Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1>C1COCC1.[Rh]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: [Rh]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Cl)cc1

Procedure:
3-(4-Chloro-phenyl)-acrylic acid (25.00 g, 0.14 mol) in THF was mixed with Rh/Al2O3 (1.00 g) and hydrogenated for 14 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give 3-(4-chloro-phenyl)-propionic acid. 3-(4-chloro-phenyl)-propionic acid was then reacted with SOCl2 (15.00 mL, 0.21 mol) and AlCl3 (20.20 g, 0.15 mol) according to the protocols as outlined in general procedure C to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH:29]=[CH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:32]I.C([Zn]CC)C>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH:29]1[CH2:32][CH2:30]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ICI
Reactant: C=COCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: CC[Zn]CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCOC1CC1

Procedure:
1-tert-Butoxycarbonyl-2(S)-(2-vinyloxyethyl)-4-naphthoylpiperazine (0.107 g, 0.261 mmol) was dissolved in ether (5 mL) under an argon atmosphere. To this solution was added diiodomethane (0.042 mL, 0.522 mmol) and diethylzinc (0.39 mL, 1M in hexane, 0.39 mmol). The reaction was refluxed for 1 h. The reaction was quenched with water, and extracted with ethyl acetate. The organic extracts were washed with water, saturated sodium chloride, and dried over magnesium sulfate. The title compound was obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:9][C:10]1[N:19]=[C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a mixture of 2-fluoroaniline (232 mg), 2,4-dichloroquinazoline (400 mg) and N,N-dimethylformamide (4 mL), potassium carbonate (430 mg) was added and stirred at room temperature for 8 hours. The reaction mixture was diluted with water (40 mL), and the precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1-3:1) to give 2-chloro-N-(2-fluorophenyl)quinazoline-4-amine (0.22 g) as a light-yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]C)=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15]C)=[O:14].B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1[nH]c2cc(OC)ccc2c1Br
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)c1[nH]c2cc(O)ccc2c1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
Methyl 3-Bromo-6-(methyloxy)-1H-indole-2-carboxylate (0.075 g, 0.26 mmol) was dissolved in CH2Cl2 (5 mL), cooled to 0° C. under nitrogen and BBr3 (1.0 M in CH2Cl2, 1.6 mL, 1.6 mmol) added dropwise. The reaction mixture was allowed to warm to RT and stirred overnight. Ice cold water (1 mL) and EtOAc (5 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (3×5 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.005 g, 7%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 13.06 (br. s., 1H), 11.63 (br. s., 1H), 9.55 (s, 1H), 7.30 (d, 1H), 6.78 (d, 1H), 6.70 (dd, 1H). MS: m/z 256.13 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:12]=[CH2:13])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ncc(C(=O)OC)cn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 44.8 %

