Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)[CH:19]=2)[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(NC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-aminopiperidine-1-carboxylic acid ethyl ester as in General Procedure 10 to give the title compound. LCMS: m/z=601.99 (M+H+); retention time=0.86 minutes.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)c1nc(CCl)co1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(Cc1coc(C(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
A mixture of 4-chloromethyl-2-isopropyl-1,3-oxazole (1.12 g) and triethyl phosphite (2.57 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-isopropyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (1.67 g, yield 91%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:26]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([N:30]2[CH2:35][CH2:34][N:33]([C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[CH:17]4)=[O:19])[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Reactant: C1CC(N2CCNCC2)C1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN(C2CCC2)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1-cyclobutylpiperazine (commercially available), to give the desired product as a white solid (50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J15) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) according to the general procedure M. Obtained as a light yellow solid (250 mg).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11]/[CH:12]=[C:13](\[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)/[C:14](OCC)=[O:15].CO.Cl>O>[F:11]/[CH:12]=[C:13](\[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)/[CH2:14][OH:15]
Reactant: CCOC(=O)/C(=C/F)CCc1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: O
Product: OC/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cool to 0° C. a solution of diisobutylaluminum hydride (7.64 kg, 25% by weight in toluene, 13.42 mol). Add a solution of ethyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate (1.74 kg, 74.1% by weight in toluene, 5.37 mol) at such a rate that the temperature of the reaction mixture does not rise above 20° C. After the addition is complete, warm to ambient temperature. After 2 hours, cool to 0° C. Slowly, add methanol (7.73 kg) at such a rate that the temperature of the reaction mixture does not rise above 15° C. Cool to 0° C. Slowly, add water (7.96 kg) at such a rate that the temperature of the reaction mixture does not rise above 20° C. Add a concentrated aqueous solution of hydrochloric acid (7.59 kg). Warm to ambient temperature. Separate the organic layer and dry azeotropically by distillation in vacuo until the volume of the organic layer is about one half of its original volume to give the title compound as a solution in toluene.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:32])([CH3:31])[C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1.[H][H]>[Pd].C(CC(OC)=O)C>[CH3:1][O:2][C:3]([CH3:32])([CH3:31])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Agent: [Pd]
Solvent: CCCC(=O)OC
Product: COC(C)(C)CCc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Yield: 49.6 %

Procedure:
To a solution of 7-(3-methoxy-3-methylbut-1-ynyl)-3-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (110 mg, 0.258 mmol) in 1:1 methanol ethyl acetate (10 mL) was added Pd/C (5%) (274 mg, 2.58 mmol). The resulting slurry was maintained under 1 atm of hydrogen gas for 4 hours at which point another loading of Pd/C (5%) (274 mg, 2.58 mmol) was added and the reaction was maintained under 1 atm of hydrogen gas for an additional 3 hours. The reaction was filtered through a pad of celite, washing well with methanol and ethyl acetate. The derived mixture was filtered through a 0.1 micron frit and concentrated to provide 7-(3-methoxy-3-methylbutyl)-3-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (55 mg, 0.128 mmol, 49.5% yield) as a light yellow solid. MS m/z=431.2 [M+H]+. Calc'd for C25H27N4O3: 431.2.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH2:40])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH:40][C:5]([C:2]3([CH3:1])[CH2:4][CH2:3]3)=[O:7])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1
Reactant: CC1(C(=O)O)CC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1-Methylcyclopropanecarboxylic acid (435 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (553 mg, 2.17 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added (50 mL). The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamide (464 mg, 68.4% yield) was obtained as a solid.
Reaction SMILES: Cl.[NH2:2]O.C(O)C.[C:7]([CH2:13][C:14]([O:16]CC)=O)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].Cl>[OH-].[Na+]>[C:8]([C:7]1[O:12][N:2]=[C:14]([OH:16])[CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(O)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
583.7 g of hydroxylamine hydrochloride was dissolved in 2 l of a 4N aqueous solution of sodium hydroxide. 2 l of ethanol was added to the solution under cooling with ice. A 1:1 mixture of a 4N aqueous solution of sodium hydroxide and ethanol was added to the solution so that the pH thereof was adjusted to 10.0. 1,380 g of ethyl pivaloylacetate and a 1:1 mixture of a 4N aqueous solution of sodium hydroxide and ethanol were simultaneously added dropwise to the solution in such a manner that the pH of the reaction solution was 10±0.2 and the temperature thereof was 0° to 5° C. After the dropwise addition was finished, the reaction mixture was stirred at room temperature for 2 hours, and then poured into 6 kg of concentrated hydrochloric acid. The reaction mixture was allowed to stand for 12 hours. The resulting crystal was filtered off, thoroughly washed with water, and then dried. (Yield: 770 g (68.2%); m.p.: 99°-101° C.)
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5](=[O:13])[N:4]2[N:14]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:16]=[C:3]12.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5](=[O:13])[N:4]2[N:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:3]12
Reactant: CCOC(=O)c1cc2n(C)c3ccc(C)cc3c(=O)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(c1)c(=O)n1nc(C(=O)O)cc1n2C

