Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[CH:17]=[CH2:18].[OH2:19]>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[CH2:17][CH2:18][OH:19]
Reactant: C=Cc1cc(OC)c2ccccc2c1OC
Reactant: O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(CCO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.61 g of titanium tetrachloride were added to a mixture of 0.65 g of sodium borohydride and 20 ml of dry ethylene glycol dimethyl ether, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 1.83 g of 1,4-dimethoxy-2-vinylnaphthalene [prepared as described in step (b) above] in 40 ml of dry ethylene glycol dimethyl ether was then added dropwise to the resulting mixture, and the mixture was stirred for 21 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.40 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH:6]=[CH:7]1)[CH2:4][CH:3]([C:9](O)=O)[CH2:2]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:37][C:38]1[C:39](=[O:52])[N:40]([CH2:49][CH2:50][CH3:51])[C:41](=[O:48])[N:42]([CH2:45][CH2:46][CH3:47])[C:43]=1[NH2:44].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:5]12[O:8][CH:1]([CH:7]=[CH:6]1)[CH2:2][CH:3]([C:9]1[NH:37][C:38]3[C:39](=[O:52])[N:40]([CH2:49][CH2:50][CH3:51])[C:41](=[O:48])[N:42]([CH2:45][CH2:46][CH3:47])[C:43]=3[N:44]=1)[CH2:4]2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C1CC2C=CC(C1)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(=O)c2[nH]c(C3CC4C=CC(C3)O4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 8-oxa-bicyclo[3.2.1]oct-6-ene-3-carboxylic acid (0.25 mmol, 0.0386 g), HATU (0.25 mmol, 0.0952 g), and 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (Daly, J. W. et al., J. Med. Chem., 1985, 28 (4), 487) (0.25 mmol, 0.0658 g) in DMF (2.5 ml) was added iPr2NEt (0.75 mmol, 0.13 ml). The reaction was stirred overnight at room temperature. It was concentrated at the pump to remove DMF. The residue was dissolved in EtOAc and washed with 1N HCl, 5% NaHCO3, and brine and dried (MgSO4). Filtration and evaporation followed by flash column chromatography, eluting with a THF/CH2Cl2 gradient provided the desired product (0.067 g, 74%) as an oil that solidified on standing. 1H NMR (300 MHz, CDCl3): 0.90 (t, 3H, J=7.4 Hz), 0.97 (t, 3H, J=7.3 Hz), 1.53-1.72 (m, 6H), 1.95-2.03 (m, 2H), 3.0 (br m, 1H), 3.82-3.91 (m, 4H), 4.79 (br s, 2H), 6.18 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([C:29](=[O:42])[CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:14][CH:15]([C:16](=[O:28])[NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][C:29]([N:13]1[CH2:14][CH:15]([C:16](=[O:28])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:9]2[NH:8][CH2:12][CH2:11][CH:10]12)=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CC(C(=O)Nc2cccc3ccccc23)C2NCCC21)OCc1ccccc1
Reaction time: 1 h
Yield: 110.4 %

Procedure:
A solution of 55 (400 mg, 0.69 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 1 h, the solution was concentrated, diluted with EtOAc, and washed with saturated NaHCO3. The aqueous phase was back extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 56 (360 mg) which was used without further purification. Mass spectrum, m/z [473.2] (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][C:17]([OH:19])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:22]>CO.O>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c1-c1ccccc1C2CCC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cccc2c1-c1ccccc1C2CCC(=O)Cl
Reaction time: 2 h

Procedure:
3-(4-Methylfluoren-9-yl)propionic acid (3.5 g, 13 9 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. The reaction was monitored by TLC (silica RP-18, 70% methanol/water). The excess of thionyl chloride was removed under reduced pressure, the residue (an oil) was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[Br:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:19][CH2:20][CH2:21][O:22][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[C:16]([Cl:18])=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: Clc1cc(Cl)c2c(c1)CC(Cl)c1ccccc1S2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Clc1cc(Cl)c2c(c1)CC(OCCBr)c1ccccc1S2
