Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:39])[C@@H:28]([NH:38][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.3 g of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 2.2 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 80 ml of DMF, 0.9 g of HOBT and 1.3 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.7 g.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3](C(O)=O)=[N:2]1.C(=O)(O)[O-].[Na+].[I-:18].[Na+].II>ClC(Cl)C.O.ClCCl>[I:18][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[NH:1][N:2]=1
Reactant: [I-]
Reactant: O=C(O)c1n[nH]c2c1CCCC2
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: Ic1n[nH]c2c1CCCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
To a mixture of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.57 g, 3.43 mmol), and sodium bicarbonate (951 mg, 440 μL, 11.3 mmol) in dichloroethane (5 mL) and water (5 mL) were added in one portion sodium iodide (1.34 g, 8.92 mmol) and iodine (1.13 g, 4.46 mmol) and the mixture heated at to 100° C. (oil bath temperature) with vigorous stirring for 24 h. After cooling to 25° C. the mixture was diluted with dichloromethane, then washed with 10% Na2S2O3 and saturated NaHCO3. The organic phases were combined, dried (MgSO4) and concentrated to an off-white solid which was purified by chromatography (115 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give 3-iodo-4,5,6,7-tetrahydro-1H-indazole (674 mg, 2.72 mmol, 79.2%) as a white solid. MS (M+H)+=249 (>90% purity); 1H NMR (CDCl3) δ: 2.75 (t, J=5.7 Hz, 2H), 2.35 (t, J=5.7 Hz, 2H), 1.61-1.90 (m, 4H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:43][B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([OH:75])=O>O1CCCC1.O>[F:43][C:70]1[CH:69]=[CH:68][C:67]([CH2:72][C:73]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:75])=[CH:66][CH:71]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Cc1ccc(F)cc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18 mmol), ethyldiisopropylamine (0.068 mL, 0.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl, 0.038 mg, 0.2 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (HOBt, 0.027 mg, 0.2 mmol) and 2-fluorophenyl acetic acid (0.031 mg, 0.2 mmol) were dissolved in tetrahydrofurane (3.0 mL). The reaction mixture was stirred at ambient temperature for 3 h. Then it was diluted with water and extracted with ethyl acetate (3×). The combined organic phases were dried on sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, heptane, ethyl acetate 4:1/1:1). The title compound (0.025 g, 33%) was obtained as an off-white solid; MS: m/e=412.6 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[OH-].[Na+].O.[C:16]([O:20][C:21](N=[N+]=[N-])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([NH:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: NCC1=C(CC(=O)O)CC=CC1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CC=CC1

Procedure:
To a stirred solution of 8.0 g. (0.048 mole) of α-(2-aminomethyl-1,4-cyclohexadienyl)acetic acid and 3.8 g. (0.096 mole) of NaOH in 150 ml. of water was added a solution of 10.3 g. (0.072 mole) of t-butoxycarbonylazide in 80 ml. of THF and the mixture was stirred for 18 hours at room temperature. The THF was removed under reduced pressure and the residual solution was washed with ether (2 × 100 ml.), acidified with 6 N HC1 and extracted with ether (3 × 100 ml.). The combined extracts were washed with water (2 × 100 ml.) and a saturated NaCl solution (100 ml.), dried with Na2SO4 and evaporated to dryness. The oily residue was triturated with n-hexane to give 10.5 g. (82%) of colorless powder melting at 113° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH3:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:9][C:5]1[CH:4]=[C:3]([CH2:12][CH3:13])[C:2]([Cl:1])=[CH:8][C:6]=1[NH2:7]
Reactant: CCc1cc([N+](=O)[O-])c(N)cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(N)c(N)cc1Cl
Yield: 100 %

