Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:23][CH3:24])[C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1.C(OC([N:32]1[C:36]([CH3:37])=[CH:35][C:34]([NH2:38])=[N:33]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:23]([N:19]([C:16]1[CH:17]=[CH:18][C:13]([N:4]2[N:3]=[C:2]([NH:38][C:34]3[CH:35]=[C:36]([CH3:37])[NH:32][N:33]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1)[C:20](=[O:22])[CH3:21])[CH3:24]
Reactant: CCN(C(C)=O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCN(C(C)=O)c1ccc(-n2nc(Nc3cc(C)[nH]n3)c3ccccc3c2=O)cc1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
N-[4-(4-Bromo-1-oxo-1H-phthalazin-2-yl)-phenyl]-N-ethyl-acetamide (0.10 g, 0.027 mmol), 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.006 g, 0.03 mmol), Cs2CO3 (0.01 g, 0.03 mmol), tris-(dibenzylideneacetone)-dipalladium (0.001 g, 0.001 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.002 g, 0.003 mmol) under nitrogen were heated to 100° C. for 18 hours, and then allowed to cool to RT. H2O was added and the solvent was evaporated in vacuum. Purification via chromatography gave the title compound (0.003 g, 23% yield). 1H-NMR: (400 MHz, D6-DMSO) 9.28 (1H, s), 8.51 (1H, d), 8.38 (1H, d), 7.99 (1H, t), 7.91 (1H, t), 7.87 (2H, d), 7.41 (2H, d), 6.25 (1H, s), 3.69 (2H, q), 2.20 (3H, s), 1.81 (3H, s), 1.07 (3H, t); MS (ESI+)=403.34 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(O)[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1>OS(O)(=O)=O>[CH3:1][C:2]1[N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][C:18]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)c(C)c(C(=O)OCC)c1=O
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(C)c(C(=O)OCc2ccccc2)c1=O

Procedure:
4 g. of 2,6-dimethyl-3,5-dicarboethoxy-N-phenyl-4-pyridone (prepared as described in Example 1) were dissolved in 20 ml. of benzyl alcohol, 4 drops of concentrated H2SO4 were added and the mixture was stirred and heated for 7 hours at 130°, at the same time distilling off the produce ethanol. The benzyl alcohol solution was washed with a saturated solution of sodium bicarbonate and the slurry was extracted several times with chloroform. The extracts were combined and dried over magnesium sulphate, and the chloroform was distilled off in vacuo. The oily residue was dissolved in 50 ml. of ether and 50 ml. of petrolether 40'-60° were added. After cooling in a dry ice-acetone bath and scratching, 2,5g. of 2,6-dimethyl-3-carboethoxy-5-carbobenzyloxy-N-phenyl-4-pyridone, m.p. 142° were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1C(=O)O
Product: O=c1[nH]c2ccccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 95.5 %

Procedure:
3.10 g (14.3 mmol) of 4-chlorobenzenesulfonylisocyanate and 2.00 g (14.4 mmol) of 2-aminobenzoic acid were treated in the same way as in Example 1 to obtain 4.60 g of the above-identified compound (yield 94.4%). Properties: colorless crystal, Melting point: 214°-215° C., PMR (δppm, DMSO-d6): 7.10 (1H,d), 7.20 (1H,t), 7.66 (2H,d), 7.70 (2H,d), 7.84 (1H,d), 7.15 (2H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH:31]([CH3:33])[CH3:32])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 23A (60 mg, 0.19 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (51 mg, 0.26 mmol) to yield 30 mg (35%).
Reaction SMILES: [C:1]([NH:5][OH:6])(=[O:4])[CH2:2][CH3:3].[CH3:7][N:8]=[C:9]=[O:10]>C(N(CC)CC)C.C(Cl)Cl>[CH3:7][NH:8][C:9]([N:5]([O:6][C:9]([NH:8][CH3:7])=[O:10])[C:1](=[O:4])[CH2:2][CH3:3])=[O:10]
Reactant: CN=C=O
Reactant: CCC(=O)NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(OC(=O)NC)C(=O)NC
Reaction time: 48 h

