Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]([F:23])([F:24])[F:25])=[O:26])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(c1ccccc1OC(F)(F)F)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 4-(2-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.34 mmol, 1 eq.) in 1 mL of dichloromethane was added 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and triturated with diethyl ether to give the title compound as a white solid (0.365 g, 88%). Exact mass calculated for C13H13F3N1O2 274.1. MS (ESI) m/z 274.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:16]([F:19])([F:18])[F:17])[OH:15])[N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:16]([F:19])([F:18])[F:17])[OH:15])[N:3]=1
Reactant: Cc1ccc2c(N=C(c3ccccc3)C(O)(c3ccccc3)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(NC(c3ccccc3)C(O)(c3ccccc3)C(F)(F)F)cccc2n1
Reaction time: 2 h
Yield: 6.6 %

Procedure:
484 mg (2 mmol) Diethyl(phenyloxomethyl)phosphonate and 2,2,2-trifluoroacetophenone are stirred in 3 ml DMF together with 14 mg (0.22 mmol) potassium cyanide for 3 hours (Demir et al. J. Org. Chem. 2005, 70, 10584-87). Direct chromatographic purification on silica gel (ethyl acetate in hexane 33%) yields 580 mg phosphoric acid (1-benzoyl-2,2,2-trifluoro-1-phenylethyl)diethyl ester. 250 mg (0.6 mmol) of the phosphoric acid ester are stirred for 18 hours in 10 ml diethyl amine and 1 ml water. Evaporation and flash chromatography on silica gel (ethyl acetate in hexane 33%) yield 80 mg 3,3,3-trifluoro-2-hydroxy-1,2-diphenylpropan-1-one. 80 mg (0.29 mmol) 3,3,3-trifluoro-2-hydroxy-1,2-diphenylpropan-1-one, 0.2 ml tetra t.-butyl othotitanate and 45 mg (0.29 mmol) 5-amino-2-methylquinolin are refluxed for 18 hours in 3 ml toluene and 0.1 ml acetic acid. The reaction mixture is poured into water after cooling and filtrated through a path of cellites after stirring for 15 minutes and diluting with ethyl acetate. The phases were separated and the aqueous layer was extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated to yield 90 mg of raw β-[(2-methylquinolin-5-yl)imino]-α-phenyl-α-(trifluoromethyl)benzeneethanol. To 30 mg of the raw imine in 2 ml methanol and 0.5 ml THF are added 20 mg sodium borohydride in two portions. The mixture is stirred over 2 hours, after that period quenched by addition of acetone and saturated ammonium chloride solution and diluted with ethyl acetate. The phases are separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Preparative thin layer chromatography on silica gel (ethyl acetate in hexane 50%) yields 2 mg of the title compound and 8 mg of the starting material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.I[CH3:22]>C(#N)C.C(=O)([O-])[O-].[Ag+2].F[B-](F)(F)F.[Ag+]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([O:11][CH3:22])[CH2:7]1
Reactant: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: CI
Agent: [Ag+2]
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COC(=O)C(CC1CCC(OC)C1)c1ccc(Cl)c(Cl)c1
Yield: 34.1 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (prepared as in Example 36, 194.1 mg, 0.61 mmol), silver carbonate (320.6 mg, 1.16 mmol), silver tetrafluoroborate (131.0 mg, 0.67 mmol), and iodomethane (72 μL, 1.16 mmol) in acetonitrile (6.1 mL) was stirred at 25° C. for 48 h. The resulting reaction mixture was then heated under reflux for 24 h. The reaction mixture was then filtered through a pad of celite, and the celite pad was washed well with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-methoxy-cyclopentyl)-propionic acid methyl ester (68.8 mg, 34%) as a yellow oil which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH2:8][C:9]#[N:10])C.[CH:12](O)=[O:13].[OH-].[K+].O>C(O)C>[C:9]([CH2:8][CH2:7][N:6]([CH:12]=[O:13])[CH2:5][C:4]([OH:3])=[O:11])#[N:10]
Reactant: O=CO
Reactant: CCOC(=O)CNCCC#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CCCN(C=O)CC(=O)O
Temperature: 0 °C

