Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3-methyl-4-trifluoromethylphenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.128 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as an off-white solid (0.077 g, 15%). MS (ISN) 526.4 [(M−H)−]; mp 180° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[NH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)CN
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1F

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyano-2-fluorobenzyl bromide (Fluorochem) and tert-butyl glycinate. It was isolated as a yellow oil (1.8 g, 74%). 1H NMR (DMSO-d6, 300 MHz) δ 7.82-7.77 (m, 1H), 7.71-7.63 (m, 2H), 3.82 (s, 2H), 3.22 (s, 2H), 2.58 (br s, 1H), 1.40 (s, 9H). LC/MS (Method B): 265.0 (M+H)+. HPLC (Method A) Rt 2.23 min (Purity: 98.0%).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][NH:28]2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][N:28]2[C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])=[CH:24][CH:23]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: Clc1ccc2c(c1)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), 6-Chloro-2,3-dihydro-1H-indole (62 mg, 0.45 mmol) and K2CO3 (110 mg, 0.80 mmol) in DMF (1 mL) was stirred at room temperature overnight. Then water (10 mL) was added and the desired product was precipitated out. The crude product was purified by prep-HPLC to give 55 mg rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=443
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[N:36][C:35]4[C:34](=[O:38])[NH:33][C:32]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])=[N:31][C:30]3=4)[C@@H:26]([F:45])[C@@H:25]2[OH:46])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:49](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>>[Si:49]([O:46][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[N:36][C:35]3[C:34](=[O:38])[NH:33][C:32]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])=[N:31][C:30]2=3)[C@H:26]1[F:45])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2F)c(=O)[nH]1

Procedure:
This compound is prepared from 9-[2-deoxy-5-O-(4,4'-dimethoxytrityl)-2-fluoro-β-D-arabinofuranosyl]-N2 -isobutyrylguanine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12].N([O-])=O.[Na+].C1(C)C=CC=CC=1.[BrH:24]>O>[Br:24][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12]
Reactant: Br
Reactant: Cc1c(N)ccc(C(=O)O)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Br)ccc(C(=O)O)c1F
Reaction time: 1 h

Procedure:
In 14 ml of 4.7% hydrobromic acid was suspended 0.55 g of 4-amino-2-fluoro-3-methylbenzoic acid, and 3.7 g of cupric bromide was added thereto. To the resulting suspension was added dropwise a solution of 0.38 g of sodium nitrite in 4 ml of water under ice-cooling over a period of 15 minutes, and the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 24 hours. To the reaction mixture was added 20 ml of toluene and the organic layer was separated. The organic layer obtained was washed with 20 ml of 20% hydrobromic acid, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. n-Hexane was added to the resulting residue and the crystals were collected by filtration to obtain 0.68 g of colorless 4-bromo-2-fluoro-3-methylbenzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])OC4C=CC=CC=4)=[CH:28][CH:27]=3)[N:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.FC1C=C(S([C:53]([C:56]2C=C(N3CCOC[C@@H]3C)N=C(C3C=CC(NC(=O)OC4C=CC=CC=4)=CC=3)[N:57]=2)(C)C)(=O)=O)C=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:57][CH2:56][CH3:53])=[O:41])=[CH:28][CH:27]=3)[N:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nc(CS(=O)(=O)c3cc(F)cc(F)c3)cc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
The following compounds were made in an analogous fashion from either phenyl N-[4-[4-[(3,5-difluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-[2-(3,5-difluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[C:14]([OH:16])=O)[CH3:9].[NH2:28][C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][CH:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[C:14]([NH:28][C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:16])[CH3:7]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
Oxalyl chloride (2.1 mL, 24.0 mmol) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (5.72 g, 20.0 mmol) in DCM (100 mL) and the mixture stirred at ambient RT for 4 hours. The mixture was evaporated in vacuo to a residue, which was taken up in DCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine (2.29 g, 21.0 mmol) and pyridine (1.94 mL, 24.0 mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo to a residue, which was partitioned between water (50 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 30% ethyl acetate in isohexane, and crystallised from ethyl acetate/isohexane to give the desired compound (5.52 g).
Reaction SMILES: [CH2:1]([N:5]([C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[CH2:1]([N:5]([C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=3)[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl ({[butyl-4-(4-oxo-1-piperidinyl)anilino]carbonyl}amino)acetate (which was obtained in Example 367) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.1 Hz, 3 H), 1.17 (t, J=7.1 Hz, 3 H), 1.15–1.40 (m, 6 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.90 (s, 3 H), 3.49 (t, J=6.9 Hz, 2 H), 3.55–3.60 (m, 2 H), 3.65 (d, J=5.9 Hz, 2 H), 4.04 (q, J=7.1 Hz, 2 H), 4.48 (dd, J=7.9, 4.4 Hz, 1 H), 5.60 (t, J=5.9 Hz, 1 H), 6.80 (d, J=8.2 Hz, 1 H), 6.90–7.10 (m, 5 H), 7.17 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 606.3 (MH+); HRMS Calcd. for C29H44N5O7S (MH+): 606.2956. Found: 606.2955.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:15][CH3:16])[C:6]=1[F:17].C(OCC)(=O)C.N>CN(C)C=O>[CH2:15]([O:14][C:7]1[C:6]([F:17])=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH3:13])[C:2]#[N:3])[CH3:16]
Reactant: N#C[Cu]
Reactant: CCOc1ccc(Br)c(F)c1OCC
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#N)c(F)c1OCC
Temperature: 155 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Copper(I)cyanide (6.8 g, 68.3 mmol) was added to a solution of 1-bromo-3,4-diethoxy-2-fluorobenzene (12.0 g, 45.6 mmol) in N,N-dimethylformamide (DMF) (60 mL) at room temperature, and this was then stirred at 155° C. for 3 hours. The reaction solution was cooled on ice. Following addition of ethyl acetate and 28% aqueous ammonia, the organic layer was separated and washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed after filtration, and the residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 9.0 g of the subject compound (yield: 94.3%).
Reaction SMILES: [CH2:1]([S:8]([NH:11][CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]=2[O:16][CH:15]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:1]([S:8]([N:11]([CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]=2[O:16][CH:15]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c(CCNS(=O)(=O)Cc3ccccc3)coc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c(CCN(Cc3ccccc3)S(=O)(=O)Cc3ccccc3)coc12
Temperature: 25 °C
Reaction time: 27 h
Yield: 57 %