Procedure:
From 3.5 g of 4,9-dihydro-4,7-dimethyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester, 50 ml of 1 N aqueous sodium hydroxide and 200 ml of methanol, following the procedure of Example 14, there is obtained 4,9-dihydro-4,7-dimethyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid; mp 269° C., after crystallization from dimethylformamide/ ethanol.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([N:13]2[C:17]([SH:18])=[N:16][N:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22](=[O:23])[O:21]1>CN(C)C=O>[C:30]1([C:20]2([S:18][C:17]3[N:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:14]=[N:15][N:16]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22](=[O:23])[O:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1OC(Cl)(c2ccccc2)c2ccccc21
Reactant: Sc1nnnn1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OC(Sc2nnnn2-c2ccccc2)(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 300 ml of dried dimethylformamide, was added 14.56 g (0.12 mol.) of potassium tert-butoxide and 18 g (0.1 mol.) of 1-phenyl-5-mercaptotetrazole. The mixture was stirred for 20 minutes at room temperature. Thereafter, to the mixture cooled to 5° C. and kept there, was gradually added dropwise a solution prepared by adding 25 g (0.1 mol.) of 3-chloro-3-phenylphthalide to 75 ml of dried dimethylformamide. At the conclusion of the dropwise addition, the cooling bath was removed, and the mixture was stirred for 2 hours at room temperature. Thereto, 300 ml of a saturated aqueous solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate repeatedly. The extract was washed with water, and the resulting organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was filtered off with suction, and the filtrate was concentrated to yield 35 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 700 g, eluate: hexane-ethyl acetate (3:1 by vol.) mixture). Thus, the intended compound, 3-phenyl-3-(1-phenyltetrazole-5-ylthio)phthalide (1), was obtained in the form of white crystals. Yield 21.5 g, Melting Point 137°-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].O1[CH2:38][CH2:37]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:37]=[CH:16][CH:15]=[CH:14][N:11]=3)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (100 mg, 0.209 mmol) produced in Example (99a), 2-(tributyltin)pyridine (0.08 mL, 0.25 mmol), cesium fluoride (68 mg, 0.448 mmol) and dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), followed by stirring for 3 hours at an external temperature of 90° C under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 43 mg of the title compound as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O>[Pd].C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]
Reactant: COCCCCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COCCCCNc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a toluene solution (350 mL) of N-(4-methoxybutyl)-2-nitroaniline were added 10% Pd/C (K-type, 50% water-containing product, 10.0 g) and toluene (100 mL). The mixture was stirred at 20-30° C. for 3 hr under a hydrogen pressure (0.1 MPa). Under a nitrogen stream, the catalyst was filtered off and the residue was washed with toluene (100 mL). Water in the filtrate was removed by partitioning, magnesium sulfate (25.0 g) was added at 20-30° C., and the mixture was stirred at the same temperature for 30 min. Magnesium sulfate was filtered off and the residue was washed with toluene (100 mL) to give a toluene solution of N-(4-methoxybutyl)-o-phenylenediamine (yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>[Pd].CO>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: Fc1cccc2ncccc12
Agent: [Pd]
Solvent: CO
Product: Fc1cccc2c1CCCN2
Reaction time: 8 h
Yield: 70.1 %

Procedure:
Palladium on carbon (10%, 1.25 g) was added to a solution of 5-fluoroquinoline (2.5 g, 16.99 mmol) in methanol and the reaction was overnight at room temperature under an atmosphere of hydrogen. The reaction mixture was filtered through Celite and concentrated in vacuo to afford 5-fluoro-1,2,3,4-tetrahydroquinoline as a colorless oil (1.80 g, 70%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:26]=[CH:25][C:20]([NH:21]C(=O)C)=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:26]=[CH:25][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1

Procedure:
1-(5-Benzyloxymethyl-1,4-oxathian-2-yl)-N4 -acetylcytosine (0.31 g) was dissolved in methanol (10 ml), and 0.43M sodium methoxide solution (1 ml) was added to the solution. The resultant mixture was stirred at room temperature for one hour to complete the reaction. The reaction mixture was neutralized with acetic acid, and the solvent was removed by evaporation under reduced pressure to obtain pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11](C(OCC3C=CC=CC=3)(O)C)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:14]2[C:9]([O:8][CH2:7][C:6]3[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[CH:38]([OH:40])[CH3:39])=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(COc2ccc(C(C)(O)OCc3ccccc3)cc2OCc2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(COc2cccc(C(C)O)c2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Yield: 91.5 %

