Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]([F:38])([F:37])[CH2:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)O.[C:39]([O:43][C:44]([NH:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:48]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:39]([O:43][C:44]([N:46]([CH:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:18][CH2:17][C:16]([F:38])([F:37])[F:15])[C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:48]=1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: OC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
Diisopropyl azodicarboxylate (50 μL, 0.25 mmol) was added to a room temperature solution of 4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (84 mg, 0.24 mmol), methyl 6-(tert-butoxycarbonylamino)nicotinate (74 mg, 0.29 mmol), and triphenylphosphine (65 mg, 0.25 mmol) in 1.5 mL THF. The resulting solution was stirred overnight at room temperature. The solution was partitioned between dichloromethane and water. The organic layer was dried over MgSO4 and concentrated to give a colorless solid. Purification by silica gel chromatography provided methyl 6-(tert-butoxycarbonyl(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)amino)nicotinate (30 mg, 21%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.99-9.01 (m, 1H), 8.17-8.21 (m, 1H), 7.63-7.69 (m, 4H), 7.49-7.54 (m, 3H), 7.39-7.44 (m, 2H), 5.98-6.08 (m, 1H), 3.92 (s, 3H), 2.61-2.74 (m, 1H), 2.39-2.54 (m, 1H), 2.17-2.36 (m, 2H), 1.31 (s, 9H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:17])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)[C@@H]1CCCN(CCCCOc2ccccc2)C1
Yield: 90 %

Procedure:
A mixture of 4-phenoxy-1-butylbromide (10 g, 44 mmol), (R)-3-piperidine-carboxylic acid ethyl ester (15 g, 44 mmol), potassium carbonate (18 g, 131 mmol) and methyl isobutylketone (100 ml) was heated at reflux overnight. The reaction mixture was allowed to cool and then filtered. The solvent was evaporated from the filtrate in vacuo and the residue was purified by column chromatography on silica gel (300 g, heptane/ethyl acetate=4/1) to give 12.1 g of (R)-1-(4-phenoxy-1-butyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Cl[CH2:16][CH2:17][C:18](Cl)=[O:19].CCN(C(C)C)C(C)C>C1COCC1>[F:2][C:3]([F:13])([F:14])[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:17][C:18](=[O:19])[NH:12]2)=[CH:9][CH:10]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(c2ccc(OC(F)(F)F)cc2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.9 %

Procedure:
The compound was prepared according to Rees and Tsoi Chem. Commun. 2000, 415. A suspension of (4-trifluoromethoxyphenyl)-hydrazine hydrochloride (300 mg, 1.32 mmol, 1.00 eq), 3-chloropropionyl chloride (167 mg, 1.32 mmol, 1.00 eq), and PS-DIEA (1.30 grams (g), 5.28 mmol, 4.00 eq) in THF (20 mL) was stirred at ambient temperature for 12 h. The solution was then filtered, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (120 mg, 37%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](=S)[NH:12][C:11]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>P(Cl)(Cl)(Cl)=O>[Cl:18][C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][C:11]=2[N:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: S=c1[nH]c2cc(-c3ccccc3)ccc2o1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 640.1 %

