Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=O)(C)(C)C.C[Si]([N:20]=[C:21]=[O:22])(C)C.C(Cl)[Cl:24]>>[ClH:24].[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]([C:21]([NH2:20])=[O:22])[CH2:10]2
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: ClCCl
Product: Cl
Product: NC(=O)N1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.5 g, 11.7 mmol) in CH2Cl2 (50 mL) was treated with trimethylsilyl isocyanate (14 mL, 117 mmol). The resultant mixture was stirred at rt for 4 h., concentrated and redissolved in CH2Cl2 (50 mL). To this solution was added HCl (4.0 N in 1,4-dioxane, 12 mL), and the resultant mixture was stirred at rt for 3 h. Concentration afforded the title compound as a white powder (2.4 g, 99%). MS (ESI): mass calcd. for C7H13N3O, 155.1; m/z found, 156.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[O:18])[CH:15]=3)[N:10](CO)[N:9]=2)[CH:5]=[CH:6][CH:7]=1>CO>[NH3:9].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc2c(c1)c(-c1cccc(F)c1)nn2CO)c1cccs1
Solvent: CO
Product: N
Product: O=C(c1ccc2[nH]nc(-c3cccc(F)c3)c2c1)c1cccs1
Yield: 141.5 %

Procedure:
By treating 17 mg of [3-(3-fluorophenyl)-1-(hydroxymethyl)-1H-5-indazolyl](2-thienyl)methanone, a by-product formed by incomplete deprotection in the above reaction, with concentrated aqueous ammonia solution in methanol, 11 mg of the title compound was further obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH2:16][CH:17]([CH2:31][C:32]1([F:37])[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:18]([NH:20][C:21]1([CH:26]([C:28](=[O:30])[NH2:29])[OH:27])[CH2:24][CH:23]([F:25])[CH2:22]1)=[O:19].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]1([CH:26]([C:28](=[O:30])[NH2:29])[OH:27])[CH2:22][CH:23]([F:25])[CH2:24]1)[CH2:31][C:32]1([F:37])[CH2:36][CH2:35][CH2:34][CH2:33]1)[CH3:15]
Reactant: NC(=O)C(O)C1(NC(=O)C(N)CC2(F)CCCC2)CC(F)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(N)=O)CC(F)C1
Yield: 68.9 %

