Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][C:6]=1[NH:7][C:8](=[O:10])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+].N#N.C[NH:20][C@@H:21]1CCC[CH2:23][C@H:22]1[NH:27][CH3:28].CC1N=CNC=1>CN(C=O)C.[Cu]I>[CH3:23][C:22]1[N:27]=[CH:28][N:20]([C:2]2[N:3]=[CH:4][S:5][C:6]=2[NH:7][C:8](=[O:10])[CH3:9])[CH:21]=1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: CC(=O)Nc1scnc1Br
Agent: [Cu]I
Agent: Cc1c[nH]cn1
Agent: N#N
Solvent: CN(C)C=O
Product: CC(=O)Nc1scnc1-n1cnc(C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
N-(4-bromothiazol-5-yl)acetamide from example 1.5 (1 g, 4.52 mmol), CuI(869 mg, 4.52 mmol) and Cs2CO3 (2.9 g, 9.1 mmol) were combined in a flask (backfilled with N2). Trans-N,N′-dimethylcyclohexane-1,2-diamine (630 mg, 4.52 mmol) and 4-methyl-1H-imidazole (446 mg, 5.4 mmol) in DMF (10 mL) were added and the mixture was stirred at 90° C. overnight. After the mixture was cooled to room temperature, the mixture was filtered through a syringe filter (washed with DMF). The filtrate purified by prep-HPLC to give 200 mg of the pure title compound (yield: 20%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH2:10][CH3:11]
Reactant: Cc1ccc(O)cn1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(C)nc1
Yield: 42.5 %

Procedure:
A mixture of 16.5 g (0.15 mol) of 5-hydroxy-2-methylpyridine (commercially available), 18.8 g (0.15 mol) of n-propyl bromide and 8.00 g (0.06 mol) of anhydrous potassium carbonate with 100 ml of acetone was refluxed for 24 hours, the solvent was removed, 100 ml of water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:4) to give 9.63 g of an oily product (yield 42.1%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH2:7]2.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[CH:22]1[CH:21]=[CH:20][C:19]2[S:15][N:16]=[C:17]([N:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[CH:5]=[C:6]5[CH2:7][C:8](=[O:14])[NH:9][C:10]5=[CH:11][C:12]=4[Cl:13])[CH2:28][CH2:29]3)[C:18]=2[CH:23]=1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1

Procedure:
To a 125 mL round bottom flask equipped with an N2 inlet and condenser are added 0.73 g (3.2 mmol) 5-(2-chloroethyl)-6-chloro-oxindole, 0.70 g (3.2 mmol) N-(1,2-benzisothiazol-3-yl)piperazine, 0.68 g (6.4 mmol) sodium carbonate, 2 mg sodium iodide, and 30 mL methylisobutyl ketone. The reaction is refluxed for 40 hours, cooled, filtered, and evaporated. The residue is chromatographed on silica gel, eluting the by-products with ethyl acetate (1 L) and the product with 4% methanol in ethyl acetate (1.5 L). The product fractions (Rf=0.2 in 5% methanol in ethyl acetate) are evaporated, taken up in methylene chloride, and precipitated by addition of ether saturated with HCl; the solid is filtered and washed with ether, dried, and washed with acetone. The latter is done by slurrying the solid with acetone and filtering. Ziprasidone is obtained as a high melting, non-hygroscopic solid product having an expected melting point of 288° C. to 288.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC.O>C(O)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Solvent: O
Solvent: CC(=O)O
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Temperature: 45 °C
Reaction time: 7 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (3.0 g, 10.71 mmol) in acetic acid (10 mL) was added methyl 2,2,2-trichloroethanimidoate (1.4 mL, 11.25 mmol). The reaction was stirred at 45° C. for 7 hr. Water (15 mL) was then added. The precipitate was collected by filtration and dried under vacuum to give the title product (3.94 g as the acetic acid salt); 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 7.01 (1H, d, J=5.0 Hz), 7.21 (2H, s), 7.75-7.46 (2H, m), 8.09-7.75 (1H, m), 8.58 (1H, d, J=5.0 Hz); LC-MS: m/z=+406/408/410/412 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]([NH:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 5 (250 mg, 1.42 mmol) in N,N-dimethylformamide (4 mL) was added 1,3-diisopropylcarbodiimide (0.268 mL, 1.70 mmol), 1-hydroxybenzotriazole hydrate (58 mg, 0.4 mmol), and t-butyl glycinate (223 mg, 1.7 mmol). The mixture was stirred at room temperature overnight, quenched with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (50:1) as the mobile phase to provide the desired product. MS (APCI): m/z 290 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:11][CH2:12]2)=[N:33][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:19]=1
Reactant: NCCc1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCC(C(=NCCc2ccccc2)c2ccc(F)cc2)CC1
Yield: 90.4 %

