Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]([NH:23][C:24]([C:26]1([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][S:16][C:15]=3[CH:22]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:32][C:26]1([C:24]([NH:23][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]4[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][S:16][C:15]=4[CH:22]=3)=[CH:9][CH:10]=2)=[O:25])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CN1C(=O)CSc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)ccc21
Solvent: O=CO
Product: CN1C(=O)CSc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(N)CCOCC4)cc3)ccc21
Yield: 51.9 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 28, step (iii), 120 mg) in formic acid (2 mL) was heated at 50° C. for 20 mins. The solvent was removed under reduced pressure and the residue azeotroped with methanol. The product was purified by reversed phase HPLC using methanol in 0.1% aqueous TFA and then converted to the free base by elution through a PL-HCO3 MP cartridge with dichloromethane/methanol to afford the titled compound (51 mg).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([C:17]1[C:18]([CH3:50])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:39][S:40]([C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)(=[O:42])=[O:41])=[O:38])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH:7]([C:17]1[C:18]([CH3:50])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:39][S:40]([C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)(=[O:41])=[O:42])=[O:38])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C2(c3ccc(-c4ccc(-c5onc(C)c5C(CCCc5ccccc5)O[Si](C)(C)C(C)(C)C)cc4)cc3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2(c3ccc(-c4ccc(-c5onc(C)c5C(O)CCCc5ccccc5)cc4)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
N-[1-(4′-{4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarbonyl]-4-methyl-benzenesulfonamide (0.121 g, 0.165 mmol) was dissolved in THF (3 mL) then tetrabutylammonium fluoride (1.0 M in THF, 0.500 mL, 0.500 mmol) was added. The reaction was stirred at room temperature and monitored by analytical TLC until complete. The mixture was submitted to standard aqueous workup then purified on silica gel to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 70.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), p-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.048 g (70%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: NCC(c1ccncc1)N1CCOCC1
Product: Cc1ccc(Cl)c(C(=O)NCC(c2ccncc2)N2CCOCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine. LCMS (MH+): m/z=360.0, tR (minutes, Method A)=0.77
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Product: CN(C)c1ccc(S(N)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
A mixture of 6-chloropyridine-3-sulfonamide (5 g, 0.0259 mol) and aqueous dimethylamine (100 ml, 40%) is stirred at rt for 13 h. The mixture is concentrated to ⅕th of its original volume and cooled. The precipitate is collected by filtration, washed with ice-cold water (10 ml) and dried under vacuum to afford 4.5 g (95%) of the title compound as a solid. mp: 133-138° C., LC/MS: (ES+) 201.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH2:22])[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1(C)C=CC=CC=1>[O:29]=[C:28]1[N:22]=[C:21]2[CH:20]=[CH:19][C:4]([O:5][CH2:6][CH2:7][CH2:8][N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)=[CH:3][C:2]2=[N:1]1
Reactant: Nc1ccc(OCCCN2CCc3ccccc3C2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C1N=c2ccc(OCCCN3CCc4ccccc4C3)cc2=N1
Yield: 49.7 %

Procedure:
A mixture of N-[(3,4-diaminophenoxy)propyl]-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.67 mmol) and CDI (162 mg, 1.0 mmol) in toluene (15 mL) was refluxed for 16 h, then evaporated. The residual solid was washed with EtOAc (2×5 mL) and CHCl3 (5 mL), then dried to give 107 mg (48%) of the title compound as a yellow powder. 1H NMR (DMSO-d6): 1.90-1.96 (m, 2H), 2.591 (d, 2H, J=7), 2.662 (t, 2H, J=5), 2.803 (t, 2H, J=5), 3.560 (s, 2H), 3.967 (t, 2H, J=6), 6.50-6.52 (m, 2H), 6.76-6.80 (m, 1H), 7.05-7.10 (m, 4H), 10.359 (s, 1H), 10.483 (s, 1H). The hydrochloride, mp. 210-5° C. (dec). Analysis, Calcd. for (C19H22ClN3O2+0.3 HCl): C, 61.55, H, 6.06, N, 11.33; Found: C, 61.57, H, 6.14, N, 11.05.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:2].[Br:28]Br.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:28][CH2:2][C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(=O)CBr)CCN(C)C2=O

