Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.FC1C=CC=CC=1S(Cl)(=O)=O>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1ccccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-fluorobenzenesulfonyl chloride (0.051 g, 0.263 mmol) the title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamide was obtained (66 mg, 0.125 mmol, 52.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.98 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 2H), 7.36-7.46 (m, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.20-7.29 (m, 1H), 6.75 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 1.40 (s, 9H). MS (ES+): 502 [M+H]+.
Reaction SMILES: CO.[C:3]([NH:10][C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:28][N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:10][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of anhydrous methanol (0.04 ml, 1.0 mmol), N-,N'-,N"-tri-Boc-guanidine (1.80 g, 5.0 mmol), and triphenylphoshine (393 mg, 1.5 mmol) in anhydrous THF (50 ml) is cooled to -5° C. under an atmosphere of argon. Diethylazodicarboxylate (DEAD, 0.22 ml, 1.5 mmol) is added dropwise at a rate such that the reaction mixture is completely colorless before addition of the next drop. After the addition is completed, the reaction mixture is refluxed for 15 h. The solution is then cooled to room temperature, and hexanes (50 ml) is added. A precipitate of excess N-,N'-,N"-tri-Boc-guanidine forms which is collected by filtration on a Buechner-funnel and washed with a mixture of THF/hexanes 1:1. The filtrate is concentrated under reduced pressure and the product (colorless oil, 182 mg, 49%) isolated by flash chromatography on silica gel (eluent: dichloromethane-ethyl ether 98:2): 1H NMR (360 MHz, DMSO-d6) δ 10.17 (s, 1H), 2.94 (s, 3H), 1.43-1.36 (27H); FAB-MS m/e (relative intensity) 396 (100, M+Na+)0.374 (91, M+H+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][CH:17]([CH3:24])[CH2:18][C:19](=[O:23])[C:20]([O-:22])=O.[Na+].Cl.[NH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30].C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH3:24][CH:17]([CH3:16])[CH2:18][C:19](=[O:23])[C:20]([NH:27][CH2:28][C:29](=[O:30])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:22]
Reactant: CC(C)CC(=O)C(=O)[O-]
Reactant: NCC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)CC(=O)C(=O)NCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of dicyclohexylcarbodiimide (DCC) (157 g) in dichloromethane (200 ml) was added dropwise over 2 hours to an efficiently stirred mixture of powdered sodium 4-methyl-2-oxopentanoate (115.5 g), 2-aminoacetophenone hydrochloride (130.4 g) and HOBT (103 g) in dichloromethane (1 liter). The mixture was stirred overnight and the insoluble dicyclohexylurea removed by filtration. The filtrate was concentrated and the residue redissolved in dichloromethane (500 ml). The mixture was filtered to remove a further quantity of dicyclohexylurea, and the filtrate was washed with saturated sodium hydrogen carbonate solution (500 ml), water (500 ml) and saturated sodium chloride solution (500 ml). The organic phase was dried and concentrated to give 4-methyl-2-oxo-N-(2-oxo-2-phenylethyl)pentanamide (C), as a foam (183.6 g), which was used without further purification; NMR (CDCl3) : 1.0 (d, 6H), 2.2 (m, 1H), 2.8 (d, 2H), 4.75 (d, 2H), 7.4-7.7 (m, 3H), 7.9 (br, 1H), 8.0 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH2:41]O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:41]([O:15][C:14](=[O:16])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
(S)-6-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid (5.00 g, 10.67 mmol) and phenyl-methanol (2.305 g, 21.34 mmol) were dissolved in 25 mL of CH2Cl2 and treated successively with N-hydroxybenzotriazole (1.933 g, 11.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 2.250 g, 11.74 mmol), and ethyl-diisopropyl-amine (2.137 ml, 12.49 mmol). After stirring for 90 min, the volatiles were removed i.V. at ambient temperature, the residue taken up in ethyl acetate, washed with water, NH4Cl-solution and brine, dried over Na2SO4, and evaporated. The crude mixture was then dissolved in 20 mL of ethanol, and the product precipitated by adding 10 mL of water. Filtration and drying yielded 5.669 g of the title compound which was recrystallized from ethanol/hexane to give 4.27 g of pure benzyl ester. MS (ISP): 559.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(Cl)ccc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(F)c2)CC1
Temperature: 80 °C

Procedure:
A mixture of 4.9 mmol 4-chloro-2-fluorobenzotrifluoride, 5.9 mmol n-Boc-piperazine, 0.05 mmol palladium acetate, 6.9 mmol sodium-t-butoxide and 0.49 mmol 2-(di-t-butylphosphino)biphenyl in 10 ml toluene was heated for 16 h at 80° C. After cooling to RT, the mixture was diluted with ether; the suspension was filtered over decalite; and the filtrate evaporated. The residue was purified on silica eluting with a gradient of heptane/EtOAc to yield after evaporation the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[CH2:21][NH:20][CH2:19][C:18](=[O:22])[NH:17]1.[H-].C(=O)([O-])O.[Na+]>ClCCCl.CCCCCC.C(O)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:20]2[CH2:19][C:18](=[O:22])[NH:17][C:16](=[O:15])[CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1CNCC(=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC(=O)C2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.1 %