Procedure:
Diisopropylethylamine (0.087 mL, 0.5 mmol) and ethyl chloroformate (0.024 mL, 0.25 mmol) were added to a stirred solution of the amine A1-b, 2-amino-N-[1-(carbamoyl-hydroxy-methyl)-3-fluoro-cyclobutyl]-3-(1-fluorocyclopentyl)-propionamide (0.23 mmol) in DMF. After 15 min sat. aq. NaHCO3 and DCM were added and the organic layer was collected and concentrated and purified on flash silica gel column using DCM-MeOH 0-10% which gave the title compound (62 mg) [M+1]+391.9.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][N:16]([C:18]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:17]=2)=[CH:9][CH:8]=1)[C:4]([O-])=[O:5].[K+].C(N(C(C)C)CC)(C)C.COCCN(S(F)(F)F)CCOC.Cl.[CH3:67][NH:68][O:69][CH3:70]>CN(C=O)C.O>[CH3:70][O:69][N:68]([CH3:67])[C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[N:15][N:16]([C:18]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH:17]=2)=[CH:11][CH:12]=1
Reactant: CNOC
Reactant: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(-c3ccc(C(OC)C(=O)[O-])cc3)cn2)cc1
Agent: COCCN(CCOC)S(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(-c3ccc(C(OC)C(=O)N(C)OC)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To an ice-cold solution of potassium 2-methoxy-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetate (1.25 g, 2.1 mmol) in anhydrous DMF (10 mL) under argon was added diisopropylethylamine (0.54 mL, 3.1 mmol) and bis(2-methoxyethyl)aminosulfur trifluoride (0.46 mL, 2.5 mmol) dropwise. The reaction was stirred for 30 min then N,O-dimethylhydroxylamine hydrochloride (0.303 g, 3.1 mmol) was added. After stirring for a further 15 min over an ice bath, the mixture was allowed to warm to room temperature and stirred for 3.5 hrs. H2O was added and the mixture was extracted with EtOAc. The combined organics were washed with H2O, saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (45-90% EtOAc-hexanes; EtOAc containing 1% Et3N) to give N,2-dimethoxy-N-methyl-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetamide (0.478 g from two reactions, 32% yield overall).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CC1Cc2ccccc2N1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3c4ccccc4CC3C)c2cc1OC
Yield: 91 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 91% yield from 2-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 154°-156.5° C.; GC-MS: 321 (M+); anal. RP18-HPLC RT: 4.93 min.).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][N:30]([CH:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)[C:31](=[O:33])[CH3:32]>>[CH3:29][N:30]([CH:34]1[CH2:38][CH2:37][N:36]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:35]1)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: CC(=O)N(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N-methyl-N-(pyrrolidin-3-yl)acetamide via General Procedure E to give 25.5 mg of 298 following reverse phase purification. MS (Q1) 504.2 (M)+
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([OH:17])=O)[N:10]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(N=C=NCCCN(C)C)C.Cl.[CH2:58]([O:65][NH2:66])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C)C=O.O>[CH2:58]([O:65][NH:66][C:15]([C@H:11]1[CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][N:10]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:17])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)O)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylic acid (206 mg, 0.5 mmol) is dissolved in N,N-dimethylformamide (20 mL) and is cooled to 0° C. To this is added 1-hydroxybenzotriazole (203 mg, 1.5 mmol), 4-methylmorpholine (0.16 mL, 1.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (117 mg, 0.61 mmol) followed, after 20 minutes, with O-benzylhydroxylamine hydrochloride (89 mg, 0.56 mmol). The reaction is stirred for 4 hours at room temperature, water (50 mL) is added and the product is extracted with ethyl acetate (3×). The combined organic phases are washed with water (2×), dried (Na2SO4) and concentrated under reduced pressure to give N-benzyloxy 1-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](CC(N)=O)(C)C.[NH2:26][CH:27]1[C:48](=[O:49])[N:29]2[C:30]([C:45]([OH:47])=[O:46])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH2:41][C:42]([OH:44])=[O:43])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([NH:26][CH:27]1[C:48](=[O:49])[N:29]2[C:30]([C:45]([OH:47])=[O:46])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH2:41][C:42]([OH:44])=[O:43])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12)=[O:12]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csnn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Phosphorus oxychloride (0.65 g.) was added under ice-cooling to dry dimethylformamide (0.31 g.) and the mixture was stirred for 30 minutes at 40° C. Dry ethyl acetate (15 ml.) was added thereto and to the suspension was added under ice-cooling 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)-acetic acid (syn isomer) (0.65 g.), after which the resulting mixture was vigorously stirred for 30 minutes at the same temperature to give a solution. On the other hand, trimethylsilylacetamide (4.20 g.) was added to a suspension of 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.20 g.) in dry ethyl acetate (50 ml.),. and the mixture was stirred for 2.5 hours at ambient temperature. To this suspension was at a time added at -20° C. the above-obtained ethyl acetate solution, and the resulting mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was extracted after addition of ethyl acetate (70 ml.) and water (35 ml.). The organic layer was extracted with a sodium bicarbonate aqueous solution (35 ml.). To the aqueous extract was added ethyl acetate (70 ml.), and the mixture was adjusted to pH 2.0 with conc. hydrochloric acid with stirring and then the ethyl acetate layer was separated. The ethyl acetate layer was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give white powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.36 g.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Mg+2].[Cl-].[Cl-].O>CN(C)C(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:14]=[CH:15][C:16]([C:19]3[NH:24][N:23]=[N:22][N:20]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 150 °C

Procedure:
The product from Example 4A (300 mg, 1.08 mmol) in N,N-dimethylacetamide (10 mL) was treated with NaN3 (0.7 g, 10.8 mmol) and MgCl2 (1.03 g, 10.8 mmol). The mixture was heated at 150° C. for 16 hours, allowed to cool to room temperature, and poured into H2O (50 mL). The mixture was filtered and the filter cake air-dried to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.97 (d, j=8.4 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 1.29 (s, 9H); MS (ESI+) m/z 322 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](N)CC2
Yield: 90.5 %

Procedure:
(S)-4-[2-(tert-Butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylbutyramide (396 mg) was dissolved in dichloromethane (5 ml), a solution of trifluoroacetic acid (5 ml) in dichloromethane (5 ml) was added to the solution under ice-cooling with stirring, and the mixture was still stirred for 15 minutes. After reaction at room temperature for 15 minutes, the reaction mixture was concentrated in vacuo. Dichloromethane, water and sodium bicarbonate were added to the resulting residue and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give (S)-4-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylbutyramide (263 mg) as an oil.
Reaction SMILES: S(O[CH:12]1[CH2:30][CH2:29][N:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]2[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:31][NH:32][CH3:33].O>CS(C)=O>[CH3:31][N:32]([CH3:33])[CH:12]1[CH2:30][CH2:29][N:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]2[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN3c4ccccc4Cc4ccccc4C3C2)cc1
Reactant: CNC
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g of 2-tosyloxy-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a] -dibenzo[ c,f]-azepine (eg.) are dissolved in 50 ml of dimethylsulphoxide. After that 15 ml of dimethylamine are added to the solution. This solution is now heated in a sealed ampoule on a vapour-bath for 2 hours. After cooling the solution, it is poured into 300 ml of water after which the mixture is extracted with 3×200 ml of ether. The ether layers are washed and then dried, whereupon the solvent is evaporated and the residue is recrystallized. Yield: 1.3 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[N:3]=1.[CH2:10]([O:12][C:13](=[O:26])[C:14]([CH3:25])([CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[S:24])[NH2:23])[CH2:18][CH2:17]1)[CH3:15])[CH3:11].[CH3:27]OC(OC)N(C)C.C(N(CC)CC)C>C(O)C>[CH2:10]([O:12][C:13](=[O:26])[C:14]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]2[S:24][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[N:3]=3)=[CH:27][N:23]=2)[CH2:20][CH2:21]1)([CH3:25])[CH3:15])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: ClCc1cccc(Br)n1
Reactant: CCOC(=O)C(C)(C)C1CCN(C(N)=S)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)C1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 2-bromo-6-chloromethylpyridine (2.14 g, 10.4 mmol) obtained in Step 1 of Example 1 in ethanol (30 ml), 2-methyl-2-(1-thiocarbamoylpiperidin-4-yl)propionic acid ethyl ester (2.44 g, 9.43 mmol) obtained in Step 1 was added and the mixture was heated at reflux for 5 hours. The reaction solution was cooled to room temperature, dimethylformamide dimethylacetal (1.9 ml, 14 mmol) and triethylamine (3.9 ml, 28 mmol) were added, and heated at reflux for 1 hour. After the reaction solution was concentrated, water was added, and the solution was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over magnesium sulfate and the residue obtained by vacuum concentration was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1 to 1:1) and the title compound (2.48 g, 60%) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][C:4]([C:6]3[CH:14]=[CH:13][C:9]4[O:10][CH2:11][O:12][C:8]=4[CH:7]=3)=[O:5])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCl)c1ccc2c(c1)OCO2
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2ccccc2)CC1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.8 %

