Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.O>CCOCC.C1COCC1>[CH2:14]1[O:15][C:16]2([CH2:21][CH2:20][C:19]([OH:22])([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:18][CH2:17]2)[O:23][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCC2(CC1)OCCO2
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To a solution of n-BuLi (1.59 M in Hexane, 45 mL. 71.6 mmol) in dry ether (150 mL) was added a solution of 3-Bromopyridine (11.24 g, 71.1 mmol) in dry ether (70 mL) dropwise at −78° C. After stirring for 10 min, a solution of cyclohexane-1,4-dione monoetylene acetal (9.25 g, 59.2 mmol) in THF (70 mL) was added over a period of 20 min at −78° C., and stirred for 3 h. To the reaction mixture was added with water. The aqueous layer was extracted with CH2Cl2, and the organic layer was washed with brine. The extracts were combined with the organic layer. After drying and concentration, the crude product was purified by column chromatography (Hexane/EtOAc=2/1) to yield 4-hydroxy-4-(3-pyridyl)cyclohexanone ethylene acetal (6.55 g, 47%) as a pale yellow powder.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[F:46][C:42]1[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=1)[CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Fc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCO
Product: O=c1[nH]nc(Cc2cccc(F)c2)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-fluorophenyl)methyl]pyridazine (Intermediate 54) except that the solvent used for the hydrogenation was ethanol and the product was recrystallised from a mixture of MTBE and heptanes.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[C:25]([Cu])#[N:26]>CN1C(=O)CCC1>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][C:20]([C:25]#[N:26])=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: N#C[Cu]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Solvent: CN1CCCC1=O
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(C#N)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 200 °C

Procedure:
A heterogeneous mixture of (1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (40 mg, 0.10 mmol) and cyanocopper (13.7 mg, 0.15 mmol) in NMP (1.0 mL) in a heavy walled tube was heated at 200° C. under microwave irradiation for 2 h. The reaction was filtered and purified by preparative HPLC to give the title compound. LCMS m/z=339.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7 and 3.4 Hz, 1H), 1.29 (td, J=8.0 and 4.7 Hz, 1H), 1.42 (s, 3H), 1.43 (s, 3H), 2.30-2.37 (m, 1H), 2.71-2.77 (m, 1H), 2.92 (d, J=17.0 Hz, 1H), 3.01 (dd, J=16.8 and 6.2 Hz, 1H), 3.71 (s, 2H), 4.29 (s, 1H), 6.90 (s, 1H), 8.72 (d, J=1.4 Hz, 1H), 9.33 (d, J=1.4 Hz, 1H).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:1][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:39])([F:38])[F:29])=[CH:32][CH:33]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(C(F)(F)F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-trifluoromethylphenol (8.100 mg, 0.050 mmol), triphenylphosphine (9.8 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.10 mg, 38.9% yield) as a thick oil: 1H NMR δ 8.06 (s, 1H), 7.49 (s, 1H), 7.44 (apparent d, 2H, J=0.6 Hz), 7.38-7.30 (m, 4H), 7.30-7.20 (m, 3H), 6.96 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.6 Hz), 5.34 (m, 1H), 3.19 (m, 2H), 2.72 (m, 2H), 2.53 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 525.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>O.CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:28]([F:29])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([OH:25])=[O:24])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Yield: 47.2 %

Procedure:
A solution of ethyl 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (50 mg, 0.11 mmol) and NaOH (21 mg, 0.55 mmol) in H2O-MeOH (1:1, 20 mL) was stirred at rt for 3 h. The mixture was acidified with 2 N HCl and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylic acid (23 mg, yield 47%) as a yellow solid. MS: m/z=443.7 (M+1, ESI+).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH-].[K+]>CCOCC>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A round-bottomed flask (200 cc) was charged with cyclopentyl alcohol (10.0 g, 0.116 mol) and p-toluenesulfonyl chloride (24.3 g, 0.128 mol), followed by the addition of ether (100 mL) to form a solution. Subsequently, a powder of potassium hydroxide (32.5 g, 0.58 mol) was added slowly to the solution as it was cooled in a water bath at 10° C. or below. After the addition, the mixture was stirred at the same temperature for an additional 2 h. After completion of the reaction, the mixture was poured into ice water (20 mL), whereupon the organic layer separated from the aqueous layer. The organic layer was dried and concentrated under vacuum to give cyclopentyl p-toluenesulfonate as a pale yellow viscous liquid (22.0 g; yield=78.9%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)([CH3:22])[CH3:21].ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:28][N:27]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: CC(C)c1ccc(N)nc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (241 mg, 0.800 mmol) in pyridine (5 mL), stirred under nitrogen at room temperature, was added 5-isopropylpyridin-2-amine (54.5 mg, 0.4 mmol). The mixture was then stirred at room temperature overnight. Dichloromethane (25 mL) was added to the mixture and the organic phase washed with water (25 mL) and brine (25 mL) then dried using a hydrophobic frit. Solvent was removed in vacuo to give the crude product. This was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient), to provide the title compound (39 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.96 min, m/z (ES+) 402 (M+H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[CH2:33][CH3:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(F)(F)C(O)=O>C(O)(=O)C>[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:24]=1[C:25]([C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH:7]=1)=[CH:26][N:27]2[CH2:33][CH3:34])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCn1ccc2c(OCc3ccccc3)cc(F)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCn1cc(C2=CCNCC2)c2c(OCc3ccccc3)cc(F)cc21
Temperature: 80 °C
Yield: 32.4 %

