Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H](C(O)=O)CCSC.[Br:10][C:11]1[CH2:17][N:16](CC2C=CC(OC)=CC=2OC)[C:15](=[O:29])[C@H:14]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][CH:12]=1>FC(F)(F)C(O)=O.ClCCl>[Br:10][C:11]1[CH2:17][NH:16][C:15](=[O:29])[C@H:14]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][CH:12]=1
Reactant: COc1ccc(CN2CC(Br)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Agent: CSCC[C@H](N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CC=C(Br)CNC1=O)OCc1ccccc1
Reaction time: 18 h
Yield: 27.2 %

Procedure:
A solution of L-methionine (274 mg, 1.84 mmol) in trifluoroacetic acid (5 mL) was added to a solution of benzyl (3R)-6-bromo-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (90 mg, 0.184 mmol) in dichloromethane (5 mL). After 18 h, the mixture was concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (17 mg). MS 339 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]2[O:13][CH:12]([CH:14]([OH:24])[CH2:15][CH2:16][NH:17]C(=O)C(F)(F)F)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO.C(Cl)Cl>>[NH2:17][CH2:16][CH2:15][CH:14]([CH:12]1[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:13]1)[OH:24]
Reactant: O=C(NCCC(O)C1CCC(CCC2CCCCC2)O1)C(F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NCCC(O)C1CCC(CCC2CCCCC2)O1

Procedure:
Deprotection of N-(3-(5-(2-cyclohexylethyl)tetrahydrofuran-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide following the method used in Example 14 gave after flash chromatography purification (4%-16% 7N NH3/MeOH—CH2Cl2 gradient) Example 15 as a colorless oil. Yield (0.033 g, 40%); 1H NMR (400 MHz, CD3OD) δ 3.62-3.84 (m, 2H), 3.45-3.57 (m, 2H), 2.71-2.88 (m, 2H), 1.80-2.05 (m, 2H), 1.39-1.80 (m, 10H), 1.09-1.37 (m, 6H), 0.87-0.99 (m, 2H); RP-HPLC tR=9.75 min; ESI-MS m/z 256.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(CC(C)C)c(C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(C(=O)O)cc1C#N
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Methyl 3-cyano-4-(2-methylpropyl)benzoate (D31) (233 mg, 1.072 mmol) was dissolved in ethanol (4 ml) and 2M aqueous sodium hydroxide (1 ml, 2 mmol) was added. The reaction was stirred for 1 h. 2M aqueous HCl (10 mL) was added and the mixture extracted with dichloromethane (20 mL+10 mL). The organic phases were isolated and dried by phase separator and combined before the solvent was removed in vacuo to give the title compound as a white solid (203 mg, 0.999 mmol). δH (d6-DMSO, 400 MHz) 13.43 (1H, br. s), 8.29 (1H, d), 8.14 (1H, dd), 7.59 (1H, d), 2.74 (2H, d), 1.96 (1H, m), 0.91 (6H, d). MS (ES): C12H13NO2 requires 203; found 202 (M−H+).
Reaction SMILES: [F:1][C:2]([F:28])([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:28][C:2]([F:1])([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(F)(F)c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)c2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[difluoro(4-methylphenyl)methyl]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (156 mg) in THF (dry) (20 mL) and MeOH (20 mL). The mixture was stirred at room temperature under hydrogen for 3 h. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (72.0 mg) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4[C:22]([C:27](=[O:37])[N:28]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[N:29]=4)=[CH:23][NH:24][C:25]=3[CH3:26])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>CO>[ClH:36].[ClH:38].[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:28]2[C:27](=[O:37])[C:22]3=[CH:23][NH:24][C:25]([CH3:26])=[C:20]([C:17]4[CH:16]=[CH:15][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:19][CH:18]=4)[C:21]3=[N:29]2)=[CH:31][CH:32]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(N2CCNCC2)cc1
Reaction time: 18 h