Procedure:
A mixture of 21.0 g of N-(2-cyanoethyl)-glycine ethyl ester and 18.3 g of formic acid is refluxed for 2 h. After concentration of this mixture underreduced pressure, the residue is taken up in 50 ml of ethanol, and cooled to 0° C.; there is then added dropwise a solution of 25.5 g of potassium hydroxide and 40 ml of water in 80 ml of ethanol. After the reaction solution has warmed up to room temperature, the solvent is evaporated off, and the residue is acidified to pH 1 with conc. hydrochloric acid. The mixture is saturated with sodium chloride and subsequently extracted with ethyl acetate. The combined organic extracts are concentrated by evaporation to thus obtain N-(2-cyanoethyl)-N-formylglycine, m.p. 112°-114° C. (compound No. 1.1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:9]O)[N:3]=[CH:2]1.S(Cl)([Cl:22])=O>O1CCOCC1>[NH:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:9][Cl:22])[N:3]=[CH:2]1
Reactant: COc1ccc(CN(CCO)Cc2c[nH]cn2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(CN(CCCl)Cc2c[nH]cn2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-(((1H-imidazol-4-yl)methyl)(4-methoxybenzyl)amino)ethanol (Step B, 14.5 g, 55.55 mmol) in anhydrous dioxane (100 mL) was added thionyl chloride (16.5 mL, 222.2 mmol) over a 10 minute period. The reaction mixture was heated at 60° C. for 3 hours, cooled to room temperature and partitioned under reduced pressure. The contents of the flask were azeotroped with dioxane (2×100 mL) and toluene (2×100 mL). The white solid c that separates out is filtered and used as such for the subsequent step without further purification (19.0 g).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ncccc2Cl)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2Cl)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-chloro-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][C:21]=1[OH:33].CO[C@@H](CC1C=CC=CC=1OCCCOC1C=CC=CC=1)C(O)=O>>[CH:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][C:21]=1[O:33][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc2c(c1)Cc1ccccc1-2
Agent: CO[C@@H](Cc1ccccc1OCCCOc1ccccc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3c(c2)Cc2ccccc2-3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 9H-fluoren-2-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C25H24O5 [M+Na]+: 427.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)([N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH:13]3[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)([N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[C:13]3[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(C1Cc2ccccc2N1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)N1CCOCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=C(c1cc2ccccc2n1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)N1CCOCC1
Reaction time: 8 h
Yield: 33.4 %

Procedure:
At room temperature, 6′-Chloro-3′-(3-chloro-benzyl)-2-(morpholine-4-carbonyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one (60 mg, 0.115 mmol) and DDQ (47 mg, 0.207 mmol) were dissolved in 5 ml toluene. After stirred overnight, the solution was concentrated and then the residue was dissolved in EtOAc. The organic layer was washed with 10% NaOH aqueous solution and dried, concentrated to obtain crude product. The crude product was purified by chromatography to obtain 20 mg yellow solid rac-6′-Chloro-3′-(3-chloro-benzyl)-2-(morpholine-4-carbonyl)-1′,3′-dihydro-[1,3′]biindolyl-2′-one. MS: 520 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:20])C2C=C(C)C(O)=C(C)C=2)[CH2:7][C:6](=[O:21])[C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]1[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[C:37]1(C(O)=O)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1>>[O:1]=[C:2]1[C@@H:8]([NH:9][C:10]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][N:38]=2)=[O:20])[CH2:7][C:6](=[O:21])[C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]1[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: Cc1cc(C(=O)N[C@H]2CC(=O)c3ccccc3N(CC(=O)OCc3ccccc3)C2=O)cc(C)c1O
Product: O=C(CN1C(=O)[C@@H](NC(=O)c2nccc3ccccc23)CC(=O)c2ccccc21)OCc1ccccc1
Yield: 92 %