Temperature: 40 °C
Reaction time: 11 h
Yield: 74.8 %

Procedure:
A mixture of 2,4,10-trichloro-10,11-dihydrodibenzo[b,f]thiepine (2.5 g, 8.6 mmol, prepared as described in Coll. Czech. Chem. Commun. 46, 781, 1981), 2-bromoethanol (12.5 g, 100 mmol) and potassium carbonate (4.0 g, 30 mmol) in dichloromethane (20 ml) was stirred at 40° C. for 11 h. The solid was filtered off and the filtrate was evaporated in vacuo. The residue (3.4 g) was dissolved in a mixture of diethyl ether and light petroleum (1:1) (40 ml) and left to stand in a refrigerator for a week, affording after isolation 2.6 g (80%) of 10-(2-bromoethoxy)-2,4-dichloro-10,11-dihydrodibenzo[b,f]thiepine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)=[O:26])[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:8]2)[N:6]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].N1C=CC=CC=1>C(Cl)Cl>[C:43]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)=[O:26])[CH2:11][CH2:10][CH:9]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:16][CH2:17]3)[CH2:8]2)[N:6]=1)(=[O:45])[CH3:44]
Reactant: Nc1nc(C2(C(=O)NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC(N3CCC(c4ccc(F)cc4)CC3)C2)cs1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C2(C(=O)NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC(N3CCC(c4ccc(F)cc4)CC3)C2)cs1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 0.040 g of the compound from EXAMPLE 44, 0.20 g of acetic anhydride and 0.40 g of pyridine in 1.0 mL of CH2Cl2 was stirred overnight, evaporated and dried in vacuo. The residue was purified by preparative TLC (10% [aq. NH4OH/MeOH 1/9]/CH2Cl2). The title compound (0.037 g) was obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.60-2.24 (m, 9H), 2.27(s, 3H), 2.50 (m, 4H), 2.85 (m, 1H), 3.20 (m, 2H), 4.55 (m, 2H), 6.83 (s, 1H), 6.97-7.20 (m,5H), 7.64 (s,2H), 7.76 (s, 1H), 9.06 (broad, 1H). LC-MS: m/z 657 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][S:21][C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)=[O:16].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][S:21][C:22]=1[O:23][CH:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2sncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnsc1OC1CCNCC1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of tert-butyl 4-(4-(5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)isothiazol-5-yloxy)piperidine-1-carboxylate (1A) (10 mg, 0.02 mmol) in CH2Cl2 (1 mL) at room temperature (25° C.) was added TFA (trifluoroacetic acid) (0.5 mL), stirred for 10 min and then concentrated in vacuo at room temperature (25° C.) to afford the product 5-amino-2-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)thiazole-4-carboxamide (1) (5 mg, 0.011 mmol)
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl.Cl.CCOC(C)=O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([CH:14]=[O:15])[CH:8]=1
Reactant: COC(Cl)Cl
Reactant: COC(=O)Oc1ccc(OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Oc1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of 4-methoxyphenyl methyl carbonate (5, 16.5 g. 91 mmol) in CH2Cl2 (205 mL) at 0° C. was added dropwise TiCl4(23.5 mL, 210 mmol) in CH2Cl2 (20 mL) over 30 min. Then MeOCHCl2 (9.3 mL, 104 mmol) in CH2Cl2 (20 mL) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction material was poured into a mixture of ice (210 g) and concentrated HCl (8.5 mL). EtOAc (200 mL) was added and the mixture was stirred vigorously for 30 min. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from EtOAc/hexanes to afford the title compound (16.6 g, 87%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 7.63 (d, J=3.1 Hz, 1H), 7.37 (dd, J=9.0, 3.1 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H); ESI MS m/z 228 [M+H2O]+.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=[S:15])[C:5]=12.[OH-].[Na+].[CH3:18]I>C(O)C>[CH3:18][S:15][C:6]1[C:5]2=[N:1][N:2]=[N:3][N:4]2[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1
Reactant: S=C1Nc2ccccc2Cn2nnnc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSC1=Nc2ccccc2Cn2nnnc21
Yield: 89 %

Procedure:
