Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]([C:12]1[C:13](=[O:23])[O:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]([CH3:4])=[O:3].[C:24](Cl)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCOCC1.N1C=CC=CC=1>[CH2:1]([CH:5]([C:12]1[C:13](=[O:23])[O:14][C:15]2[C:20]([C:21]=1[O:22][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCCC/C=C/CCCCCCCC(=O)Oc1c(C(CC(C)=O)c2ccccc2)c(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of 3-(α-acetonylbenzyl)-4-hydroxycoumarin (warfarin) (3.70 g, 12 mmol) in 120 ml anhydrous dioxane and 25 ml pyridine was added elaidic acid chloride (3.60 g, 12 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated at high vacuum. The residue was partitioned between ether and water. The organic phase was washed with tartaric acid (aq), NaHCO3 (aq) and water. The dried organic phase was concentrated and the product purified on a column of slica gel with heptane/ethylacetate (6:1) as the eluent system. Impure fractions were repurified and homogenous fractions were evaporated to give 5.1 g (70%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:26])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]2)[C:5]([F:27])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1)#[N:29].C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[N:7]=[C:6]([C@:8]3([CH3:26])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:9]3)[C:5]([F:27])=[CH:4][CH:3]=2)=[O:37])=[N:34][CH:35]=1)#[N:29]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ccc(C#N)cn3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 25 °C
Yield: 146.2 %

Procedure:
To a solution of tert-butyl ((4S,6S)-4-(6-amino-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7k, 0.101 mg, 0.13 mmol) in EtOAc (4 mL) was added 5-cyano-2-pyridinecarboxylic acid (0.042 mg, 0.28 mmol, Aldrich), di-isopropylethylamine (0.09 mL, 0.51 mmol), and 1-propanephosphonic acid cyclic anhydride (0.18 mL, 0.28 mmol, 50 wt. % solution in ethyl acetate, Alfa-Aesar). The reaction mixture was stirred at room temperature for 2 hs. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (10 mL). The organic layer was washed sequentially with water and brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the crude material was purified via silica gel flash chromatography (gradient 0-30% EtOAc in hexanes) to afford the title compound as a white solid (0.097 g, 0.19 mmol, 72% yield). MS m/z=523.2 [M+H]+. Calculated for C23H22F4N6O4: 522.4
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:14]2[NH:13][C:12](=[O:15])[C@@H:11]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1.I[CH3:27]>C1COCC1>[CH3:3][O:4][C:5]1[C:14]2[N:13]([CH3:27])[C:12](=[O:15])[C@@H:11]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CI
Reactant: COc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1N(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a suspension of sodium hydride (60 mg of 60% dispersion in mineral oil, hexane-washed, 1.5 mmol) in 5 mL of THF was added (±)-cis tert-butyl 6-methoxy-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 10, Part A (0.40 g, 1.25 mmol) in 4 mL of THF. The reaction was stirred at ambient temperature for 1 h, at which time gas evolution had ceased. Then there was added iodomethane (0.23 mL, 3.75 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was quenched with 1N HCl and was extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 0.38 g (91%) of the title compound which was used without purification.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=CC=N[CH:3]=1.C([O:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20](Cl)[C:19]([CH:23]=[CH2:24])=[N:18][CH:17]=1)(C)(C)C>>[CH2:23]([C:19]1[C:20]([CH2:1][CH:2]([CH3:7])[CH3:3])=[CH:21][C:16]([C:15]([OH:14])=[O:25])=[CH:17][N:18]=1)[CH3:24]
Reactant: O=C(O)c1cccnc1
Reactant: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Product: CCc1ncc(C(=O)O)cc1CC(C)C