Procedure:
To a solution of methyl-2-chloropyrimidine-5-carboxylate (2.084 g, 12.08 mmol) and tributyl(vinyl)tin (3.635 g, 11.46 mmol) in toluene (15 ml) was added triphenylphosphine (94.9 mg, 0.362 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (418.5 mg, 0.362 mmol). The mixture was stirred at 110° C. for 10 h under anhydrous argon. After evaporation of solvent, the residue was purified by flash chromatography (hexanes-ethyl acetate=4:1, then 1:1) to give the title compound (0.842 g) as a white solid. Mass spectrum (ESI) 166.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.26 (s, 2H), 6.95-7.01 (m, 1H), 6.82 (dd, 1H, J=1.4, 17.2 Hz), 5.92 (dd, 1H, J=1.4, 10.5 Hz), 4.01 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(NC(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)CBr)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a stirred solution of 6.07 g (40.7 mmol) Isopropyl-p-tolyl-amine, prepared as in Part A, and 4.12 g (40.7 mmol, 1 equiv) Et3N in 50 mL DCM is added 8.22 g (40.7 mmol, 1 equiv) Bromoacetyl bromide in 25 mL DCM dropwise over 30 minutes at 0° C. The reaction mixture is stirred 1 h at 0° C. followed by warming to ambient temperature and stirring 18 h. The reaction mixture is washed with 1N HCl (3×50 mL), dried (MgSO4), filtered through a pad of 20 g silica gel eluted with 400 mL DCM, and concentrated in vacuo to give 9.39 g (34.5 mmol) of 2-Bromo-N-isopropyl-N-p-tolyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.25 (d, 2H, J=8.1), 7.09 (d, 2H, J=8.3), 4.96 (m, 1H), 3.55 (s, 2H), 2.42 (s, 3H), 1.07 (d, 6H, J=6.8); TLC Rf =0.23 (EtOAc/Hexanes, 1:9).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[N:5][N:6]2[C:11]([CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].[C:33]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[N:5][N:6]2[C:11]([CH2:12][N:13]([CH3:33])[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CNC(=O)C(F)(F)F)ccnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(Cc1ccnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn12)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of N-((3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)-2,2,2-trifluoroacetamide (40 mg, 0.091 mmol) in 5 mL of acetone was added K2CO3 (50 mg) and CH3I (0.5 mL). After stirring at rt for 4 hr, the mixture was concentrated. The residue was partitioned between 10 mL of water and 10 mL of DCM. The organic layer was concentrated and purified by Pre-TLC (DCM/MeOH=20/1) to give a yellow solid (30 mg, 73%). MS (ESI) m/e [M+1]+ 451.9.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]CC.[Na+].Cl>C(O)C>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Yield: 77 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (20.0 g, 80.2 mmol) and benzaldehyde (8.19 mL, 80.2 mmol) in ethanol (113 mL) was added sodium ethoxide (2.71M, 32.5 mL, 88.3 mmol) and the reaction mixture was heated under reflux for 1 h. Hydrochloric acid (1 N, 96.3 mL) was added and the resulting mixture was extracted with toluene. The solvent was then distilled off to afford the title compound (19.1 g, 77%) as a light yellow solid. MS: m/e=308.0 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13](C)=[CH:14][C:15](O)=O.[C:19]([O:22]CC)(=[O:21])C>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][CH2:15][C:19]([OH:22])=[O:21]
Reactant: COc1ccc2ccccc2c1C(C)=CC(=O)O
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COc1ccc2ccccc2c1CCCC(=O)O
Reaction time: 15 h

Procedure:
The compound obtained in Step A (3.4 g, 1.40.10−2 mol) is solubilised in ethyl acetate (90 ml) in the presence of 5% palladium-on-carbon. The mixture is purged with argon and placed under a hydrogen atmosphere. After 15 hours' hydrogenation, the reaction mixture is filtered over Celite, rinsed and then evaporated under reduced pressure. The title product is isolated in the form of white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][CH:7]=1)=[O:5])C>[OH-].[Na+]>[F:15][C:12]([F:13])([F:14])[CH2:11][C:9]1[S:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1csc(CC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc(CC(F)(F)F)c1
Temperature: 140 °C
Yield: 20.1 %

Procedure:
5-(2,2,2-Trifluoro-ethyl)-thiophene-3-carboxylic acid ethyl ester (1.24 g, 5.2 mmol) was dissolved in IMS (10 mL) and aqueous sodium hydroxide (1 M, 10 mL) was added. The reaction was heated to 140° C. using microwave irradiation for 20 minutes and then partitioned between water and DCM. The aqueous solution was separated, acidified with 1 N hydrochloric acid and then extracted with DCM. The organic solution was dried over magnesium sulphate, filtered and the solvent removed. The resulting oil was triturated with cyclohexane and minimal diethyl ether to give the title compound (0.22 g). 1H NMR (400 MHz, CHCl3-d): δ 8.2 (s, 1H), 7.5 (s, 1H), 3.6 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:23]([CH3:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[C:23]([CH3:24])[C:22]([CH3:25])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)O)c(N)c1C
Product: Cc1ccc2c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)[nH]c2c1C
Yield: 53.3 %