To 30 mmol. of the product of Example 6 in 300 ml. of ethanol is added 33 ml. of 1 N sodium hydroxide followed by the slow addition of 54 mmol. of methyl iodide. After two hours the reaction mixture is evaporated to one fourth its volume, 100 ml. of water is added and the product is obtained by extraction into methylene chloride. The methylene chloride is removed by evaporation and the product is recrystallized from ethyl acetatehexane to afford an 89% yield (m.p. 105°-108° C.) of the title compound.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)=O)CCCC1.S(Cl)(Cl)=O.[S:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH:1]1([C:6]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: c1ccsc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)C1CCCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1cccs1)C1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Cyclopentanecarboxylic acid chloride, prepared from 100 mmol cyclopentanecarboxylic acid and 120 mmol of thionyl chloride, was dissolved in 100 mL of methylene chloride, and the solution was cooled in an ice bath. Thiophene (13.4 mL, 100 mmol) and SnCl4 (25 mL of a 1M solution in methylene chloride) were added. The reaction was warmed to room temperature and stirred for 72 hours. The reaction was quenched with 1 N HCl, and the mixture was extracted with three portions of methylene chloride. The organic extract was washed with satd aqueous NaHCO3, was dried over MgSO4, and filtered through a pad of silica gel. The solvent was removed by rotary evaporation to give 12.28 g of crude product, which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:29])([F:30])[F:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Example CK was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 1-(4-Trifluoromethyl-phenyl)-piperazine (commercial). MS (m/e): 539.1 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>CCO.C1COCC1>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: O=C(CCl)CCl
Solvent: C1CCOC1
Solvent: CCO
Product: ClCc1csc(-c2ccc(Cl)cc2)n1
Temperature: 85 °C
Yield: 77.7 %

Procedure:
A mixture of 4-chlorothiobenzamide (0.5 g, 2.9 mmol) and 1,3-dichloroacetone (0.4 g, 3.18 mmol) in EtOH-THF (20 mL-10 mL) was heated to 85° C. for 10 h. The reaction mixture was cooled to room temperature and quenched with 10% NaHCO3 solution. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 3-5% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(4-chlorophenyl)thiazole (0.55 g, yield 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.91-7.88 (m, 2H), 7.44-7.41 (m, 2H), 7.33 (s, 1H), 4.75 (s, 2H). MS (ESI) m/z: Calculated for C10H7Cl2NS: 242.97. found: 244.0 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH:32]=O)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CCO>[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH:32]=[N:2][NH:1][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COCCOc1ccnc(NN)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Solvent: CCO
Product: COCCOc1ccnc(NN=Cc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
2-Hydrazinyl-4-(2-methoxyethoxy) pyridine (0.076 g, 0.415 mmol) and 8-(tert-butyldimethylsilyloxy) quinoline-2-carbaldehyde (0.119 g, 0.415 mmol) were heated to reflux in EtOH (2 mL) for 16 hours. After cooling to ambient temperature the reaction mixture was filtered and washed with EtOH to provide 105 mg (56%) of desired product as an orange solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:24]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)#[N:25]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2C#N)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of methyl 4-(1-bromo-6-methoxynaphthalen-2-yl)benzoate (300 mg, 0.811 mmol) (see Example 12 step 1) in DMF (10 mL) was added Zn(CN)2 (191 mg, 1.62 mmol) and Pd(PPh3)4 (93.8 mg, 0.0811 mmol). The resulting mixture was stirred at 120° C. under N2 atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (60 mL), washed with H2O (20 mL×3) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by silica gel column (PE/EtOAc=200/1 to 50/1) gave the product (210 mg, yield 82%) as a solid.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:13](=O)[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>CN(C)C=O.CCOCC>[CH3:14][C:13]1[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=Cc1ccccc1)C(C)=O