Procedure:
5-(3-Chloropropionyl)-1,3-benzodioxole (3 g) and N-phenylpiperazine (2.4 g) were dissolved in DMF (20 ml), triethylamine (1.7 g) was then added and the mixture was stirred for 10 hours at room temperature. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was crystallized from methanol and the resulting crystals were recrystallized from ethanol to give 5-[3-(4-phenyl-1-piperazinyl)propionyl]-1,3-benzodioxole (4.0 g, 84% yield). The characteristics of this compound are shown in Table 3 as Compound 47.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][C:34]([NH:36][NH2:37])=[CH:35][C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)=[CH:35][C:29]=2[O:28]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccc2c(c1)OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccc2c(c1)OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2,2-difluoro-benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.0 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2].[C:13](O)([C:15](F)(F)F)=O.[C:20](OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC(C)=O>[CH3:20][C:13]1([CH3:15])[O:12][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=2[C:8](=[O:10])[O:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1ccc(O)c(C(=O)O)c1
Solvent: CC(C)=O
Product: CC1(C)OC(=O)c2cc(C#N)ccc2O1
Reaction time: 20 h
Yield: 18.5 %

Procedure:
To a suspension of 5-cyano salicylic acid (60 g, 0.368 mol) in TFA (134 mL, 1.76 mol) and TFAA (45 mL, 0.32 mol) was added dry acetone (20 mL) and heated to reflux. After each 1 h interval was added 15 mL of dry acetone for 4 times and the reflux continued for 20 h. The reaction mixture was concentrated under vacuum and crude purified by flash column chromatography over silica gel (230-400 mesh) using CH2Cl2 as an eluent to give the title compound as a white solid (12 g, 15%). TLC: CH2Cl2 (100%), Rf: 0.5
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)[CH3:33]>COCCOC>[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:33]
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 35.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-ethylphenylboronic acid (27 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.024 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product (19 mg, 36%). MS m/e 435.44 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
4-Fluoro-2-methylbenzoic acid (1.6 g, 10.3 mmol) was dissolved in CH2Cl2 (20 mL) and DMF (1 drop) and stirred as oxalyl chloride (10.3 mL, 20.8 mmol) was added. The reaction stirred for 15 minutes before the solvent was removed under reduced pressure. The product was dissolved in anhydrous CH2Cl2 and MeOH (5 mL) and stirred for a further 15 minutes. The solvent was removed under reduced pressure and purified by column chromatography on silica (2% EtOAc/Hexanes) to afford a colourless oil (1.33 g). 1H NMR (300 MHz, CDCl3): δ 7.95 (d, 1H), 6.96 (d, 1H), 6.75-6.77 (m, 1H), 3.86 (d, 3H), 2.62 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of 2,5-dichlorobenzoic acid (3 g, 15.7 mmol) in H2SO4 (16 mL) at 0° C. was added dropwise fuming nitric acid (1.4 mL, 31.4 mmol) and the reaction mixture was stirred for 5 minutes at 0° C., and was then gradually allowed to warm to over 20 minutes. The reaction was treated with ice water and extracted with EtOAc. The organic layer was washed with water and brine then dried (Na2SO4), filtered and concentrated to afford 3.54 g (48%) of 2,5-dichloro-3-nitrobenzoic acid which is contaminated with 3,6-dichloro-2-nitrobenzoic acid (40%): 1H NMR (300 MHz, CD3OD) δ 7.73 (s, 1H) 8.06 (d, J=2.6 Hz, 1H) 8.11 (d, J=2.6 Hz, 1H).