the title compound as a colourless gum (490 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH3:24])[CH3:23])(C)(C)C.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[NH2:7][CH:8]1[C:9]([CH3:24])([CH3:23])[C:10]2[CH:11]=[C:12]([C:20]([NH2:21])=[O:22])[CH:13]=[CH:14][C:15]=2[CH2:16][CH:17]1[O:18][CH3:19]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC1Cc2ccc(C(N)=O)cc2C(C)(C)C1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a slurry of trans-(7-carbamoyl-3-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (9.22 g, 26.4 mmol) in DCM (100 mL) was added 4 N HCl in dioxane (25 mL, 100 mmol) slowly. The reaction mixture was stirred at RT for 15 h, concentrated to dryness, triturated with DCM (25 mL) for 30 min, filtered, rinsed with DCM (3×15 mL), and dried under vacuum. Ethanol (100 mL) was added and the reaction mixture was concentrated under vacuum to give the HCl salt of the title compound (7.17 g) as a white powder. (m/z): [M+H]+ calcd for C14H20N2O2 249.16. found 249.1. 1H NMR (d6-DMSO, 400 mHz) δ (ppm): 8.18 (s, 3H), 8.00 (s, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.0 Hz, 1.8 Hz, 1H), 7.32 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 3.70 (m, 1H), 3.44 (s, 3H), 3.43 (m, 1H), 3.22 (m, 1H), 2.67 (dd, J=16.4 Hz, 10.2 Hz), 1.50 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([CH:10]=1)[NH2:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]1[CH:10]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[Cl:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(Br)ccc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
Under argon, 9.69 g (242.16 mmol, 60% in mineral oil) of sodium hydride were suspended in 100 ml of THF, and the mixture was cooled to 0° C. 20.0 g (96.86 mmol) of 5-bromo-2-chloroaniline, dissolved in 50 ml of THF, were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min 39.76 g (232.47 mmol) of benzyl bromide, dissolved in 150 ml of THF, were then slowly added to the reaction mixture, and the mixture was then warmed to room temperature. The mixture was stirred at RT overnight and then carefully poured onto 150 ml of ice-water. The organic phase was separated off, and the aqueous phase was then extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. Isopropanol was added to the crude product obtained, and the crystals formed were filtered off with suction and dried at 40° C. under high vacuum. This gave 14 g of the title compound. The filtrate was evaporated and the residue obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave a further 7.57 g of the title compound (total yield: 21.57 g, 58% of theory).
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([F:20])[C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[C:10]([F:20])[C:8]=2[NH:9][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1
Reactant: Nc1c(F)cc(-c2ccccc2)cc1-c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccccc2)cc(-c2ccccc2)c1Nc1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 73.7 %

Procedure:
2,4-diphenyl-6-fluoroaniline (12 mmol), bromobenzene (10 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 mmol), (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (0.3 mmol) and sodium tert-butoxie (14 mmol) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenyl-6-fluoro-N-phenylbenzenamine (2.5 g) is yielded.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[NH:19][N:20]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.CC1C=CC(S(O[CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)(=O)=O)=CC=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[N:20]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC1(C)C(=O)NN=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Product: CC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C3) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B3*HCl)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[N:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:22]=1.N1C=CC=CC=1>C(Cl)Cl>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]=[C:13]1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[O:11])[CH:28]=2)[N:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:22]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)Nc1ccc(F)cc1F
Reaction time: 24 h
Yield: 52 %

Procedure:
2,4-Difluorophenyl isocyanate (10 mg, 0.064 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) and pyridine (0.02 mL, 0.177 mmol) in CH2Cl2 (5 mL), and the mixture was stirred for 24 h. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (2% CH3OH/CH2Cl2) afforded the title compound (15 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.39 (s, 1H), 8.04 (m, 1H), 7.86 (m, 1H), 7.72 (m, 3H), 7.27 (m, 2H), 7.00 (m, 1H), 6.92 (m, 1H), 5.92 (dd, 1H, J=3.2 and 9.2 Hz), 4.02 (m, 1H), 3.85 (m, 1H), 2.67 (m, 1H), 2.14 (m, 1H), 1.71 (m, 1H), 1.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[OH-].[Na+].[CH3:13][C:14]([CH3:16])=[O:15]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reaction time: 48 h

Procedure:
A solution of 14 g of 3,4-dichlorobenzaldehyde in 65 ml of acetone is diluted with 435 ml of water and treated with a solution of 5 g of sodium hydroxide in 50 ml of water. The mixture is stirred for 48 hr, extracted with benzene, dried and concentrated in vacuo to give 3,4-dichlorobenzalacetone as an oil which crystallizes on standing.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([OH:17])([CH2:12][CH:13]([OH:16])[CH2:14]O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:17][CH2:14][CH:13]([OH:16])[CH2:12]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(O)(CC(O)CO)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC2(CC1)CC(O)CO2
Temperature: 110 °C
Reaction time: 8 h

