Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].FC1C=CC(N[C@H](CC)C(O)=O)=C([N+]([O-])=O)C=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH:7]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Product: C[C@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O

Procedure:
2,4-Difluoronitrobenzene was treated with L-alanine according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield N-(5-fluoro-2-nitrophenyl)-L-alanine. MS (ESI) m/z 229 ([M+H]+); MS (ESI) m/z 227 ([M−H]−); Anal. Calcd for C9H9FN2O4: C, 47.37; H, 3.98; N, 12.28. Found: C, 47.61; H, 4.23; N, 12.39.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][N:29]=1.BrC1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(SC)=C2)=NC=1>>[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:28]2[N:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][N:33]=2)[CH:4]=1
Reactant: CSc1c[nH]c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Reactant: Clc1ncc(-c2ccccc2)cn1
Agent: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12

Procedure:
Prepared from the product of 12b) (1.2 g, 3.2 mmol, 1.0 eq) and 2-chloro-5-phenylpyrimidine (0.604 g, 3.2 mmol, 1.0 eq) following the instructions of 1c). Yield: 700 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[CH3:27][NH:28][C:29]1[C:30]([NH2:37])=[CH:31][C:32]([CH3:36])=[C:33]([CH3:35])[CH:34]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[N:28]([CH3:27])[C:29]4[CH:34]=[C:33]([CH3:35])[C:32]([CH3:36])=[CH:31][C:30]=4[N:37]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: CNc1cc(C)c(C)cc1N
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1-c1nc2cc(C)c(C)cc2n1C
Yield: 24.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), N1,4,5-trimethylbenzene-1,2-diamine (Intermediate-31, 0.048 g, 0.32 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 2.36 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 7.33 (s, 1H), 7.41 (s, 1H), 7.47-7.59 (m, 3H), 7.66-7.78 (m, 3H), 12.5 (br s, 1H); MS (m/z): 478.29 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si]([C:18]#[N:19])(C)(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:18]([C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9][N:10]=1)#[N:19]
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-phenylpyridine N-oxide (5 g) in DCM (50 ml) was added at RT TMSCN (4 ml), and the solution was stirred for 5 min at RT. Then, dimethylcarbamoyl chloride (2.8 ml) was added at RT, and the resulting solution was stirred at RT for 48 h. To the reaction mixture was added a solution of aq. 10% K2CO3 (50 ml) and stirring was continued for 10 min. The phases were separated and the aq. layer extracted twice with DCM. The combined org. phases were dried over MgSO4 and evaporated off. Filtration over a plug of SiO2 (Hept/EA 8:2) gave 4.98 g of the desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:24]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Example 148 was prepared from N-(3-bromopropyl)-2,2-diphenyl acetamide and 2-methyl-N-[4-(4-piperidinyl) phenyl]propanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][N:19]([CH2:24][C:25]5[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=5[CH3:27])[CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Br)ccc2n1C1CCN(C2CCNCC2)CC1
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4cc(Br)ccc43)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 18, using 5-bromo-1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2-H-benzimidazol-2one and 2-methylbenzaldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH3:26])[CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1.[Si:27]([O:34][C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[CH:36]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([BH3-])#N.[Na+]>CO>[Cl:44][C:40]1[CH:39]=[C:38]([C@@H:35]([O:34][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28])[CH2:36][NH:8][C@H:9]([CH3:26])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
A mixture of 36.5 g of 5-{4-[2(R)-aminopropoxy]benzyl}thiazolidine-2,4-dione trifluoroacetate [prepared as described in Preparation 2], 98.4 g of (R)-α-(t-butyldimethylsilyloxy)-α-(3-chlorophenyl)acetaldehyde [prepared as described in Preparation 12] and 400 ml of absolute methanol was stirred at room temperature for 2.5 hours, after which the mixture was cooled using a salted ice-bath. 29.0 g of sodium cyanoborohydride were then added to the mixture in small portions, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the methanol was distilled off under reduced pressure, the residue was mixed with water and ethyl acetate, and the ethyl acetate layer was separated from the mixture. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 46.5 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:12]1>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:11][CH:12]=2)(=[O:21])=[O:22])=[O:25])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1csc2ccccc12
Reactant: COc1cc(C)nc(N)n1
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2csc3ccccc23)n1
Temperature: 25 °C

