Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].[O:4]=[S:5]1(=[O:35])[C:11]2[CH:12]=[C:13]([O:17][CH3:18])[C:14](Br)=[CH:15][C:10]=2[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:8](=[O:26])[C:7]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:6]1>CN(C=O)C>[O:4]=[S:5]1(=[O:35])[C:11]2[CH:12]=[C:13]([O:17][CH3:18])[C:14]([S:2][CH3:1])=[CH:15][C:10]=2[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:8](=[O:26])[C:7]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:6]1
Reactant: C[S-]
Reactant: CCCCC1(CCCC)CS(=O)(=O)c2cc(OC)c(Br)cc2N(c2ccc(Cl)cc2)C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CS(=O)(=O)c2cc(OC)c(SC)cc2N(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
Sodium methanethiolate (0.43 g, 6.08 mmol) was added to a solution of 1,1-dioxo-3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 96; 0.66 g, 1.22 mmol) in anhydrous DMF (11 ml) under nitrogen. The reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure and the residue was extracted with trichloromethane/water. The organic layer was separated, washed with brine, dried and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM as eluent to give the title compound 0.6 g (96%). NMR (500 MHz) 0.80–1.0 (m, 6H), 1.10–1.6 (m, 10H), 1.70–2.0 (m, 2H), 2.28 (s, 3H), 3.37–3.70 (m, 2H), 4.04 (s, 3H), 6.65 (s, 1H), 7.25–7.30 (m, 2H), 7.35–7.42 (m, 3H); m/z 510.4.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6].Cl>ClC1C=CC=CC=1>[Cl:1][C:8]1[CH:9]=[CH:10][C:14]([C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 147.2 %

Procedure:
30.5 g (0.27 mol) of chlorobenzene and 36 g (0.27 mol) of aluminium chloride are introduced into a 250 cm3 flask and 25 g (0.135 mol) of m-nitrobenzoyl chloride dissolved in 15 cm3 of chlorobenzene are added dropwise. The mixture is heated for 5 hours at between 50° and 60° C. and is then allowed to cool and is hydrolysed with 500 g of ice + 20 cm3 of concentrated HCl (d = 1.18); the batch is extracted with ether and the extract is washed with aqueous sodium hydroxide solution (strength 30 g/l) and then with water; the ether phase is dried, decolorised and then evaporated in vacuo; 26 g of the expected ketone are obtained. Melting point 97° C.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]([C:19]([NH:21][C:22]2([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:3]1.O>O1CCOCC1>[F:35][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]([C:19]([NH:21][C:22]2([C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a solution of methyl 4-(1-(4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (enantiomer 1) (D137a) (140 mg, 0.28 mmol) in dioxane (3 ml) and water (3 ml) LiOH H2O (47 mg, 1.12 mmol) was added and the mixture was left stirring at RT for 16 hrs. Dioxane was evaporated off then acetic acid was added to the aqueous layer until the solution reached the value of p≈4. The solid was filtered off and dried under vacuum to afford the title compound (E18) (90 mg)
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)[CH:10]=1)[C:5](OC)=[O:6].[BH4-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.CCOC(C)=O>[C:25]1([C:11]2[CH:10]=[C:9]([CH:4]([CH2:3][OH:2])[CH2:5][OH:6])[CH:14]=[CH:13][C:12]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C(CO)CO)cc2C2=CCCCC2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a mixture of 2-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-malonic acid dimethyl ester (as prepared in the previous step, 30.0 mg, 0.0710 mmol) and NaBH4 (13.4 mg, 0.355 mmol) in 1 mL of tert-butyl alcohol (t-BuOH) at 80° C. was added MeOH (50 μL) over 5 min. The resulting mixture was stirred at 80° C. for 16 h under Ar. After cooling to RT, the mixture was treated with 10% aq citric acid to a pH of 7. The mixture was then treated with 30 mL of EtOAc, washed with H2O (5 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 1-5% MeOH-DCM to afford 14.1 mg (61%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.00 (s, 1H), 7.54 (dd, 1H, J=8.2, 2.3 Hz), 7.46 (d, 1H, J=2.3 Hz), 7.27 (d, 1H, J=8.2 Hz), 5.59 (m, 1H), 3.71-3.84 (m, 4H), 3.29 (m, 1H), 2.15-2.29 (m, 4H), 1.67-1.84 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H22N4O3, 367.2 (M+H). found 366.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14][CH3:15])[C:6]2[O:10][C:9]([CH:11]=[O:12])=[CH:8][C:7]=2[CH:13]=1.[BH4-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14][CH3:15])[C:6]2[O:10][C:9]([CH2:11][OH:12])=[CH:8][C:7]=2[CH:13]=1
Reactant: COc1cc(OC)c2oc(C=O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(OC)c2oc(CO)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Compound 4 (460 mg, 2.23 mmol) was dissolved in THF (5 mL) and EtOH (1 mL). NaBH4 (102 mg, 2.68 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1 h. Solvents were evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (1:1) to give 5 (388 mg, 82%) as an oil. m/z=209.08 (M+H). 1H NMR (500 MHz, CDCl3): δ: 6.62 (1H, s, H-3), 6.60 (1H, s, H-6), 6.46 (1H, s, H-4), 4.76 (2H, s, 2-CH2), 3.99 (3H, s, OMe), 3.85 (3H, s, OMe). 13C NMR (500 MHz, CDCl3): δ: 157.23 (C-5), 156.72 (C-1), 145.36 (C-7), 139.50 (C-1a), 129.38 (C-4a), 104.62 (C-3), 96.96 (C-6), 94.58 (C-4), 57.98 (2-CH2), 55.95 (OMe), 55.83 (OMe).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18]([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[C:28](OCC)(OCC)(OCC)[CH3:29]>>[CH3:28][C:29]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:26][CH:27]=2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Reactant: CCOC(C)(OCC)OCC
Product: CCOC(=O)C(CC)Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1
Temperature: 25 °C