Procedure:
A mixture of 5-chloro-4-ethyl-2-nitroaniline (supplied by the Sigma-Aldrich Library of Rare Chemicals, 2.62 g, 13.1 mmol), tin (II) chloride dihydrate (14.7 g, 65.3 mmol) and ethyl acetate (130 ml) was heated under reflux for 22h. The mixture was cooled and partitioned between 1M aqueous sodium hydroxide (500 ml) and ethyl acetate (500 ml). The aqueous layer was extracted with ethyl acetate (250 ml), and the combined organic solutions were washed with saturated aqueous sodium chloride (100 ml), dried (MgSO4) and concentrated under reduced pressure to give 1,2-diamino4-chloro-5-ethylbenzene (2.70 g, >100%) as a white solid which was used directly without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([N-:11]C(C)C)(C)C.[Li+].CO[N:18](C)[C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[C:20]1([C:19]2[C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[NH:11][N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1ccncc1
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(-c2n[nH]c3ccncc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2 M aqueous solution of sodium hydroxide (20 mL, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 4-chloropyridine hydrochloride (3.18 g) in tetrahydrofuran (20 mL, manufactured by Kanto Chemical Co., Inc.) to neutralize the solution, and then the mixture was extracted with ethyl acetate (3×50 mL), washed with brine mL), and dried (MgSO4). The solvent was then evaporated to give 4-chloropyridine. 4-Chloropyridine was added dropwise to a solution of lithium diisopropylamide (23% solution in tetrahydrofuran/ethylbenzene/heptane, 14.1 mL, manufactured by Sigma-Aldrich Corp.) in tetrahydrofuran (40 mL, manufactured by Kanto Chemical Co., Inc.) at −78° C., and the mixture was stirred for 30 minutes. Subsequently, N-methoxy-N-methylbenzamide (3.55 mL, manufactured by Sigma-Aldrich Corp.) was further added to the mixture at the same temperature, and while the temperature was gradually raised to room temperature, the mixture was stirred overnight. A saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×50 mL), washed with brine (50 mL), and dried (MgSO4). The solvent was then evaporated, isopropanol (20 mL, manufactured by Kanto Chemical Co., Inc.) and hydrazine hydrate (5.0 mL, manufactured by Tokyo Chemical Industry Co., Ltd.) were added to the obtained residue, and the mixture was stirred for one hour at room temperature. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×30 mL), washed with brine (50 mL), and dried (MgSO4). The solvent was then evaporated, and a saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (3×50 mL), washed with brine (50 mL), and dried (MgSO4), and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 4.1 g of the title compound. LC-MS: HPLC retention time 0.64 minutes, m/z (M+H) 232, condition C-1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:17][C:14]1[CH:13]=[C:12]2[NH:11][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:10])[N:16]2[N:15]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=C(O)c1cccnc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc2[nH]c3ncccc3c(=O)n2n1
Reaction time: 2 h

Procedure:
157 g. of 2-chloropyridine-3-carboxylic acid and 194 g. of 5-amino-3-methylpyrazole are heated together in 500 ml. of diphenyl ether for 10 minutes at 215°. After this time, the mixture is allowed to stand at room temperature for 2 hours and is then filtered. The crystalline 2-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin- 9(4H)-one is washed with methanol and recrystallized from dimethylformamide, yield: 120 g. (64%); m.p. >300°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[C:7]2([CH3:15])[CH3:14])([O-:3])=[O:2].[CH2:16]([I:18])[CH3:17]>>[I-:18].[CH2:16]([N+:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH3:15])([CH3:14])[C:8]=1[CH3:13])[CH3:17]
Reactant: CCI
Reactant: CC1=Nc2ccc([N+](=O)[O-])cc2C1(C)C
Product: CC[N+]1=C(C)C(C)(C)c2cc([N+](=O)[O-])ccc21
Product: [I-]
Yield: 53.1 %