Procedure:
To an ice cold solution of α-chloro-3,4-dihydroxypropiophenone (2) (1.0 g; 4.98 mMol.) in pyridine (3 ml) is added acetic anhydride (1.2 ml) After 1.5 hours at room temperature, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water, dried, and concentrated under reduced pressure to give α-chloro-2,3-diacetoxypropiopheonen (3) (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1.[OH-:24].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:24])=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 0 °C
Yield: 34.9 %

Procedure:
A mixture of 0.1 g of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 1.0 g of sodium hydroxide, 10 ml of water and 20 ml of ethanol was refluxed for 3 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/benzene (4/1), thereby obtaining a solid substance. This substance was recrystallized from benzene-n-hexane to give 35 mg (yield: 35%) of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a powder having a melting point of 152°-153° C.
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]1[O:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:8]1=[O:22].C(N)C=C.[Cl-:27].[Na+]>C(OCC)C.ClCCl.C(N(CC)CC)C>[Cl:27][CH:7]1[O:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:8]1=[O:22]
Reactant: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Reactant: [Cl-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C=CCN
Solvent: CCOCC
Product: O=C1C(Cl)OCN1c1cccc(C(F)(F)F)c1

Procedure:
Methanesulphonyl chloride (0.9 g) dissolved in diethylether (2 ml) was added to a stirred solution of 5-hydroxy-3-(3-trifluoromethylphenyl)oxazolidin4-one (1.0 g, Example 2, Step 4) in dichloromethane (6 ml). Triethylamine (0.8 g) dissolved in ether (2 ml) was added and the mixture allowed to exotherm to 35° C. After 2 hours the mixture was cooled in an ice-water bath and a solution of allylamine (0.92 g) in ether (2 ml) added dropwise. After 1 hour the mixture was treated with aqueous sodium chloride (20 ml), extracted with ether (3×80 ml), the extract dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the crude product as a yellow gum (1.3 g). 1H NMR (CDCl3): δ 3.49(2 H,d); 5.13(1 H,dd); 5.21 (1 H,s); 5.3(1 H,m); 5.44(1 H,d); 5.48(1H,dd); 5.9(1 H,m); 7.5-7.8(4 H,m).
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH2:8]1[C:12]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:11][CH2:10][NH:9]1.C(O)(=O)C>CC(O)C>[CH2:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:4]1[CH2:5][O:1][C:2](=[O:7])[CH:3]=1
Reactant: O=C1COC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=C1C=C(N2CCC3(CCNCC3)C2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available furan-2,4(3H,5H)-dione (0.433 g, 4.33 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (commercially available from multiple vendors, acetic acid salt, 0.65 g, 2.2 mmol) in 20 mL i-PrOH was heated in a sealed tube at 110° C. overnight. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in 30 mL DCM and 5 mL TFA and stirred at rt for 1 h. The mixture was concentrated, and the residue was purified by preparative TLC (10%2N NH3 in methanol-DCM). LC/MS: [(M+1)]+=223
Reaction SMILES: [NH2:1][C:2]([O:8][CH:9]([CH3:11])[CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[SH2:12].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]([O:8][CH:9]([CH3:11])[CH3:10])=[C:3]([C:4]#[N:5])[C:6](=[S:12])[NH2:7]
Reactant: S
Reactant: CC(C)OC(N)=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)OC(N)=C(C#N)C(N)=S

Procedure:
In the manner of Example V, part B, 117.6 g of 3-amino-2-cyano-3-isopropoxy-2-propenenitrile were allowed to react with excess hydrogen sulfide gas in a solution of 157.4 g of triethylamine and 250 ml of pyridine. The volatile materials were removed under reduced pressure and water was added to the residue. The yellow precipitate was collected and dried. The dried solid was recrystallized from isopropanol to yield 123 g of 3-amino-2-cyano-3-isopropoxy-2-propenethioamide, mp 170° (decomposes). The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:35]=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([C:30]([F:33])([F:32])[F:31])[CH:19]=3)[S:17][C:13]=2[CH:12]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:32][C:30]([F:31])([F:33])[C:20]1[CH:19]=[C:18]([C:16]2[S:17][C:13]3[CH:12]=[C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:36])=[O:5])[CH:35]=[CH:34][C:14]=3[N:15]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
3-{[2-(2-Trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid tert-butyl ester (31 mg, 0.0605 mmol) is dissolved in TFA/CH2Cl2 (1/1) (1 mL). The solution is stirred at room temperature for an hour. The mixture is concentrated and purified by reversed phase preparative LC/MS to give 10 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 8.54 (s, 1H), 8.35 (d, 1H), 8.22 (s, 1H), 8.18 (d, 2H), 7.68 (d, 1H), 7.45 (m, 3H), 7.37 (m, 2H), 4.44 (s, 2H), 3.36 (m, 2H), 2.80 (m, 2H); MS (ES+) 457.0 (M+H+).