Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]2[O:16][CH2:17][CH2:18][O:19][C:14]=2[CH:13]=1)=O)C>C1COCC1>[O:16]1[C:15]2[CH:20]=[CH:21][C:12]([CH2:10][OH:9])=[CH:13][C:14]=2[O:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc2c(c1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a suspension of LAH (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0° C. under N2. The mixture was stirred at room temperature for 1 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol (10.6 g). 1H NMR (300 MHz, DMSO-d6) δ 6.73-6.78 (m, 3H), 5.02 (t, J=5.7 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.17-4.20 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([O:15]C)=O)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC1C=C(C2C=C(C(O)=O)ON=2)C=CC=1.S(Cl)(Cl)=O.[NH2:36][NH2:37]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([NH:36][NH2:37])=[O:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2cccc(F)c2)no1
Reactant: NN
Agent: O=C(O)c1cc(-c2cccc(F)c2)no1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: NNC(=O)c1cc(-c2cccc(F)c2)no1

Procedure:
A mixture of methyl 3-(3-fluorophenyl)isoxazole-5-carboxylate (prepared according to the literature method: T. T. Dang, U. Albrecht and P. Langer, Preparation 2006, No. 15, 2515-252; or treatment of 3-(3-fluorophenyl)isoxazole-5-carboxylic acid with thionyl chloride and methanol) (5.55 g, 25 mmol, 1.0 equiv.), hydrazine (960 mg, 30 mmol) and MeOH (100 mL) was refluxed for 1 h and concentrated. The residue was washed with dichloromethane and dried in vacuum to give 3-(3-fluorophenyl)isoxazole-5-carbohydrazide (5.6 g, quant.). LRMS (M+H+) m/z 222.0
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH:32](=[O:34])[CH3:33]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:32]([OH:34])[CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(C)O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.35 mL (2.5 mmol) of diisopropylamine in 10 mL of THF at 0° C. was treated with 1.6 mL of 1.0 M n-butyllithium solution in hexanes. The resulting mixture was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 540 mg (2.0 mmol) of ethyl 2-(1-tert-butoxycarbonyl-piperidin-4-yl)acetate (from Piperidine 35, Step A) in 2 mL of THF was added and the resulting solution was stirred cold for 30 min. Acetaldehyde (0.17 mL, 3.0 mmol) was added and the resulting mixture was warmed to 0° C. The reaction was quenched with 10 mL of sat'd NH4Cl and the resulting mixture was partitioned between 50 mL of ether and 25 mL of water. The organic layer was separated, dried over MgSO4 and concentrated. Flash chromatography on 20 g of silica gel using 2:1 v/v hexanes/EtOAc as the eluant afforded the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccccc1)c1cc(F)c(F)cc1F
Reaction time: 2 h

Procedure:
A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,N-diisopropylethylamine (34 mL, 129 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was triturated with hexane to yield an off-white solid product upon evaporation, and the hot hexane-soluble fraction of the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](=[CH:13][N:14]([CH3:16])C)[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH2:25](N)C>C(Cl)(Cl)Cl>[CH2:16]([NH:14][CH:13]=[C:9]1[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:6]2[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12])[CH3:25]
Reactant: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Reactant: CCN
Solvent: ClC(Cl)Cl
Product: CCNC=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Temperature: 100 °C

Procedure:
A mixture consisting of 5 gm of 7-chloro-5-(2'-chloro-phenyl)-1,3-dihydro-3-(dimethylamino-methylene)-2H-1,4-benzodiazepin-2-one and 75 ml of ethylamine was heated for 20 minutes at 100°C in closed tube. Thereafter, the reaction mixture was quickly cooled, diluted with chloroform and evaporated to dryness in vacuo. The yellow, solid residue was recrystallized from absolute ethanol, yielding the compound of the formula ##SPC7##
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][CH:7]1[C:12](=[O:13])[NH:11][C:10](=[S:14])[NH:9][C:8]1=[O:15].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)C>O>[OH:15][C:8]1[C:7]([CH3:6])=[C:12]([OH:13])[N:11]=[C:10]([S:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=1
Reactant: CCOC(=O)CBr
Reactant: CC1C(=O)NC(=S)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSc1nc(O)c(C)c(O)n1
Yield: 54.3 %