Procedure:
5-Nitro-2,3,3-trimethylindole (518 mg, 2.54 mmol) and ethyl iodide (2.5 ml, 4.85 g, 31 mmol, excess) were mixed and heated to reflux for 8 hours. After cooling to room temperature the excess ethyl iodide was removed by a gentle nitrogen stream and the residue was dissolved in chloroform and filtered through a plug of silica. The silica was washed with chloroform (1 volume) and the combined filtrates were rotary evaporated to give the product as a yellow oil, (486 mg, 1.35 mmol, 53% yield).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17]CC2C=CC=CC=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH2:28])C1C=CC=CC=1.Cl[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:15][C:14]1[C:9](=[O:8])[C:10]([CH2:26][CH2:27][NH:28][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=2)=[C:11]([CH3:25])[C:12](=[O:17])[C:13]=1[CH3:16]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCN)c(C)c1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC1=C(C)C(=O)C(CCNc2cc(C(F)(F)F)ccn2)=C(C)C1=O
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirring solution of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl) ethanamine (500 mg, 1.3 mmol) in DMSO (1 mL) was added 2-chloro-4-trifluoromethyl pyridine (256 mg, 2.0 mmol, 1.5 equiv.) and diisopropyl ethyl amine (578 μL, 3.3 mmol, 2.5 equiv.). The resulting solution was stirred at 100° C. for 12 hr, after which time HPLC analysis indicated that the reaction was complete. The mixture was brought to 80° C., water (3 mL) was added, and the resulting suspension was stirred for 30 min. The mixture was subsequently brought to ambient temperature and stirred for an additional 30 min, after which the solids were collected by filtration. After drying in vacuo, 750 mg crude brown solids were obtained containing the desired product. The crude material was taken up in trifluoroacetic acid (6 mL) and treated with thioanisole (393 μL, 3.35 mmol). After stirring at ambient temperature for 1 hour, HPLC analysis indicated that the reaction was complete. Volatiles were removed in vacuo and the residue was taken up in 25 mL ethyl acetate. The organic layer was washed with water, 1 M aqueous sodium bicarbonate, and brine (10 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude hydroquinone (450 mg) was dissolved in acetonitrile (7 mL) and cooled in an ice-water bath. To the stirring solution was added an aqueous solution of ceric ammonium nitrate (1.46 g, 7.6 mmol in 2 mL) in a dropwise fashion. The reaction was deemed complete by TLC analysis when approximately 90% of the reagent was added. At this point, the mixture was partitioned between ethyl acetate and brine (15 mL each), and the organic layer was removed. The remaining aqueous layer was made basic by addition of 10 mL 1 M aqueous sodium bicarbonate, and extracted with ethyl acetate (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to produce 500 mg brown oil. Purification by silica gel chromatography (gradient elution 0→35% ethyl acetate in heptane) afforded 2,3,5-trimethyl-6-(2-(4-(trifluoromethyl)pyridin-2-ylamino)ethyl)cyclohexa-2,5-diene-1,4-dione as a bright yellow solid (85 mg). 1H-NMR (400 MHz, CDCl3) 8.15 (d, 1H), 6.76 (m, 2H), 3.49 (m, 2H), 2.86 (t, 2H), 2.08 (s, 3H), 2.01 (s, 6H). M+=338.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (16.7 g, 0.1 mol) (Crescent) and 3-chlorobenzaldehyde (14.1 g, 0.1 mol) (Aldrich) in methanol (100 mL) was added pyrrolidine (7.1 g, 0.1 mol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 h. After cooling to 4° C., the resulting precipitate was collected and dried to give 20 g of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. MS: 291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH2:11])[CH3:10].[C:12](OC)(OC)(OC)[CH2:13][CH3:14].[N:21]#[C:22][NH2:23]>>[C:22]([N:23]=[C:12]([NH:11][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH3:10])[CH2:13][CH3:14])#[N:21]
Reactant: CC(N)c1ccc(Cl)cc1Cl
Reactant: CCC(OC)(OC)OC
Reactant: N#CN
Product: CCC(=NC#N)NC(C)c1ccc(Cl)cc1Cl
Yield: 84.4 %

Procedure:
1.85 g of 1-(2,4-dichlorophenyl)ethylamine, 1.63 g of trimethyl orthopropionate and 0.46 g of Cyanamide were heated under reflux for about 30 minutes. The volatile components were removed under reduced pressure and the residue was then titrated with water. Filtration and drying gave 2.22 g of N′-cyano-N-[1-(2,4-dichlorophenyl)ethyl]propaneimidamide of logP of 2.56.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]1[CH:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>C(Cl)Cl>[Br:1][CH2:21][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:12])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(CO)cc1F
Solvent: ClCCl
Solvent: CSC
Product: N#Cc1ccc(CBr)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0° C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to −20° C. then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile, as described in Step C above, (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0° C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified after chromatography (silica gel, 5-10% EtOAc/hexane).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(O)C>O.[Pd]>[CH:6]1([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: NCC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C(O)CNC1CCCCC1

Procedure:
338 g of glycine (4.5 mols) is dissolved in 1.5 liters of deionized water. The solution is put into a 1-gallon autoclave. 25 g of 10% Pd on C, 551 g of cyclohexanone (5.6 mols) and 500 ml of ethanol are added. Hydrogenation is carried out at 60° C. between 56.2 and 70.3 kg/cm2. In the course of three hours a pressure drop corresponding to 98.4 kg/cm2 is observed.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[N:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:29][C:30]1[CH:31]=[C:32]([N+:37]([O-:39])=[O:38])[CH:33]=[CH:34][C:35]=1F.O>CN(C=O)C.CCO>[Cl:1][C:2]1[C:3]([N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:35]1[CH:34]=[CH:33][C:32]([N+:37]([O-:39])=[O:38])=[CH:31][C:30]=1[F:29]
Reactant: O=c1cc[nH]c(N=C(c2ccccc2)c2ccccc2)c1Cl
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 32.73 %