Procedure:
Methyl (3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetate (143 mg) was dissolved in DMF (3 ml), and potassium carbonate (49 mg) and benzyl bromide (0.13 ml) were added to the obtained solution, followed by stirring the resulting mixture at room temperature for 27 hours and then at 50° C. for 14.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with 1N hydrochloric acid and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1-1/1) using silica gel to obtain the desired compound (100 mg, yield: 57%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]1=O.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]2[C:18]([C:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]=3[NH:17]2)=[CH:19][CH:20]=1
Reactant: O=C(O)C1CCCC(Br)C1=O
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(O)C1CCCc2c1[nH]c1cc(C(F)(F)F)ccc21

Procedure:
Under the conditions as described in Example 1(a), 10 g. of the ethyl ester of 3-bromo-2-oxocyclohexanecarboxylic acid is reacted with 3-trifluoromethylaniline to obtain the ethyl ester of 7-trifluoromethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([N:17]=[C:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[CH2:10]([N:17]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][C:19]2[CH2:20][CH2:21][CH2:22][C:18]1=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CN=C2CCCC2)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(n1Cc1ccccc1)CCC2
Reaction time: 2 h

Procedure:
Add dropwise 3.9 gm of ethyl bromopyruvate in 50 ml of ethanol to a flask containing 3.46 gm of benzyliminocyclopentane and 2.0 g of triethylamine in 50 ml of ethanol at 0° C., stir for 2 hours, then heat to reflux for 2 hours. Concentrate the reaction mixture and partition between 1N HCl and ether. Dry the ether extract over magnesium sulfate, filter, ooncentrate under high vacuum to obtain a brown oil and distill in a kugelrohr at 190°-210°/0.1 mm to obtain the title compound of Part A as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:13][C:12]([C:14](=[O:31])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:19][CH:18]=3)=[N:11][CH:10]=2)[N:4]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CC(O)C.O.[Br-].[Zn+2].[Br-]>[NH:32]1[C:1]([C:3]2[N:4]=[C:5]([C:9]3[O:13][C:12]([C:14](=[O:31])[CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:19][CH:18]=4)=[N:11][CH:10]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2][N:34]=[N:33]1
Reactant: N#Cc1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Product: O=C(CCc1ccc(COc2ccccc2)cc1)c1ncc(-c2cccc(-c3nnn[nH]3)n2)o1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2-Cyano-6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine (98 mg, 0.24 mmol), sodium azide (31 mg, 0.48 mmol), and zinc bromide (27 mg, 0.12 mmol) were dissolved in i-PrOH/H2O (1:2, 2.1 mL) and warmed at reflux for 24 h. The reaction solution was allowed to cool to ambient temperature and was quenched with aqueous 1 N HCl. The solution was diluted with EtOAc and the organic phase was washed with saturated aqueous NaCl, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by tritration in 3% CH2Cl2/ether to provide 1-(5-(6-(1H-tetrazol-5-yl)pyridin-2-yl)oxazol-2-yl)-3-(4-(phenoxymethyl)phenyl)propan-1-one as a pale yellow solid (60 mg, 55%): NMR (DMSO-d6, 600 MHz) δ 8.25-8.24 (m, 3H), 8.08-8.05 (m, 1H), 7.38 (d, 2H, J=8.0 Hz), 7.31-7.27 (m, 4H), 6.99 (d, 2H, J=8.7 Hz), 6.92 (t, 1H, J=7.3 Hz), 3.47 (t, 2H, J=7.5 Hz), 3.02 (t, 2H, J=7.5 Hz); 13C NMR (DMSO-d6, 150 MHz) δ 207.8, 188.3, 159.7, 158.7, 153.0, 147.3, 141.6, 141.2, 136.2, 130.8, 129.7, 129.6, 129.2, 124.1, 123.3, 122.0, 116.1, 70.2, 32.0, 30.0; HR ESI-TOF m/z 453.1681 (M+H+, C25H20N6O3, requires 453.1670).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].Cl[C:44]1C=CC(Cl)=C[C:45]=1[S:51](Cl)(=O)=O>>[S:51]1[C:45]2[CH:44]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]4[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=3)[NH:25][CH:24]=[C:23]4[CH:32]3[CH2:33][CH2:34][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:36][CH2:37]3)[CH:17]=[CH:18][CH:19]=2)(=[O:10])=[O:11])=[CH:2]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5csc6ccccc56)c4)cc23)CC1
