Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CO.O1CCCC1>[OH:3][CH:4]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=O)c1c(-c2ccccc2)sc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(O)c1c(-c2ccccc2)sc2ccccc12
Reaction time: 1 h
Yield: 43.5 %

Procedure:
Sodium borohydride (53 mg, 1.40 mmol) was added to a solution of ethyl 2-oxo-2-(2-phenyl-1-benzothiophen-3-yl)acetate (2b) (430 mg, 1.38 mmol) in a mixture of methanol (10 mL) and tetrahydrofuran (5 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour, quenched with water (2 mL) and concentrated in vacuo. The residue was diluted with dichloromethane (20 mL), washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (dichloromethane/ethanol 99/1) to afford the desired alcohol (2c) as a white solid (190 mg, 0.60 mmol, 44%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[CH:33]([CH3:35])[CH3:34].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)C=O
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)CN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 110 mg (0.26 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 2.5 mL chloroform was treated with 0.24 mL (2.6 mmol) isobutyraldehyde and 170 mg (0.78 mmol) NaBH3(CN), followed by the addition of 2.5 mL methanol. The mixture was stirred at ambient temperature for 1 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 468 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:39][C:35]([CH3:38])([CH3:34])[CH2:36][NH:37][C:29]([C:26]1[CH:27]=[CH:28][C:20]2[C:19]3[S:32][C:16]([C:14]([N:13]([C:3]4[CH:4]=[CH:5][C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=4[Cl:1])[CH3:33])=[O:15])=[CH:17][C:18]=3[CH2:24][CH2:23][O:22][C:21]=2[CH:25]=1)=[O:30]
Reactant: CC(C)(N)CN
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)NCC(C)(C)N)cc2OCC3)c(Cl)c1

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-methylpropane-1,2-diamine, HATU and DIPEA in THF to give 340 as a colorless solid after reverse phase HPLC. MS: (ESI+) 555.3
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O[C:14]([S-:16])=S)C.[K+].O.Cl.[N:20]1C=CC=CC=1>>[C:8]([C:7]1[CH:6]=[CH:5][C:4]2[O:10][C:14]([SH:16])=[N:20][C:3]=2[CH:2]=1)#[N:9]
Reactant: CCOC(=S)[S-]
Reactant: c1ccncc1
Reactant: N#Cc1ccc(O)cc1N
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#Cc1ccc2oc(S)nc2c1

Procedure:
3-Amino-4-cyanophenol (6.71 g) was dissolved in pyridine (100 mL), and potassium ethylxanthate (8.82 g) was added thereto. The mixture was refluxed for 2 hr. After allowing to cool, iced water (200 mL) was added to the reaction mixture, and conc. hydrochloric acid (40 mL) was added thereto. The precipitated solid was collected by filtration to give 5-cyano-2-mercaptobenzoxazole (5.62 g) as a gray powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH2:8]([C@@:11]1([CH3:32])[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C@H:14]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[O:13][C:12]1=[O:31])[CH:9]=[CH2:10]>C(OCC)(=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C@H:15]([C@H:14]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[OH:13])[CH2:16][C@:11]([CH3:32])([CH2:8][CH:9]=[CH2:10])[C:12]([NH:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4])=[O:31])[CH:22]=[CH:21][CH:20]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Reactant: CC(C)[C@H](N)CO
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)C(C)C
Temperature: 100 °C