Procedure:
To a 2-L CHEMGLASS® reactor was added the crude 3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one (from above, now in DMF) and cesium carbonate (300.52 g, 923 mmol) followed by the addition of 3,4-difluoronitrobenzene (118.15 mL, 1065 mmol). The mixture was heated to approximately 90° C. with stirring for 2 h. The mixture was cooled to 25° C. with stirring for 10 min. To this solution was added water (1 L). The mixture was extracted with EtOAc (1 L) and the aqueous phase was discarded. The organics were concentrated to afford an oil. The oil was dissolved into EtOH (200 mL) (heating sometimes required). After the solution was allowed to stand at 25° C. for 4 h, a solid was collected by filtration to afford 3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (104.00 g; 32.73% yield) as a yellow solid. 1H NMR (CDCl3) δ 6.52 (d, 1H, J=5.6 Hz), 6.80 (dd, 1H, J=8.1, 9.1 Hz), 7.21-7.60 (m, 8H), 7.78-7.95 (m, 2H), 8.00 (m, 1H), 8.11 (dd, 1H, J=2.5, 9.6 Hz), 8.17 (d, 1H, J=5.6 Hz); MS (ESI+) m/z 448.01 (M+H)+.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:28]([NH:30][C:31]2([C:34]#[N:35])[CH2:33][CH2:32]2)=[O:29])[CH2:25][CH2:26][CH3:27])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:34]([C:31]1([NH:30][C:28](=[O:29])[C@@H:24]([NH:23][C@@H:18]([C:15]2[CH:16]=[CH:17][C:12]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)[C:19]([F:22])([F:21])[F:20])[CH2:25][CH2:26][CH3:27])[CH2:33][CH2:32]1)#[N:35]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(C)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was synthesized in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1%-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between p-tolylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex. MS (+ESI): 430 [M+1]+
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)CCC1=O.Cl>CCOCC>[C:18]([N:15]1[CH2:16][CH:17]=[C:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[CH:11]=2)[CH2:13][CH2:14]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Agent: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)N1CC=C(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 4-fluorophenylboronic acid by procedures analogous to that described in INTERMEDIATE 2. The title compound was converted to HCl salt by treating it with 2M HCl in Et2O. Mass spectrum (ESI): 521.5 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].C([N:19]([CH2:22][CH3:23])CC)C.[CH3:24][C:25]([CH3:32])([C:29](Cl)=[O:30])[C:26](Cl)=[O:27].[Cl-].[NH4+]>ClCCl>[C:7]1([C@H:2]([NH:1][C:26](=[O:27])[C:25]([CH3:32])([CH3:24])[C:29]([NH:19][C@@H:22]([C:23]2[C:10]3[C:11](=[CH:16][CH:7]=[CH:8][CH:9]=3)[CH:12]=[CH:13][CH:14]=2)[C:3]([CH3:4])([OH:5])[CH3:2])=[O:30])[C:3]([OH:5])([CH3:6])[CH3:4])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(O)[C@@H](N)c1cccc2ccccc12
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C(=O)N[C@@H](c1cccc2ccccc12)C(C)(C)O)C(=O)N[C@@H](c1cccc2ccccc12)C(C)(C)O
Temperature: -10 °C
Reaction time: 0.05 h
Yield: 102.2 %

Procedure:
Under a nitrogen atmosphere, 2 g of (S)-1-amino-1-(1-naphthyl)-2-methyl-2-propanol, 1.1 g of triethylamine (dehydrated), and 17 mL of dichloromethane (dehydrated) were mixed and then cooled to an inner temperature of −10° C. 0.8 g of dimethylmalonic acid dichloride was added dropwise thereto over 3 minutes and the resulting mixture was warmed to room temperature. The mixture was stirred as such for 6 hours to effect reaction. After completion of the reaction, 20 mL of an aqueous saturated ammonium chloride solution was added thereto to separate into layers. The organic layer obtained was washed three times with 25 mL of water and concentrated. The concentrated residue was dried under reduced pressure at an inner temperature of 40° C. to obtain 2.5 g of N,N′-bis[(1S)-(1-naphthyl)-2-hydroxy-2-methylpropyl]-2,2-dimethylpropane-1,3-diamide (yield: 100%).