Procedure:
To the product of Example 42 (0.042 g, 0.08 mmol) was added a saturated solution of hydrogen chloride in methanol, and the resulting solution was allowed to age for 18 h. The solvent was then evaporated, and the residue was azeotroped with toluene. The residue was crystallised from methanol-ethyl acetate, and recrystallised from hot ethanol to afford the title compound as a yellow solid; 1H NMR (500 MHz, DMSO-d6) 67 12.47 (br s), 9.05 (br s), 8.52 (1H, s), 8.14 (2H, d, J 9.0 Hz), 7.43 (4H, m), 7.10 (2H, d, J8.8 Hz), 3.46 (4H, m), 3.26 (4H, m), 2.28 (3H, s); MS (ES+) m/z 420/422[MH]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[F:20][C:21]([F:37])([F:36])[C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][C:25]3[CH:34]=[CH:35][C:22]([C:21]([F:20])([F:36])[F:37])=[CH:23][CH:24]=3)=[CH:28][CH:29]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5 Step A and 4-(4-trifluoromethylPhenoxy)-phenol in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H21F3O5 [M−H]−: 469.2
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:27]3[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccnn3C)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (81 mg, 0.576 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL) and water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-pyrazol-5-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.32 (s, 1H), 7.18 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 6.01 (s, 1H), 3.6 (s, 2H), 3.2 (s, 3H), 3.0 (m, 4H), 2.7 (m, 4H), 2.52 (s, 3H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14](=[O:16])[NH2:15])=[CH:12][N:11]([C:17]3([CH2:30][C:31]#[N:32])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[N:10]=2)=[CH:4][CH:3]=1.[CH3:33][C:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[C:37]([CH3:48])[O:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+].C1COCC1>CO.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.O>[C:14]([C:13]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[C:34]([CH3:33])=[N:35][O:36][C:37]=3[CH3:48])=[CH:3][CH:4]=2)=[N:10][N:11]([C:17]2([CH2:30][C:31]#[N:32])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:12]=1)(=[O:16])[NH2:15]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(Br)cc3)n2)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: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1noc(C)c1-c1ccc(Nc2nn(C3(CC#N)CCN(C(=O)OC(C)(C)C)CC3)cc2C(N)=O)cc1
Temperature: 25 °C

Procedure:
tert-Butyl 4-{3-[(4-bromophenyl)amino]-4-carbamoyl-1H pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example #2-2) (50 mg, 0.10 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (22 mg, 0.10 mmol), potassium carbonate (55 mg, 0.40 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) was suspended in 2:1 THF:water (1.2 mL) and heated to 100° C. for 16 hours. The mixture was then cooled to ambient temperature, diluted with MeOH, and filtered through a 0.45 micron nylon syringe filter. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase preparative HPLC (using a gradient elution of 35-70% MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and lyophilized to afford the title compound, Example #14.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([C@@H:33]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:34][CH2:35][N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:20]=2)[CH:11]=1)(C)(C)C.Cl>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([C@@H:33]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:34][CH2:35][N:36]([CH:37]([CH3:39])[CH3:38])[CH:40]([CH3:42])[CH3:41])[CH:20]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2cccc(CCNC(=O)OC(C)(C)C)c2)ccc1OCc1ccccc1)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2cccc(CCN)c2)ccc1OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl{2-[3-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethoxy)phenyl]ethyl}carbamate (Preparation 37, 1.3 g, 2.0 mmol) dissolved in dichloromethane (5 ml) and hydrochloric acid (4M in dioxin) added. Mixture stirred at room temperature for 3 hours under nitrogen. Solvent was removed in vacuo, and residue dissolved in dichloromethane (100 ml) and aqueous sodium hydroxide (1M, 100 ml), aqueous separated and extracted with dichloromethane (100 ml). Combined organics were dried (magnesium sulphate) and the solvent was removed in vacuo to furnish the title compound as an oil, 880 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[Na+]>OS(O)(=O)=O.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([OH:16])([C:14]([NH2:15])=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
1-Benzyl-4-hydroxy-piperidine-4-carbonitrile (5 g, 23.12 mmol) is dissolved in a mixture of H2SO4 (18 mL) and H2O (2 mL) at 0° C. The mixture is warmed to room temperature for 14 hours, transferred into cold 2 N NaOH and adjusted to pH>8. The solid is filtered and washed with H2O, and dried over sodium sulfate to give the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:10]1[CH:15]=[C:14]([I:16])[C:13]([CH3:17])=[CH:12][N:11]=1)C(OC)=O)=[O:4].[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:4])[NH:5][C:10]1[CH:15]=[C:14]([I:16])[C:13]([CH3:17])=[CH:12][N:11]=1
Reactant: COC(=O)N(C(=O)OC)c1cc(I)c(C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1cc(I)c(C)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
Dimethyl(4-iodo-5-methylpyridin-2-yl)imidodicarbonate (110 g, 310 mmol) was added to a mixture of MeOH (1500 mL) and 1M NaOH (620 mL). The reaction mixture was allowed to stir at rt for 1.5 h and was then concentrated. EtOAc and water were added to the residue and the solution was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give methyl(4-iodo-5-methylpyridin-2-yl)carbamate (68 g, 60%) which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(S)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
4-Fluoro-2-(trifluoromethyl)benzenesulphonyl chloride (2.0 g) was dissolved in dioxane (12 mL) under a N2-atmosphere at ambient temperature. Water (3.0 mL) and tris-(2-carboxylethyl)phosphine hydrochloride (8.73 g) was added afterwards. The reaction mixture is stirred under reflux for 6 h. The reaction mixture is cooled to 25° C. and dissolved with water (30 mL). The product is extracted with CH2Cl2 (100 mL) several times. The combined organic layers are washed with water and dried over Na2SO4. The organic layer is filtrated and evaporated to dryness to yield 1.27 g (85%) of a colorless liquid which is used without further purification. MS (ESI): m/z=194.9 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.Cl[C:21]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][N:8]([C:21]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH2:7]1
Reactant: Fc1cccc(OC2CNC2)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(F)c2)C1