Procedure:
5-Phenyl-3H-benzooxazole-2thione (227 mg, 1.0 mmol) was dissolved in phosphorus oxychloride (1.6 mL). Phosphorus pentachloride (208 mg, 1.0 mmol) was added and the mixture was placed in an oil bath at 100° C. for 3 h. The mixture was allowed to cool to RT and concentrated. The crude residue was concentrated from CH2Cl2 (3×). The crude reaction product was triturated with hexanes (40 mL), and the resulting solids were collected by filtration. The solids were washed with hexanes (20 mL×3) and dried to afford 1.47 g (73%) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, 1H, J=1.3 Hz), 7.60-7.56 (m, 3H), 7.55-7.52 (m, 1H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H), 13C NMR (CDCl3, 100 MHz) δ 151.6, 151.4, 141.9, 140.7, 139.3, 129.2, 127.8, 127.7, 125.2, 118.4, 110.7; MS (Cl) m/z 230.1 (M+1); HPLC retention time=5.41 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:21]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:20][N:19]=[CH:18][N:17]=2)[CH2:12]1.[ClH:35].CO>>[ClH:35].[NH:25]1[CH2:26][CH2:27][CH:22]([C:21]2[C:16]([O:15][CH:13]3[CH2:12][N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:14]3)=[N:17][CH:18]=[N:19][CH:20]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc2nc(N3CC(Oc4ncncc4C4CCNCC4)C3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of tert-butyl 4-(4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-5-yl)piperidine-1-carboxylate (307 mg, 0.66 mmol) in HCl/MeOH (10 mL, saturated with HCl gas) was stirred at room temperature for 1 hour. Then it was concentrated to give 2-(3-((5-(piperidin-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)quinoline hydrochloride which was used in the next step below without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine following a procedure analogous to that described for Intermediate 10. LC (method 3): tR=1.10 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)[CH:4]=1)#[N:2].C(=O)([O-])[O-:35].[K+].[K+].CS(C)=O.OO>C(OCC)(=O)C>[F:33][C:32]1[C:27]([C:23]2([CH2:22][NH:14][C:11]3[N:12]=[N:13][C:8]([N:5]4[CH:6]=[CH:7][C:3]([C:1]([NH2:2])=[O:35])=[CH:4]4)=[CH:9][CH:10]=3)[CH2:26][CH2:25][CH2:24]2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-n2ccc(C#N)c2)nn1
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)c1ccn(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
t-butyl 6-(3-cyano-1H-pyrrol-1-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (120 mg, 267 μmol), potassium carbonate (147 mg, 1.1 mmol), and DMSO (3 mL) were combined in a vial and cooled to 0° C. Hydrogen peroxide (700 uL) was added dropwise, and the reaction was warmed to rt and stirred for 1 h. The reaction was then poured into ethyl acetate (50 mL), washed with water (3×20 mL), and the organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in 50% TFA/CH2Cl2 (2 mL) and stirred for 30 min. The reaction was then concentrated and purified using reverse phase chromatography to give 29 mg of 1-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-pyrrole-3-carboxamide as a tan solid (M+H=367.1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:27]2[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (0.41 g, 2.1 mmol) and DIEA (0.31 ml, 1.8 mmol) in THF (10 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (0.20 g, 1.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (DCM:EtOAc=2.5:1) to give the title compound as a yellow solid (0.19 g, 45%). MS: Calcd.: 298; Found: [M+H]+ 299.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1csc2nc(-c3cnccn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12]OC(C)(C)C>C(Cl)Cl.C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([NH2:11])=[CH:3][C:2]=1[F:1]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CC(C)(C)OCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cc(F)c(Cl)cc1C(=O)O
Reaction time: 1.5 h
Yield: 111.2 %

Procedure:
To a solution of 4-fluoroanthranilic acid (0.882 g, 5.69 mmol) in methylene chloride (50 mL) and acetic acid (10 mL) is added tert-butyl hypochlorite (0.71 mL, 6.25 mmol) solution in dichloromethane (1 mL) dropwise over 1 minute. After 90 minutes, the reaction mixture is washed with water and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated to afford 5-chloro-4-fluoroanthranilic acid (1.20 g). MS CI: m/e 188 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH:9](OC)[N:8](C(OCC2C=CC=CC=2)=O)[C@@H:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1)=[O:4].[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CC(OC)N(C(=O)OCc2ccccc2)[C@@H](C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1CCN[C@@H](C(=O)OC(C)(C)C)C1

