Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:27][C:28]1[N:29]([CH3:33])[N:30]=[CH:31][N:32]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][CH2:27][C:28]2[N:29]([CH3:33])[N:30]=[CH:31][N:32]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: Cn1ncnc1CCl
Reactant: Oc1nn2c(-c3ccccc3F)nncc2c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 84.8 %

Procedure:
To a stirred solution of 3-bromo-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.2073 g, 0.671 mmol) in anhydrous DMF (10 ml) under nitrogen was added cesium carbonate (0.8731 g, 2.680 mmol), then solid 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.1703 g, 1.014 mmol). The mixture was stirred at room temperature for 22.5 h, then at 60° C. for 2.33 h. This was then partitioned between water (40 ml) and ethyl acetate (40 ml). The aqueous layer was further extracted with ethyl acetate (2×40 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc) to give 0.2299 g (85%) of the title compound as a white solid: mp=215-219° C. (CH2Cl2-EtOAc-isohexane); 1H NMR (360 MHz, CDCl3) δ 3.87 (3H, s), 5.52 (2H, s), 7.28 (1H, m), 7.39 (1H, t, J=7.5 Hz), 7.65 (1H, m), 7.77 (1H, t, J=7.5 Hz), 7.87 (1H, s), 9.22 (1H, s); MS (ES+) m/e 404/406 [MH]+. Anal. Found C, 44.41; H, 2.53; N, 24.04%. C15H11BrFN7O requires C, 44.57; H, 2.74; N, 24.26%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH:21]=2)=[O:19])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCl>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:21]=2)=[O:19])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(C(=O)NNC(=O)C2CCNCC2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of t-butyl 4-[3-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-carbazoyl]-2-(t-butoxycarbonylmethoxy)phenoxyacetate (360 mg) and TFA (4 ml) in dichloromethane (8 ml) was stirred at ambient temperature for 5 hours. The solvent was removed by evaporation and the residue was triturated with ether to give the title compound as a solid; NMR Spectrum (d6 -DMSO) 1.68-2.02 (m, 4H), 2.55-2.68 (m, 1H), 2.85-3.05 (dt, 2H), 3.2-3.4 (br d, 2H), 4.74 (s, 2H), 4.78 (s, 2H), 6.97 (d, 1H), 7.4 (s, 1H), 7.47 (dd, 1H), 8.5 (br s, 2H), 9.9 (s, 1H), 10.2 (s, 1H); Mass Spectrum (+ve FAB, MeOH/NBA): 396 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(O)C.[CH:31]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH2:32]>>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:32][CH2:31][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: C=CS(C)(=O)=O
Solvent: CCO
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CCS(C)(=O)=O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) in ethanol (4.0 mL, 0.068 mol) was added methyl vinyl sulfone (0.0703 mL, 0.000786 mol) via syringe. The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 491 (213.4 mg) as a colorless solid. MS(ESI+) 488.2. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2, 1H), 7.20 (dd, J=8.3, 1.7, 1H), 7.05 (d, J=1.6, 1H), 5.85-5.64 (m, 1H), 4.36 (t, J=5.0, 2H), 3.62 (m, 3H), 3.42 (t, J=5.0, 2H), 3.15 (m, 4H), 3.06 (s, 3H), 2.85 (m, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([NH2:17])=[O:16].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15](=[O:16])[NH2:17])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Yield: 96 %