Procedure:
To a mixture of 3-(3-fluorophenoxy)azetidine) (D50) (106.73 mg, 0.638 mmol) and triethylamine (0.11 ml, 0.798 mmol) in methanol (3 ml), 2-Chloro-5-(trifluoromethyl)nicotinic acid (120 mg, 0.532 mmol) was added and the mixture was heated 10 min (2 cycles of 5 min each) under microwave irradiation at 150° C. After solvent evaporation the residue was purified by SPE-Si cartridge (25 g) eluting with a mixture dichloromethane/methanol from 100/0 to 50/50. Collected fraction after solvent evaporation afforded the title compound (D121) (83 mg)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH2:14])=O)[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.[Si:16]([O:23][CH2:24][C@:25]1([CH3:34])[S:31][CH2:30][CH2:29][N:28]=[C:27](SC)[CH2:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:28]4[CH2:29][CH2:30][S:31][C@:25]([CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:34])[CH2:26][C:27]4=[N:14][N:13]=3)[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: NNC(=O)C1(c2ccc(Br)cc2F)CC1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of the compound (2.00 g, 7.32 mmol) obtained in Example 14-4) and the compound (2.57 g, 8.06 mmol) obtained in Example 4-1) in n-butanol (40 mL) was stirred at 140° C. for 8 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.86 g, quant.) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([CH3:38])[CH:36]=O.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:34][CH:35]([CH3:38])[CH3:36])[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CC(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml).). 2-Methylpropionaldehyde (0.104 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 09.2858, C26H37N2O2 requires 409.2855; LC-MS: (M+H)+ 409.2, tr 5.97 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([OH:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>O1CCCC1.C(OCC)(=O)C>[C:31]([O:23][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=[CH:9][C:8]=1[S:11]([NH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])(=[O:33])[CH3:32]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(O)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(C(C)(C)C)ccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a cooled (0° C.) solution of 35 (137.2 mg; 0.39 mmol) and triethylamine (0.06 mL; 0.46 mmol) in tetrahydrofuran (2 mL) was added acetyl chloride (0.03 mL; 0.46 mmol). After addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, aqueous saturated sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes to yield the title compound as a white foam (67.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[F:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[C:49]2([OH:55])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][C:49]([C:41]3[N:40]([CH2:39][C:38]4[CH:56]=[CH:57][C:35]([F:34])=[CH:36][CH:37]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)([OH:55])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 144 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.20 g, 0.38 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazol-2-yl]-4-hydroxy-piperidine (0.15 g, 0.46 mmol), and potassium carbonate (0.16 g, 1.13 mmol) in tetrahydrofuran/water (3/1) (40 mL). Heat to reflux. After 6 days, cool and evaporate in vacuo to obtain a residue. Partition the residue between dichloromethane and water. Extract the organic layer with 1 M hydrochloric acid solution, a 5% sodium bicarbonate solution, and water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting sequentially with 10/1 ethyl acetate/methanol and 2/1 ethyl acetate/methanol to give the title compound: Rf=0.57 (silica gel, 2/1 ethyl acetate/methanol).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]([N:32]([C:37]2[C:55]([CH:56]3[CH2:58][CH2:57]3)=[CH:54][C:40]3[C:41]([C:51](O)=[O:52])=[C:42]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[O:43][C:39]=3[CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:25][C:26]1[CH:27]=[C:28]([N:32]([C:37]2[C:55]([CH:56]3[CH2:58][CH2:57]3)=[CH:54][C:40]3[C:41]([C:51]([NH:2][CH3:1])=[O:52])=[C:42]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[O:43][C:39]=3[CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)N(c1cccc(Br)c1)c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1C1CC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 1 h
Yield: 79.3 %

Procedure:
HATU (237 mg, 0.624 mmol) was added to a solution of 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylic acid (283 mg, 0.520 mmol), methylamine hydrochloride (70.2 mg, 1.040 mmol) and DIEA (0.318 mL, 1.819 mmol) in DMF (2 mL) at room temperature. The mixture was stirred for one hour. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate) to give 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (230 mg, 79%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (s, 1H) 8.12 (s, 1H) 7.96 (dd, J=8.98, 5.47 Hz, 2H) 7.60 (t, J=2.05 Hz, 1H) 7.27-7.54 (m, 5H) 7.18 (s, 1H) 3.41 (s, 3H) 2.82 (d, J=4.69 Hz, 3H) 2.07-2.22 (m, 1H) 0.65-1.09 (m, 3H) 0.41 (m, 1H). LCMS (m/z, ES+)=557, 559 (M+H, M+2).