Procedure:
A mixture of (S)-2-amino-3-methylbutan-1-ol (550 mg, 5.33 mmol) and (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (Example 261, Step H, 2nd compound, 500 mg, 1.332 mmol) was heated to 100° C. for 24h. After cooling to room temperature, the residue was dissolved in ethyl acetate and washed 3× with 1N HCl (5 mL) followed by sat. aq. NaCl solution (5 mL). The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]#[N:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:1][C:2]1[C:3]([CH:12]([CH3:16])[C:13]#[N:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [Li]CCCC
Reactant: Cc1cc2ccccc2cc1CC#N
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2ccccc2cc1C(C)C#N
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a stirred solution of (3-methyl-2-naphthalenyl)acetonitrile (2.17 g, 12 mmol) in dry THF (125 mL) cooled to -78° C. was added n-BuLi (8.44 mL, 13.5 mmol; 1.6M solution in hexanes)dropwise over 10 minutes. The resulting orange solution was stirred for 20 minutes at -78° C. and MeI (1.92 g, 13.5 mmol) was added in one portion. The reaction mixture was stirred at -78° C. for 1.25 hours and quenched with saturated NH4Cl (20 mL). After warming to room temperature, the volatiles were removed in vacuo and the residue was diluted with H2O (150 mL). The aqueous phase was extracted with Et2O (2×150 mL). The combined organic layers were washed with saturated NaCl (1×150 mL) and dried (MgSO4). Removal of the solvent in vacuo afforded the product as a light yellow solid (2.34 g, 100%). This material was of sufficient purity to be used as such.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.[C:15](=[O:18])(O)[O-:16].[Na+].O>O1CCOCC1.O>[C:4]([O:16][C:15]([N:2]1[CH2:5][CH:4]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3]1)=[O:18])([CH3:6])([CH3:5])[CH3:3]
Reactant: O=C([O-])O
Reactant: O=C(c1ccc(Cl)cc1)C1CNC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2ccc(Cl)cc2)C1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A solution of azetidin-3-yl-(4-chloro-phenyl)-methanone hydrochloride (50 g, 210 mmol) in dioxan:water 1:1 (800 ml) is added powdered sodium bicarbonate (61.7 g, 730 mmol) and the reaction mixture cooled to 10° C. Di-tbutyl-dicarbonate (52.6 g, 240 mmol) is added portion wise and the reaction mixture allowed to warm to room temperature with stirring for 1.5 hours. The reaction mixture is poured into water (1500 ml) and the resulting white precipitate filtered off and dried under vacuum to afford 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.45 (9H), 4.10 (1H), 4.20 (4H), 7.47 (2H), 7.80 (2H)
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[N:23]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:30])[CH2:24]2.Cl>C1COCC1.CCCCCC.C(O)C>[Cl:16][C:17]1[C:22]([C:25]2([OH:30])[CH:26]3[CH2:29][N:23]([CH2:28][CH2:27]3)[CH2:24]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1cnccn1
Reactant: O=C1CN2CCC1C2
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2nccnc2Cl)CN2CCC1C2
Reaction time: 0.17 h