Procedure:
A solution of 7 g of 6B in 50 ml of triethyl orthoacetate was heated at 140° C. for 2 hours. The resulting mixture was cooled to room temperature, absorbed on silica gel and chromatographed, using the eluent described in Example 1, to give 6, as a viscous oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1([CH3:30])[CH:15]([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:29])[CH:12]=2)[O:7]1>O.C(O)C>[N:1]([CH2:17][CH2:16][CH:15]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:29])[CH:12]=2)[O:7][C:6]1([CH3:5])[CH3:30])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3cc(F)ccc3OC2(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2ccc(F)cc2CC1CCN=[N+]=[N-]

Procedure:
A solution of 1.62 g (24.9 mmol) of sodium azide in 10 ml of water is added to a solution of 6.3 g (16.6 mmol) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in 100 ml of ethanol. The mixture is boiled under reflux for 18 hours. After cooling, the ethanol is evaporated off in vacuo and water is added to the residue. The aqueous mixture is extracted with diethyl ether. The combined organic phases are washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 4.13 g (100% of the theoretical yield) of 3-(2-azidoethyl)-2,2-dimethyl-6-fluoro-chroman in the form of a light-yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1([CH2:8][OH:9])[CH2:6][OH:7].[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=O)[CH2:11][CH3:12].C(OCC)(OCC)OCC.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:11]([C:10]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[O:9][CH2:8][C:2]2([O:3][CH2:4][CH2:5][O:1]2)[CH2:6][O:7]1)[CH3:12]
Reactant: CCC(=O)CC(=O)OC
Reactant: OCC1(CO)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: CCC1(CC(=O)OC)OCC2(CO1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
The 1,3-dioxolan-2,2-diyldimethanol (4 g, 29.8 mmol), which was obtained at another time in the same manner as described in the steps (4a)-(4c), was mixed with methyl propionylacetate (5.6 ml, 44.6 mmol) and triethyl orthoformate (5.2 ml, 31.3 mmol), and p-toluenesulfonic acid monohydrate (163 mg, 0.856 mmol). The mixture was stirred at room temperature for 3 hours. To the mixture, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was washed with water twice and with an aqueous saline solution, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-3/1-1/1 gradient) and a desired fraction(s) was concentrated to obtain the title compound (2.63 g, yield: 35.8%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:19][C:20]#[N:21])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:20]([CH2:19][N:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])[N:7]=2)=[CH:9][CH:10]=1)[S:15]([CH3:18])(=[O:17])=[O:16])#[N:21]
Reactant: Nc1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)N(CC#N)c1ccc(-c2ccnc(Cl)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N(CC#N)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)c(C(=O)O)c3)n2)cc1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
N-(4-(2-chloropyrimidin-4-yl)phenyl)-N-(cyanomethyl)methanesulfonamide (171 mg, 0.53 mmol), 5-amino-2-morpholinobenzoic acid (142 mg, 1.2 eq.) and p-toluene sulfonic acid monohydrate (98 mg, 0.98 eq.) were suspended in 1,4-dioxane (8 mL) and heated at 100° C. overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo. The residue was taken up in ethyl acetate (80 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was then dried and concentrated in vacuo. The residue was repeatedly triturated with methanol (5 mL then 3 mL) to afford, as a cream solid, 5-(4-(4-(N-(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid (101 mg, 37%). 1H NMR (300 MHz, d6-DMSO) δ 17.23 (1H, s) CO2H; 9.99 (1H, s); 8.74 (1H, d, J=2.7 Hz); 8.62 (1H, d, J=5.0 Hz); 8.33 (2H, d, J=8.7 Hz); 8.01 (1H, dd, J=2.8, J=8.7 Hz); 7.69 (1H, d, J=9.1 Hz); 7.63 (2H, d, J=8.7 Hz); 7.52 (1H, d, J=9.1 Hz); 4.97 (2H, s); 3.81 (4H, m); 3.21 (3H, s); 3.06 (4H, m). LC-ESI-MS (method C): rt 5.4 min.; m/z 509.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[N:11]=[C:10]2[SH:19])=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[N:11]=[C:10]2[S:19][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: Fc1ccc2c(c1)nc(S)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCSc1nc2cc(F)ccc2n1Cc1ccc(Cl)cc1