Procedure:
A mixture of 1-t-butoxycarbonyl-4-oxopiperidine (9.06 g) and 2,6-dioxopiperazine (3.99 g) was dissolved in 1,2-dichloroethane (170 ml), and acetic acid (20 ml) of triacetoxyboronsodium hydride (9.64 g) were added to the solution, followed by stirring at room temperature for 17 hours. Then, water was added to the reaction solution under ice-cooling, and sodium hydrogencarbonate was added to the solution to neutralize acetic acid. The reaction solution was charged into a separating funnel to separate an aqueous layer from an organic layer. The aqueous layer was extracted with chloroform, and the extracted organic layer was then combined with the above organic layer. The combined organic layer was washed with a saturated saline solution and then dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography (350 g, chloroform→chloroform:methanol=60:1) to give a crystal. Then, n-hexane was added to the crystal, and the crystal was collected by filtration to give 6.46 g (62%) of 4-(1-t-butoxycarbonylpiperidin-4-yl)-2,6-dioxopiperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH:13](=O)[C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([CH:17]=[O:18])[CH:15]=1.C(OC(=O)C)(=O)C.CCCCCC>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
A stirred solution of 7-chloroquinaldine [J. Org. Chem. 42, 911 (1977)] (4.46 g, 25 mmol) and isophthalaldehyde (5.02 g, 37.5 mmol) in acetic anhydride (7.1 ml, 75 mmol) and xylene (25 ml) was heated under reflux for 7 hours. Crystals formed on cooling. Hexane (25 ml) was added slowly to give crude product, m.p. 146°-150°.
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2.[CH3:21]I.O>CN(C=O)C>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:21])[C:15](=[O:20])[CH:14]=[CH:13]2
Reactant: O=c1ccc2cc(OCCCCCBr)ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 440 mg) was suspended in DMF(20 ml), and was cooled to 0° C. in ice water bath. 6-(5-Bromopentyloxy)-1H-quinolin-2-one(3.1 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Methyl iodide(1.9 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound(2.68 g) as a yellow powder.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:26]=1[C:27]#[N:28]
Reactant: COC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-methyl 2-(1-aminoethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (140 mg, 0.54 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (83 mg, 0.54 mmol) and 1,1′-dimethyltriethylamine (190 μL, 1.1 mmol) in n-butanol (3 mL) was stirred at 120° C. After 18 h, the mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent to give (S)-methyl 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate: LC-MS (ESI) m/z 378.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:20].[CH3:21][Zn]C.CO.Cl>O1CCOCC1.C(OCC)(=O)C>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:20])=[C:2]([CH3:21])[CH:10]=3)[C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[Zn]C
Reactant: COC(=O)c1cn(C2CCCC2)c2cc(Br)c(F)cc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cn(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 88 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of methyl 6-bromo-1-cyclopentyl-5-fluoro-1H-indole-3-carboxylate (3.4 g, 10 mmol), dimethylzinc (1.2 M, 16.7 mL, 20 mmol) and PdCl2dppf (163 mg, 0.2 mmol) in dioxane (20 mL) was stirred at 88° C. for 2 hr under nitrogen atmosphere. The mixture was then cooled and methanol was added in slowly followed by 2 N HCl. The mixture was treated with ethyl acetate, washed with water and brine, dried and evaporated. The residue was purified by flash chromatography with dichloromethane and hexane (1:1) to give methyl 1-cyclopentyl-5-fluoro-6-methyl-1H-indole-3-carboxylate (2.66 g, yield 97%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8]O)=[CH:5][CH:4]=1.N.[H][H]>[Pd].CC(O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: N
Solvent: CC(C)O
Product: NCc1ccc(C(F)(F)F)cc1
Yield: 92.6 %

Procedure:
The second step of the process of the present invention was conducted as follows. At first, a 1-liter autoclave equipped with a mechanical stirrer was charged with 300 g (1.59 mol) of 4-trifluoromethylbenzaldehyde oxime, 460 g of 2-propanol, and 15 g of a catalyst (i.e., a carbon powder (50% wet) carrying thereon 5% palladium), followed by introduction of 40 g of liquid ammonia and then introduction of hydrogen to have a pressure of 1 MPa. Then, the reaction mixture was stirred, while the reaction temperature was maintained at 20° C. and while hydrogen was gradually introduced into the autoclave in a manner to maintain the total pressure at 1 MPa. After conducting the reaction for 4 hr, the reaction was stopped, followed by removing the catalyst by filtration. As a result of analyzing the obtained reaction liquid by gas chromatography, 4-trifluoromethylbenzylamine was formed at a yield of 92.6%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13]([C:15](O)=[O:16])=[CH:12][CH2:11][C@@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[F:58][C:59]([F:70])([F:69])[C:60]1[N:61]=[C:62]2[CH2:67][NH:66][CH2:65][CH2:64][N:63]2[CH:68]=1>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:11][CH:12]=[C:13]([C:15]([N:66]2[CH2:65][CH2:64][N:63]3[CH:68]=[C:60]([C:59]([F:70])([F:58])[F:69])[N:61]=[C:62]3[CH2:67]2)=[O:16])[CH2:14]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)O)=CC[C@@H]1c1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)N2CCn3cc(C(F)(F)F)nc3C2)=CC[C@@H]1c1cc(F)c(F)cc1F
Temperature: 0 °C
Yield: 106.5 %