Procedure:
A solution of 7.2 ml of 2,2,6,6-tetramethylpiperidine in 300 ml of THF was cooled to -5° C. as 25 ml of 1.6M butyllithium (0.04 mol) in hexane was added dropwise. The reaction was stirred 10 min then cooled to -77° C. as 3 ml of 2-chloropyrazine in 7 ml of THF was added dropwise. After another 15 min, 4.4 g of 1-azabicyclo[2.2.1]heptan-3-one (0.0396 mol) in 10 ml of THF was added and the reaction stirred 1 h. A solution of 8 ml of conc. HCl in 4 ml of ethanol was added and the cooling was removed. When the temperature reached -10° C., 100 ml of water was added, the organics were evaporated, and the residue treated with 11 ml of 5N NaOH. The solvent was reduced to a small volume, ca. 50 ml, the mixture cooled in ice-water, and the solid collected by filtration. The aqueous fraction was extracted 3× with 50 ml of CHCl3, the extracts added to the solid filtrate, and the total volume of the mixture taken to 500 ml with more CHCl3. The mixture was heated to boiling, dried, filtered, and the solvent evaporated to give a brown solid. The solid was recrystallized from isopropanol to give 4.1 g of tan crystalline (26), mp 220° C. dec. NMR ppm (CDCl3) 1.55-1.9 (2H, m), 2.27 (1H, m), 2.42-2.58 (2H, m), 2.75 (2H, m), 2.95 (1H, m), 3.5 (1H, d) 3.6 (1H, d), 8.3 (1H, d) 8.42 (1H, d). Anal. C10H12ClN3O requires C: 53.22; H: 5.36; N: 18.62%. Found C: 53.10; H: 5.20; N: 18.41%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[CH:40][NH:41]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH:39]=[CH:40][NH:41]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc4[nH]ccc34)n(-c3ccccc3)c(=O)c12
Yield: 3.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (140 mg, 0.32 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (116 mg, 0.48 mmol), sodium carbonate (2M, 715 μl, 1.43 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40 mg, 0.05 mmol) according to the method described in Example 3 to give 6 mg (4% yield) of the title compound as a mixture of diastereoisomers. Purity 99%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:23][C:24]1[C:28]([CH3:30])([CH3:29])[O:27][C:26](=O)[CH:25]=1>C1COCC1>[Br:23][C:24]1[C:28]([CH3:30])([CH3:29])[O:27]/[C:26](=[C:5]2/[C:6](=[O:12])[NH:7][C:8]3[C:4]/2=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=3)/[CH:25]=1
Reactant: CC1(C)OC(=O)C=C1Br
Reactant: O=C1Cc2cc(F)c(F)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5,6-difluorooxindole (450 mg, 2.66 mmol) in THF (20 mL) at 0° C., was added 1M LiHMDS in THF (5.3 mL, 5.3 mmol). The reaction mixture was stirred at 0° C. for 10 minutes. 4-bromo-5,5-dimethyl-5H-furan-2-one (340 mg, 1.78 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 min., and then at room temperature for an additional 30 min and quenched with 2.5M aqueous H2SO4 (3 mL). The resulting mixture was stirred at room temperature for 16 hours and poured into water (100 mL). The precipitates were filtered, washed with water and dried in vacuo to yield (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 547 mg, 90%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2S[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.Cl[C:31]1C([N+]([O-])=O)=C(Cl)N=C[N:32]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[N:32]=[CH:31][C:15]3[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:17]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl(trans-3-(quinazolin-2-ylamino)cyclobutyl)carbamate, which was synthesized analagous to intermediate 10, (1.71 g, 5.44 mmol) was dissolved in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 20 minutes after which the solution was evaporated to dryness under reduced pressure. The crude oil was further dried under high vacuum then dissolved in dry dimethylsulfoxide (40 mL). 4,6-Dichloro-5-nitropyrimidine (1.5 g, 7.73 mmol) was added followed by potassium carbonate (1.8 g, 13.02 mmol) and the reaction heated at 60° C. After 2 hours the mixture was cooled and diluted with water (300 mL). The product precipitated out and was filtered off using a sintered glass frit. It was dried on the frit and used without purification.
Reaction SMILES: S(Cl)(Cl)=O.[Cl-:5].[Al+3].[Cl-].[Cl-].[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:5])=[O:16])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1

Procedure:
2 equivalents of thionyl chloride and 0.1 g of aluminum chloride are added to 10 g (0.06 mole) of 4-methoxybenzoic acid in suspension in 60 ml of petroleum ether. This reaction mixture is refluxed for 5 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes in the presence of petroleum ether at 0° C.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:7]1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:14][CH3:15])[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH3:13]
Reactant: CCC(O)(CC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCC1(CC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (7.0 mL) was added dropwise to 3-(2,2′-bithiophene-3-yl)pentan-3-ol (IIa) (2.67 g, 11 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (100 mL) and water (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford pure dark yellow oil (Ia) (1.2 g, 47%). 1H-NMR (CDCl3): δ=7.21 (d, J=4.8 Hz, 2H), 7.00 (d, J=4.8 Hz, 2H), 1.98 (q, J=6.8 Hz), 4H), 0.70 (t, J=7.0 Hz, 6H). 13C-NMR (CDCl3): δ=157.89, 137.36, 125.09, 122.16, 54.76, 30.71, 9.74.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[H][H]>C(O)(C)C.O1CCCC1.[Pd]>[CH2:6]1[CH:1]([CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH:4]([OH:7])[CH2:5]1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OC1CCC(C2CCC(O)CC2)CC1