Procedure:
N-tert-butyloxycarbonyl glycine 1a (5 g, 28.56 mmol) and L-prolinamide (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide and the mixture was cooled to 0° C. Then 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were added with stirring. The reaction mixture was warmed up to room temperature and stirred overnight. The reaction was monitored by thin layer chromatography (TLC) until the disappearance of the starting materials. N,N-dimethylformamide was evaporated below 50° C. The resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the title compound (S)-[2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, yield 95.8%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:22]([C:21]([OH:24])=[O:23])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: COc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(C(=O)O)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To 450 mg of 3-(3-fluorophenyl)-7-methoxy-1H-indazole-5-carbonitrile were sequentially added 6 ml of glacial acetic acid, 2 ml of water and 2 ml of concentrated sulfuric acid, followed by stirring at 100° C. for one day. After standing to cool, water was added to the reaction mixture and the resulting crystals were collected by filtration. The crystals were sequentially washed with isopropanol and diethyl ether, to give 428 mg of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:35])[NH:27][C:26](=[O:28])[CH:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:32]3[CH2:33][CH2:34][CH:29]([CH:25]4[CH2:24][C:23]([CH3:22])([CH3:35])[NH:27][C:26]4=[O:28])[CH2:30][CH2:31]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)CC(C2CCNCC2)C(=O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(C2CCN(C(=O)c3ccc(N4CC(F)(F)C4)c(OCC4CC4)n3)CC2)C(=O)N1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5,5-dimethyl-3-(piperidin-4-yl)pyrrolidin-2-one hydrochloride in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=463.6 [MH+].
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH2:24][CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[H-].[Na+].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([CH2:24][CH3:25])[C:28]1=[O:29]
Reactant: CCNc1nc(SC)ncc1CNc1c(F)c(OC)cc(OC)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(SC)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 4.92 g (11.58 mmol) of (5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-ethyl-amine in 85 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The reaction mixture was treated with 1.16 g (28.95 mmol) of sodium hydride and continued stirring at 0° C. for 30 minutes. After 30 minutes, 5.63 g (34.74 mmol) of 1,1′-carbonyldiimidazole was added and continued to stir at 0° C. for an additional 30 minutes. After 1 hour, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture heated at reflux overnight under nitrogen atmosphere. Evaporated the tetrahydrofuran and partitioned the residue between dichloromethane and water. The aqueous layer was extracted one time with 250 mL dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified using medium-pressure chromatography eluting with 2:1 hexanes/ethyl acetate to give 4.23 g (92%) of the title compound: mp 165° C.–168° C. MS (APCI) (m+1)/z 397.1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([NH:16][CH3:17])=[CH:13][C:14]=2[CH3:15])[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[N:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[N:45]=[CH:44][C:43]([C:46]([N:16]([CH3:17])[C:12]3[N:11]=[CH:10][C:9]([CH2:8][N:6]4[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@@H:2]([CH3:1])[CH2:7]4)=[C:14]([CH3:15])[CH:13]=3)=[O:47])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1
Reactant: CNc1cc(C)c(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1
Reactant: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N(C)C(=O)c2ccc(Oc3ccc(F)cc3)nc2)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (2S)-2-methyl-4-{[4-methyl-6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate (D101) (0.038 g, 0.11 mmol) was dissolved in dry DCM (2 mL). Triethylamine (0.016 g, 0.16 mmol) was added dropwise and after 5 minutes a solution of the acid chloride from step 1 in dry DCM (2 mL) was added dropwise. The reaction mixture was then left stirring under argon at room temperature overnight. Saturated aqueous NaHCO3 (15 mL) was added and the aqueous layer extracted with DCM (3×5 mL). The organic extracts were dried (Na2SO4) and the crude product was purified by column chromatography. Elution with a 0-100% EtOAc/petroleum ether gradient gave the title compound as a colourless oil (0.026 g). MS (ES): MH+ 550.4
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[CH3:21]>>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[C:15]([CH3:21])[CH:16]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(N)ccc1Br
Product: Cc1cc(N)ccc1-c1cccc([N+](=O)[O-])c1
Yield: 61.9 %