Procedure:
A mixture of 15.56 g (0.045 mol) of N-benzenesulfonyl-4-(p-fluorobenzoyl)-piperidine, 8.50 g (0.0702 mol) of phenethylamine and 0.20 g (0.0013 mol) of benzenesulfonic acid in 400 mL of toluene was heated at reflux for 111 hr. Water was removed from the reaction mixture with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute Na2CO3. The CH2Cl2 solution was dried (MgSO4), and the solvent was removed in vacuo. The residue was recrystallized from ether to give 18.32 g (90.5%) of title compound as a light tan solid, mp 123°-126° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(-c3cccc(C(F)(F)F)c3)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(Cc2ccc(-c3cccc(C(F)(F)F)c3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a mixed solution of the compound (260 mg, 0.65 mmol) obtained in Example 39c in ethanol/tetrahydrofuran (v/v=1/1, 6 mL) was added 2N aqueous sodium hydroxide solution (1.3 mL, 2.6 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (160 mg, 69%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([Cl:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=2)=[N:33]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(Cl)c(C(F)(F)F)c3)[nH]c2=O)c1
Yield: 65.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-chloro-3-(trifluoromethyl)benzo yl isocyanate (Intermediate-100, 2.0 g), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.1 Hz, 2H), 7.36 (d, J=9.3 Hz, 1H), 7.43 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 8.10-8.18 (m, 2H), 8.27 (s, 1H), 12.82 (s, 1H); MS (m/z): 487.29 (M+H)+.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@@H:6]([C:9]([SH:12])([CH3:11])[CH3:10])[CH2:5]1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[CH2:18](O)[CH3:19]>S(=O)(=O)(O)O>[CH2:18]([O:2][C:1]([C@@H:4]1[CH2:8][S:7][C@@H:6]([C:9]([SH:12])([CH3:10])[CH3:11])[CH2:5]1)=[O:3])[CH3:19]
Reactant: CCO
Reactant: CC(C)(S)[C@H]1C[C@H](C(=O)O)CS1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@@H]1CS[C@@H](C(C)(C)S)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of trans-4-carboxy-2-(1-mercapto-1-methylethyl)tetrahydrothiophene (compound No. 8-1, 50 mg) in ethanol (3 ml), one drop of concentrated sulfuric acid was added under nitrogen atmosphere and the mixture was stirred for 1.5 hours. After cooling, the reaction mixture was week alkalized with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 53 mg of the titled compound (compound No. 12-1).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH:22]1([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: ClC(Cn1ccnc1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
779 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to a solution of 3 g of methyl 4-mercaptobenzoate in 24 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 3.8 g of 1-(2-chloro-2-cyclohexylethyl)imidazole in 36 ml of dry dimethylformamide was added to the resulting solution, and the reaction mixture was then heated at 60°-70° C. for 13.5 hours. At the end of this time, the resulting mixture was treated and purified by the same method as described in Example 1, to give 3.3 g of the title compound as an oil.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=O.[Na+].[SH:28][C:29]1[S:33][C:32]([CH2:34][C:35]([NH2:37])=[O:36])=[N:31][N:30]=1>>[S:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:16][C:14]([NH:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:24]([OH:26])=[O:25])=[C:6]([CH2:5][S:28][C:29]3[S:33][C:32]([CH2:34][C:35](=[O:36])[NH2:37])=[N:31][N:30]=3)[CH2:23][S:22][C@H:9]12)=[O:15]
Reactant: NC(=O)Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [Na+]
Product: NC(=O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1

