Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:6])([CH3:5])[C:3]#[CH:4].N12CCN(CC1)CC2.Br[C:16]1[S:20][C:19]([C:21]2[N:22]=[C:23]3[N:27]([C:28]=2[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[CH:25][S:24]3)=[CH:18][CH:17]=1.C(Cl)Cl>C(#N)C>[C:30]([NH:29][C:28]1[N:27]2[C:23]([S:24][CH:25]=[CH:26]2)=[N:22][C:21]=1[C:19]1[S:20][C:16]([C:4]#[C:3][Si:2]([CH3:6])([CH3:5])[CH3:1])=[CH:17][CH:18]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2sccn12
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)Nc1c(-c2ccc(C#C[Si](C)(C)C)s2)nc2sccn12
Yield: 22.5 %

Procedure:
4.1 g (3.5 mmol) tetrakis(triphenyl)phosphine-palladium(0), 17.2 g (175.4 mmol) trimethyl-silylacetylene and 7.9 g (70.2 mmol) 1,4-diazabicyclo[2.2.2]octane were consecutively added to a suspension of 12.5 g (35.1 mmol) 6-(5-bromothiophene-2-yl)-N-tert-butylimidazo[2,1-b]thiazole-5-amine in acetonitrile (150 ml). The reaction solution was heated for 72 h under reflux and subsequently concentrated in a vacuum. 3.0 g (7.9 mmol, 23%) N-tert-butyl-6-(5-((trimethylsilyl)ethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine ([MH+] 374.1) was obtained by CC (DCM/AE 95:5).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br>C(O)C>[CH2:9]([NH:5][NH:4][C:1](=[O:3])[CH3:2])[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:7]=1
Reactant: BrCc1ccccc1Br
Reactant: CC(=O)NN
Solvent: CCO
Product: CC(=O)NNCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 129.4 %

Procedure:
Acetic hydrazide (1.78 g, 24 mmol) was dissolved in ethanol (20 mL) and cooled to 0° C. A solution of 2-bromobenzyl bromide (2 g, 8 mmol) in ethanol (10 mL) was added slowly and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography with ethyl acetate-hexane as eluent to give acetic acid N′-benzyl-hydrazide (1.7 g, 87%) as a white solid.
Reaction SMILES: O1CCCC1.C[Si]([C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:31]2[CH:36]=[CH:35][C:34]([C:37]#[C:38][Si](C)(C)C)=[CH:33][CH:32]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)(C)C.[F-].[K+]>CO>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]#[CH:10])=[CH:17][CH:16]=2)[C:31]2[CH:36]=[CH:35][C:34]([C:37]#[CH:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1ccc(N(c2ccc(C#C[Si](C)(C)C)cc2)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(N(c2ccc(C#C)cc2)c2ccc(C#C)cc2)cc1
Temperature: 50 °C
Yield: 74.9 %