Procedure:
In pressure vessel, tert-butyl 4-oxopiperidine-1-carboxylate (370 mg, 1.86 mmol) was dissolved in acetic acid (3 mL) and then 4-(benzyloxy)-1-ethyl-6-fluoro-1H-indole (200 mg, 0.74 mmol) was added, followed by trifluoroacetic acid (1 mL). The reaction mixture was heated to 80° C. for 1 hour. Volatiles were evaporated and then water was added. The pH was adjusted to ˜12 with 15% aqueous NaOH and partitioned between EtOAc-water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude product. The resulting residue was purified on alumina column chromatography eluting with DCM/methanol (0-6%) to afford 37-3 (84 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ (ppm) 8.78 (br. s, 2H), 7.51-7.41 (m, 5H), 7.27 (s, 1H), 6.99 (dd, J=9.9 Hz and 2.1 Hz, 1H), 6.63 (dd, J=11.8 Hz and 2.1 Hz, 1H), 5.84, (br. s, 1H), 5.16 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.46 (br. s, 2H), 2.93 (br.s, 2H), 2.61 (br. s, 2H), 1.31 (t, J=7.2 Hz, 3H). LCMS: calc 350.4 and found: 351.1 [MH]+.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH:21][C:22]1([CH3:33])[CH2:30][C:29]2[C:24](=[CH:25][C:26]([CH3:32])=[C:27]([CH3:31])[CH:28]=2)[CH2:23]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([O:9][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2([CH3:33])[CH2:30][C:29]3[C:24](=[CH:25][C:26]([CH3:32])=[C:27]([CH3:31])[CH:28]=3)[CH2:23]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1cc2c(cc1C)CC(C)(NCc1ccccc1)C2
Reactant: Cc1ccc(C2CO2)cc1[N+](=O)[O-]
Product: Cc1cc2c(cc1C)CC(C)(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Temperature: 110 °C

Procedure:
A mixture of 2-(4-methyl-3-nitro-phenyl)-oxirane and benzyl-(2,5,6-trimethyl-indan-2-yl)-amine is heated at 110° C. for 48 hours. The material is used without further purification. ES+MS m/e 538 (MH+)
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(OC(C)C)(=O)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21]>CCCCCCC>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC1Cc2ccccc2C1
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Product: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with 2-aminoindan, (104 g, 0.781 mole) and isopropyl acetate (200 mL) at 20-25° C. The solution was cooled to 0-5° C. Ethyl trifluoroacetate (133 g, 0.936 mol) was added over 40 minutes while maintaining the internal temperature at 0-10° C. (in a 0-5° C. bath). The thick slurry was stirred at 0-10° C. for 2 hours. The reaction mixture is warmed to 20-25° C. over 30 minutes and heptane (60 mL) was added. The slurry was stirred for 30 minutes and the solids were collected by filtration over a polypropylene filter paper in a Büchner funnel with suction. The filter cake was washed with 0.003% (w/v) Stadis-450 (4.5 mg Lot # 200 Dolder)/heptane (3×50 mL) or until the filtrate was colorless. The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 149.2 g (83.4% yield) of N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide as a beige white solid.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH3:13][C:14](=[CH2:16])[CH3:15].C([O-])(O)=O.[Na+]>O>[C:14]([O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])([CH3:16])([CH3:15])[CH3:13]
Reactant: O=C(O)C1CCCCC1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.8 %