Procedure:
Sodium cephalothin (1.05 g, 2.5 mmole) and 5-mercapto-1,3,4-thiadiazol-2-yl-acetamide (0.48 g, 2.75 mmole) were reacted together as described in example 1b. The reaction mixture was poured onto ice, washed with ethyl acetate, covered with ethyl acetate and acidified. The product precipitated as a pale yellow solid, this was filtered off, washed with water and ethyl acetate and dried, 0.87 g, (68.1%); t.l.c. (SiO2 ; B.A.W.; 12:3:5) Rf=0.41; νmax (95% ethanol) 276 nm (ε=12300); δ[(CD3)2SO] 3.85 (2H,s, C2 methylene), 3.95 (2H,s, --CH2CONH--), 4.19 (2H,s, --CH2CONH2), 4.41 and 4.67 (2H, AB quartet, J 14 Hz, --CH2S--), 5.22 (1H,d, J 5 Hz, C6 proton), 5.90 (1H,dd, J 5 and 8 Hz, C7 proton), 6.8-8.1 (6H,m, --CO2H, --CONH2 and thienyl protons), 8.85 (1H,d, J 8 Hz, --CONH--).
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][C:7]=1B(O)O)=[O:2].Br[C:22]([CH3:24])=[CH2:23].[F-].[Cs+]>O1CCOCC1>[C:22]([C:7]1[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:4][C:3]=1[CH:1]=[O:2])([CH3:24])=[CH2:23]
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1B(O)O
Reactant: C=C(C)Br
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O

Procedure:
To a mixture of 2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid (0.330 g, 1.10 mmole), 2-Bromo-propene (0.399 g, 3.30 mmole) and cesium fluoride (0.585 g, 3.85 mmole) in dioxane (5 mL), is bubbled with nitrogen gas for 15 minutes. The catalyst PdCl2 (dppf) (0.033 g) is then added to the mixture. The reaction is heated under reflux for 16 hours. The solvent is removed on rota vapor, and the resulting residue is partitioned between ethyl acetate (20 ml) and water (20 mL). The aqueous layer is extracted with more ethyl acetate (20 mL). The combined organic solution is washed with brine (3×50 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, eluting with 0-15% ethyl acetate in hexane and concentrated to provide the titled compound as pale yellow crystalline.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.[BrH:19]>>[BrH:19].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: COc1ccc(C2CCCNC2)c2c1NC(=O)C2
Agent: Br
Product: O=C1Cc2c(C3CCCNC3)ccc(O)c2N1

Procedure:
A mixture of 1.5 g of the product of Example 1 in 15 ml of concentrated hydrobromic acid (d=1.49) was refluxed for 2 hours 30 minutes under an inert atmosphere and after evaporating to dryness under reduced pressure, taking up the residue with benzene, concentrating to dryness, adding 2 ml of ethanol, filtering the crystals obtained, drying under reduced pressure, and purifying by crystallization from ethanol, 1.4 g of 1,3-dihydro-7-hydroxy-4-(3-piperidinyl)-2H-indol-2-one hydrobromide melting at 190° C., then 250° C. were obtained.
Reaction SMILES: [CH3:1][Si:2]([CH:5]([Si:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])[CH3:3].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(#N)C>[CH3:1][Si:2]([CH:5]([O:16][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C(Cl)[Si](C)(C)C
Reactant: C=C(C)C(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: C=C(C)C(=O)OC([Si](C)(C)C)[Si](C)(C)C
Reaction time: 96 h
Yield: 59.4 %