Procedure:
To a mixture of 180 ml of tetrahydrofuran (THF) and 240 ml of methanol were added 13.84 g (0.026 mol) of tri(4-trimethylsilylethynylphenyl)amine and 4.53 g (0.078 mol) of potassium fluoride. The reaction mixture was heated at 50° C. for 5 h, cooled down to room temperature, and solvent was removed under the reduced pressure. The residue was extracted with ether and the ether layer was washed with distilled water. The washed ether layer was concentrated to give crude product. The crude product was purified by column chromatography on silica gel by eluting with hexane to give 6.182 g (75%) of tri(4-ethynylphenyl)amine of which NMR spectrum was shown in FIG. 9 and mp was 115° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:23][C:24]3[CH:25]=[C:26]([NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[C:27]([Cl:30])=[N:28][CH:29]=3)=[N:3][CH:4]=[C:5]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:6]=2)[N:9]=1
Reactant: CN(C)S(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
To a stirred solution of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 384, Step 2, 0.0614 g, 0.202 mmol) and N′-(5-amino-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (KY, 0.050 g, 0.199 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 0.80 mL, 0.80 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aqueous phase was acidified to a pH of about 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g, eluent: iPrOH in CHCl3 0%-25%) to afford N′-(5-((3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(4-morpholinylmethyl)-2-pyridinyl)amino)-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (0.0437 g, 44% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.28 (s, 1H) 9.57 (s, 1H) 8.82 (s, 1H) 8.76 (d, J=2.35 Hz, 1H) 8.53 (d, J=2.35 Hz, 1H) 8.29 (d, J=2.35 Hz, 1H) 7.74-7.98 (m, 2H) 3.57 (t, J=4.21 Hz, 4H) 3.48 (s, 2H) 2.79 (s, 6H) 2.46 (s, 3H) 2.35-2.43 (m, 4H). m/z (ESI, positive ion): 535.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH3:9])=[N:6][CH:7]=1.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])=[CH:7][N:6]=2)[CH3:9])=[O:22])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: NCC(F)(F)F
Reactant: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(NCC(F)(F)F)cn2)cc1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a 10.0 ml microwave reaction tube was added N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide (0.100 g, 0.277 mmol), trifluoroethylamine (0.025 ml, 0.332 mmol), NaOtBu (0.042 g, 0.441 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.018 g, 0.029 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.015 mmol) and 2.5 ml of anhydrous toluene. N2 was bubbled through the mixture while stirring for 5 minutes. Then it was heated at 120° C. for 15 minutes in a microwave reaction chamber. Cooled to room temperature, filtered and concentrated. The residue was purified using reverse phase HPLC to afford 2-(4-isopropylphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.291 (d, J=6.84 Hz, 1H); 8.174 (s, 1H); 7.516 (d, J=8.79 Hz, 1H); 7.357 (d, J=8.79 Hz, 1H); 7.167 (d, J=8.30 Hz, 2H); 7.141 (d, J=8.30 Hz, 2H); 5.823 (br s, 1H); 5.106 (dq, J=7.32 Hz, 1H); 3.692 (br d, J=7.57 Hz, 2H); 3.543 (d, J=14.90 Hz, 1H); 3.501 (d, J=15.14 Hz, 1H); 2.852 (sept, J=6.83 Hz, 1H); 1.563 (d, J=7.08 Hz, 3H); 1.199 (d, J=7.08 Hz, 6H); MS (Electrospray): m/z 380.1 (M+H).
Reaction SMILES: [SH2:1].[CH3:2][C:3]1([C:20]#[N:21])[CH2:7][CH2:6][C:5]([CH2:18][CH3:19])([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:4]1>N(CCO)(CCO)CCO.C(O)C>[CH2:18]([C:5]1([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:4][C:3]([CH3:2])([C:20](=[S:1])[NH2:21])[CH2:7][CH2:6]1)[CH3:19]
Reactant: CCC1(COCc2ccccc2Cl)CCC(C)(C#N)O1
Reactant: S
Solvent: OCCN(CCO)CCO
Solvent: CCO
Product: CCC1(COCc2ccccc2Cl)CCC(C)(C(N)=S)O1
Reaction time: 6 h

Procedure:
Excess hydrogen sulfide was condensed into a stainless steel bomb containing 2.94 g of the chromatographically purified trans-nitrile, tetrahydro-2-methyl-5-ethyl-5-[(2-chlorophenylmethoxy)methyl]-2-furancarbonitrile, (ca>9:1 trans-cis by proton NMR), 10 ml ethanol, and 0.15 g triethanolamine catalyst. The sealed bomb was kept at 55±3° C. for 6 hours during which time the internal pressure rose to 350 psi. After cooling, the reaction mixture was concentrated on a rotary evaporator. The residue was purified by dry column chromatography on silica gel using 96.4 hexane:tetrahydrofuran as eluent. The white cyrstalline desired product weighed 1.10 g, mp 78°-80° C.
Reaction SMILES: C1COCC1.C([O:9][C:10](=[O:24])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][CH2:19][C:20]#[CH:21])=[C:13]([F:22])[C:12]=1[F:23])C#C.O.[OH-].[Li+].Cl>O>[CH2:19]([O:18][C:14]1[C:15]([F:17])=[CH:16][C:11]([C:10]([OH:24])=[O:9])=[C:12]([F:23])[C:13]=1[F:22])[C:20]#[CH:21]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)c(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a mixed solution of 10 ml of THF and 10 ml of water, 6.5 g of the obtained 4-(2-propynyloxy)-2,3,5-trifluorobenzoic acid 2-propynyl ester and 2.0 g of lithium hydroxide monohydrate were added, followed by stirring at room temperature for 2 hours and further stirring at 50° C. for 2 hours. The reaction mixture obtained by concentration under reduced pressure until the entire volume was reduced to about half was acidified by adding hydrochloric acid and the obtained solid was collected by filtration. The solid was dried and washed with hexane, and 4.0 g of 4-(2-propynyloxy)-2,3,5-trifluorobenzoic acid was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]([O-:48])(=[O:47])[CH3:46].[Na+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][O:48][C:45](=[O:47])[CH3:46])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCOC(C)=O)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 17 h
Yield: 32.4 %

