Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][N:16]1[C:20]([CH:21]([NH2:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:19][CH:18]=[N:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:20]([CH:21]([NH:27][S:34]([C:32]2[S:33][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:36])=[O:35])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:19][CH:18]=[N:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(CC)C(N)c1ccnn1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1OCc1ccccc1
Yield: 62.5 %

Procedure:
In a flask containing a mixture of triethylamine (0.045 mL, 0.325 mmol) and {1-[1-(benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutyl}amine (0.081 g, 0.296 mmol) in CH2Cl2 (1 mL) at ambient temperature was added 5-chlorothiophene-2-sulfonyl chloride (0.064 g, 0.296 mmol). After 16 h the mixture was diluted with CH2Cl2 (10 mL) and poured into saturated aqueous NaHCO3 (10 mL). The organic phase was separated and washed sequentially with 1N HCl solution, distilled water, brine and then dried over MgSO4, filtered, and concentrated to an oil. Purification by flash chromatography (hexane/EtOAc, 4:1) afforded the product as a solid (0.084 g, 62%). Mass Spectrum (+ESI): 454 (M+H)+.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:52]=[CH:51][C:16]([CH2:17][O:18][C:19](=[O:50])[CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[CH:15][C:14]=1[O:53][CH2:54][CH:55]1[CH2:57][CH2:56]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:48][CH2:49]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][C:19]([O:18][CH2:17][C:16]1[CH:51]=[CH:52][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:15]=1)=[O:50]
Reactant: CC(C)(C)OC(=O)N(c1ccc(COC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(COC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.5 %

Procedure:
(S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzyloxy)-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (70 mg, 0.08 mmol) was dissolved in DCM (1 ml), and HCl 4M in Dioxane (500 μM) was added. The mixture was stirred at RT for 3 hours. The reaction was quenched with water, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by Preparative reverse-phase HPLC to yield 10 mg of the final product (Yield: 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39]([N:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:12]2[CH2:11][CH:10]([N:22]([C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=3)[CH3:37])[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13]2)=[O:15])[CH2:17][CH2:18]1)=[O:40])[CH3:43]
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound 4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid ethyl ester was prepared from N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using ethyl chloroformate instead of 4-fluorobenzoyl chloride and was obtained as a light brown foam. MS m/e: 630.3 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:37]I>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:17]=3)=[CH:10][N:11]2[CH3:37])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(CN(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(CN(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3)cn(C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the ester 124 (473 mg, 1.02 mmol) in DMF (15 ml) was added 60% NaH (45 mg, 1.12 mmol). The solution was stirred for one hour at room temperature under nitrogen, cooled to 0° C., treated with MeI (170 μl, 1.12 mmol), warmed to room temperature and stirred overnight under nitrogen. The mixture was partitioned between water and AcOEt, organic layer was collected, dried over MgSO4 and concentrated in vacuo to yield 454 mg (93%). 1H-NMR (DMSO) δ: 7.99 (m, 1H), 7.56 (dd, J=1.4, 8.2 Hz, 1H); 7.47 (m, 1H); 7.27 (s, 1H); 6.86 (d, J=8.8 Hz, 2H); 6.75 (d, J=9.0 Hz, 2H); 4.86 (s, 2H); 3.83 (s, 3H); 3.76 (s, 3H); 3.67 (t, J=4.8 Hz, 4H); 3.01 (t, J=4.8 Hz, 4H); 1.37 (s, 9H).
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].Br[CH2:37][C:38]([NH2:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:32][CH2:31]5)=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CCNCC3)cc1-2
Reactant: NC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CCN(CC(N)=O)CC3)cc1-2

Procedure:
Following the procedure for 319, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt was alkylated with bromoacetamide to give 357 isolated as a white solid (167 mg, 86%). LCMS: RT=7.55 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.23 (1H, d, J=2.30 Hz), 8.06 (1H, s), 7.14 (1H, dd, J=8.34, 2.37 Hz), 7.10 (2H, s), 6.95 (1H, d, J=8.26 Hz), 5.79-5.68 (1H, m), 4.33-4.27 (2H, m), 3.41-3.35 (2H, m), 2.92-2.81 (4H, m), 2.50 (1H, m), 2.17 (2H, dd, J=12.36, 10.20 Hz), 1.78 (2H, d, J=12.48 Hz), 1.73-1.61 (2H, m), 1.53 (6H, d, J=6.61 Hz)
Reaction SMILES: CS(Cl)(=O)=O.[N:6]([CH2:9][C@H:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][C@@H:12]([CH2:23]O)[O:11]1)=[N+:7]=[N-:8].[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26]>C(Cl)Cl.C(OCC)C>[N:6]([CH2:9][CH:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][CH:12]([CH2:23][N:27]2[CH2:28][CH2:29][CH2:26][CH2:25]2)[O:11]1)=[N+:7]=[N-:8]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C)c2c1CC(CN1CCCC1)OC2CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.146 mL, 1.89 mmol) is added dropwise to a solution of 0.453 g (1.72 mmol) of [1R,3S] 1-azidomethyl-3,4-dihydro-3-hydroxymethyl-5-methoxy-8-methyl-1H-2-benzopyran, the product of Step 4 of Example 142, and 0.36 mL (2.58 mmol) of triethylamine in 15 mL of methylene chloride at 0° C. The reaction mixture is stirred for 30 min at 0° C. then transferred to a separatory funnel and diluted with 45 mL of diethyl ether. The layers are separated and the organic layer is washed with 2×20 mL of water, 2×20 mL of 1 N hydrochloric acid and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in 20 mL of N,N-dimethyl formamide (DMF) and an excess amount of pyrrolidine is added to this solution. The reaction mixture is heated at 95° C. for 2.5 h then poured into 75 mL of water. The aqueous solution is extracted with 3×40 mL of diethyl ether. The combined ether extracts are washed with 2×30 mL of water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluted to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>O1CCCC1>[CH:20]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH:13]=[CH:14]1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(O)cc21

