Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=[O:15])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.[CH3:25][O-:26].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=[O:15])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:26][CH3:25])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.1 %

Procedure:
0.35 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one, 0.96 g of sodium methoxide (28%-methanol solution) and 6 ml of methanol were mixed and stirred for 14 hours under reflux with heating. Next, to the reaction mixture was added 0.96 g of sodium methoxide (28% methanol solution), and stirred for 9 hours under reflux with heating. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: hexane+tert-butyl methyl ether), to obtain 0.25 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methyl-2H-pyridazin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[N:12](C(OC(C)(C)C)=O)[C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccc(Cl)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(Cl)cc1

Procedure:
Dissolve 3-[(p-chlorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (15 mL). Add trifluoracetic acid (5 mL) and stir for 5 hours. Concentrate the reaction in vacuo, dilute with ethyl acetate (100 mL), wash with saturated sodium carbonate, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound (1.3 g).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[O:33]1[C:37](=[O:38])[CH2:36][CH2:35][C:34]1=[O:39].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([OH:39])=[O:33])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CCC(=O)O1
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCN(C(=O)CCC(=O)O)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) was dissolved in DMF (4 ml), and dihydrofuran-2,5-dione (50 mg) and K2CO3 (125 mg) were added thereto, followed by stirring at room temperature for 1 hour. Water and 1 M hydrochloric acid were added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-4-oxobutanoic acid (168 mg).
Reaction SMILES: [Li]CCCC.CCCCCC.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].CC(C)([O-])C.[K+].[C:32](=[O:34])=[O:33]>C1COCC1.O>[F:12][C:13]1[C:21]([C:32]([OH:34])=[O:33])=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][C:14]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=C=O
Reactant: Fc1cc2[nH]ccc2cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(C(F)(F)F)cc2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A 1.6 molar solution of n-BuLi in hexane (1.38 ml, 2.2 mmol) was diluted with 3 ml THF and cooled to −78° C. Then, a solution of 203 mg of 6-fluoro-5-trifluoromethyl-1H-indole (1 mmol) in 1 ml THF was added dropwise, keeping the internal temperature below −70° C. After 5 min a solution of 269 mg potassium tert-butoxide (2.4 mmol) in 1 ml THF was added, again keeping the internal temperature below −70° C. The reaction mixture was then stirred for 2 h. Then dry ice was added and the mixture was allowed to warm to 10° C. Water was added and the phases were separated. The aqueous phase was washed twice with ether, then acidified with 1 N HCl solution and extracted several times with DCM. The combined DCM extracts were dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining residue was triturated with pentane. Final filtration yielded 105 mg (42%) of 6-fluoro-5-trifluoromethyl-1H-indole-7-carboxylic acid as an off-white solid. 1H-NMR (DMSO-d6, 300 MHz): δ 6.63 (m, 1H), 7.43 (t, J=3 Hz, 1H), 8.15 (d, J=7 Hz, 1H), 11.49 (br s, 1H), 13.70 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH2:37][CH:38]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([NH:37][CH:38]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39]2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)NC2CCN(C(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60.2 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (711 mg) and tert-butyl 3-amino-1-pyrrolidinecarboxylate (372 mg) in methylenechloride (15 ml) was added N-ethyldiisopropylamine (0.51 ml), and the mixture was stirred under reflux for 17 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% methanol/methylenechloride to give tert-butyl 3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-pyrrolidinecarboxylate (511 mg) as a solid.