Procedure:
9 g of 1-(4-chlorophenylmethyl)-2-mercapto-5-fluorobenzimidazole, prepared in Example 15, and 4.4 ml of ethyl 4-bromobutyrate are refluxed for 5 hours in 100 ml of acetone in the presence of 6.3 g of potassium carbonate. The solvent is evaporated off under vacuum, the residue is taken up with water and then extracted with ethyl acetate and the extract is washed with a dilute solution of sodium hydroxide. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 11.9 g of ethyl 4-[1-(4-chlorobenzyl)-5-fluorobenzimidazol-2-yl]mercaptobutanoate in the form of an oil, which is used as such for the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: NCCO
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)NCCO
Yield: 82.2 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (210 mg, 0.46 mmol) was reacted with ethanolamine (0.17 ml, 2.7 mmol) to give the title compound as a solid (185 mg, 83%), except that the mixture was heated at 65° C. for 2 hours. NMR Spectrum 1.65 (d, 3H), 3.21-3.25 (m, 2H), 3.42-3.46 (m, 2H), 4.75 (t, 1H), 5.23 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.73 (t, 1H), 7.77-7.79 (m, 3H) 8.21 (s, 1H), 8.48 (m, 1H), 8.54 (s, 1H), 8.57 (s, 1H), 10.75 (br s, 1H); Mass spectrum MH+ 490.
Reaction SMILES: C(OC([CH2:11][NH:12][C@H:13]1[CH2:38][CH2:37][C@:15]2([O:19][CH2:18][C@H:17]([C:20]3[CH:25]=[C:24]([N:26]4[CH:30]=[CH:29][N:28]=[C:27]4[C:31]([F:34])([F:33])[F:32])[CH:23]=[CH:22][C:21]=3[O:35][CH3:36])[CH2:16]2)[C@@H:14]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=O)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:11][NH:12][C@H:13]1[CH2:38][CH2:37][C@:15]2([O:19][CH2:18][C@H:17]([C:20]3[CH:25]=[C:24]([N:26]4[CH:30]=[CH:29][N:28]=[C:27]4[C:31]([F:33])([F:34])[F:32])[CH:23]=[CH:22][C:21]=3[O:35][CH3:36])[CH2:16]2)[C@@H:14]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1
Reactant: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NCC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CN[C@H]1CC[C@@]2(C[C@@H](c3cc(-n4ccnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Reaction time: 3 h