Procedure:
To 25 ml of anhydrous acetonitrile containing 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine was added 2.4 g of benzothiophene-3-sulfonyl isocyanate with stirring. The mixture was heated to boiling, allowed to cool to room temperature and then stirred overnight. The resultant precipitate was filtered off and washed with ether to yield 2 g of the desired product, m.p. 180°-181° C. It showed absorption by NMR (60 MC) at 2.24 δ (6-CH3 group), 3.8 δ (4-OCH3), 6.2 δ (5-H on pyrimidine), 7-8 δ (aryl H's on benzo) and 8.3 δ (H on thiophene portion).
Reaction SMILES: [N:1]1([C:7]([CH3:12])=[CH:8][C:9](=O)[CH3:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:13][C:14]([F:24])([F:23])[C:15](=O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)(=O)C>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[C:15]([C:14]([F:24])([F:23])[F:13])=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:8][C:9]=1[CH3:10])[CH3:21]
Reactant: CC(=O)C=C(C)N1CCOCC1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 33 %

Procedure:
A mixture of 4-morpholin-4-yl-pent-3-en-2-one (2.50 g, 14.8 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (3.0 g, 16.3 mmol) in acetic acid (40 ml) is heated at 120° C. for 3 h. After completion of the reaction (monitored by TLC), the solvent is distilled off, the residue is taken up in water (20 ml) and the pH of the mixture was adjusted to pH=8 with 25% aqueous ammonia. The aqueous layer is extracted with ethyl acetate (2×20 ml) and the combined organic layers are dried over sodium sulfate, evaporated and the crude product is purified by column chromatography (silica gel, 10% ethyl acetate/cyclohexane) to afford 2-methyl-4-morpholin-4-yl-6-(trifluoromethyl)-benzoic acid ethyl ester (1.55 g, 4.89 mmol, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C([O-])CCC.[Na+].[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>C(O)CCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])[CH2:10][N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(C)(C)C1(COc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: CCCC[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)C(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 36.8 %

Procedure:
376 g of crude 2-(4-chlorophenoxymethyl)-2-(1,1,2-trimethylpropyl)-oxirane dissolved in 400 ml of n-butanol are added dropwise to a boiling solution of 13.4 g (0.14 mol) of sodium butanolate and 97 g (1.4 mols of 1,2,4-triazole in 400 ml of n-butanol in 1.5 hours. After boiling under reflux for 22 hours, the solvent is removed by distillation under reduced pressure and 500 ml of dichloromethane are added to the residue. Precipitated 2-(4-chlorophenoxymethyl)-1-(1,2,4-triazol-4-yl)-3,3,4-trimethylpentan-2-ol (15 g; melting point 173°-174° C.) is filtered off from the mixture, the filtrate is washed twice with 250 ml of water each time and dried over anhydrous sodium sulphate and the solvent is removed by distillation. The residue is chromatographed on silica gel using trichloromethane as eluant. 174 g of 2-(4-chlorophenoxymethyl)-1-(1,2,4-triazol-1-yl)-3,3,4-trimethylpentan-2-ol are thus obtained in the form of colorless crystals of melting point 59°-60° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:21]Br.N>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[C:5]([Br:21])=[CH:4][N:3]=1
Reactant: Nc1nccc(NCC2(CO)CCC2)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Br)c(NCC2(CO)CCC2)n1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To 2-amino-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (0.21 g, 1.0 mmol) was added acetic acid (3 ml) and the mixture was heated to 110° C. Sodium acetate 3 hydrate (0.18 g) was added and bromine (60 μl) dissolved in acetic acid (0.5 ml) was dropwise added at 70° C. After cooling, water was added to the reaction mixture and the mixture was neutralized with aqueous ammonia under ice-cooling, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was recrystallized from acetone to give colorless prism crystals (0.21 g, 72.4%), m.p. 156-158° C. (acetone).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][OH:17]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH2:15][CH2:16][OH:17])[N:3]=1
Reactant: OCCCBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Br)nn(CCCO)c1Br
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (2.0 g; 7.38 mmol) in DMF (9.5 ml) was added over 15 minutes to a suspension of NaH (0.32 g, 8.0 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (16 ml) with stirring and under an inert atmosphere. After stirring for 15 minutes, a solution of 3-bromo-1-propanol (1.0 g; 7.19 mmol) in DMF (3.2 ml) was added dropwise. The reaction mixture was heated at 80° C. for 2 hours (monitored by TLC) and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (20 ml, 1/1) was added. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude reaction product was obtained as a black oil (1.9 g, 79%), which was used without further purification in the amination step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].I[C:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[N:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]3=[N:32][CH:31]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: Ic1cnc2ccccn12
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cnc3ccccn23)cc1OC(C)c1ccccc1Cl