Procedure:
To a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in DCM (75 mL) concentrated sulfuric acid (765 mg, 7.8 mmol) was added. At a temperature between −15° C. and −10° C. isobutylene (10.94 g, 195 mmol) was introduced over 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 72 h. Then a second portion of isobutylene (10.94 g, 195 mmol) was introduced over 1 h at −10° C. The reaction mixture was stirred at room temperature for an additional 20 h, then NaHCO3 (7.864 g, 93.6 mmol) was added before the mixture was stirred at room temperature for another 1 h. Water (50 mL) was added under stirring. After 45 min the reaction mixture was worked up and washed until neutral. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar) to afford 10.9 g (76%) cyclohexanecarboxylic acid tert-butyl ester as a colorless oil. 1H-NMR (CDCl3, 400 MHz): ppm 1.12-1.54 (m, 14H), 1.55-1.99 (m, 5H), 2.12-2.22 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([F:11])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N#CCc1ccc(Br)cc1F
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1ccc(-c2cccc(Cl)c2)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A suspension of 4-bromo-2-fluorobenzyl cyanide (3.50 g, 16.35 mmol), 3-chlorobenzeneboronic acid (2.68 g, 17.17 mmol), Pd(OAc)2 (0.110 g, 0.491 mmol), K2CO3 (5.65 g, 40.9 mmol) and tetrabutylammonium bromide (5.80 g, 17.99 mmol) in water (14 ml) is allowed to stir under nitrogen at 70° C. for 1 hour. The reaction mixture is cooled to room temperature, and diluted with EtOAc. The two phases are separated. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 70:30) to give 2-(3′-chloro-3-fluorobiphenyl-4-yl)acetonitrile (3.52 g); HPLC retention time=1.17 minutes (condition B); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.81 (s, 2H) 7.29-7.45 (m, 5H) 7.50-7.55 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][NH:15][CH3:16].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:15]([CH3:16])[CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNC
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(CN(C)C)c1
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-bromo-5-formylbenzoate (1.8 g, 7.4 mmol, prepared as described in WO 2003048111 from dimethyl 5-bromoisophthalate, Alfa Aesar) in methylene chloride (20 mL) was added a solution of 2.0 M dimethylamine in tetrahydrofuran (7.4 mL, 15 mmol). This mixture was stirred for 15 minutes, followed by the addition of sodium triacetoxyborohydride (4.7 g, 22 mmol). The resulting mixture was stirred overnight. Saturated sodium bicarbonate solution was added and the product was extracted with ethyl acetate. The combined organic extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford a light yellow oil. Yield: 1.87 g (93%); LC-MS: 272.0, 274.0 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, 1H), 7.89 (dd, 1H), 7.69 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[C:3]=1[O:10][CH:11]([F:13])[F:12].C(OC(=O)C)(=[O:16])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][OH:16])[C:3]=1[O:10][CH:11]([F:13])[F:12]
Reactant: Cc1c(OC(F)F)c(Cl)cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: OCc1nccc(Cl)c1OC(F)F
Temperature: 110 °C

Procedure:
70 ml of acetic anhydride was added to 7.61 g of 4-chloro-3-difluoromethyl-2-methylpyridine N-oxide (VI), which was heated at 110° C. for 1 hour. The solvent was distilled off under reduced pressure, and thereafter, saturated aqueous sodium bicarbonate solution was added thereto and the resulting mixture was extracted with ether. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 90% ethanol and 2.36 g of sodium hydroxide was added thereto and the resulting mixture was heated at 80° C. for 2 hours. The solvent was distilled off under reduced pressure, and thereafter, water was added thereto and the resulting mixture was extracted with chloroform. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chlorohorm) to obtain 1.55 g of 4-chloro-3-difluoromethyl-2-hydroxymethylpyridine (VII).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[O:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Cc1ccc(O)c(N)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
2-Amino-4-methylphenol (1.15 g, 9.34 mmol) was added to a solution of 4-bromophenyl isothiocyanate (2.00 g, 9.34 mmol) in tetrahydrofuran (35 mL) and the reaction was stirred at room temperature for 16 h. Anhydrous copper (II) sulfate (14.06 g, 88.10 mmol), silica gel (14.06 g), and triethylamine (1.3 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and then added to a silica pad and purified using 1:5 ethyl acetate:heptane (2 L) followed by diethyl ether as the eluent to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a light brown solid (2.30 g, 81%);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:22])[C@@H:13]([CH3:31])[CH2:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21](=[O:22])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:13]([CH3:31])[CH2:12]2)[C:41](=[O:43])[CH3:42])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc([N+](=O)[O-])cc3)C[C@@H]2C)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccc([N+](=O)[O-])cc3)CC2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-[4-(4-nitro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-methoxy-phenyl)-methanone (1.00 equiv.) in methylene chloride was added diisopropylethylamine (1.05 equiv) followed by acetyl chloride (1.00 equiv). The mixture was stirred at rt 48 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-(4-nitro-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide; which was reduced to N-(4-amino-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide using excess NH4CO2H, catalyic Pt(sulfided), in ethanol at reflux for 30 m., followed by filtration and concentration. The amine was used without further purification due to inherent chemical instability.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH3:7])=[C:2]=[S:3].[CH:8]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH2:4]([NH:1][C:2]([NH:15][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:3])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCN=C=S
Reactant: NC1CCCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=S)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution prepared by dissolving 1-isothiocyanatobutane (3.0 ml, 26.0 mmol) in dichloromethane (5 ml) was slowly added to a solution prepared by dissolving 1-cycloheptylamine (3.3 ml, 26.0 mmol) in dichloromethane (20 ml) at 0° C. for 15 minutes. Triethylamine (7.3 ml, 52.1 mmol) was added to the mixed reaction solution and stirred at room temperature for 2 hours. After confirming completion of the reaction, distilled water (10 ml) was added to the reaction solution, and 1N of an HCl aqueous solution was added to neutralize. After separating an organic layer, a aqueous layer was extracted over dichloromethane (3×20 ml), and the organic layer was dried on sodium sulfate anhydrous, filtered and concentrated. The concentrated organic layer was purified by flash column chromatography (hexane:ethylacetate=3:1), thereby obtaining a target compound as a yellow liquid (4.1 g, 68%). The compound was used in the subsequent reaction.