Reaction SMILES: [C:1]1([CH:7]([NH:19][S:20]([CH2:23][C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:21])[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CCOC(C)=O>[Br-:28].[O:31]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][N+:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:19][S:20]([CH2:23][C:24]([F:26])([F:27])[F:25])(=[O:22])=[O:21])[CH2:12]2
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)CC(F)(F)F)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NS(=O)(=O)CC(F)(F)F)c1ccccc1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(2,2,2-trifluoroethyl-sulfonamido)acetate (C78) (60 mg, 0.15 mmol) in EtOAc (2 ml), was added 2-bromo-1-phenylethanone (35.3 mg, 0.18 mmol). The reaction was stirred at RT for 16 hours. Then the solvent was evaporated, and the crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-(2,2,2-trifluoroethylsulfonamido)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (5 mg; 6% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1.[Li]CCCC.[C:17](=[O:19])=[O:18]>C1COCC1>[CH:7]1([N:5]2[CH:6]=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=[N:4]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C=O
Reactant: Brc1cnn(C2CCCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnn(C2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of 4-bromo-1-cyclopentyl-1H-pyrazole (9.0 g, 42 mmol) in THF (100 mL) at −78° C. under nitrogen was added a solution of n-BuLi in hexanes (2.5 M, 18.5 mL, 46.2 mmol). The resulting mixture was stirred at −78° C. for 30 min. Dry-ice (solid CO2) was added at −78° C. and the reaction mixture was allowed to slowly warn to RT overnight. The solvent was removed under reduced pressure. Water was added, and the mixture was acidified (pH 3) by the addition of aq. HCl. The aqueous layer was extracted with EtOAc, and the extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized (EtOAc-petroleum ether) to provide 1-cyclopentyl-1H-pyrazole-4-carboxylic acid (3.5 g, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.50 (br s, 1 H), 8.31 (s, 1 H), 7.85 (s, 1 H), 4.78 (m, 1 H), 2.16-1.68 (m, 8 H); MS (ESI) m/z: 181.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[CH:25]=[C:26]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:36]([C:31]3[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=4)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Product: Cc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methyl-biphenyl-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>ClCCl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:12]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1ccc(Br)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)ethanol (3.01 mmol) in dichloromethane (5 mL) and pyridine (10 mL) was treated with 4-(dimethylamino)pyridine (0.151 mmol) and acetic anhydride (9.04 mmol). The reaction was stirred overnight at room temperature. At this point the reaction was diluted with dichloromethane (100 mL). The organic layer was washed three times with 1N aq HCl, once with saturated aq sodium bicarbonate, and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale beige oil (710 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 1.96 (s, 3 H) 2.90 (t, J=6.44 Hz, 2 H) 4.20 (t, J=6.57 Hz, 2 H) 7.26-7.43 (m, 2 H) 7.51 (dd, J=9.73, 1.89 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: N#Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C#N)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-cyano-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.97 min; [M+H]+=402.37.
Reaction SMILES: C(OC([N:8]([CH:27]1[CH2:29][CH2:28]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:26])[O:24][CH3:25])[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:27]1([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:26])[O:24][CH3:25])[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=2)[CH3:10])[CH2:29][CH2:28]1
Reactant: CCc1ncc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc1CCCNC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncc(C(C)NC2CC2)cc1CCCNC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-ethylpyridin-3-yl)propyl]carbamate (204 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice-cooled aqueous saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: chloroform→chloroform/methanol=21/1) to give methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-ethylpyridin-3-yl}propyl)carbamate [REx(113-8)] (142 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[NH2:18].O.[Cl-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCCC>[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[NH:18][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CC(=O)Nc1c(Br)cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of diketene (57.71 mL, 748.2 mmol) was added dropwise over 2 h to a stirred solution of title compound of Step A (34.57 g, 149.6 mmol) and 4-dimethylaminopyridine (914 mg, 7.48 mmol) in dry tetrahydrofuran (450 mL) at room temperature under a nitrogen atmosphere. The reaction was allowed to stir at room temperature overnight. First, water was added to the reaction, and then the reaction mixture was poured into water. The mixture was saturated with sodium chloride and was extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give a brown oil. The brown oil was suspended in 1-chlorobutane. The resultant precipitate was filtered from this suspension to afford the title compound of Step B as a brown solid melting at 136°-138° C. (21.67 g, 46%). 1H NMR (CDCl3): δ2.35 (s,3H), 2.41 (s,3H), 3.63 (s,2H), 7.69 (s,2H), 9.6 (br s, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([N:29]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])C(=O)OCCCC)[C:10]3[N:11]([C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22](=[O:27])[NH:23][CH:24]5[CH2:26][CH2:25]5)=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O>ClCCl>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([NH:29][CH2:37][CH2:38][C:39]([F:40])([F:41])[F:42])[C:10]3[N:11]([C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([NH:23][CH:24]5[CH2:25][CH2:26]5)=[O:27])=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCCOC(=O)N(CCC(F)(F)F)c1cc(NC2CCCC2)nn2c(-c3ccc(C(=O)NC4CC4)c(C)c3)cnc12
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(NC4CCCC4)nn23)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 90 mg (153 μmol) ert-butyl {6-(cyclopentylamino)-3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,2-b]pyridazin-8-yl}(3,3,3-trifluoropropyl)carbamate which was prepared according to intermediate example 453a in 1 mL dichloromethane were added 177 μL trifluoroacetic acid and the mixture was stirred for 2 hours at 23° C. The mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 64.1 mg (82%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][NH:18][CH3:19].C(O)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:18]([CH3:19])[CH3:17])[CH:3]=1
Reactant: CNC
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)c1cc(Br)ccc1C=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a suspension of 4-bromo-2-fluorobenzaldehyde (500 mg, 2.46 mmol) and potassium carbonate (340 mg, 2.46 mmol) in 5 mL of dry N,N-dimethylformamide was added dimethylamine/ethanol solution (0.67 mL, 5.6 M, 3.8 mmol) at room temperature. After being stirred at 110° C. overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a yellow oil (458 mg, 81%).