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.0 Eq.), 3-Iodo-imidazo[1,2-a]pyridine (108 mg, 0.44 mmol, 1.2 Eq.) and Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.55 mL, 1.10 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% EtOAc/petroleum Ether) to give the sub-title compound as am off-white solid (61 mg, 0.15 mmol, 40%); 1H NMR (400 MHz, CDCl3) δ 1.77 (3H, d), 3.96 (3H, s), 5.86 (1H, q), 6.89 (1H, s), 7.28-7.43 (4H, m), 7.67 (1H, dd), 7.72-7.78 (1H, m), 7.83 (1H, s), 8.32 (2H, d).
Reaction SMILES: [CH2:1]([N:3]([CH2:11]C)[C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])C.Cl[C:14]#[N:15]>O.C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][N:3]([CH3:11])[C:4](=[O:10])[CH:5]([C:14]#[N:15])[C:6]([CH2:8][Cl:9])=[O:7]
Reactant: N#CCl
Reactant: CCN(CC)C(=O)CC(=O)CCl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: CN(C)C(=O)C(C#N)C(=O)CCl
Yield: 75.3 %

Procedure:
10.0 gm. (0.05 mole) of copper acetate was dissolved hot in 150 ml of H2O and added to a solution of 19.1 gm. (0.1 mole) of γ-chloroacetoacetic acid diethyl amide in 150 ml of benzene. After brief stirring the green benzene solution was separated and dried over MgSO4. Then 6.2 gm. (0.1 mole) of ClCN were introduced into the benzene solution -- the temperature was kept at 20° to 30° C. The precipitated CuCl2 was filtered off and the benzene solution was precipitated. 14.2 gm of α-cyano-γ-chloroacetoacetic acid dimethylamide was obtained, which corresponds to 65.6 percent of theoretical.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][C:5]2[N:4]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:23][N:24]=2)[N:3]=1
Reactant: Clc1cc(-c2ccncc2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Clc1nn2c(-c3ccccc3)nnc2cc1-c1ccncc1
Yield: 41.7 %

Procedure:
A mixture of 3,6-dichloro-4-(pyridin-4-yl)pyridazine (390 mg, 1.7 mmol), benzoyl hydrazine (260 mg, 1.9 mmol), triethylamine (270 ml, 1.9 mmol) and p-toluenesulphonic acid (32 mg, 0.2 mmol) in xylene (mixture of isomers) (5 ml) was stirred and heated at reflux under nitrogen for 20 hours. The mixture was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous was further extracted with dichloromethane (×3). The combined extracts were dried (sodium sulphate), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 3% methanol/dichloromethane to afford the title compound (218 mg, 42%) as a pale yellow solid. 1H NMR (360 MHz, d6-DMSO) δ 7.60-7.69 (5H, m), 8.36-8.38 (2H, m), 8.72 (1H, s), 8.78-8.80 (2H, m). MS (ES+) m/e 308 [MH]+, 310 [MH]+.
Reaction SMILES: OS(O)(=O)=O.[BrH:6].[NH2:7][C:8]1[NH:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]1[S:15][C:16]2[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][C:17]=2[N:18]=1.[OH-].[Na+]>>[Br:6][CH2:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([C:9]3[C:10]([CH3:13])=[N:11][NH:12][C:8]=3[NH2:7])[S:15][C:16]=2[CH:22]=1
Reactant: Br
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CO)cc2s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Temperature: 25 °C