Reactant: Nc1ccccc1S
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-[(phenyl)methylene]-3-oxobutanoic acid, methyl ester (13.0 g., 63.7 mmole) in dry dimethylformamide (20 ml.) is treated dropwise with 2-aminothiophenol (8.85 g. of 90%, 63.7 mmole). A slight release of heat is noted. The reaction is stirred at room temperature for 6 hours and then heated at 65° for 72 hours. It is cooled to room temperature and diluted with ether. The resulting solution is thoroughly washed with water, sodium bicarbonate and brine. After drying over anydrous magnesium sulfate, the solvent is stripped off to give a yellow solid. It is triturated with isopropyl ether and filtered off to provide 6.93 g. of light yellow crystals. Recrystallization from isopropyl ether-dichloromethane gives an analytically pure sample of 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid, methyl ester; m.p. 154°-156°. TLC(silica gel, hexane:acetone, 70:30) Rf =0.35.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].Cl.[F:26][C:27]1([F:35])[CH2:31][NH:30][C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1.CO>C(Cl)Cl>[F:26][C:27]1([F:35])[CH2:31][N:30]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CC(F)(F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 17 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4,4-difluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.) were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 383 as a white solid (29 mg, 17%). LCMS: RT=3.14 min, [M+H]+=459. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1 H, s), 7.85 (1 H, d, J=0.64 Hz), 7.55 (1 H, br), 7.15 (1 H, br), 6.05 (1 H, s), 5.93-5.81 (1 H, m), 4.61 (1 H, dd, J=9.53, 4.24 Hz), 4.58-4.49 (4 H, m), 4.00-3.98 (2 H, m), 2.91-2.90 (1 H, m), 2.45 (1 H, dd, J=13.51, 4.18 Hz), 2.25 (3 H, s), 1.49 (6 H, dd, J=6.59, 3.35 Hz)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(cc1Br)N(C(C)=O)CC2
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A stirred solution of 1-acetyl-6-bromoindolin-5-ol (Tetrahedron 1973, 29(8), 1115; 40 g, 0.15 mole) in DMF (500 ml) was treated with K2CO3 (61 g, 0.45 mole) and iodomethane (11.7 ml, 0.19 mole) and maintained at room temperature for 20 h, then concentrated under vacuum to 200 ml. The residue was treated with water (200 ml) and the precipitate filtered off, dried and recrystallised from EtOAc to afford the title compound as a white solid (35.7 g, 85%). MH+ 270/272.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.O([Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:14]1([S:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([NH2:1])[C:3]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([O:27][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:25][CH2:26]4)=[C:4]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (5.00 g, 13.0 mmol) was dissolved in DCM (50 mL) and 2,6-lutidine (6.0 mL, 51.8 mmol) was added. The mixture was cooled to 0° C. and tert-butyldimethylsilyl triflate (8.90 mL, 38.9 mmol) was added dropwise. The mixture was allowed to return to room temperature and stirred for 16 h. The mixture was concentrated under vacuum, then the residue was dissolved in methanol (10 mL). This mixture was stirred at room temperature for 90 min, then concentrated. The residue was suspended in water and extracted with DCM (×3). The combined organic extracts were washed sequentially with 10% aqueous citric acid, saturated aqueous NaHCO3 and brine, then dried (Na2SO4) and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: DCM to 25% ethyl acetate in DCM) gave 3.09 g (48%) of trans 1-benzenesulfonyl-N*4*-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4,5-diamine. LCMS (Method B, ESI): RT=3.99 min, m+H=501.1; NMR (400 MHz, CDCl3) δ: 8.14 (d, 2H), 7.84 (s, 1H), 7.54 (m, 1H), 7.45 (m, 3H), 6.55 (d, 1H), 3.70 (m, 2H), 2.35-1.85 (m, 6H), 1.46 (m, 2H), 1.30 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).