Procedure:
Was prepared by the method reported in 14a by reaction of 12 and isoquinoline-1-carboxylic acid to afford 930 mg (92%) of the title compound.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][NH:23][CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[C:13]([NH2:27])[N:12]=2)[CH2:7][CH2:6]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:62]1([C:67]2[N:72]=[CH:71][C:70]([CH2:73][C:74](O)=[O:75])=[CH:69][CH:68]=2)[CH2:66][CH2:65][CH2:64][CH2:63]1>>[CH3:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][N:23]([C:74](=[O:75])[CH2:73][C:70]5[CH:71]=[N:72][C:67]([N:62]6[CH2:63][CH2:64][CH2:65][CH2:66]6)=[CH:68][CH:69]=5)[CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[C:13]([NH2:27])[N:12]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)Cc1ccc(N2CCCC2)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccc(N5CCCC5)nc3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine trihydrochloride (180 mg, 0.43 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (190 mg, 0.43 mmol) and triethylamine (0.30 mL, 2.1 mmol) were added to 2-(6-(pyrrolidin-1-yl)pyridin-3-yl)acetic acid (0.4 mmol, from the above step) in N,N-dimethylformate (5 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by Prep-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=513.2.
Reaction SMILES: [Na].[C:2]([C:4]1[C:5](=[O:17])[NH:6][C:7](=[O:16])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)#[N:3].ClC(Cl)(F)SCl.[Cl:24][C:25]([Cl:29])([Cl:28])[S:26]Cl>>[C:2]([C:4]1[C:5](=[O:17])[N:6]([S:26][C:25]([Cl:29])([Cl:28])[Cl:24])[C:7](=[O:16])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)#[N:3]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: N#Cc1cn(-c2ccccc2)c(=O)[nH]c1=O
Agent: FC(Cl)(Cl)SCl
Agent: [Na]
Product: N#Cc1cn(-c2ccccc2)c(=O)n(SC(Cl)(Cl)Cl)c1=O

Procedure:
The sodium salt of 5-cyano-1-phenyl-uracil is reacted with each of dichlorofluoromethane sulphenyl chloride and trichloromethane sulphenyl chloride following the foregoing procedure to yield 5-cyano-3-dichlorofluoromethane sulphenyl-1-phenyl-uracil and 5-cyano-1-phenyl-3-trichloromethane sulphenyl uracil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1[N:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[N:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1Cc2cc(-c3ccc(C(F)(F)F)nn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 102.2 %

Procedure:
A mixture of (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (350 mg, 0.80 mmol, prepared in Step F in Example 26), 3-chloro-6-(trifluoromethyl)pyridazine (176 mg, 0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL) and N,N-dimethylformamide (4 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.04 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (373 mg, 28%) as a brown oil: ESI MS m/z 456 [M+H]+.
Reaction SMILES: NC1C=CC=CC=1.Cl[C:9](OCC1C=CC=CC=1)=[O:10].C([O-])(O)=O.[Na+].[C:24]1([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2C=CC=CC=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OC[C@H]1OC1)(=O)CCC>CN(C=O)C.O.CC(C)=O.O>[OH:10][CH2:9][CH:33]1[O:32][C:31](=[O:40])[N:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:34]1
Reactant: O=C(Nc1ccccc1)OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCCC(=O)OC[C@@H]1CO1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C1OC(CO)CN1c1ccccc1

