Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7]2=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][C:51](O)=[O:52])=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:51](=[O:52])[CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([CH3:42])=[CH:44][CH:45]=2)[C:7]1=[O:12]
Reactant: Cc1ccc(CCC(=O)O)cc1
Reactant: CN(C)CCn1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CCC(=O)Nc2cccc3c(=O)n(CCN(C)C)ccc23)cc1
Yield: 40 %

Procedure:
5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one (50 mg, 0.2 mmol), HATU (99 mg, 0.26 mmol), 3-(4-methylphenyl)propionic acid (42 mg, 0.26 mmol) and DIPEA (110 mg, 0.86 mmol) were stirred in methylene chloride (3 mL) at room temperature for 16 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2 gradient) gave N-[2-(2-Dimethylamino-ethyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-3-p-tolyl-propionamide as a white solid (31 mg, 0.08 mmol, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:23][S:24]C1C2C=C(C=O)SC=2N=CN=1.N1C2SC(C=O)=CC=2C=NC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[C:16]([S:24][CH3:23])[C:11]=2[CH:10]=1
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Reactant: CSc1ncnc2sc(C=O)cc12
Agent: O=Cc1cc2cncnc2s1
Product: COc1ccc(CN=Cc2cc3c(SC)ncnc3s2)cc1OC

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 14 but using 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (intermediate 15) in place of thieno[2,3-d]pyrimidine-6-carbaldehyde (intermediate 13). White solid (76 mg, 97%);
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=2)[C:4](=[O:27])[O:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:9]=2)[C:4](=[O:27])[O:3]1
Reactant: CC1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: CC1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1

Procedure:
A solution of tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate (850 mg, 2.27 mmol) was stirred in 4N HCl in Dioxane for 4 hours. The excess solvent was then removed to give the free amine as the HCl salt. LC-MS (IE, m/z): 275 [M+1]+.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH:2]1[C:7]([OH:9])=O.[CH:10]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([S:23]([CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)(=[O:25])=[O:24])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:12][CH2:11]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[CH:10]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([S:23]([CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:7]([CH:2]5[CH2:1][NH:6][C:4](=[O:5])[NH:3]5)=[O:9])[CH2:31][CH2:32]4)(=[O:24])=[O:25])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:11][CH2:12]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Reactant: O=C1NCC(C(=O)O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(C(=O)C4CNC(=O)N4)CC3)ccc2n1CC1CC1
Reaction time: 15 h

Procedure:
To a solution of 2-imidazolidone-4-carboxylic acid (12 mg, 0.093 mmol) in dichloromethane (1 mL) was added 1-(cyclopropylmethyl)-2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazole (STEP D of Example 5, 25 mg, 0.062 mmol), triethylamine (13 microL, 0.093 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.093 mmol) at room temperature, then stirred. After 15 h, 2-imidazolidone-4-carboxylic acid (12 mg, 0.093 mmol) was added to the mixture and stirred at room temperature. After 2 days, the mixture was washed with water (0.5 mL). The organic layer was mounted to a strong cationic exchange column (SCX) which was preconditioning with methanol (4 mL). SCX was washed with methanol (4 mL). Finally SCX was washed with 1 mol/L ammonia in methanol (5 mL), the product was collected a collection tube and concentrated at under reduced pressure by centrifugal concentrator. The residue (25 mg) was purified by prep-LC-MS(“process A”).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.CO.N.[SH2:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30](=[S:36])[NH2:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reactant: S
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reaction time: 48 h
Yield: 70 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-[1-(2-cyanopyridin-4-yl)piperidin-4-ylmethylamino]benzamide (50 mg, 0.11 mmol) and 1:2 methanol:tetrahydrofuran (3 mL); and the solution was treated with ammonia (g), sealed, and allowed to stir for 2 days. The mixture was then treated with hydrogen sulfide (g), sealed and allowed to stir for 2 days. The mixture was concentrated and the residue purified by column chromatography (SiO2: 2% methanol in methylene chloride) affording 38 mg (70%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>ClCCl.[Cl-].[Na+].O>[Cl:14][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCO)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
4-methoxy-phenethyl alcohol (15.2 g, 10 mmol) were dissolved in 200 ml of dichloromethane and at 0° C., 7.35 ml of thionyl chloride were added. The reaction mixture was allowed to warm to room temperature over 1/2 hour. After stirring for 20 hours, the mixture was added to brine and extracted with dichloromethane. The dichloromethane was evaporated to obtain an oil which was chromatographed on silica gel using a mixture of 30% ethyl acetate/hexane as the eluent to obtain 8.8 g (51%) of the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH3:48])[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH2:46][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([CH3:48])=[CH:40][CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNC(=O)c2ccc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and 2-(p-tolyl)ethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(F)c1
Product: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Reaction time: 1 h
Yield: 299.2 %