Procedure:
Propiohydroxamic acid (4.5 grams), methyl isocyanate (6.0 grams), and a few drops of triethylamine were stirred for about one hour in about 50 ml of methylene chloride. The resulting solution was allowed to stand at room temperature for about 48 hours, after which the solvent was removed by evaporation leaving a residue. The residue was recrystallized from a mixture of methylene chloride and hexane leaving the desired, N-((methylamino)carbonyl)-N-(((methylamino)carbonyl)-oxy)propionamide as white crystals, m.p. 90.5°-92.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[SH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].ICCCCCCCCCCCCSCCC(OC)=O>CCCCCC.CCOCC>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCS
Reactant: BrCCCCCCBr
Agent: COC(=O)CCSCCCCCCCCCCCCI
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)CCSCCCCCCBr
Yield: 35.3 %

Procedure:
1,6-dibromo-hexane (1.6 g. 13 mmol) and methyl 3-mercapto-propionate (13 mmol) were caused to react according to the procedure for compound 1. The product 5 (1.3 g, 35% yield) was isolated as an oil by column chromatography (hexane/ether 1:1). TL (hexanelether 1:1) Rf=0.6. 1H-NMR δ1.4 (m, 12H, CH2), 2.52 (t, 2H, C(2)H2), 2.61 (t, 2H, C(5)H2), 2.8 (t, 2H, C(3)H2), 3.40 (t, 2H, C(10)H2), 3.7 (s, 3H, COO—CH3).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([N:16]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:4])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]1=[O:13])[CH3:15]
Reactant: CCN
Reactant: Cc1cc2c(oc1=O)CCCC2=O
Product: CCn1c2c(cc(C)c1=O)C(=O)CCC2

Procedure:
Prepared analogously to Example 5(b) from 3-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and ethylamine.
Reaction SMILES: O[C:2]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C2(O)CN(C(=O)OC(C)(C)C)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate (1.1 g, 3.9 mmol) in DCM (15 mL) at 0° C. was added triethylsilane (5 mL, 31 mmol) followed by TFA (1 mL, 13.8 mmol). The reaction mixture was allowed to warm to rt and stirred overnight. The mixture was then diluted with a satd. sodium bicarbonate solution and extracted with DCM (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude product which was purified by silica gel chromatography eluting with 10% ethyl aceate in hexane to give pure tert-butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate (380 mg, 1.37 mmol, 34.8% yield). LCMS (Method 107): (ES-API), m/z 264.0 (M+H) RT=2.128 min; 1H NMR (400 MHz, DMSO-d6) δ 7.31-7.20 (m, 2H), 6.96-6.87 (m, 2H), 4.27-4.17 (m, 2H), 3.82-3.69 (m, 6H), 1.41 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C.CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-4,6-dimethyl-pyrimidine (1.50 g, 10.52 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.53 g, 12.62 mmol, 1.2 equiv; commercially available) and N-ethyl diisopropylamine (2.15 mL, 1.63 g, 12.62 mmol, 1.2 equiv) in acetonitrile (8 mL) and DMAc (2 mL) was heated by microwave irradiation to 160° C. for 1 h and then to 180° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.47 g (46%) of the title compound. MS (ISP): 307.5 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][N:11]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[CH:20][C:15]=2[O:14][CH2:13][C:12]1=[O:26]>O1CCOCC1>[CH3:10][N:11]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][N:2]([CH3:1])[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:20][C:15]=2[O:14][CH2:13][C:12]1=[O:26]
Reactant: CNCc1ccccc1
Reactant: CN1C(=O)COc2cc(CCCCBr)ccc21
Solvent: C1COCCO1
Product: CN(CCCCc1ccc2c(c1)OCC(=O)N2C)Cc1ccccc1