Procedure:
To a solution of concentrated H2SO4 (0.3 mL) and hydrobromic acid (0.6 mL, 48%) was added [2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazol-6-yl]-methanol (52 mg, 0.2 mmol). The resulting mixture was refluxed for 2 hrs. Upon cooling to room temperature, the mixture was poured into ice water resulting a milky solution. The suspension was neutralized to pH 3-4 with 5% NaOH solution. The resulting cream coloured solid was isolated by filtration, washed with water and air-dried to yield 58 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine. The crude material was used in the subsequent step without further purification.
Reaction SMILES: CON(C)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC#N>CCOCC>[CH:14]1([O:13][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=2[O:11][CH3:12])[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1ccc(C(=O)N(C)OC)cc1OC1CCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(C(=O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
To an ice bath cooled stirred solution of N-methoxy-N-methyl-3-cyclopentoxy-4-methoxybenzamide (1.2 g, 4.3 mmol) in 15 mL of anhydrous ether was added a 3 M solution of phenylmagnesium bromide (3.6 mL, 10.8 mmol) in ether dropwise over a 20 minute period. A white gum precipitated from the mixture and dry THF (6 mL) was added to facilitate stirring. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction was then quenched at 0° C. with a saturated aqueous solution of ammonium chloride (8 mL). The resulting mixture was allowed to warm to room temperature and was diluted with ethyl acetate (10 mL). The organic layer was separated and sequentially washed with 1 N citric acid (2×10 mL), saturated NaHCO3(aq) (2×10 mL), and brine (2×10 mL). The organic layer was then dried over MgSO4, filtered and concentrated in vacuo to give a viscous oil. The crude product was purified by flash column chromatography (silica gel, methylene chloride) and the resulting product was then dried in vacuo (40° C., <1 mmHg) to afford 0.75 g (60%) of a slightly impure product as a white solid: mp 73.5-75.0° C.; 1H NMR (CDCl3) δ 7.80-7.72 (m, 2H), 7.63-7.15 (m, 5H), 6.94-6.79 (m, 1H), 4.91-4.78 (m, 1H), 3.92 (s, 3H), 2.09-1.50 (m, 8H) also some impurity in the aromatic region; 13C NMR (CDCl3) δ 195.7, 153.9, 147.5, 138.3, 131.8, 129.7, 128.1, 125.1, 120.3, 115.5, 110.3, 80.5, 56.1, 32.7, 24.1; HPLC (Waters Nova-Pak/C18 column, 3.9×150mrn, 4 micron, 1 mL/min, 60/40, CH3CN/0.1% H3PO4(aq)) 6.2, min 99%.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:5]([NH:6][CH:7]([CH3:11])[C:8](Cl)=[O:9])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.Cl.[CH3:21][NH:22][OH:23].C([O-])(=O)C.[Na+]>C(Cl)Cl.O>[CH3:21][N:22]([C:8](=[O:9])[CH:7]([NH:6][C:5]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=1[N+:17]([O-:19])=[O:18])[CH3:11])[OH:23]
Reactant: CNO
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of 2.0 g of 2-(4-methyl-2,6-dinitroanilino)propionyl chloride, prepared as in Example 1, in 50 ml of methylene chloride was added dropwise to a stirred solution of 2.0 g of N-methylhydroxylamine hydrochloride and 6.0 g of sodium acetate in 50 ml of water at 0°-5° C. The mixture was stirred for 2 hours, after which the organic layer was spearated, dried and evaporated to dryness. The yellow residue was recrystallised from benzene to give 3, m.p.: 171°-172° C.