Procedure:
A solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.50 g, 1.35 mmol; Example 7, step 7), bromine (0.24 g, 1.49 mmol), 33% hydrobromide in glacial acetic acid (10 drops) in chloroform (15 mL) was stirred at room temperature for 6 hours. The mixture was treated with aqueous sodium bicarbonate and diluted with chloroform. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 20 to 80% ethyl acetate in hexane to afford the title compound. ES MS M+1=407, 409
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4cncnc4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3cccc(-c4cncnc4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
The reaction mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)benzo[d]thiazol-6-yl)acetate (9 mg, 0.0157 mmol), excess NaOH, in MeOH/THF (1:1, 2 mL) was heated at 45° C. overnight. After reaction finished, the solvent was removed and the residue was dissolved in MeOH and purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C30H26ClN3O3S: 544.1 (M+H+); Found: 544.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 9.18 (s, 1H), 9.16 (s, 2H), 8.40 (s, 1H), 8.12 (d, J=4 Hz, 1H), 7.91-7.88 (m, 2H), 7.71-7.67 (m, 2H), 7.60-7.58 (m, 3H), 5.26 (s, 1H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: ClCCC(O)CCC.[I-].[Na+].[I:11][CH2:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17].S(=O)(=O)(O)O.[CH3:24][C:25](=[CH2:27])[CH3:26]>C(Cl)Cl.CC(=O)CC>[C:25]([O:18][CH:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][I:11])([CH3:27])([CH3:26])[CH3:24]
Reactant: CCCC(O)CCI
Reactant: C=C(C)C
Agent: CCCC(O)CCCl
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCCC(CCI)OC(C)(C)C

Procedure:
A mixture of 23.4 g. of 1-chloro-3-hexanol [Fourneau, et. al., Bull. Soc. Chem. France, 25, 367 (1919)] in 300 ml. of 2-butanone containing 30 g. of sodium iodide is stirred at the reflux temperature for 18 hours. The cooled solution is filtered and the mother liquor is taken to dryness. Distillation of the residue affords 32.9 g. (84%) of 1-iodo-3-hexanol, b.p. 105° C. (10 mm). Treatment of this material in 500 ml. of methylene chloride, containing 4 ml. of concentrated sulfuric acid, with isobutylene according to the procedure described in Example 492 gives 27 g. of crude material. Chromatography on florisil affords 16 g. of product; λmax. 7.22 and 7.37μ (tert-butyl group).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:6][CH:5]=1.[CH3:29]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([O:28][CH3:29])([CH3:26])[CH3:27])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
Sodium hydride (60% in oil, 17.5 mg, 0.438 mmol) was added to a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-2-ol (150 mg, 0.365 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature. After stirring 5 min, methyl iodide (77.7 mg, 0.548 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (133 mg, 0.313 mmol, 86%).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[C:27]([Cl:42])[C:6]=1[C:7]([NH:9][C@H:10]([C:23]([O:25]C)=[O:24])[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([OH:21])[CH:15]=1)=[O:8]>O.O1CCCC1.CO>[Cl:4][C:5]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[C:27]([Cl:42])[C:6]=1[C:7]([NH:9][C@H:10]([C:23]([OH:25])=[O:24])[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([OH:20])[CH:19]=1)=[O:8]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cc(O)cc(O)c2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A solution of lithium hydroxide monohydrate (160 mg, 3.8 mmol) in water (10 mL) was added to a solution of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine, methyl ester (490 mg, 0.85 mmol) in tetrahydrofuran/methanol (3:1; 40 mL). The solution was stirred at room temperature overnight and then the solvent was evaporated. Tetrahydrofuran and water (75 mL each) were added followed by 1 M HCl (10 mL). The cloudy white solution was heated at approx. 50° C. for 10 min and then allowed to stand overnight at room temperature. The solvents were evaporated and the residue was dissolved in methanol/water (1:4; 60 mL) and purified by HPLC in 10 mL portions. Fractions homogeneous for the product were pooled and lyophilized to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine (308.5 mg, 65%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C@@H:5]([NH:7]C(=O)OCC1C=CC=CC=1)[CH3:6])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C@@H:5]([NH2:7])[CH3:6])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(OCC)[C@H](C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of (S)-benzyl 1,1-diethoxypropan-2-ylcarbamate (844 mg, 3.00 mmol) in methanol (50 ml) was added 5% palladium on carbon (30 mg) and the mixture was stirred at room temperature for 2 hr under hydrogen atmosphere. The reaction mixture was filtered on Celite and washed with methanol (200 ml) and the filtrate was concentrated in vacuo to obtain the title compound (442 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)OCc2ccccc2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3CCCC[C@H]3C(=O)OCc3ccccc3)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 57.3 %

Procedure:
With 2.00 g of the compound obtained in Step 113-1 and 1.42 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 1.74 g of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:6]=[CH:7][CH:8]=1.[BrH:21]>>[BrH:21].[OH:2][C:3]1[C:4]2[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][NH:11][CH2:10][CH2:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCNCC(O)c2ccccc2)c1
Agent: Br
Product: Oc1cccc2c1C(c1ccccc1)CNCC2