Procedure:
To stirred 90° C. polyphosphoric acid (150 g) was added 10.72 g (7.65 mmol) of 3-fluorobenzoic acid and 6.98 g (7.5 mmol) of aniline and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 130° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 60 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 50 mL of 3N HCl added, the mixture poured into 750 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the resulting solid extracted with methylene chloride. The dried (MgSO4) solution was filtered and the solvent removed to yield a brown solid. Recrystallization from ethanol-hexane (1:3) returned a greenish yellow solid that was chromatographed on silica gel (methylene chloride) to yield 4.83 g (30%) of yellow 4-amino-3'-fluorobenzophenone, mp 98°-100° C. 1H NMR (300 MHz, CDCl3): 4.21 (s, 2H, NH2) 6.66-6.70 (m, 2H, aromatic) 7.23-7.26 (m, 1H, aromatic) 7.39-7.51 (m, 3H, aromatic) 7.69-7.72 (m, 2H, aromatic). MS (CI, CH4): 216 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1B(O)O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)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>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Cc1cnc(C)c(Cl)n1
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(C)cnc2C)c(OC)c1
Temperature: 75 °C

Procedure:
A mixture of 3-chloro-2,5-dimethyl-pyrazine (283 mg, 2.0 mmol), 2,4-dimethoxyphenylboronic acid (455 mg, 2.5 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 5 mol %) in DME (12 mL) and sodium carbonate (1M in water, 4 mL) is heated at 75° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, and washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (25% ethyl acetate in hexanes) yields 3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazine as an oil MS: 245.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:21]([N:23]2[CH2:27][CH:26]([CH2:28][OH:29])[CH:25]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[CH2:24]2)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>C(Cl)Cl.CCOCC>[C:11]1([C:21]([N:23]2[CH2:27][CH:26]([CH:28]=[O:29])[CH:25]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=4)[CH2:33][CH2:32]3)[CH2:24]2)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1cccc2ccccc12)N1CC(CO)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=CC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.6 %

Procedure:
To a solution of 0.1 mL (1.2 mmol) of oxalyl chloride in 10 mL of CH2Cl2 at −78° C. was added 0.17 mL (2.37 mmol) of DMSO and the reaction mixture was stirred for 10 min. To this reaction mixture at −78° C. was added a solution of 0.26 g (0.59 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidine in 10 mL of CH2Cl2. After stirring for 10 min. at 78° C., 0.41 mL (2.9 mmol) of Et3N was added and the reaction was allowed to warm to rt. The reaction mixture was poured into ether and washed twice with sat'd NaHCO3 solution and once with sat'd NaCl solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give 0.29 g of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]2[N:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21](OC)=[O:22])[CH:14]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:12][C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]2[C:20]([CH2:21][OH:22])=[CH:25][CH:26]=[CH:27][N:28]=2)[CH:14]=1
Reactant: COC(=O)c1cccnc1Nc1cc(C)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncccc2CO)no1
Reaction time: 1 h
Yield: 108.3 %