Yield: 6 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting 1-benzothiophene-3-sulfonyl chloride (82 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 3.9 mg the title compound (6%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH:39][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[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: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 66.8 %

Procedure:
4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (155 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (150 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (100 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[C:22]([NH:21][CH2:20][C:19]([N:16]1[CH2:17][CH2:18][CH:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:13][CH2:12]2)[CH2:15]1)=[O:32])=[O:31]
Reactant: Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.9 %

Procedure:
To N-(2-(3-(4-(2-aminophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (Example #4.149, 0.063 g, 0.13 mmol) in DCM (1 mL) was added triethylamine (0.037 mL, 0.26 mmol) and methanesulfonyl chloride (0.011 mL, 0.14 mmol). The reaction mixture was stirred at room temperature for about 16 h. The solvent was removed in vacuo and the residue was purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 5% to 60% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford 3,4-dichloro-N-(2-(3-(4-(2-(methylsulfonamido)phenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)benzamide (0.0052 g, 0.009 mmol). RP-HPLC (Table 1, Method a) Rt 2.07 min; m/z: (M+H)+ 553.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](N)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].C(#N)C.N([O-])=[O:26].[Na+]>OS(O)(=O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([OH:26])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(O)nc(-c2ccc(Cl)c(OC)c2F)n1
Yield: 60 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (300 mg, 0.97 mmol, see U.S. Pat. No. 7,300,907 B2 for preparation) was slurried in 10 mL 1M H2SO4 plus 3 mL acetonitrile, heated to 75° C. and treated in portions with sodium nitrite (350 mg, 5 mmol) over a period of 10 minutes. After 40 minutes the mixture was cooled and the yellow precipitate was taken up in 40 mL ethyl acetate, washed with 10 mL water, washed with 10 mL brine, dried, and evaporated to give 170 mg (60% yield) 6-hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester; MS m/z 312, 1H NMR (DMSO-d6): δ 7.49 (m, 3H), 3.95 (s, 3H), 3.86 (s, 3H)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br.C1(C)C=CC=CC=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.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.C(O)C>[F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)COc1ccccc1Br
Reactant: Nc1cccc(B(O)O)c1
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: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)COc1ccccc1Nc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of 1.0 g (3.93 mmol) of 2-trifluoroethoxyphenyl bromide (Example 3, Step A) in 39 Ml of toluene was added 0.136 g (0.118 mmol) of tetrakis(triphenylphosphine)palladium(0), 0.56 g (4.31 mol) of 3-aminophenylboronic acid, 47 Ml (94.1 mmol) of a 2M solution of sodium carbonate and 8 Ml of ethanol and the reaction mixture was heated at 90° C. for 22 hr. The reaction mixture was cooled to RT, and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc and the combined organic fractions were washed with water and brine and dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4:1 hexanes:EtOAc) to give the title compound. Mass Spectrum (ESI) m/e M+1 268.1.