Procedure:
365 mg (1.68 mmol) of 4-chlorobenzenesulfonylisocyanate and 230 mg (1.40 mmol) of 2-amino-3,4-dimethylbenzoic acid were treated in the same way as in Example 1 to obtain 272 mg of the above-identified compound (yield 53.6%). Properties: colorless crystal, Melting point; 241°-245° C., PMR (δppm, DMSO-d6): 2.21 (3H,s), 2.32 (3H,s), 7.06 (1H,d), 7.63 (1H,d), 7.75 (2H,d), 8.18 (2H,d), 10.64 (1H,br).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45]>>[C:44]([NH:47][C:28]([C:25]1[C:24]2[CH:33]=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:21]([N:35]3[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]3)=[C:22]([F:34])[C:23]=2[O:27][N:26]=1)=[O:30])([CH3:46])([CH3:45])[CH3:43]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NC(C)(C)C)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 2-methylpropan-2-amine
Reaction SMILES: C(NCC)C.[OH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19].O>CN(C=O)C>[NH2:20][C:16]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]=1[C:18]#[N:19]
Reactant: N#CCC#N
Reactant: O=C(CO)c1ccccc1
Solvent: CCNCC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2)coc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 3.78 ml (36.7 mmol) diethylamine dropwise to a mixture of 10 g (73.4 mmol) hydroxyacetophenone and 4.852 g (73.4 mmol) malononitrile in 24 ml DMF with cooling at RT. Stir the dark mixture for 2 h at RT and then add slowly to water (200 ml), with stirring and cooling. Continue stirring the precipitate for 30 min at approx. 10° C., filter with suction, suspend in water twice more, and filter with suction again. Dry the residue at high vacuum to constant weight. 10.99 g (81.2% of theor.) of the target compound is obtained as a yellowish-brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19]C)[CH:11]=3)=[CH:4][CH:3]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:21]3[CH2:22][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CC3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(N)cc2)n(C2CC2)c2cc(O)ccc12
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-aminophenyl)-1-cyclopropyl-6-methoxyindole-3-carbonitrile (2.02 g, 6.7 mmol), prepared in example 1CG, step E, in dry DCM (30 mL), at −30° C., is added boron tribromide (8.35 g, 3.15 mL, 33.3 mmol). The mixture is stirred at −30° C. ˜−15° C. for 1.5 h and then brought to ambient temperature and stirred for 15 min. The mixture is poured into saturated NaHCO3 and ice and stirred for 1 h. The volatiles are removed on a rotovap and the precipitate is collected via filtration and washed with water and then dried under a stream of N2 to provide 2-(4-aminophenyl)-1-cyclopropyl-6-hydroxyindole-3-carbonitrile in quantitative yield.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][CH:12]([OH:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.17 h
Yield: 10 %

Procedure:
Pregna-1,4,20-trien-3-one (3, 0.26 g, 088 mmol) in 25 mL of anh. ether was reduced under argon atmosphere with lithium aluminum hydride (250.5 mg, 6.601 mmol) for 2 h and then quenched with 2.50 g of Glauber's salt. The resulting suspension was stirred 70 min., filtered, and washed twice with 50 mL portions of ether. After concentrating the combined filtrates under reduced pressure the residue was purified using preparative TLC (35% ethyl acetate/hexanes on alumina to give white needles (26.1 mg, 87.4 μmol, 10%) m.p. 98°-128° C. (NA-1993B-81)
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[NH:20][N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>O1CCOCC1.[Cu]I>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5])[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 24.5 %

Procedure:
Into a solution of 2-bromo-4-chloronicotinaldehyde 103a (446 mg, 2.05 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one 101h (300 mg, 1.36 mmol) in dioxane (50 mL) was added KAcO (267 mg, 2.72 mmol), CuI (259 mg, 1.36 mmol), and 4,7-dimethoxy-1,10-phenanthroline (327 mg, 1.36 mmol). After bubbling nitrogen through the resulting solution for 30 min, the mixture was stirred at 90° C. for 10 h. It was allowed to cool down to room temperature and H2O (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 10:1 PE/EA to afford 103b (120 mg, 25%). LCMS: [M+H]+ 360. 1H NMR (500 MHz, CDCl3) δ 10.36 (s, 1H), 8.69 (d, J=5.5, 1H), 8.28 (d, J=2.0, 1H), 7.28-7.56 (m, 3H), 1.49 (s, 9H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 101 %