Procedure:
To a solution of 4.0 g (0.0475 mole) of sodium bicarbonate in 40 ml of water was added with stirring 7.5 g (0.0475 mole) of 5-methyl-2-thiobarbituric acid. Ethyl bromoacetate (7.9 g, 0.0475 mole) was then added and 40 ml of ethanol to make a clear solution. After one-half hour a precipitate was formed. Stirring was continued for one-half hour at room temperature. The precipitate was collected and recrystallized from ethanol to give 6.3 g of (4,6-dihydroxy-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester mp. 211°-214°C.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:27]=[C:26]([CH3:28])[C:8]([O:9][C:10]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([NH:20][CH:21]([CH:24]=[O:25])[CH2:22][CH3:23])[C:11]=2[C:12]([NH2:14])=[O:13])=[C:7]([CH3:29])[CH:6]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH3:29])[C:8]([O:9][C:10]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([NH:20][CH:21]([CH2:22][CH3:23])[CH:24]([OH:25])[CH3:1])[C:11]=2[C:12]([NH2:14])=[O:13])=[C:26]([CH3:28])[CH:27]=1
Reactant: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O)C(C)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of MeMgBr in dry THF was added a solution of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinamide in dry THF at −78° C. The mixture was stirred at −78° C. for 2 hr, then quenched with dilute acid. After standard extraction and purification, the title compound was obtained. 1H NMR(CDCl3) d 9.8(d,1H), 7.9(nbrs,1H), 7.05(s,2H), 6.27(s,0.5H), 6.24(s,0.5H), 5.6(brs,1H), 3.91(m,0.5H), 3.89(m,0.5H), 3.51(m,0.5H), 3.3(m,0.5H), 2.09(s,9H), 1.5-1.8(m,2H), 1.26(d,3H), 0.98(t,3H) ppm.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B#B>C(Cl)Cl.O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Agent: B#B
Agent: OCCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: BrCCCCCCCCc1ccccc1

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenylocatanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-triimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:6][C:7](=[O:24])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH:20]=[N:19][CH:18]=2)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:9])([CH3:5])[CH3:4].[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.ClCCl>[CH3:23][O:22][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][CH2:25][C:26]2[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=2)=[O:24])[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][CH:20]=[N:19][CH:18]=1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN)ccc1-c1cnco1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CNCc2ccc(C)cc2)ccc1-c1cnco1

Procedure:
30 mg (0.09 mmol) of N-(2-amino-1,1-dimethyl-ethyl)-N′-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 11.3 mg (0.095 mmol) of 4-methylbenzaldehyde and 30 mg (0.14 mmol) of sodium triacetoxyborohydride were dissolved in 2 ml of a 5% acetic acid dichloromethane mixture for 16 hours. The reaction mixture was then diluted with 8 ml of dichloromethane and washed with water, saturated sodium hydrogen carbonate and brine. The resulting organic solution was then dried with magnesium sulphate, filtered and evaporated to give N-[3-methoxy-4-(5-oxazolyl)phenyl-N′-[2-(4-methylbenzylamino)-1,1-dimethylethyl]oxalamide as a yellow solid MS: m/e 437.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.II.[I:14]([O-])(=O)(=O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][C:7]=1[I:14]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N)c(I)n1
Temperature: 60 °C
Reaction time: 48 h
Yield: 152.9 %

Procedure:
A mixture of methyl 5-aminopyridine-2-carboxylate (2.92 g), iodine (3.9 g) and sodium periodate (1.64 g) in N,N-dimethylformamide (24 mL) was stirred at 60° C. for 2 days. The reaction mixture was cooled to room temperature. To the reaction mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 10 minutes. The crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give methyl 5-amino-6-iodopyridine-2-carboxylate (3.26 g). To sodium hexamethyldisilazide (1.03 mol/L tetrahydrofuran solution, 7.68 mL) was added a solution of methyl 5-amino-6-iodopyridine-2-carboxylate (1 g) in tetrahydrofuran (5 mL) in a dropwise manner at −14° C., and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of di(tert-butyl)dicarbonate (0.82 g) in tetrahydrofuran (3 mL) in a dropwise manner, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (13.6 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added 2-propanol (2.8 mL) and water (3.4 mL), and the mixture was stirred at 80° C. for 30 minutes, and then stirred at room temperature for 30 minutes. The crystals were collected by filtration. The collected crystals were washed with a mixed solvent (2-propanol/water=5/6), and dried under reduced pressure to give the title compound (0.82 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)O)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)[Cl:21])[CH3:2]
Reactant: CCOC(=O)C(O)c1ccc(-n2cccn2)cc1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)c1ccc(-n2cccn2)cc1