Procedure:
6-Ethyl-5-isobutyl-nicotinic acid is prepared in analogy to Nicotinic acid 3 from 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester and 2,4,6-tri-(2-methyl-propenyl)cycloboroxane pyridine complex, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971); LC-MS: tR=0.64 min, [M+1]+=207.98.
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17]C#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:20]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: ClCCN1CCOCC1
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN1CCOCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and N-(2-chloroethyl)morpholine.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]([NH:26][NH:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=O)=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[N:27][N:26]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NNC(=O)N1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCOCC3)o2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
Pyridine (2.0 mL) was added to a solution of N′-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)morpholine-4-carbohydrazide (0.38 g, 0.94 mmol) in dry DCM (10 mL). (CF3SO2)2O (2.0 mL) was then added slowly at −10° C. The reaction mixture was stirred at rt for 0.5 h then saturated NaHCO3 was added at −10° C. very slowly. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried with Na2SO4, concentrated, and purified by silica gel column chromatography (0 to 1:50 MeOH/DCM) to give (2S,5R)-6-(benzyloxy)-2-(5-morpholino-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.12 g, 33%). ESI-MS (EI+, m/z): 386 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:25][C:11]1[C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[O:14][C:10]=1[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1Cl
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of afford 5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.7 g, 2.77 mmol) in CHCl3 (10 mL), NBS (0.84 g, 4.72 mmol was added portionwise at RT. The reaction mixture was then stirred for 1 h. and diluted with DCM (20 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (340 mg, 37%) as a thick syrup.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:8].[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][O:2]2)=[O:8])[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CN1CCN(C(=O)C2CCCO2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(C(=O)C2CCCO2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 39.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 237, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)acetamido)propanamide (19.3 mg, 39.9%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.24 (s, 1H), 8.03 (d, 1H), 7.61 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.99 (m, 4H), 4.70 (m, 1H), 4.65 (t, 1H), 4.53 (s, 2H), 3.78-3.72 (m, 4H), 3.35 (m, 6H), 3.04 (s, 2H), 2.44 (m, 2H), 1.97 (dd, 2H), 1.80 (m, 2H). MS (EI) for C33H37FN4O6. found 605.7 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:21][CH:22]=[C:23]([Cl:26])[CH2:24]Cl>O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:24][C:23]([Cl:26])=[CH:22][Cl:21])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: ClC=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(Cl)cnn1CC(Cl)=CCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
To a mixture of 10.8 g of 4,5-dichloro-3(2H)-pyridazinone and 9.5 g of anhydrous potassium carbonate were added 65 ml of N,N-dimethylformamide and stirred for 10 minutes at room temperature. Then, 10.0 g of 1,2,3-trichloro-1-propene (mixture of E-from and Z-form) were added to the mixture solution and were stirred for 6 hours at 40° C. The solution was poured into a large quantity of water and extracted with benzene, and freed of solvent by distillation under reduced pressure to give 6.0 g of the intended compound (mixture of E-form and Z-form). The compound thus obtained was separated into isomer (m.p.: 93.7°-94.6° C., 112.8°-114.8° C.) by means of column chromatography (on silica gel, eluting with benzene).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][CH2:14][CH3:15].[Li+].[OH-]>C1COCC1.CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:16])=[O:2])=[C:7]([NH:13][CH2:14][CH3:15])[CH:8]=1
Reactant: CCNc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1cc(F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid methyl ester (128 mg, 0.57 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid (88 mg, 73%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid (40 mg, 0.19 mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethylamine hydrochloride (55 mg, 0.19 mmol) and N-methylmorpholine (31 μL, 0.28 mmol) in THF (4 mL) was added 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 58 mg, 0.21 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.9 mg, 6%) after purification by column chromatography (EtOAc:hexane=1:10 to 2:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH:18]=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH3:21][O:22][C:23]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](/[CH:18]=[CH:25]/[C:24]1[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:23]=1[O:22][CH3:21])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1cc([N+](=O)[O-])ccc1/C=C/c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reaction time: 5 h

Procedure:
The aldehyde (846) was reacted with (2-methoxy-4-nitrobenzyl) (triphenyl)phosphonium bromide (582) prepared as described in example 432 using the procedure described in method 2, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA;aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/pentane) the diene (583) as an orange solid (the pure E isomer) (63%), mp 156–159° C. 1H NMR (CDCl3) δ 8.23 (br s, 1H), 7.87 (dd, J=8.5, 2.1 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.3 Hz, 2H), 7.32 (t, J=7.2 Hz, 1H), 7.28 (d, J=17.1 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 7.20 (d, J=16.7 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.97 (dd, J=8.7, 2.5 Hz, 1H), 6.63 (br s, 1H), 5.11 (s, 2H), 4.01 (s, 3H). Found: C, 71.69; H, 4.94; N, 7.11. C24H20N2O4 requires C, 71.99; H, 5.03; N, 7.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](N)=[S:11]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11]
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Solvent: Clc1ccccc1
Product: S=C=Nc1c(Cl)cccc1Cl