Procedure:
This compound was made according to the General Method 14 (EXAMPLE 191) from 3-nitrobenzene boronic acid (673.2 mg, 3.82 mmol) and 4-bromo-3-methylaniline (710.2 mg, 3.82 mmol) to afford 540 mg (62%) of 4-amino-2-methyl-3'-nitrobiphenyl (structure 82 of Scheme XXI, where R1 =R3-5 =R6 =R8 =H, R2 =nitro, R7 =methyl). Data for 4-amino-2-methyl-3'-nitrobiphenyl: 1H NMR (400 MHz, acetone-d6) 8.13 (dd, J=7.5, 1.1, 1H), 8.09 (dd, J=3.9, 1.8, 1H), 7.73 (ddd, J=7.7, 1.6, 1.4, 1H), 7.66 (dd, J=8.0, 7.8, 1H), 6.99 (d, J=8.0, 1H), 6.60 (m, 1H), 4.73 (br s, 1H), 2.18 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:13][CH2:14][CH3:15])=[N:8]2.[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=4)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[N:8]2[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[N:23]([C:22]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:24]=[N:25][N:26]=2)=[CH:39][CH:38]=1
Reactant: CCCc1nc2ncnc(Cl)c2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of NaH (0.016 g of a 60% dispersion in oil, 0.4 mmol) in dry dimethylformamide (1.5 ml) was added 6-Chloro-8-propylpurine (0.044 g, 0.25 mmol) at room temperature. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (0.139 g, 0.25 mmol) was added. The resulting mixture was warmed to room temperature and then stirred at 40° C. for 3 hours. The reaction was cooled, and the content of the flask was poured into ice-water (50 ml) and extracted with ethyl acetate (3×15 ml). The combined organic phase was washed with brine and then dried over anhydrous Na2SO4. Removal of the solvent gave the crude product as a foam which was purified by flash-chromatography on silica-gel using ethyl acetate/hexane (1:3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[N:12]([CH3:16])[N:13]=[N:14][CH:15]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[N:12]([CH3:16])[N:13]=[N:14][CH:15]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1nncc1C(=O)c1cc(Cl)ccc1N
Solvent: c1ccncc1
Product: Cn1nncc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Following the general procedure for synthesis of N-arylbenzenesulfonamides, 28 mg (0.12 mmol) of (2-Amino-5-chloro-phenyl)-(3-methyl-[1,2,3]triazol-4-yl)methanone and 56 mg (0.24 mmol) of 4-tert-butylphenylsulfonyl chloride were combined in 0.5 ml of anhydrous pyridine at 60° C. to give, after purification, the title product as a pale yellow solid: 1H NMR CD3OD δ (ppm): 1.20 (s, 9H), 4.15 (s, 3H), 7.37 (d, 2H), 7.52 (d, 2H), 7.59-7.62 (m, 2H), 8.27 (d, 1H), 8.53 (s, 1H); MS: (M+H)/z=433.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([F:30])[CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)#[N:2].[OH:43]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([F:30])[CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)(=[O:43])[NH2:2]
Reactant: OO
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)c(F)cc32)C1c1cccc(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)c(F)cc32)C1c1cccc(Cl)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.23 g, 0.38 mmol) prepared in Example 112 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.64 g, 5.6 mmol), then aqueous solution (1N) of NaOH (1.9 mL, 1.9 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichloromethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.17 g, 72%)
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].[C:34]([O:38][C:39]([CH2:41][CH2:42][C:43]#[CH:44])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:44]#[C:43][CH2:42][CH2:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCCC(=O)OC(C)(C)C
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCCC(=O)OC(C)(C)C)cc2C(F)(F)F
Yield: 82 %

Procedure:
The title compound (34.9 mg, 82%) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (40.9 mg, 0.0720 mmol) and 4-t-butoxycarbonyl-1-butyne by the procedure similar to that described in Reference Example 21.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:5]=[C:4]([CH2:15][Br:37])[CH:3]=1
Reactant: OCc1cc(Br)cc(-c2ccccc2Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-c1cc(Br)cc(CBr)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
177 mg (0.60 mmol) of the compound from Example 115A and 187 mg (0.71 mmol) of triphenyl-phosphine were dissolved in 4 ml of THF, and 237 mg (0.71 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically [Method 19]. This gave, in a purity of 79%, 129 mg (60% of theory) of the target compound, which were immediately reacted further.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22](Cl)(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([OH:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>C1COCC1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22]([O:39][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOS(=O)(=O)NC(=O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of [1,1':3',1"-terphenyl]-2'-yl(chlorosulfonyl)carbamate (5.0 g, 12.9 moles) in 75 mL THF was added dropwise to a solution of n-dodecyl alcohol (2.4 g, 12.9 mmoles) and triethylamine (1.3 g, 12.9 mmoles) in 100 mL THF at ~15° C. under an atmosphere of N2. The mixture was allowed to warm to room temperature for 16 hours, then concentrated in vacuo and partitioned between H2O and EtOAc. The EtOAc layer was dried with MgSO4 and evaporated to give a white solid. Chromatography (SiO2, 10% EtOAc/hexanes) gave 2.95 g of the title compound, mp 124°-126° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[OH:21][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(C2(O)CCNCC2)cc1

Procedure:
30 g of N-benzyl-4-hydroxy-4-(4-methylphenyl)-piperidine in a mixture of equal parts of ethyl acetate and ethanol with palladium (5% on charcoal) is hydrogenated until one equivalent of hydrogen has been absorbed to give 4-hydroxy-4-(4-methylphenyl)-piperidine, m.p. 137°-138° (from ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
300 mg (1.04 mmol) of the compound of Example 6A, 301 mg (1.14 mmol) of the compound of Example 24A and 473 mg (1.24 mmol) of HATU were initially charged in 3.6 ml of DMF, 0.36 ml (2.07 mmol) of N,N-diisopropylethylamine was added and the mixture was stirred at RT for two days. The reaction was then directly separated into its components by preparative HPLC (Method 18). This gave 180 mg (31% of theory) of the title compound.