Procedure:
0.04 mol of N-methyl-N-benzylamine and 0.02 mol of 4-methyl-7-(4-bromobutyl)-2,3-dihydro-3-oxo-1,4-benzoxazine, the latter being dissolved beforehand in 120 cm3 of dioxane, are introduced into a 100-cm3 ground-necked flask fitted with a reflux condenser. The mixture is heated to reflux for 96 hours with magnetic stirring. After cooling, the reaction mixture is filtered and the filtrate is then evaporated on a water bath under vacuum. The residue is taken up with 50 cm3 and alkalinized with 10 cm3 of normal sodium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8](O)=[O:9])=[C:6]([F:15])[C:5]=1[F:16].S(Cl)([Cl:19])=O>>[CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8]([Cl:19])=[O:9])=[C:6]([F:15])[C:5]=1[F:16]
Reactant: O=S(Cl)Cl
Reactant: COCc1c(F)c(F)c(C(=O)O)c(F)c1F
Product: COCc1c(F)c(F)c(C(=O)Cl)c(F)c1F
Reaction time: 3 h

Procedure:
4-(Methoxymethyl)-2,3,5,6-tetrafluorobenzoic acid [5.0 g prepared by a process similar to that described in European Patent Application No. 54360] was dissolved in thionyl chloride (50 cm3) and heated to the reflux temperature with stirring for 3 hours. The excess thionyl chloride was evaporated under reduced pressure to yield 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzoyl chloride (ca 5 g) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11]Cl)[CH3:9].[N+:15]([C:18]1[N:22]2[N:23]=[C:24]([SH:27])[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1)([O-:17])=[O:16].C1CCN2C(=NCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:13][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:9])[CH2:10][CH2:11][S:27][C:24]1[CH:25]=[CH:26][C:21]2[N:22]([C:18]([N+:15]([O-:17])=[O:16])=[CH:19][N:20]=2)[N:23]=1
Reactant: CN(CCCl)c1ccnc(CO)c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(S)nn12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CN(CCSc1ccc2ncc([N+](=O)[O-])n2n1)c1ccnc(CO)c1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 71.2 %

Procedure:
0.33 g (1.28 mmol) of {3-chloro-4-[(2-chloro-ethyl)methylamino]pyridin-2-yl}methanol and 0.33 g (1.68 mmol) of 3-nitroimidazo[1,2-b]pyridazine-6-thiol are dissolved in 10 ml of anhydrous dimethylformamide under an argon atmosphere, and the solution is treated with 0.25 ml (1.53 mmol) of DBU and then stirred at 50° C for 5 h. It is then cooled to room temperature and diluted with ethyl acetate. The precipitate is filtered off, washed with ethyl acetate and diethyl ether and dried. 0.36 g (71%) of the title compound is isolated as a pale beige solid. M.p. 189-191° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2ccccn2)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccn2)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 5-methyl-3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (4.1 g, 18 mmol) in THF (229 mL) at 0° C. was added lithium aluminum hydride (367 mg, 10 mmol). And the resulting mixture stirred for 1 h at room temperature. Water (1.9 mL) was added carefully followed by aqueous sodium hydroxide (15%, 1.9 mL) and water (0.54 mL). The resulting suspension was stirred for 15 min at ambient temperature and filtered over Hyflo®. Concentration and trituration with heptane afforded the title compound (2.88 g, 86%) as a light yellow solid. MS: m/e=191.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][CH3:13])=[CH:3]1.CCN(CC)CC.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]([CH3:13])[C:21](=[O:24])[CH:22]=[CH2:23])=[CH:3]1
Reactant: C=CC(=O)Cl
Reactant: CNCc1cn(C)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Reaction time: 1 h