Procedure:
A solution of 156.9 g. of 1-(2,6-dichlorophenyl)thiourea in 1 1. of chlorobenzene was refluxed for 20 hours and concentrated. The resulting oil was triturated with 1 1. of hot hexane which was filtered. On cooling overnight, 52 g. (36%) of 2,6-dichlorophenylisothiocyanate, m.p. 41°-42° separated. Concentration of the filtrate gave an additional 64.2 g. (44%), m.p. 41°-43° in two crops. Recrystallization of a sample from hexane gave the analytical sample, m.p. 41°-42°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][N:27]=[C:26]([N:35]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[N:25]=4)=[C:20]([C:44]([N:46]4[CH2:55][CH2:54][C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:47]4)=[O:45])[CH:19]=3)=[O:17])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=[C:26]([N:35]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[N:25]=4)=[C:20]([C:44]([N:46]4[CH2:55][CH2:54][C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:47]4)=[O:45])[CH:19]=3)=[O:17])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCCCN(CCCC)c1ncc(C(=O)OCC)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(Cl)cc4c3)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ncc(C(=O)O)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(Cl)cc4c3)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 55 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
To a solution of ethyl 4-(4-(7-chloronaphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-(dibutylamino)pyrimidine-5-carboxylate (Example 319, 23 mg, 0.03 mmol) in THF (1.0 mL) and MeOH (1.0 mL) was added 2N NaOH (0.15 mL, 0.30 mmol). The resulting reaction mixture was stirred at 55° C. for 3 h. At 0° C., the reaction mixture was neutralized to pH 3-4 with aq. 1N HCl. The solution was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (14 mg, 63%). MS(ESI+) m/z 754.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH2:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OCc2cccnc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
To a solution of 0.40 g (1.187 mmol) of the product of Example 31 dissolved in 5.0 mL of DMF was added 0.409 g (2.492 mmol) of 3-picolyl chloride hydrochloride and 1.03 g (7.477 mmol) of potassium carbonate. The reaction mixture was then stirred at room temperature for 18 h, diluted with water and extracted with ether. The organics were then extracted with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extrrcted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide 0.34 g (55%) of the desired product as a brown oil. Electrospray Mass Spec: 520.2 (M+H)+
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:27])=[N:10][C:6]=2[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([F:40])[C:38]=1[F:39]>>[CH3:27][C@@H:12]1[CH2:13][N:14]([C:17]2[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16][N:11]1[C:9]1[NH:8][C:7]2[C:2]([C:35]3[CH:34]=[C:33]([F:32])[C:38]([F:39])=[C:37]([F:40])[CH:36]=3)=[CH:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][C:6]=2[N:10]=1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
7-Bromo-2-{(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-5-(trifluoromethyl)-1H-benzoimidazole (152 mg, 0.3 mmol, Example 79) and 3,4,5-trifluorophenylboronic acid (88 mg, 0.5 mmol, Lancaster) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 560 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].[H-].[Na+].Br[CH2:37][C:38]([O:40]CC)=[O:39].[OH-].[Na+]>O1CCCC1.C(O)C>[F:1][C:2]([F:32])([F:33])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:37][C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)CBr
Reactant: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)COCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product of step (c) (750 mg) in tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in mineral oil, 91 mg). The reaction was stirred at 20° C. for 30 minutes then ethyl bromoacetate (335 μl) was added and the reaction was stirred for a further 15 hours. Ethanol (1 mL) was then added and the stirring continued for 5 minutes. Sodium hydroxide solution (2M, 10 mL) was added and the resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was then partitioned between dichloromethane (40 mL) and water (40 mL). The aqueous layer was acidified to pH 1 by the addition of hydrochloric acid (2M) and then extracted with dichloromethane (2×40 mL). The combined organic layers were dried and the solvent removed in vacuo to give the title compound as a yellow oil (612 mg).
Reaction SMILES: Br[C:2]1[C:16]([F:17])=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28](B(O)O)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C(O)(C)C.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>[CH:18]1([NH:21][C:22](=[O:23])[C:24]2[CH:29]=[C:28]([C:2]3[C:16]([F:17])=[CH:15][C:5]4[C:6]([C:9]5[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=5)=[N:7][O:8][C:4]=4[CH:3]=3)[C:27]([CH3:33])=[C:26]([F:34])[CH:25]=2)[CH2:19][CH2:20]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: Fc1cc2c(-c3ccncc3)noc2cc1Br
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2onc(-c3ccncc3)c2cc1F
Yield: 60.7 %

Procedure:
The procedure for Example 1 was followed using 6-bromo-5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazole (Intermediate 6, 25 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (24 mg), tetrakis(triphenylphosphine)palladium(0) (1 mg) and saturated aqueous sodium hydrogen carbonate (0.25 ml) in isopropanol (1 ml). Elution of the SPE cartridge (silica, 1 g) with cyclohexane/ethyl acetate (100:0 to 66:33) gave the title compound as a white solid (21 mg).