Procedure:
A mixture of (2R,4S)-6-methoxy-piperidine-1,2,4-tricarboxylic acid 1-benzyl ester 2-tert-butyl ester 4-methyl ester (4.85 g, 11.9 mmol) and 10% palladium on carbon (500 mg) in 100 mL of ethanol was shaken under a 45 psi atmosphere of hydrogen gas for 1.5 hours. The mixture was filtered through nylon and the filtrate was concentrated to provide (2R,4R)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester as light yellow oil, which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:34][O:35][C:36](=[O:58])[C@@H:37]([NH:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH:38]([CH3:40])[CH3:39]>N1C=CC=CC=1>[CH3:34][O:35][C:36](=[O:58])[C@@H:37]([NH:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:52]=[CH:53][C:54]([NH:57][C:20]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=5)[C:6]=4[C:2]=3[CH3:1])=[O:21])=[CH:55][CH:56]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH:38]([CH3:40])[CH3:39]
Reactant: Cc1c(C(=O)O)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5cccc([N+](=O)[O-])c5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To 100 mg (0.34 mmol) of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid was added 2 mL of oxalyl chloride and the resulting mixture was refluxed for 2 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 1 mL of dichloromethane and was added to a mixture of 183 mg (0.5 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 41 mg of (S)-3-methyl-2-(4′-{[3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid methyl ester as white solid.
Reaction SMILES: [F:1][CH:2]([C:8](=O)[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH3:14]>C1(C)C=CC=CC=1>[NH2:14][C:8]([C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: N
Reactant: CCOC(=O)C(F)C(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)=C(N)C(F)(F)F

Procedure:
Ethyl 2,4,4,4-tetrafluoro-3-oxobutanoate (81 g.) in toluene (60 ml) was stirred and heated to 70° C. whereupon ammonia gas was bubbled in until an uptake of 6.8 g. was recorded. The reaction was then set for reflux and water removed azeotropically. Approximately 10 ml of water was removed. After cooling, the solvent was removed under reduced pressure and the residue distilled to give ethyl 3-amino-2,4,4,4-tetrafluoro-2-butenoate b.p. 79°-86° C./20 mm, 44 g.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Clc1nccc(-c2cccs2)n1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nccc(-c4cccs4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-thiophen-2-yl-pyrimidine. MS (ESI) mass calcd. for C27H24N4OS, 452.57; m/z found, 453.1 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Cl.[CH3:18][NH:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([N:19]([OH:20])[CH3:18])=[NH:11]
Reactant: N#Cc1ccccc1N1CCCCS1(=O)=O
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(O)C(=N)c1ccccc1N1CCCCS1(=O)=O
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzonitrile and N-methylhydroxylamine hydrochloride (1.67 g, 20 mmol) in 1:1 water/ethanol (70 mL) was added sodium carbonate (1.06 g, 10 mmol) and the resulting mixture stirred at 90° C. for 18 h. After cooling and concentration, the resulting residue was suspended in MeOH/CHCl3 (100 mL, 1:9). The insoluble solids were removed by filtration and concentration of the filtrate gave the crude product as an amber oil (3.5 g) that was carried on without further purification. LCMS calcd for C12H17N3O3S (M+H): 284.35; found: 284.27.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])(C)(C)C>O1CCOCC1.Cl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][CH2:16][O:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[NH2:7]
Reactant: Cc1ccc(OCCCN(C)C)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(OCCCN(C)C)c(N)c1
Reaction time: 12 h

Procedure:
To a stirred solution of [2-(3-dimethylamino-propoxy)-5-methyl-phenyl]-carbamic acid tert-butyl ester (617 mg, 2.0 mmol) in 5 mL of dioxane was added hydrochloric acid (2 mL; 4N in dioxane). After stirring for 12 hours, the reaction was diluted with 20 mL of 1N hydrochloric acid and washed with ethyl acetate (2×30 mL). The aqueous layer was basified with 10% aqueous sodium carbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate was washed with brine (1×30 mL), there dried (MgSO4), and filtered. The filtered solution was concentrated under reduced to yield the corresponding aniline.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][CH2:5][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8].C=O.[C:19](=O)([O-])[OH:20].[K+]>>[OH:20][CH2:19][C:6]([C:11]([O:13][CH3:14])=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[O:15][CH3:16]
Reactant: COC(=O)C(CCC(OC)OC)C(=O)OC
Reactant: O=C([O-])O
Agent: C=O
Agent: [K+]
Product: COC(=O)C(CO)(CCC(OC)OC)C(=O)OC
Yield: 95 %