Procedure:
To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (9.81 g: 40 mmole) in dichloromethane (49 ml) in a nitrogen atmosphere under ice cooling, triethylamine (6.67 ml: 48 mmole) and methanesulfonyl chloride (3.70 ml: 48 mmole) are added. The mixture is stirred for 20 minutes to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as a crude oil (13.05 g). Yield: 101%.
Reaction SMILES: BrC1C=CC(C2C=NC=CC=2)=CC=1.C1([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22](C3C=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)[CH:21]=2)=[O:19])CC1.C(NC(C1C(=O)C2C(=NC=CC=2)N(C2C=CC=C(B3OC(C)(C)C(C)(C)O3)C=2)C=1)=O)(C)C>>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][N:24]=2)[C:29](=[O:30])[C:20]([C:18]([NH2:17])=[O:19])=[CH:21]1
Reactant: CC1(C)OB(c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)OC1(C)C
Agent: Brc1ccc(-c2cccnc2)cc1
Agent: CC(C)NC(=O)c1cn(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)c2ncccc2c1=O
Product: NC(=O)c1c[nH]c2ncccc2c1=O

Procedure:
Following the procedure of Step 3 of Example 31 but substituting 3-bromo-5-methylsulfonylpyridine from Step 2 above for 3-(4-bromophenyl)pyridine, and N-cyclopropyl-1-[3-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 for N-isopropyl-1-[3-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the N-Cyclopropyl-1-[3-(5-methylsulfonylpyridin-3-yl)]phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cccc1Br
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: Cn1cccc(Br)c1=O
Yield: 78.8 %

Procedure:
A mixture of 3-bromo-1H-2-pyridone (740 mg, 4.25 mmol), potassium carbonate (1.18 g, 8.5 mmol) and iodomethane (2.65 mL, 42.5 mmol) in DME (10 mL) was heated to reflux overnight. The mixture was filtered, washing with ethyl acetate and the filtrate was evaporated to dryness. The residue was purified by dry column chromatography over 27 g of silica gel, eluting with ethyl acetate to give 3-bromo-1-methyl-2-pyridone (0.63 g, 79%). LRMS (electrospray), positive ion, 188 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9](C3C=CC=CC=3)[O:10][C:3]=12>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:9][O:10][C:3]1[C:4]([NH2:8])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccnc2nc(-c3ccccc3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C)ccnc1N
Temperature: 25 °C
Yield: 7.4 %

Procedure:
86 mg of the 7-methyl-2-phenyl[1,3]oxazolo[4,5-b]pyridine [159-1] was dissolved in a mixture solvent of 4 mL of tetrahydrofuran and 4 mL of ethanol, 1.64 mL of an aqueous solution of sodium hydroxide 33% was added thereto, and heated overnight under reflux. After cooling back to room temperature, the reaction solution was concentrated under reduced pressure. To the obtained residue, 5 mL of dichloromethane and 3.4 mL of an aqueous solution of sodium hydroxide 33% were added and stirred. Thereto, 28 μL of methyl iodide and 30.5 μL of Adogen 464 (phase transfer catalyst, Aldrich Corporation) were added, and stirred overnight at room temperature. Water was added, the reaction solution was extracted with chloroform, and the organic layer was washed with phosphate buffer pH 7.0, water, and saturated brine in the subsequent order. The organic layer was dried over anhydrous sodium sulfate, the insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by preparative thin-layer chromatography, to obtain 4.2 mg of 3-methoxy-4-methylpyridin-2-amine [159-2] as a light brown solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23]2[C:24]([CH3:32])=[CH:25][C:26]([CH:29]([NH2:31])[CH3:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:26]3[CH:25]=[C:24]([CH3:32])[C:23]([O:22][CH2:21][C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:34][CH:33]=4)=[CH:28][N:27]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ncc1OCc1ccc(F)cc1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCc1ccc(F)cc1
Yield: 69 %

Procedure:
The title compound is prepared in 69% yield (527 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (516 mg, 1.85 mmol, Step-1 of Intermediate-1) and 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (550 mg, 1.85 mmol, Amine-79, single enantiomer) in a similar manner to Intermediate-2.