Procedure:
A solution of 3.5 g. (0.0129 mol) of N-[2-(3-methoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine in 40 ml. of 48% hydrobromic acid is refluxed for two hours and then concentrated to dryness. The solid residue (equal mixture of 7-hydroxy and 9-hydroxy benzazepines) is chromatographed on a silica gel column, eluting with methanol in chloroform to first remove the 7-hydroxy isomer and then to yield the product 9-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 134°-150° C. (int.).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C>[OH-].[Na+]>[N:8]1([CH2:7][CH2:6][CH2:5][C:4]([OH:14])=[O:3])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCN1CCOCC1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
4-Morpholin-4-yl-butyric acid ethyl ester (about 25 mmol) was suspended in 100 mL of NaOH 10%, and the mixture was heated at reflux for 10 hours. The reaction mixture was then allowed to cool down to room temperature and washed with AcOEt. The aqueous layer was recovered by extraction and acidified at 0° C. with HCl 37% to pH 4 and concentrated under reduced pressure. The residue was treated with EtOH and the sodium chloride which precipitated was filtered off. The crude was treated with acetone and filtered; evaporation of the solvent under reduced pressure afforded 3.2 g of the title compound as a white solid in 72% overall yield of steps a) and b).
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=1.[NH2:25][C:26]1[C:27]([N:44]2[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45]2)=[C:28]2[CH:34]=[CH:33][N:32]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:29]2=[N:30][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH:25][C:26]2[C:27]([N:44]3[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH2:45]3)=[C:28]3[CH:34]=[CH:33][N:32]([S:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)(=[O:37])=[O:36])[C:29]3=[N:30][CH:31]=2)=[O:24])[N:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (114.1 mg, 0.8539 mmol) in DCM (1.0 mL) was added slowly to a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, Step 2, 74.2 mg, 0.308 mmol) in DCM (1.0 mL). The mixture was stirred at room temperature for 2 h. A solution of tert-butyl {(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (125.1 mg, 0.2653 mmol) in DCM (2.0 mL) was added, followed by pyridine (217.3 mg, 2.747 mmol), and the mixture was then stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark oil (175.3 mg, 95%). LCMS calc. for C33H33F2N6O5S2 (M+H)+: m/z=695.2. found 695.2.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:11][N:12]([CH3:34])[C:13]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(O)[CH2:15][CH2:14]1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[OH-].[Na+]>ClCCl.O=O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:16]2([C:3]3[NH:4][C:5]4[C:10]([C:2]=3[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:17][CH2:18][C:13]([N:12]([CH3:11])[CH3:34])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:14][CH2:15]2)=[CH:25][CH:24]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: COc1ccc(C2(O)CCC(c3ccccc3)(N(C)C)CC2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(c3[nH]c4ccccc4c3C)CCC(c3ccccc3)(N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-methyl-1H-indol (393 mg, 3 mmol) and the more non-polar 4-dimethylamino-1-(4-methoxyphenyl)-4-phenylcyclohexanol (651 mg, 2 mmol) were dissolved in absolute dichloromethane (50 ml) with the exclusion of oxygen, mixed with trifluoromethane sulphonic acid trimethylsilyl ester (581 μl, 3 mmol) and stirred for 16 h at room temperature. For work up the batch was mixed with 5N NaOH (50 ml) and stirred for 1 h at room temperature. The aqueous phase was separated and extracted with dichloromethane (3×25 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. A raw product was isolated that was separated by chromatography [silica gel 60 (50 g); ethyl acetate (1000 ml)]. The product was obtained as a white solid with a yield of 600 mg (68%) and a melting point of 90-95° C. This concerned a mixture of two diastereoisomers (approx. 1:1), which could not be separated because of the identical Rt value.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:4]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution containing 600.0 mg (2.25 mmol) of 2,3-dihydro-6-(2-trimethylsilylethynyl)-(4H)-1-benzothiopyran-4-one and 100.0 mg (0.72 mmol) K2CO3 in 15 ml MeOH was stirred at room temperature for 20 hours. The solution was diluted with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced preesure afforded the title compound as an orange solid. 1H NMR (CDCl3): δ 8.17 (1H, d, J=1.8 Hz), 7.40 (1H, dd, J=1.8, 8.2 Hz), 7.19 (1H, d, J=8.2 Hz), 3.22 (2H, t, J=6.3 Hz), 3.08 (1H, s) 2.94 (2H, t, J=6.3 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2[N+:7]([O-])=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[N:10][C:5]=2[C:4]([CH3:19])([CH3:18])[O:3]1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][C:2]1([CH3:20])[C:6]2[N:7]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:9]=[N:10][C:5]=2[C:4]([CH3:19])([CH3:18])[O:3]1
Reactant: CC1(C)OC(C)(C)c2c1nnc(-c1ccccc1)[n+]2[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC1(C)OC(C)(C)c2nc(-c3ccccc3)nnc21

Procedure:
To a solution of 0.271 grams (0.001 mole) 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro-[3,4-e]-as-triazine-4-oxide and 0.246 grams (0.003 mole) cyclohexene in 4 ml. absolute ethanol is added 10 milligrams of 10% palladium on charcoal and the resulting mixture is refluxed under an atmosphere of nitrogen for 18 hours. The catalyst is removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from ether/hexane to give 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro[3,4-e]-as-triazine, m.p. 90°-91°C.