Procedure:
Bis(trimethylsilyl)chloromethane (Aldrich) (14.68 g, 0.075 mole), sodium methacrylate (8.96 g, 0.0825 mole), Adogen 464 (Aldrich) (1.70 g), and phenothiazine (0.05 grams) were placed in a round bottom flask equipped with a condenser, mechanical stirrer and a nitrogen inlet. The flask was charged with 200 ml acetonitrile and heated to reflux while stirring. After 4 days, the mixture was filtered to remove the solids and the solvent was removed in a rotary evaporator. Fractional distillation under reduced pressure gave 10.90 grams (60% yield) of a clear liquid at 46-48° C. at 0.5 mm pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=2)[CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (210 mg, 0.77 mmol) [prepared according to the procedure of Example 188], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (294 mg, 0.764 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (442 mg, 0.94 mmol) in chloroform (7.6 mL). DIEA (670 μL, 3.84 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (238 mg, 0.43 mmol, 56%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[NH:9]C(=O)C.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:25](OCCC(C)C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:25][NH:9][C:3]=12
Reactant: CC(=O)Nc1c(Br)ccnc1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccnc2cn[nH]c12
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a solution of N-(4-bromo-2-methylpyridin-3-yl)acetamide (0.6 g, 2.62 mmol) in toluene (26.2 ml) was added potassium acetate (0.308 g, 3.14 mmol) and acetic anhydride (0.743 ml, 7.86 mmol). The mixture was stirred for 15 minutes and isopentyl nitrite (0.806 ml, 6.02 mmol) was added and the reaction was heated at 85° C. for 4 hours. The reaction was cooled and partitioned between ethyl acetate (75 mL) and water (75 mL). The organic layer was separated, dried over MgSO4, and concentrated to a brown oil. The oil was purified on silica column chromatography eluted with methanol:dichloromethane (3:97). Concentration of product fractions afforded 7-bromo-1H-pyrazolo[4,3-b]pyridine (90 mg, 0.454 mmol, 17.35% yield) as an amber solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (1H, d, J=4.80 Hz) 8.32-8.40 (1H, m) 8.40-8.51 (1H, m) 13.89 (1H, br. s.). MS [M+H] found 197.9.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH:20](O)[CH3:21].N1C=CC=CC=1.O=S(Cl)Cl.O>C(Cl)Cl>[CH3:21][CH:20]1[O:18][C:4]2[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[C:11]([C:2](=[O:1])[C:3]=2[CH2:19]1)=[CH:10][CH:9]=[CH:8][N:7]=3
Reactant: CC(O)Cc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1Cc2c(n(-c3ccccc3)c3ncccc3c2=O)O1

Procedure:
A suspension of 4-hydroxy-3-(2-hydroxypropyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (1 g.) in CH2Cl2 was stirred in an atmosphere of nitrogen. To this was added pyridine (1.5 ml.). To this mixture was added a solution of SOCl2 (1.5 ml.) in CH2Cl2 (10 ml.) dropwise over a period of 15 minutes. The mixture was stirred overnight at room temperature then water was added. The CH2Cl2 layer was separated, dried and evaporated. Recrystallization from isopropanol yielded the product, m.p. 207°-209° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:32][CH2:31][CH:28]3[CH2:30][CH2:29]3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC2CC2)c1

Procedure:
Example 129 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 1-cyclopropylmethanamine to give the title compound (0.015 g).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[C:1]1([NH:7][N:8]=[C:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccc1
Product: CCOC(=O)CC(C)=NNc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of phenyl hydrazine (125 g, 1150 mmol) and ethyl 3-oxobutanoate (100 g, 770 mmol) in terbutyl dimethyl ether (1000 mL) acetic acid (2 mL) was added. The resulting mixture was stirred at 0° C. for 1 h. The solvent was evaporated under vacuum. The residue (220 g) was used as such for next step.