Procedure:
6-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1)#[N:2].[C:10]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[C:1]([C:3]1[S:4][C:5]([CH:8]=[CH:18][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:6][CH:7]=1)#[N:2]
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C=O)s1
Solvent: C1CCOC1
Product: N#Cc1ccc(C=CC(=O)c2ccccc2)s1
Yield: 56.6 %

Procedure:
A mixture of 2-cyano-5-formylthiophene (4 g) and benzoylmethylenetriphenylphosphorane (11.09 g) in tetrahydrofuran (40 ml) was refluxed for 30 minutes. The reaction mixture was evaporated in vacuo to give 3-(5-cyano-2-thienyl)-1-phenyl-2-propen-1-one (3.95 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27](Br)[CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34].C1COCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>CN(C=O)C.O.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]>[CH3:32][N:33]([CH3:34])[C:27]1[CH:28]=[C:23]([S:20]([NH:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C:11]([NH:10][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])=[O:12])[CH2:14][CH2:15]2)(=[O:22])=[O:21])[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ncc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)cc1Br
Reactant: CNC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)cc1N(C)C

Procedure:
Trans-4-(5-Bromo-6-methoxy-pyridine-3-sulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 223, 65 mg, 0.126 mmol), dimethylamine in THF (2M, 630 ul, 1.26 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), X-phos (6 mg, 0.013 mmol), sodium tert-butoxide (61 mg, 0.63 mmol) were dissolved in DMF (2 ml). The reaction mixture was microwaved at 180° C. for 15 min., after which LCMS indicated the reaction was complete. The mixture was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were concentrated in vacuo to a yellow oil which was purified via column chromatography using a biotage SP1, 25+M column, with 80% EtOAc in heptane as an isocratic gradient. Product containing fractions were concentrated in vacuo and repurified via reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA). Product containing fractions were collected and lyophilized to yield the title compound as a white solid (25.3 mg, 28%). MS MH+ 479.1
Reaction SMILES: [H][H].[CH2:3]([N:10]([CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-])=O)[CH:35]=2)[NH:30][C:29]=1[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Ni]>[NH2:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)=[C:28]2[CH2:27][CH2:26][N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Agent: [Ni]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a stirred solution of N-{4-[4-(benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}amino)butyl]phenyl} methanesulfonamide (491 mg in 30 mL absolute ethanol) was added ca. 30 mg of Raney® nickel. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 2.5 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 2:3; then 1:3) gave the title compound (344 mg).
Reaction SMILES: CN(C)C([Cl:5])=O.C(Cl)(Cl)=O.[CH:11]1([NH:17][S:18](=[O:21])(=O)[OH:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>ClCCCl>[CH:11]1([NH:17][S:18]([Cl:5])(=[O:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C(=O)Cl
Reactant: O=S(=O)(O)NC1CCCCC1
Agent: O=C(Cl)Cl
Solvent: ClCCCl
Product: O=S(=O)(Cl)NC1CCCCC1
Temperature: 83 °C
Yield: 58 %

Procedure:
A solution of 15 parts of dimethylcarbamic acid chloride in 310 parts of 1,2-dichloroethane is saturated with 30 parts of phosgene at 25° C and 89.5 parts of cyclohexylsulfamic acid are then added. The reaction mixture is heated to 83° C whilst continuing to introduce phosgene. In total, 330 parts of phosgene are introduced in the course of 13 hours. After removing the solvent and the dimethylcarbamic acid chloride under reduced pressure, the residue is distilled, and 57 parts (58% of theory) of cyclohexylsulfamic acid chloride of boiling point 208°-127° C/0.1 mm Hg and melting point 42°-44° C are obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[N:4]([CH2:22][C@H:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[C:3](=[O:31])[N:4]([CH2:22][C@H:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1c(Br)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
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: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 90 °C