Procedure:
Under a nitrogen gas stream, 0.75 g (20 mmol) of lithium aluminum hydride was added to tetrahydrofuran (70 mL) under ice cooling, and a tetrahydrofuran (30 mL) solution of 2.3 g (9.9 mmol) of methyl 2-(5-methyl-3-isoxazolyl)aminonicotinate was added dropwise to the above solution. The resulting mixture was stirred for one hour under ice cooling. Ethyl acetate was added to the reaction mixture, and 8.0 mL of a 10% aqueous solution of sodium hydroxide was further added thereto. Insoluble materials were filtered off. The filtrate was concentrated, and the residue was dissolved in ethyl acetate, dried, filtered, and concentrated. Thus, 2.2 g of the title compound was obtained as an orange-colored viscous product (yield: quantitative).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[OH-].[Na+].[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18](Cl)=[O:19]>O.C(Cl)Cl>[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([NH:10][C:8](=[NH:9])[O:7][CH3:6])=[O:19]
Reactant: COC(=N)N
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=N)NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
13.5 g (0.11 mole) of O-methyl-isourea sulfate are dissolved in 50 ml of water and 100 ml of methylene chloride. 16 g of 50% strength aqueous sodium hydroxide solution (0.2 mole) and 24 g (0.1 mole) of 2,4-dichlorophenoxyacetyl chloride are simultaneously added dropwise from two separate vessels at 0° C., with vigorous stirring. The mixture is stirred at 0° C. for 1 hour and at 40° C. for 3 hours and the organic phase is separated off, washed twice with 100 ml of water and dried over sodium sulfate.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24](=[O:26])[NH2:25])[CH:17]=1)[CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C1COCC1.CN(C1C=CN=CC=1)C>[C:34]([O:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24](=[O:26])[NH2:25])[CH:17]=1)[CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)COc1cccc(C(O)C(c2ccccc2)C2SCCCS2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC(c1cccc(OCC(N)=O)c1)C(c1ccccc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5 (192 mg, 0.5 mmol) in 10 mL THF was added DMAP (2 mg), triethylamine (70 mL, 0.5 mmol), and acetic anhydride (94 mL, 1.0 mmol). The solution was stirred at room temperature for 4 h, and then partitioned between ethyl acetate (50 mL) and 5% sodium bicarbonate (50 mL). The organic phase was washed with water (3 X 5 50 mL), dried with Mg2SO4, and evaporated to yield a colorless oil. Yield 205 mg (98%). IR: 3479, 3331 (br), 1747, 1694, 1589, 1 443, 1224, 1033, 910, 718 cm-1. 1H NMR (CDCl3, TMS) d 7.740 (dd, J=8.15, 1.55 Hz, 2 H), 7.348-7.281 (m, 3 H), 7.111 (t, J=7.96 Hz, 1 H), 6.801 (dd, J=8.18, 2.53 Hz, 1 H), 6.686 (d,J=7.59 Hz, 1 H), 6.521 (s, 2 H), 6.312 (s, 1 H), 6.136 (s, 1 H), 4.238 (s, 2 H), 2.751-2.597 (m, 4 H), 2.104 (s, 3 H), 1.933-1.857 (s, 1 H). 13C NMR (CDCl3, TMS) d 171.080, 169.318, 156.012, 136.974, 130.771, 128.402, 128.045, 127.738, 122.586, 115.072, 114.635, 79.890, 66.982, 63.133, 27.270, 27.109, 24.568, 20.848. Anal. Calcd. for C21H23NO4S2 : C, 60.41; 11, 5.55; N, 3.5. Found: C, 5 9.92; H, 5.76; N, 3.14.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3(O)[CH2:21][CH2:20][O:19][CH:18]3[CH3:22])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]([CH3:22])[O:19][CH2:20][CH:21]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1OCCC1(O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC1OCC=C1c1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 0.65 mmol 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-2-methyl-tetrahydro-furan-3-ol (Example A64(a)) and 1.81 mmol triethylamine in 2 ml dichloromethane at 0° C. was added dropwise a solution of 0.84 methanesulfonyl chloride in 0.3 ml dichloromethane. The mixture was stirred at room temperature for 2 h and then re-cooled to 0° C. 1.94 mmol DBU was added and the mixture stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a colourless oil (33% yield). MS (m/e): 292.1 ([M+H]+, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1.[C:28](#[N:31])[CH:29]=[CH2:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:24][C:22]1([CH3:25])[CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([C:7]3[C:6]4[C:10](=[C:2](/[CH:30]=[CH:29]/[C:28]#[N:31])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21]1
Reactant: C=CC#N
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cccc34)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(/C=C/C#N)cccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 228 and acrylonitrile, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, isovaleryl chloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white foam from Et2O: m.p. 83°-102° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:13]([CH3:15])([CH3:14])[C:12]([O:11][CH2:9][CH3:10])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)nc1
Reaction time: 48 h
Yield: 72.1 %

Procedure:
To a solution of 6-chloropyridin-3-ol (5 g, 38.6 mmol) and ethyl-2-bromo-2-methylpropanoate (6.01 ml, 40.5 mmol) in acetonitrile (50 mL) was added cesium carbonate (27 g, 83 mmol). The material was stirred vigorously for 48 hours. The mixture was taken up in water (100 ml) and ethyl acetate (100 ml) and transferred to a separatory funnel and shaken. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried (magnesium sulfate), filtered and stripped. The crude material was purified via preparative HPLC (silica gel; 50 g column) eluting with 5-30% ethyl acetate/hexanes to provide the desired product as light white-yellow mobile oil (6.78 g).
Reaction SMILES: CO.[CH:3]([C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21](C)C)=[O:19])[CH2:12][CH2:13]2)[CH2:7][C@H:6]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)=O.[C:31](=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>C(OCC)(=O)C>[C:3]([C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:13]2)[CH2:7][C@H:6]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)#[CH:31]
Reactant: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2OC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#C[C@@H]1[C@H]2CC[C@H](CCCC(=O)OC)CO[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 28.4 %

Procedure:
To a methanol solution (2.3 mL) of the compound (180 mg) produced in Example 13, potassium carbonate (94 mg) and a Bestmann reagent (dimethyl-1-diazo-2-oxopropyl phosphonate) (105 mg) were added, followed by stirring at room temperature for 6 hours. Further, potassium carbonate (47 mg) and the Bestmann reagent (53 mg) were added, followed by stirring at room temperature overnight. The reaction mixture was cooled to 0° C.; diluted with ethyl acetate; and then separated by adding water. The organic layer was washed with water and a saturated saline; dried with magnesium sulfate; then filtered; and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→65:35) to obtain a titled compound (47 mg) having the following physical property values.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[Cl-:15].[Ca+2].[Cl-].O>CS(C)=O>[Cl:15][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: [Cl-]
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Agent: [Ca+2]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(C(F)(F)F)ccc(F)c1Cl
Temperature: 145 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
To a solution of 50.9 g of 2,3-difluoro-6-trifluoromethylbenzonitrile in 240 ml of dimethyl sulfoxide (DMSO) was added 53.3 g of calcium chloride and the mixture was stirred for 6 hours at a temperature of from 140 to 150° C. After cooling, the reaction mixture was further added with 240 ml water and extracted with 240 ml and 100 ml hexane twice. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent therein was distilled under reduced pressure. The crude product obtained was distilled under reduced pressure to obtain 38.9 g of the title compound.