Procedure:
In 1 l of isopropanol was dissolved 100 g (0.54 mol) of biphenyl-4,4'-diol, and 5 g of anhydrous sodium carbonate and 5 g of 5% palladium-on-carbon were added to the solution. The mixture was subjected to reduction reaction in an autoclave at 100° C. and at a hydrogen pressure of 5 kg/cm2 for 25 to 30 hours. After completion of the reaction, the reaction mixture was filtered, and the isopropanol was removed from the filtrate by distillation under reduced pressure to recover a part of dicyclohexyl-4,4'-diol. The crystals obtained as a filter cake were dissolved in 500 ml of tetrahydrofuran while hot and filtered. The tetrahydrofuran was removed from the filtrate by distillation under reduced pressure to obtain dicyclohexyl-4,4'-diol. Both crystals were combined, suspended in 1 l of n-hexane while hot, and allowed to stand at 5° to 6° C. for 1 hour. The precipitated crystals were colleoted by filtration and dried under reduced pressure to obtain 93 g (0.47 mol) of a compound of formula: ##STR28## Melting Point: 179°-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][C@@H:28]1[CH2:29][CH2:30][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester following general procedure B to afford 4-((R)-1-tert-butoxycarbonyl-pyrrolidin-3-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester 381 mg). Thus obtained amino-ester (208 mg, 0.5 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish 3-[(R)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (194 mg). LCMS: m/z 523 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:21][C:22]([S:26](Cl)(=[O:28])=[O:27])=[C:23]([CH3:25])[N:24]=1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:26]([C:22]2[S:21][C:20]([CH3:19])=[N:24][C:23]=2[CH3:25])(=[O:28])=[O:27])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2,4-dimethylthiazole-5-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,4-dimethylthiazole-5-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.3 (s, 3H), 2.6 (s, 3H), 5.7 (s, 1H), 5.9 (dt, 1H), 7.1 (q, 1H), 7.2 (d, 1H), 7.3 (m, 1H), 7.4 (d, 1H), 7.4 (s, 1H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C@H:15]([OH:29])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:14]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C@H:15]([O:29][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]2)[CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(Cl)cc1[C@H](O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of NaH (5.64 g, 0.141 mol) in the mixed solvent of DMF (70 mL) and THF (70 mL) at −25° C. was added dropwise a solution of (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (16 g, 47 mmol) in anhydrous THF (100 mL), the reaction mixture was stirred for 1 hr at rt. A solution of ethyl bromoacetate (15.6 g, 94 mmol) in anhydrous THF (70 mL) was added dropwise to the above mixture at −10-−5° C. After addition, the reaction mixture was stirred for 2-3 hr at rt. The reaction was quenched with saturated NH4Cl solution (100 mL) and EtOAc (500 mL) was added. The organic layer was washed with water (5×50 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (8 g, 18.8 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.[I:26][C:27]1[CH:42]=[CH:41][C:30]([CH2:31][NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[I:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(I)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(I)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Prepared using General Procedure 8: To a stirring solution of 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (1.38 g, 3.92 mmol), tert-butyl 2-((4-iodobenzyl)amino)acetate INT-35 (1.36 g, 3.92 mmol) and TEA (0.82 ml, 5.88 mmol) in DMF (8 mL) was added HATU (1.56 g, 4.11 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with EA (150 mL) and washed successively with NaHCO3 (100 mL) and brine (100 mL). The organics were pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 2.05 g (75%) of tert-butyl 2-(N-(4-iodobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-36. LCMS-ESI (m/z) calculated for C30H30F3IN2O5: 682; found 627 [M−tBu+H]+, tR=2.90 min (Method 10). 1H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 7.76-7.68 (m, 2H), 7.62 (dd, J=7.0, 1.8 Hz, 2H), 7.44 (d, J=8.3 Hz, 1H), 7.37-7.30 (m, 2H), 7.27-7.13 (m, 3H), 7.12-6.97 (s, 1H), 4.59 (s, 1H), 4.50 (s, 1H), 3.92 (m, 2H), 3.85 (s,2H), 3.83 (s, 3H), 1.41 (s, 4.5H), 1.31 (s, 4.5H).