Procedure:
To compound 2a (40 mg, 0.08 mmol) in 0.25 mL/0.75 mL of H2O/dioxane in a 4 mL vial was added 2-chlorophenyl boronic acid (0.12 mmol) and sodium carbonate (51 mg, 0.48 mmol, 6 eq). Nitrogen gas was bubbled through the solution for 1 minute and tetrakis(triphenylphosphine)palladium (9.24 mg, 0.008 mmol) was added. The resulting mixture was sealed and heated at 90° C. overnight. After cooling to ambient temperature, the precipitate was removed by filtration and was purified by prep. LC-MS to give 2b.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[CH:12][C:11]=1[CH2:10][C@H:9]3[CH2:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(OCC)(=O)C.[C].[Pd]>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[CH:12][C:11]=1[CH2:10][C@H:9]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:45])([F:46])[C:41]([F:42])([F:43])[F:44])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C(CCCCCCC=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Ethyl 11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)-9-undecenoate (970 mg, 1.48 mmol) was dissolved in ethyl acetate (30 ml), and 10% palladium carbon (300 mg) was added to the resulting solution followed by stirring for 4 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered and concentrated to give ethyl 11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-penta-fluoropentyl)undecanoate (946 mg, Yield 97%) as an oil.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]2)[CH2:2]1.C(OC([NH:18][C:19]1[S:23][C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:21][C:20]=1[C:32](O)=[O:33])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:18][C:19]1[S:23][C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:21][C:20]=1[C:32]([NH:10][C:8]1[CH:7]=[N:6][N:5]([CH:3]2[CH2:4][O:1][CH2:2]2)[CH:9]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Nc1cnn(C2COC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2COC2)c1
Yield: 9 %

Procedure:
Following the procedures as described in Example 113, 1-(oxetan-3-yl)-1H-pyrazol-4-amine, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 138 as a white solid (10 mg, 9%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.36 (s, 1H), 7.86 (s, OH), 7.67-7.41 (m, 1H), 7.28 (t, J=8.4, 1H), 5.46-5.26 (m, 2H), 4.90 (s, 1H), 4.40 (d, J=5.7, 2H). ESIMS m/z=378.0 (M+1)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:26])(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To the solution of (1-benzhydryl-2-oxo-pyrrollidin-3-yl)-carbamic acid tert-butyl ester (41) (1.2 g, 3.26 mmol) in CH2Cl2 (20 ml) was added CF3CO2H (8 ml). The resulting mixture was stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium hydrogen carbonate (20 ml). The organic was dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2: MeOH (10:1) to give the desired product in 97% yield.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[C:11]([C:31]([F:34])([F:33])[F:32])[CH:10]=2)O1.[NH2:36][C:37]1[C:38]([C:46]#[N:47])=[N:39][C:40](Cl)=[CH:41][C:42]=1[NH:43][CH3:44].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>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].O>[NH2:36][C:37]1[C:42]([NH:43][CH3:44])=[CH:41][C:40]([C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]3)=[C:11]([C:31]([F:32])([F:33])[F:34])[CH:10]=2)=[N:39][C:38]=1[C:46]#[N:47]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(F)(F)F)CC1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2ccc(OCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C
Yield: 70.3 %

Procedure:
The mixture of tert-butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate (2.41 g), 3-amino-6-chloro-4-(methylamino)picolinonitrile (0.8 g), tris(dibenzylideneacetone)dipalladium (201 mg), tricyclohexylphosphine (147 mg) in a mixed solvent of dioxane (30 ml) and water (15 ml) was heated under nitrogen at 100° C. for 3 hours. After cooling to room temperature, the mixture extracted with ethyl acetate (200 ml), organic layer dried over sodium sulphate, solvent removed under reduced pressure, residue was columned on silica gel using 20:1 DCM:MeOH as eluant to give tert-butyl 4-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)-piperidine-1-carboxylate (1.6 g) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.N1CCC(C2CC3C(=CC=CC=3)NC2=O)CC1>>[N:12]1([CH:11]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2Cc3ccccc3NC2=O)CC1
Agent: O=C1Nc2ccccc2CC1C1CCNCC1
Product: O=C1Nc2ccccc2CC1N1CCNCC1

Procedure:
tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperazine-1-carboxylate (640 mg, 1.9 mmol) was reacted in a manner analogous to the preparation of 3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one. Title compound was obtained as light brown solid in quantitative yield. MS m/e (M+H)+=232.4.
Reaction SMILES: C(C1N(C)C=C(C=O)C=1)#N.NCC1N(C)C(C#N)=CC=1.[N:21]([CH2:24][C:25]1[CH:26]=[C:27]([C:31]#[N:32])[N:28]([CH3:30])[CH:29]=1)=[N+]=[N-]>>[NH2:21][CH2:24][C:25]1[CH:26]=[C:27]([C:31]#[N:32])[N:28]([CH3:30])[CH:29]=1
Reactant: Cn1cc(CN=[N+]=[N-])cc1C#N
Agent: Cn1c(C#N)ccc1CN
Agent: Cn1cc(C=O)cc1C#N
Product: Cn1cc(CN)cc1C#N

Procedure:
4-Aminomethyl-1-methylpyrrole-2-carbonitrile was prepared starting from 5-cyano-1-methylpyrrole-3-carbaldehyde similar to the synthesis of 5-aminomethyl-1-methylpyrrole-2-carbonitrile. However, the 4-azidomethyl-1-methylpyrrole-2-carbonitrile was advantageously reduced by a Staudinger reaction (see, for example, S. Nagarajan et al., J. Org. Chem. 52 (1987) 5044-6).