Procedure:
In Scheme 4, aniline (62) and benzyl chloroformate (63) are reacted in the presence of NaHCO3 and acetone:water (2:1) to generate benzyl N-phenylcarbamate (64), which when reacted with Cs2CO3 and (S)-(+)-glycidyl butyrate (65), in DMF solution gives the 5-(hydroxymethyl)-3-phenyloxazolidin-2-one (66), which upon treatment with NaIO4, RuCl3, H2O generates (67).
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: C=CCn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.13 ml of allyl bromide were used. As a result, 297 mg of 3-allyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1C[O:36]CC1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@@:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])([CH2:1][CH2:2][CH2:3][OH:36])[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCCO)(c2ccccc2F)OC1=O
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (80 mg, 0.18 mmol) in THF (10 mL) was added BH3 THF (1.5 mL, 1 mol/L) at 0° C. under nitrogen. The formed mixture was stirred for 2 h. The reaction was quenched by water. Then aq NaOH (0.3 mL, 3 mol/L) solution and H2O2 (3 mL) was added to the above mixture. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc, and the combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (15 mg, 17%). LC-MS Method 2 tR=1.48, min, m/z=452.2; 1H NMR (CD3OD) 1.22-1.34 (m, 2H), 1.53 (d, 3H), 1.62-1.73 (m, 1H), 1.98-2.33 (m, 4H), 2.61 (d, 1H), 3.13 (m, 1H), 3.51 (m, 2H), 5.61 (m, 1H), 7.01-7.19 (m, 5H), 7.23 (m, 1H), 7.31-7.43 (m, 4H), 7.53 (m, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C.Cl>CN1CCCC1=O.O>[Br:21][C:18]1[CH:19]=[CH:20][C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
A mixture of 5.0 g of 1-t-butoxycarbonyl piperazine, 6.36 gm of 2,5-dibromopyridine and 10.4 gm diisopropylethylamine in 50 ml of 1-methyl-2-pyrolidinone is kept for 12 hours at 150° C. Upon cooling to ambient temperature and addition of 10 ml water, the mixture is acidified with concentrated hydrochloric acid heated for 15 minutes and upon cooling extracted 2×5 ml ethyl ether. The aqueous layer is then neutralized with aqueous ammonium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract is collected, washed with 20 ml water and dried over Na2SO4. The crude product (4.3 gm) obtained after removing the solvents solidifies upon standing. This material is used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:14][C:15]([N:17]1[C@H:22]([C:23](=[O:34])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[CH2:21][C@@H:20]3[C@H:18]1[CH2:19]3)=[O:16])[CH:11]=[C:10]2[C:35](=[O:37])[CH3:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:35]([C:10]1[C:9]2[C:13](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[N:12]([CH2:14][C:15]([N:17]2[C@H:22]([C:23](=[O:34])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[CH2:21][C@@H:20]3[C@H:18]2[CH2:19]3)=[O:16])[CH:11]=1)(=[O:37])[CH3:36]
Reactant: COC(=O)c1cccc2c(C(C)=O)cn(CC(=O)N3[C@@H]4C[C@@H]4C[C@H]3C(=O)NCc3cccc(Cl)c3F)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2c(C(=O)O)cccc12
Reaction time: 18 h

Procedure:
To a solution of 3-acetyl-1-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indole-7-carboxylic acid methyl ester Example 541 (110 mg, 0.209 mmol) in THF (3 mL) and water (0.3 mL) was added 2N LiOH (1.05 mL, 2.09 mmol). Stirring of the reaction mixture was continued at RT for 18 h. A 1N HCl solution was added to adjust to pH=2-3 and the resulting aqueous suspension was filtered. The solid was washed with water then dried in vacuo. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions the title compound as a white solid. MS (LC/MS): 512 [M+H]+; tR (HPLC conditions k): 3.34 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH:20](C(OCC)=O)[C:21]([O:23]CC)=[O:22])[C:16]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A mixture of diethyl 2-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-ylmethyl]malonate (9.41 g), 4N aqueous potassium hydroxide solution (30 ml), and ethanol (30 ml) was refluxed for 1 hour. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was dissolved in pyridine (20 ml), which was stirred at 110° C. for 2 hours. After removal of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionic acid (7.52 g, yield: 99%). This was recrystallized from ethyl acetate-hexane. Melting point: 147–148° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[C:5]=2[C:4](O)=[N:3][CH:2]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:4]1[C:5]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]=3[NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]c3cnccc3c12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1ncnc2[nH]c3cnccc3c12
Temperature: 75 °C

Procedure:
A mixture of 9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-4-ol (264 mg, 1.4 mmol) and triethylamine (750 μL) in 5 mL POCl3 was heated at 75° C. for 18 hours. Toluene was added to the cooled reaction mixture and the solvents were then removed in vacuo to give the title compound as a brown oil (290 mg). LC-MS (1) Rt 1.25 min; m/z (ES+) 205/207.