Procedure:
The starting compound is obtained in the following manner: 2.46 g (10 mmoles) of 4-(pyrazol-1-yl) mandelic acid ethyl ester and 10 ml of thionyl chloride are heated to 40° C. for 10 minutes, the excess thionyl chloride is distilled off. α-chloro-4-(pyrazol-1-yl) phenylacetic acid ethyl ester (oil) is obtained.
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[Cl:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:1])=[O:9])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a mixture of 28% aqueous ammonia (19.3 g, 317 mmol, 4.0 eq) and toluene (30 mL) was dropwise added a 4-chloromethylbenzoyl chloride. (15.0 g, 79.3 mmol)/toluene (30 mL) solution under ice-cooling. The mixture was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with water (9 mL) and toluene (9 mL), and dried in vacuo at 40° C. to give the title compound (13.36 g, yield 99.3%) as white crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.Br[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:19]>>[N:7]1([CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:19])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(Cn1cnc2ccccc21)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
A solution of potassium tert-butoxide (1.7 mL of 1 M solution in THF, 1.7 mmol,) was added to a solution of 1H-benzoimidazole (165 mg, 1.4 mmol) in anhydrous TBF (3 mL). The reaction mixture was stirred for 20 min at ambient temperature. 2-Bromo-N-(3-trifluoromethyl-phenyl)-acetamide (Example 92 part A) was added (261 mg, 0.93 mmol) and the mixture was stirred at 55° C. for subsequent 24 h. The crude product was purified on a preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M aqueous NH4Ac/CH3CN). The pooled fractions were lyophilized to afford 81 mg (27%) of the title compound. Calculated for C16H12F3N3O m/z: 319.29, found 320.0 [M+H]+. 1H NMR (400 MeOH) δ ppm 5.2 (s, 2H), 7.3 (m, 2H), 7.4 (d, J=7.6 Hz, 1H), 7.5 (m, 2H), 7.7 (d,J=7.1 Hz, 1H), 7.8 (d, J=8.6 Hz, 1H), 8.0 (s, 1H), 8.2 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14](F)[CH:13]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([S:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)#[N:11]
Reactant: SCCc1ccccc1
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)c(SCCc2ccccc2)c1
Temperature: 75 °C

Procedure:
Phenylethylmercaptan (2.14 ml, 16 mmol) was added to a stirred suspension of 4-cyano-2-fluorobenzaldehyde (2.23 g, 15 mmol) and potassium carbonate (2.21 g, 16 mmol) in dimethylformamide (10 ml) at room temperature under nitrogen atmosphere. The mixture was heated to 75° C. for 1 hour, then cooled and diluted with water (15 ml). A yellow solid precipitated and was filtered, washed with water and then crystallised from cyclohexane (250 ml) to give pale needles of 4-cyano-2-(2-phenylethylthio)benzaldehyde, m.p. 89° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:39]=[CH:38][C:15]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[C:21]3[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][CH2:29][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:15]3[CH:38]=[CH:39][C:12]([Cl:11])=[CH:13][CH:14]=3)([OH:17])[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:19]=2)[NH:24][C:23](=[O:28])[CH:22]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(CCc3cccc(Cl)c3)c2c1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (201 mg, 2.368 mmol, 4.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.495 mL, 2.392 mmol, 4.04 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)quinolin-2(1H)-one (250 mg, 0.592 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (4 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a tan solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](C3C=CC=CC=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:44][CH2:43][C:35]4([CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:23])([F:22])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1N=C(N2CCC3(CN(C(OC(C)(C)C)=O)[C@H](C(OCC)=O)C3)CC2)C=C(O[C@H]([C:80]2[C:85](Br)=[CH:84][CH:83]=[CH:82][C:81]=2Br)C(F)(F)F)N=1>>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:44][CH2:43][C:35]4([CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:21])([F:23])[F:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(O[C@H](c2cc(-c3ccccc3)ccc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4c(Br)cccc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Product: Nc1nc(O[C@H](c2c(-c3ccccc3)cccc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 51a) starting with (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product of Step 4, example 63ao).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH2:7]N)[C:3]([OH:5])=[O:4].[CH2:9]([O:16][C:17]([NH:19][C:20]([N:32]1C=CC=N1)=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]([N:19]([CH2:7][CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])[C:20]([NH2:32])=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: NCC[C@H](O)C(=O)O
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)OCc1ccccc1)N(CC[C@H](O)C(=O)O)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2(S)-hydroxy-4-amino-butyric acid (0.059 g, 0.50 mmol) in DMF (2 ml) was added N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.26 g, 0.70 mmol) followed by DIPEA (0.87 mL, 4.99 mmol) and the reaction was heated to 80° C. and stirred overnight. The crude mixture was purified on a 2-inch reverse-phase HPLC column to yield N,N′-bis-Cbz-2(S)-hydroxy-4-guanidino-butyric acid: MS: m/z (M+H)+ calcd. 430.15, found 430.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14].[Cl:16]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:16])[C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCc1c(O)c(Cl)cc(C(=O)OC)c1O
Reaction time: 17 h

Procedure:
A solution of 2.1 g (0.01 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 1.6 g (0.012 mol) of N-chlorosuccinimide in 50 mL of carbon tetrachloride was stirred at reflux for 9.5 hours. Additional N-chlorosuccinimide (1.6 g) was added and reflux was continued for 17 hours. 0.8 g of N-chlorosuccinimide was added and reflux was continued for 8 hours. Water was added. The organic layer was separated and washed with sodium thiosulfate solution, sodium bicarbonate solution, dried and concentrated under reduced pressure to give 5-chloro-2,4-dihydroxy-3-propylbenzoic acid methyl ester. Recrystallization from hexane gave analytically pure material, mp 75°-76°.