Procedure:
The hydroxymethylation of dimethyl 4,4-dimethoxybutane-1,1-dicarboxylate was carried out. The diester (23.4 g, 0.10 mol) was added dropwise to a mixture of formalin (8.1 ml, 0.10 mol) and potassium hydrogen carbonate (0.8 g, 8 mmol) over 20 min. The mixture was stirred at room temperature for 6 hours until the starting ester was completely consumed. A saturated aqueous solution of ammonium sulfate (35 ml) was added to the reaction mixture. The mixture was then extracted with three 60 ml portions of ethyl ether and the combined extracts were dried over anhydrous magnesium sulfate. The salt was filtered off and rotary evaporation of the solvent from the filtrate gave the product, at 95% yield, as viscous oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2.CN(C)C=O.[OH-].[Na+]>O1CCCC1>[O:22]=[C:16]1[CH2:15][C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][CH2:11][O:10][C:8](=[S:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:17]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: S=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1Cc2c(CCOC(=S)Nc3ccccc3)cccc2N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.9 %

Procedure:
Phenyl isothiocyanate (0.45 mL, 3.75 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (443 mg, 2.5 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 20 hours and then 70° C. for 8 hours. One mL of dimethylforamide was added to the mixture to make it homogenous and the heating was continued for another 42 hours. The reaction was cooled, poured into 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol/ethyl acetate/hexane to give 452 mg (58%) of phenyl-thiocarbamic acid O-[2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl]ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[NH:16]([C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].C([O-])(O)=O.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:10]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)cc1
Reactant: NNc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ncccn2)n1
Temperature: 60 °C

Procedure:
To a solution of 1-(4-fluorophenyl)-4-methyl-1,3-pentanedione (preparation disclosed in Example 1, Step A) (155 g, 0.74 mol) in 1 l glacial acetic acid was added, under a N2 atmosphere at room temperature, 90 g (0.82 mol) of 2-hydrazinopyrimidine (prepared according to J. Chesterfield et al., J. Chem. Soc., 3478, 1955). This was heated to 60° C. for one hour, cooled to room temperature and poured into 4 l saturated NaHCO3 aqueous solution. The resulting mixture was extracted with EtOAc and the organic layer was separated and washed with water and brine. This solution was dried over MgSO4, filtered and concentrated in vacuo. The crude reaction mixture was flash chromatographed on a silica gel column, eluting with 10% EtOAc-toluene yielding 16.4 g of 2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine and 94 g of 5(3)-4-fluorophenyl)-3(5)-(1-methylethyl)-1H-pyrazole, mp 102°-103° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH2:8](O)[CH2:9]CC.C(OC(=O)C=C)C.C(O)C>C1(C=CC(O)=CC=1)O.[C-]#N.[K+]>[C:4]([O:3][CH2:1][CH2:2][CH2:8][CH3:9])(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)OCC
Reactant: CCCCO
Agent: Oc1ccc(O)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: C=CC(=O)OCCCC
Reaction time: 4.5 h
Yield: 96.7 %

Procedure:
500 g of ethylacrylate (5 mole), 92.5 g of n-butanol (1.25 mole) and 0.148 g of hydroquinone (250 ppm) are added to a 1 liter round-bottomed flask. By conducting air through by way of a 1 m vigreux column, the azeotrope is dehydrated. After cooling of the contents of the flask to 60° to 70° C., 6 g of potassium cyanide (1%) are added, and the ethylacrylate/ethanol-azeotrope is distilled-off at 77° C. at the head of the column. After 4 to 5 hours, the trans-esterification is completed. After cooling down of the flask, the potassium cyanide is filtered off and the filter residue is washed out with a little ethyl acrylate. The filtrate is processed by fractional distillation. 155 g of n-butyl acrylate = 97% are obtained.