Procedure:
To a stirred solution of 1-methyl-3-(methylaminomethyl)-1H-indole (1.0 g, 5.7 mmole) and Et3N (0.8 mL, 5.7 mmole) in CH2Cl2 (50 mL) at 0° C. was added acryloyl chloride (0.47 mL, 5.8 mmole) in one portion. After stirring for 1 h the reaction was washed with cold H2O and brine, then was dried (MgSO4) and concentrated under vacuum. This material was used without further purification.
Reaction SMILES: C([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[C:22]([CH:23]=O)[C:21]=1[OH:29]>>[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[C:22]([CH:23]=[N:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])[C:21]=1[OH:29]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=Cc1cc(Br)cc(Br)c1O
Product: CC(C)[C@H](N=Cc1cc(Br)cc(Br)c1O)C(=O)O
Yield: 68 %

Procedure:
The desired product was prepared in the same manner as the latter half procedure of Reference Example 1. That is, carbobenzoxy-(S)-valine piperizide (0.32 g, 1 mmol) was hydrogenated and then condensed with 3,5-dibromosalicylaldehyde (0.42 g, 1.5 mmol) to obtain 0.30 g (68%) of the desired N-(3,5-dibromosalicylidene)-(S)-valine piperizide, which was further recrystallized from methanol. m.p. 143.2°-145.4° C. [α]26D +50.1° (c 0.97, CHCl3)
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11]([OH:13])=O)[CH2:10][C:5]=2[N:4]=[CH:3]1.[C:14]1([CH:24]([NH2:26])C)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:24][NH:26][C:11]([CH:9]2[CH2:8][CH2:7][C:6]3[NH:2][CH:3]=[N:4][C:5]=3[CH2:10]2)=[O:13])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(N)c1cccc2ccccc12
Reactant: O=C(O)C1CCc2[nH]cnc2C1
Agent: Cl
Product: O=C(NCc1cccc2ccccc12)C1CCc2[nH]cnc2C1
Yield: 65.5 %

Procedure:
By a similar procedure as described in Example 1 using 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid, hydrochloride (2.2 g, 10 mmol) and 1-(naphth-1-yl)ethylamine (1.6 g, 10 mmol), 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid (naphth-1-ylmethyl)amide (2.0 g, 67%) was obtained. The free base was dissolved in 1 N hydrochloric acid (5 ml) and the mixture was diluted with H2O (10 ml). On standing a precipitate was formed which was isolated and dried to give the title compound (0.95 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH3:10])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:1]([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH3:10])[CH2:4]1)#[N:2]
Reactant: CC(CN1CCC(C#N)C1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CN1CCC(C#N)C1)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-(3-cyano-pyrrolidin-1-yl)-1-methyl-ethyl]-amide (37 mg, 0.062 mmol) was dissolved in dichloromethane (0.8 ml) and cooled in ice bath. Trifluoroacetic acid (0.4 ml) was slowly added and the reaction was stirred at room temperature for 2 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1.2 ml). Ethylenediamine (0.25 ml, 3.7 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 15 mg (52%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-(3-cyano-pyrrolidin-1-yl)-1-methyl-ethyl]-amide. MS: (M+H)+=463; mp=206-209° C. 1H NMR (300 MHz, DMSO-d6) δ: 12.83-12.94 (m, 1H), 9.10 (s, 1H), 8.38-8.51 (m, 2H), 8.04-8.13 (m, 1H), 7.99-8.04 (m, 1H), 7.30-7.39 (m, 1H), 4.20-4.36 (m, 1H), 4.18 (s, 3H), 3.07-3.22 (m, 1H), 2.53-2.88 (m, 5H), 1.99-2.15 (m, 1H), 1.74-1.92 (m, 1H), 1.33 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[CH:3][CH:2]=1.CSC.C(#N)C.[Br:24]Br>C(Cl)Cl>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][C:9]([Br:24])=[CH:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(-n3cccc3)cc2)cc1
Reactant: BrBr
Solvent: CSC
Solvent: CC#N
Solvent: ClCCl
Product: Brc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Temperature: 10 °C
Yield: 40 %