Procedure:
To the product of Example 145 (21 mg, 32 μmol) in acetone (2 mL) was added tetra-n-butylammonium iodide (24 mg, 65 μmol). The solution was stirred at 40° C. for 17 h prior to the addition of sodium acetate (50 mg, 0.64 mmol). The reaction solution was heated at 75° C. for 48 h. After cooling the solution was diluted with EtOAc (25 mL), washed with satd NaHCO3 (20 mL) and water (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude sample was chromatographed (silica gel, DCM) to provide the title compound (7 mg, 33%). 1H-NMR (CDCl3) δ 7.87 (1H, s), 7.60 (1H, dd), 7.30-7.35 (3H, m), 7.17-7.22 (3H, m), 6.60 (1H, dd), 6.48 (1H, d), 5.27 (2H, s), 4.72 (1H, s), 4.39 (2H, t), 4.16 (2H, t), 3.69 (2H, q), 3.16 (2H, s), 3.08 (3H, s), 2.43 (6H, s), 2.06 (3H, s), 0.91 (3H, t); MS(ESI): 675 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[NH:20]1[CH:24]=[C:23]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH:22]=[N:21]1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:23]1[CH:22]=[N:21][NH:20][CH:24]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1ccccc1-c1cn[nH]c1
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1c(-c2ccccc2-c2cn[nH]c2)nc2cc(-c3cnc(N)nc3)ccc21
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (150 mg, 0.58 mmol) in DMF (5 mL) is added 2-(1H-pyrazol-4-yl)-benzaldehyde (100 mg, 0.58 mmol) at room temperature. Oxone (360 mg, 0.58 mmol) in H2O (1 mL) is added and the reaction is stirred at the same temperature for 3 hours. The reaction is poured into water (75 mL) and sodium thiosulfate (sat., 15 mL). The product is extracted into EtOAc (3×) and the combined organics are then dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (12 g silica gel, 0-10% MeOH/CH2Cl2) gives the title compound (25 mg, 10%). LCMS (ESMS): m/z 410.20 (M++1)
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:30])[CH2:21][CH2:20]3)[N:9]=2)[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.Cl.[OH-].[Na+]>>[F:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[C:10]([N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[S:22](=[O:30])[CH2:21][CH2:20]2)[N:9]=1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@H]3F)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(N[C@@H]3CNC[C@H]3F)c2c1

Procedure:
A mixture of benzyl trans-3-fluoro-4-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}pyrrolidine-1-carboxylate (200 mg, 0.35 mmol) and an aqueous solution of hydrochloric acid (5 mL, 6 N) was refluxed for 6 hours. The resulting mixture was basified by adding an aqueous solution of sodium hydroxide (1 N) to pH 10, and then extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired compound as a yellow solid. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.76 (m, 3 H), 7.45 (m, 4 H), 5.32 (m, 3 H), 4.61 (s, 3 H), 3.70-3.11 (m, 6 H), 2.41 (s, 3 H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:38][C:39]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C)C=O.O>[F:38][C:39]1[C:44]([NH:45][C:11](=[O:12])[C:10]2[CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][C:9]=2[O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: Nc1cccnc1F
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1F)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 0.12 g, 0.34 mmol), EDC (0.16 g, 0.84 mmol) and HOBT (0.13 g, 0.84 mmol) in dimethylformamide (2 ml) was stirred in air at room temperature for 1 h. 2-Fluoropyridin-3-amine (0.04 g, 0.37 mmol) was then added in one charge. The reaction mixture was stirred at 25° C. overnight. Another batch of HOBT (0.13 g, 0.84 mmol), EDC (0.161 g, 0.842 mmol) and 2-fluoropyridin-3-amine (0.04 g, 0.37 mmol) was added into the mixture and heating was continued at 40° C. for 38 hours. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (60 ml×3). The organic phases were combined, washed with brine (50 ml×3), dried over anhydrous MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 40 g, eluent: dichloromethane/methanol=50:1, 1 L). The solid was washed by methanol (3 ml×2) and dried in vacuo to yield the title compound as a grey solid. 31 mg.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C>[Br:18][C:8]1[C:9]([OH:12])=[N:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(O)nc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1cnc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution crude of 5-ethanesulfonyl-pyridin-2-ol prepared above, and sodium acetate (3.74 g, 45.6 mmol) in acetic acid (50 mL) was added a solution of bromine (7.3 g, 46.0 mmol) in acetic acid (10 mL) dropwise over a period of 1 hour. After being stirred at room temperature overnight, additional bromine (7.3 g, 46.0 mmol) in acetic acid (10 mL) was added dropwise to the reaction mixture over a period of 1 hour. After being stirred overnight, the reaction mixture was warmed to 30° C. and stirred for 2 hours. The mixture was concentrated in vacuo to remove the solvent. The residue was triturated with water (100 mL). The solid was collected by filtration, washed with a dilute solution of sodium thiosulfate and dried in vacuo to afford 3-bromo-5-ethanesulfonyl-pyridin-2-ol (9.1 g, 75%, two steps) as a white solid (reference: Bargar, T. M. et al., J. Heterocyclic Chem. 22 (1985) 1583-1592).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.CCOC(C)=O>[C:20]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1CCc2c(O)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Reaction time: 0.08 h
Yield: 114.8 %