Reaction SMILES: ON[C:3]([CH2:5][N:6]([CH2:20]C(C)C)[C:7](=[O:19])[CH2:8][CH:9]([CH2:15]C(C)C)[C:10]([N:12](C)C)=[O:11])=[O:4].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:45]([O:52]N)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH2:45]([O:52][C:3]([CH2:5][N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH:9]([CH3:15])[C:10]([NH2:12])=[O:11])=[O:4])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)CC(CC(=O)N(CC(=O)NO)CC(C)C)C(=O)N(C)C
Reactant: NOCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(CC(=O)N(C)CC(=O)OCc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 40.9 %

Procedure:
N4 -(Hydroxycarbamoyl-methyl)-2,N4 -diisobutyl-N1,N1 -dimethyl-succinamide (1.30 g, 0.0041 mol) was dissolved in DMF (10 ml) and treated at 0° C. with NMM (0.56 g, 0.0041 mol) followed by EDC (0.95 g, 0.005 mol) and HOBt (0.67 g, 0.005 mol). The reaction mixture was allowed to stir at 0° C. for 20 minutes and then at ambient temperature for 2 hours before O-benzylhydroxylamine (0.76 g, 0.0062 mol) was added. The reaction mixture was allowed to stir at room temperature for a further 1.5 hours. The solvent was removed under reduced pressure and the resulting crude oil was taken up in ethyl acetate (100 ml). The solution was washed consecutively with saturated aqueous NaHCO3, 1M HCl and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to a crude oil. The crude oil was purified by flash chromatography (silica gel, gradient elution with 5% to 10% methanol in dichloromethane) to give the title compound as a white solid (0.49 g, 29%). 1H NMR: δ(CD3OD), 7.38-7.21 (5H, br m). 4.75 (2H, s), 4.11-3.65 (2H, br m), 3.25 (1H, br m), 3.17-2.97 (2H, br m), 3.07 (3H, s), 2.81 (3H, s), 2.79-2.24 (2H, br m), 1.75 (1H, br m), 1.55-1.25 (3H, br m) and 0.91-0.64 (12H, br m).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22].ClCCl>N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccc(Cl)c(Cl)c2)CS1)c1ccccc1
Yield: 29.7 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (as prepared in example 1) (8.99 g, 39.8 mmol) was reacted with 8.3 g (39.6 mmol) of 3,4-dichlorobenzoylchloride in-dichloromethane (30 mL) and pyridine (9.6 mL) as described in Example 2 to yield 4.86 g of the desired compounds in 1:1 ratio.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:26]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:30]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate (0.96 g) in a mixed solvent of acetone (10.0 mL)-acetonitrile (10.0 mL)-water (10.0 mL) were added osmium oxide (fixed catalyst I) (0.34 g) and sodium periodate (2.86 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The insoluble substance was removed by filtration, and the filtrate was washed with saturated aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.17 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[SH:11])[C:6]#[N:7])#[N:2].[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:1]#[N:2])(=[O:19])[CH3:18]
Reactant: N#Cc1ccc(S)c(C#N)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2C#N)SC[C@H]1OC(C)=O
Yield: 40.5 %

Procedure:
If the procedure described in Preparation I is followed starting from 1.5 g (9.10-3 mol) of 3-cyano-4-mercaptobenzonitrile, 2.78 g (11.10-3 mol) of mercuric cyanide, Hg(CN)2, and 3.66 g (11.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.65 g (yield: 40.5%) of the expected product are obtained.