Procedure:
To a mixture of N-biphenyl-4-yl-1H-pyrrole (500 mg, 2.28 mmol), dimethylsulfide (0.25 mL, 3.4 mmol), CH2Cl2 (30 mL), and acetonitrile (10 mL) at −10° C. was added dropwise a solution of bromine in CH2Cl2 (5 mL) over 15 minutes. The mixture was allowed to warm to 10° C. over 2 hours. The resultant mixture was washed with 1M pH 7 phosphate buffer (50 mL) and extracted with CH2Cl2 (25 mL). The combined organic layers were dried over Na2SO4 and concentrated to a crude residue which was purified via flash column chromatography with 0-10% CH2Cl2/hex gradient eluant to furnish 240 mg (40%) of N-(biphenyl-4-yl)-3-bromo-1H-pyrrole as a white solid, mp 141-3° C. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=8.1 Hz), 7.49-7.34 (m, 5H), 7.12 (s, 1H), 7.02 (t, 1H, J=2.6 Hz), 6.36 (dd, 1H, J=3.2, 1.7 Hz). Anal. Calculated for C16H12NBr: C, 64.45; H, 4.06; N, 4.70; Br, 26.80. Found: C, 64.37; H, 4.10; N, 4.64; Br, 26.69.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:3])[CH3:2].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:19])[C@@H:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:3])[CH3:2]
Reactant: CCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxononyl)-2-oxazolidinone (10.09 g), prepared in Referential Example 71, and tert-butyl bromoacetate (30 ml), the desired compound (12.62 g) was obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([N:7]=[N:8][C:9]([C:17]#[N:18])([CH3:16])[CH2:10][C:11]([O:13]CC)=[O:12])([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([N:7]=[N:8][C:9]([C:17]#[N:18])([CH3:16])[CH2:10][C:11]([OH:13])=[O:12])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC(C)(C#N)N=NC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC(C)(C#N)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5.6 grams (0.07 moles) of 50% sodium hydroxide in 20 ml of methanol was added 11.25 grams (0.05 moles) of ethyl 3-t-butylazo-3-cyanobutyrate (from Example XXVI). The reaction mixture was stirred for 1 hour at room temperature, poured into 100 ml of water and extracted with 50 ml of pentane to remove any unsaponified ester. The aqueous layer was separated, acidified with HCl to a pH of 1. A solid formed which was filtered off, washed with water and pentane and air dried. The solid weighed 6.0 grams. The infrared spectrum of a nujol mull of the solid was in agreement with the structure of 3-t-butylazo-3-cyanobutyric acid. The melting point was 136°-145°C (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[C:15]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)=[N:16][C:17]([NH:20][CH2:21][CH2:22][NH:23]C2C=CC(C(F)(F)F)=CN=2)=[N:18][CH:19]=1>>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][CH2:22][CH2:21][NH:20][C:17]2[N:16]=[C:15]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[C:14]([C:10]3[NH:9][CH:13]=[CH:12][N:11]=3)=[CH:19][N:18]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: N#Cc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)cc1
Product: N#Cc1ccc(-c2nc(NCCNc3cc(Cl)ncn3)ncc2-c2ncc[nH]2)cc1

Procedure:
4-[2-({2-[(6-chloropyrimidin-4-yl)amino]ethyl}amino)-5-imidazolylpyrimidin-4-yl]benzenecarbonitrile was prepared from 4,6-dichloropyrimidine using the general method for 4-{5-imidazolyl-2-[(2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amino]pyrimidin-4-yl}benzenecarbonitrile.
Reaction SMILES: [N:1]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]=[S:3].[C:9]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[C:9]1([N:15]2[CH2:20][CH2:19][N:18]([C:2]([NH:1][C:4](=[O:5])[O:6][CH2:7][CH3:8])=[S:3])[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)N=C=S
Solvent: CC(C)=O
Product: CCOC(=O)NC(=S)N1CCN(c2ccccc2)CC1
Yield: 71.5 %

Procedure:
To a solution of ethyl isothiocyanatoformate (8.1 g, 62 mmol) in acetone (30 mL) was added 1-phenylpiperazine (10 g, 62 mmol), and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated, and the crude crystal was recrystallized from ethyl acetate to obtain a title compound (13 g, yield 73%).