Procedure:
(3S,5R,6R,7S)-7-(N-(Benzyloxycarbonyl)methylamino)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane (7.0 mg, 0.011 mmol) in 0.30 mL of ethanol and 0.24 mL of acetic acid was hydrogenated on the Parr shaker at 47 psi, using 2.3 mg of 20% palladium(II) hydroxide on carbon. After 3 h, the mixture was filtered through 0.45 micron filter and the filtrate was evaporated. The residue was taken in 2.0 mL of ethyl acetate and washed with 1.0 mL of saturated aqueous sodium bicarbonate followed by 1.0 mL of brine. Drying over sodium sulfate and evaporation gave N-methyl((3S,5R,6R,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]non-7-yl)amine. 1NMR (400 MHz, CD3OD): δ7.45 (dd, 2H, J=9, 6 Hz ), 7.29 (d, 1H, J=1 Hz ), 7.21 (d, 1H, J=1 Hz ), 7.19 (dd, 1H, J=9, 2 Hz ), 7.01 (t, 2H, J=9 Hz ), 7.00 (d, 1H, J=9 Hz ), 6.58 (d, 1H, J=2 Hz ), 4.12-4.00 (m, 2H), 3.84-3.75 (m, 1H), 3.79 (s, 3H), 3.13 (d, 1H, J=10 Hz ), 3.05 (t, 1H, J=8 Hz ), 2.54-2.42 (m, 1H), 2.52 (s, 3H), 2.28 (dd, 1H, J=13, 8 Hz ), 2.27-2.20 (m, 1H), 2.07 (ddd, 1H, J=13, 10, 9 Hz ), 1.91 (dd, 1H, J=13, 11 Hz ), 1.90-1.80 (m, 1H). Mass spectrum (NH3/CI): m/z=490.1 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Sodium hydride (0.35 g, 8.6 mmol, 60% in mineral oil) was added to a solution of 4-tert-butyloxycarbonyl-piperazin-2-one (0.86 g, 4.3 mmol) in dimethylformamide (20.0 mL) at 0° C. The reaction was stirred at 0° C. for 0.5 h. To this mixture was added 2-bromoethoxy-tert-butyldimethylsilane (2.3 mL, 10.8 mmol) and the reaction was stirred for 2 h at room temperature. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20% ethyl acetate in hexanes) gave 4-tert-butyloxycarbonyl-1-[2-(tert-butyldimethylsilyloxy)ethyl]-piperazin-2-one (1.17 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.OC=[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][C:17]2=1
Reactant: O=C1CCCCC1=CO
Reactant: COc1ccc(N)cc1
Product: COc1ccc2[nH]c3c(c2c1)CCCC3=O

Procedure:
6-Methoxy-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from p-anisidine and 2-(hydroxymethylene)cyclohexanone in a similar manner as described above to give a tan solid. 1H-NMR (CDCl3): δ 8.77 (br s, 1H), 7.32 (d, 1H), 7.06 (d, 1H), 7.03 (s, 1H), 3.88 (s, 3H), 2.98 (t, 2H), 2.66 (t, 2H), 2.28 (m, 2H); MS m/z 216 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]>[Zn].C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c(SC)s1
Temperature: 50 °C

Procedure:
A flask with 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.06 mmol, Example 118, step c) and zinc dust (4 mg, 0.06 mmol) was dissolved with 1 mL acetic acid and heated to 50° C. for 4 hours. TLC analysis indicated the formation of a new spot. The reaction mixture was concentrated in vacuo and purified by elution through Celite® using 10% MeOH in DCM. The crude product was carried on without further purification. ESI-MS (m/z): Calcd. for C12H10BrNO4S3: 407.9 (M+H); found: 408.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=1[S:44](Cl)(=[O:46])=[O:45].O>ClCCl>[CH3:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([S:44]([C:36]3[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:35]=3[CH3:34])(=[O:45])=[O:46])[C:13]2=[O:26])=[CH:20][CH:19]=1)([CH3:24])[C:22]#[N:23]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2ncc3c(c2c1)n(-c1ccc(C(C)(C)C#N)cc1)c(=O)n3S(=O)(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added 2-methyl-5-nitrobenzene-1-sulfonyl chloride (103.35 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 20 mg (12%); 1H NMR (CDCl3, 300 MHz): δ 9.560 (s, 1H), 9.155-9.163 (d, 1H, J=2.4 Hz), 8.384-8.420 (dd, 1H, J=8.4, 2.4 Hz), 8.050-8.079 (d, 1H, J=8.7 Hz), 7.696-7.724 (d, 2H, J=8.4 Hz), 7.538-7.564 (d, 1H, J=7.8 Hz), 7.458-7.486 (d, 3H, J=8.4 Hz), 6.708 (s, 1H), 2.760 (s, 3H), 2.236 (s, 3H), 1.742 (s, 6H); MS: m/z 542 (M+).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 41 %

Procedure:
As described for example 324, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (100 mg, 41%) which was obtained as a light brown solid. MS: m/e=396.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][C:22]=2[F:24])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 25.9, 29.6, 42.6, 60.2, 104.7 (t, J 25.8), 112.0 (dd, J 22.9 and 3.5), 127.3, 129.6, 131.5 (d, J 8.8), 131.5 (d, J 9.8), 139.1, 139.4, 159.9 (dd, J 252.0, 11.7) and 163.0 (dd, J 252.0, 11.7).