Procedure:
To a solution of 4-hydroxy-indan-1-one (1.0 g, 6.75 mmol) in CH2Cl2 (20 mL) was added imidazole (690 mg, 10.12 mmol). The mixture was stirred for 5 minutes, to which was added portionwise tert-butyldimethylsilyl chloride (1.05 g, 5.31 mmol). The mixture was stirred for 3 hours at room temperature and was diluted with EtOAc. The organic layer was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-(tert-butyl-dimethyl-silanyloxy)-indan-1-one (1600 mg, 90%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[C:15]1([NH:14][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1c[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol), aniline (0.46 mL, 5^ mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (959 mg, 5 mmol) in 50% aqueous dioxane (10 mL) was allowed to stir at ambient temperature for 17.5 hours, then concentrated in vacuo. The residue was cooled in an ice water bath, aqueous 3.6 N hydrochloric acid was added, and the precipitate collected, rinsed with aqueous 3.6 N hydrochloric acid then water and dried. Recrystallization from ethyl alcohol afforded N-phenyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 35) (164 mg). mp 225-226° C.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[C:8]([Cl:19])[CH:7]=1.Br[C:23]1[CH:24]=[CH:25][C:26]2[S:32](=[O:34])(=[O:33])[CH2:31][CH2:30][C:29]([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH3:52])[CH:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:40][CH:39]=3)=[O:36])=[CH:28][C:27]=2[CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].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.O>[Cl:19][C:8]1[CH:7]=[C:6]([C:23]2[CH:24]=[CH:25][C:26]3[S:32](=[O:34])(=[O:33])[CH2:31][CH2:30][C:29]([C:35]([NH:37][C:38]4[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH3:52])[CH:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[CH:40][CH:39]=4)=[O:36])=[CH:28][C:27]=3[CH:53]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCCOc1ccc(OB([O-])[O-])cc1Cl
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: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 3-chloro-4-(3-ethoxypropoxy)phenyl borate (194 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg). Under argon atmosphere, the suspension was stirred for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (47 mg). Under argon atmosphere, the mixture was heated at 100° C. for 8 hours and cooled. To the mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate:ethano=18:1) and recrystallized from ethanol (23 ml) to give colorless crystals of 7-[3-chloro-4-(3-ethoxypropoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 131) (229 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][C@H:16]4[C@:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[C@H:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC3C[C@H]4[C@]5(CN(CC(F)(F)F)S(=O)(=O)N5)[C@H](CC4)CC=3C=2)O1.[C:64]([O:68][C:69]([N:71]1[CH2:76][CH:75]=[C:74](B2OC(C)(C)C(C)(C)O2)[CH2:73][CH2:72]1)=[O:70])([CH3:67])([CH3:66])[CH3:65]>CS(C)=O>[C:64]([O:68][C:69]([N:71]1[CH2:72][CH:73]=[C:74]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][C@H:16]5[C@:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[C@H:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)[CH2:75][CH2:76]1)=[O:70])([CH3:67])([CH3:65])[CH3:66]
Reactant: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3ncc(Br)s3)cc2C1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(-c3ccc4c(c3)C[C@H]3CC[C@@H](C4)[C@]34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1

Procedure:
Prepared using [6S,9R,11R]2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-bromothiazol-2-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole]1′,1′-dioxide (prepared using the homochiral boronate from Example 24 Step 1 by the method described for Example 36 Steps 1–2) and the boronate from Example 39 Step 2 using the method described for Example 36 Step 3. MS (ES+) 625 ([MH]+); [α]D=−11 (c=0.62, DMSO, 23° C.).