Procedure:
The product of step c) (5.2 g, 0.021 mol) was dissolved in dry pyridine (60 ml), placed under nitrogen and cooled with an ice-bath. Tosyl chloride (4.8 g, 0.025 mol) was dissolved in pyridine (30 ml) and added dropwise. The reaction was heated at 110° C. After 5 hours another 2.2 g (0.011 mol) tosyl chloride was added in 20 ml pyridine at room temperature and the heating was continued overnight.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([SH:21])[CH2:19][SH:20]>>[OH:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]2[S:21][CH2:18][CH2:19][S:20]2)=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: SCCS
Product: CC(C)(C)c1cc(C2SCCS2)cc(C(C)(C)C)c1O

Procedure:
Molar amounts of 3,5-di-tert.butyl-4-hydroxy benzaldehyde and 1,2-ethane dithiol are condensed by the method described in Example 1 to yield the 2-(4'-hydroxy-3', 5'-di-tert.butyl phenyl)-1,3-dithiolane of formula VII, ##SPC6##
Reaction SMILES: [CH3:1][NH2:2].FC(F)(F)S(O[C:9]1[C:10]([Br:27])=[CH:11][C:12]2[CH:18]([CH3:19])[CH2:17][N:16]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:15][CH2:14][C:13]=2[N:26]=1)(=O)=O.C1COCC1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:27][C:10]1[C:9]([NH:2][CH3:1])=[N:26][C:13]2[CH2:14][CH2:15][N:16]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:17][CH:18]([CH3:19])[C:12]=2[CH:11]=1
Reactant: CN
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(OS(=O)(=O)C(F)(F)F)c(Br)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 62 %

Procedure:
A mixture of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-2-ol (30.0 mg, 85.0 μmol), Tf2O (50 μl), K2CO3 (18 mg) and DCM (1 ml) was stirred for 16 h at room temperature. The mixture was extracted with sat. aq. NaHCO3, dried over Na2SO4, concentrated in vacuo and purified by column chromatography to yield 11.0 mg (26%) of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate. A mixture of methylamine (50 μl), 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate (11.0 mg, 22.7 μmol), and THF (1 ml) was heated to reflux for 15 h. The reaction mixture was parted between sat. aq. NaHCO3 and EtOAc. The organic layer was dried, concentrated in vacuo and purified with column chromatography to give 5.2 mg (62%) of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 486.2 (M+H+). A mixture of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine (5.2 mg, 14.2 μmol), K2CO3 (15 mg), MeOH (1 ml) and H2O (100 μl) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 2.1 mg (55%) of 3-bromo-N,5-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 271.2 (M+H+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:38]3[CH2:39][CH2:40]NCC=3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1>CS(C)=O>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][CH:39]3[CH2:40][CH2:23][N:22]([CH2:12][CH:13]4[O:27][C:17]5=[C:18]6[C:23](=[CH:24][CH:25]=[C:16]5[O:15][CH2:14]4)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]6)[CH2:21][CH2:20]3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCC(Cc2c[nH]c4cc(Cl)ccc24)CC1)O3
Temperature: 75 °C

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.55 g, 1.4 mmole) and 6-chloro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 3.4 mmole) were combined in 10 mL of DMSO. The mixture was heated at 70-80 ° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with 400 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was column chromatographed on silica gel using 0-2% methanol/chloroform. The product fractions were concentrated in vacuum to give 0.27 g of the (S)-enantiomer of the title compound as an amorphous orange solid, which retains 0.35 equivalents of chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH:31][C:18]([C:17]2[CH:16]=[N:15][N:11]3[C:12]([CH3:14])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 441.3 [(M+H)+]; mp 250-251° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.O.O[N:28]1[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1>CN(C)C=O>[ClH:1].[NH2:28][C@@H:32]1[CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N[C@@H]1CCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 23 h
Yield: 188.6 %

Procedure:
The compound obtained in Referential Example 61 (1.40 g) was dissolved in N,N-dimethylformamide (15 mL), and to the solution were added 5-chloroindole-2-carboxylic acid (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g), and 1-hydroxybenzotriazole monohydrate (473 mg), followed by stirring at room temperature for 23 hours. The solvent was distilled away under reduced pressure, and to the residue were added methylene chloride and saturated aqueous sodium hydrogencarbonate. The resultant precipitate was collected by filtration, and the precipitate was washed with ethyl acetate, methylene chloride, and methanol. Aside from this, the filtrate was partitioned, and the organic layer was separated, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride:methanol=19:1), to thereby give a pale-yellow solid. This pale-yellow solid was combined with the precipitate collected by the above-described filtration, and this mixture was dissolved in methylene chloride (10 mL). Trifluoroacetic acid (10 mL) was added thereto, and the thus-obtained mixture was stirred at room temperature for 3 hours. The solvent was distilled away under reduced pressure, and to the residue were added methylene chloride and 1N aqueous sodium hydroxide. The resultant precipitate was collected by filtration. The organic layer of the filtrate was separated, and was dried over sodium sulfate anhydrate. To the solution was added the precipitate collected by the above-described filtration, and a 4N HCl-dioxane solution (20 mL) was added thereto. The solvent was distilled away under reduced pressure, and after methylene chloride (10 mL) and a 4N HCl-dioxane solution (10 mL) were added to the residue, the solvent was distilled away again under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration, to thereby give the title compound (1.83 g).