Procedure:
(4R,5S)-5-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-cyclohex-1-enecarboxylic acid (98.4 g) and EDCI (60.8 g 0.32 mol), HOBT (43 g, 0.32 mol) were mixed in THF/DMF (120 mL/120 mL). The mixture was cooled to 0° C. and diisopropylethyl amine (151.5 mL, 0.86 mol) was added slowly. The mixture was stirred for approximate twenty minutes, and then 2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine HCl salt (83.9 g, 0.32 mol) was added. The mixture was stirred overnight, and concentrated in vacuo. Ethyl acetate (1000 mL) was added followed by 1N HCl (750 mL). The mixture was extracted with ethyl acetate, and the combined organic extract was washed with saturated NaHCO3 (750 mL), water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an oil (153.6 g). The crude amide (228 g) was dissolved in 470 mL of EtOH, and 1350 mL of hexanes was added with stirring. After stirring overnight, the solid was collected by filtration, washed with 450 mL of 50% Et2O/hexanes and then dried in vacuum at 45° C. to give 165.8 g (73%) of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O>[C:16]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:8])[CH3:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A solution of methyl 3-amino-5-tert-butylthiophene-2-carboxylate (20.0 g, 93.9 mmol), benzyl chloroformate (80.4 mL, 563 mmol), Na2CO3 (1.10 g, 9.93 mmol), toluene (400 mL) and water (50 mL) was heated at the reflux temp. for 18 h. Volatiles were removed under reduced pressure. The resulting oil was dissolved in EtOAc, washed with water and a concentrated NaCl solution, dried (MgSO4) and concentrated under reduced pressure to afford methyl 3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxylate as a crude oil in quantitative yield.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH3:28].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH3:28]
Reactant: CCCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 5 °C
Reaction time: 16 h

Procedure:
A solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2propyl]-2-phenothiazinecarbothioamide (0.9 g) and propylamine (3 cc) in absolute ethanol (18 cc) is saturated with hydrogen sulphide, and the mixture is brought to a temperature in the region of 100° C. for 16 hours. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to obtain a yellow oil. This oil is purified by chromatography on a column (height: 25 cm; diameter 2.5 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting successively with methylene chloride (100 cc) and then a mixture (95:5 by volume) (300 cc) of methylene chloride and methanol and collecting 50-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (1 g) is dissolved in ethanol (9 cc) under reflux and treated with a boiling solution of fumaric acid (0.29 g) in ethanol (5 cc). The mixture is allowed to cool and is maintained for 4 hours at a temperature in the region of 5° C. The crystals formed are drained, washed with ice-cold ethanol (2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 35° C. N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (1.12 g) is thereby obtained in the form of yellow crystals, m.p. 150°-152° C.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[C:11]([CH2:15][C:16](OC)=[O:17])(=O)[CH2:12][CH3:13].Cl>CO>[CH2:12]([C:11]1[N:10]=[CH:8][NH:9][C:16](=[O:17])[CH:15]=1)[CH3:13]
Reactant: CCC(=O)CC(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(=O)[nH]cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium methoxide (4.19 kg, 77.6 mol) and formamidine acetate (3.0 kg, 28.8 mol) in methanol (45 L) at 5°-10° C. was added slowly a solution of methyl propionylacetate (2.5 kg, 19.2 mol) in methanol (10 L) maintaining the temperature below 20° C. throughout the addition. The resulting mixture was stirred at room temperature overnight after which time the pH was adjusted to 7 by the addition of concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure to ca.10 L in volume, diluted with water (10 L) and was extracted with 2-butanone (2×30 L). The combined organic extracts were concentrated under reduced pressure to ca. 2 L in volume and diluted with ethyl acetate (4 L). The desired product crystallised from the solution (2.4 kg, 70%) and was recrystallised from isopropanol to yield a product of m.p. 132°-134° C. Found: C,58.45; H,6.37; N,22.41; C6H8N2O requires: C,58.05; H,6.50; N,22.57%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:28]=[O:29])C.O>C1COCC1>[CH:28]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1)=[O:29]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C=O)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of tert-butyl 4-bromonaphthalen-1-ylcarbamate (29) (3.00 g, 9.31 mmol) in THF (100 mL) at −78° C. under nitrogen was added n-BuLi (1.6M in hexane, 20.4 mL, 32.6 mmol) and the reaction mixture was stirred at −78° C. for 1 hr. Neat DMF (4.50 mL, 58.1 mmol) was added and the reaction mixture was stirred at −78° C. for 1 hr, then warmed to RT and stirred for a further 1 hr. Water (5 mL) was added and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was triturated with isohexane to afford the title compound (30) as a beige solid (2.20 g, 87%): m/z 272 (M+H)+ (ES)+.