Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCc4ccccc4)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid benzyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and benzyl chloroformate (414 μl, 2.90 mmol). The title compound was obtained as yellow powder (8 mg, 2%).
Reaction SMILES: [OH-:1].[K+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.OO.Cl>CO>[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:1])=[O:12])=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(OCCF)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(OCCF)cc1
Temperature: 65 °C
Yield: 63 %

Procedure:
To a stirred solution of 50% w/v KOH (1.3 ml) and 4-(2-fluoroethoxy)benzaldehyde (0.5 g, 2.98 mmol) in MeOH (6 ml) at 65° C. was added dropwise over 20 min aqueous hydrogen peroxide (30 wt. % in water, 2.45 ml). On completion of the addition the reaction mixture was heated at 65° C. for a further 10 min. On cooling to room temperature, the reaction mixture was acidified with 1 M HCl and extracted with Et2O (3×30 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give a solid which was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.278 g, 63%) as a colourless solid.
Reaction SMILES: Cl[C:2]1[N:11]2[C:12](=[S:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>C(O)(=O)C.[Zn]>[C:15]1([N:13]2[C:12](=[S:21])[N:11]3[CH2:2][NH:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]3=[N:14]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: S=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Agent: [Zn]
Solvent: CC(=O)O
Product: S=c1n(-c2ccccc2)nc2n1CNc1ccccc1-2

Procedure:
A mixture of 5-chloro-2-phenyl-1,2,4-triazolo[4,3-c]-quinazolin-3-thione (200 mg, 0.64 mmol) and zinc dust (10 mg, 150 mmol) in acetic acid (5 ml) was heated to reflux temperature. The reaction was filtered, neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×50 ml). The combined organic layers were dried over Na2 SO4 and evaporated under reduced pressure. The residue was washed with ethanol and filtered to afford 2-phenyl-5,6-dihydro-1,2,4-triazolo[4,3-c]quinazolin-3-thione (compound 29), m.p. 222°-223° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(Cl)cccc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,6-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (32.5 mg) with purity >90%. MS (pos) m/z 395.1, 397.1.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([C:10]1[C:11](=[O:20])[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=1.O>CN(C)C=O>[CH2:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([C:10]1[C:11](=[O:20])[N:12]([CH2:35][C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: ClCc1cccnc1
Reactant: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2n(Cc2cccnc2)c1=O
Temperature: 25 °C
Yield: 37.1 %

Procedure:
To a solution of 1.01 g of N,N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide in 13 ml of N,N-dimethylformamide was added 136 mg of 60% sodium hydride/oil, followed by stirring at room temperature for an hour. To the reaction solution was added 434 mg of 3-picolyl chloride, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane−ethyl acetate=7:13−1:19) and recrystallized from ethyl acetate to give 0.47 g of N,N-dihexyl-1-(3-picolyl)-1,2-dihydro-2-oxoquinoline-3-carboxamide.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: Cn1ccnc1S
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cn1ccnc1Sc1nccnc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to Example 1 by using 1-methyl-1H-imidazole-2-thiol (228 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 4 hr.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N12CCN(CC1)CC2>CCC(C)=O>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([O:12][C:5]2[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([NH:1][C:30](=[O:31])[NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][CH:4]=2)[N:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Agent: C1CN2CCN1CC2
Solvent: CCC(C)=O
Product: COC(=O)c1nc(NC(=O)Nc2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Yield: 71.1 %

Procedure:
2 g (6.5 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate, 0.77 g (7.15 mmol) of phenyl isocyanate and a catalytic amount of crystals of 1,4-diazabicyclo-[2.2.2]-octane were added to 50 ml of MEK, and the mixture was stirred and refluxed for 4 hours. After completion of the reaction, the product was filtered and washed with MEK to obtain the desired product as colorless transparent crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(CO)cc1
Temperature: 25 °C

Procedure:
Mix 4-ethoxybenzaldehyde (3.3 g, 22 mmol), sodium borohydride (830 mg, 22 mmol) and absolute ethanol (25 mL). Stir at room temperature until the reaction is complete, pour onto dilute hydrochloric acid and extract into ethyl acetate. Separate the organic phase and extract the aqueous phase with ethyl acetate (2×). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 4-ethoxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C(F)(F)F)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A mixture of 1-(2-(3,5-dichlorobenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (0.78 g, 2.1 mmol), t-butyl piperazine-1-carboxylate (0.41 g, 2.2 mmol), N,N-diisopropylethylamine (0.8 mL, 4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (0.31 g, 28%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1 H), 7.67 (d, 1 H), 7.31 (s, 1 H), 7.21 (s, 2 H), 6.13 (dd, 1 H), 5.70 (d, 1 H), 4.42 (d, 2 H), 3.54 (m, 4 H), 3.38 (m, 4 H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 531; Observed: 532 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([N:15]([CH3:17])[CH3:16])=O)=[CH:2]1.B.CO.C(O)(=O)C(O)=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[CH2:13][N:15]([CH3:17])[CH3:16])=[CH:2]1
Reactant: CN(C)C(=O)c1ccccc1Sc1c[nH]c2ccccc12
Agent: B
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(1H-Indol-3-ylsulfanyl)-N,N-dimethyl benzamide (1 mmol) was dissolved in dry tetrahydrofuran (30 mL). To the mixture was added 3 mL 1 M borane in tetrahydrofuran and the mixture was stirred at room temperature for 24 hours. Methanol (5 mL) was added and the mixture stirred at room temperature for 30 min and then evaporated in vacuo. The mixture was redissolved in ethyl acetate (100 mL) and washed with saturated sodium hydrogen carbonate (20 mL), dried over anhydrous MgSO4 and evaporated in vacuo. The product was crystallized as an oxalate salt by dissolution in acetone and addition of one equivalent of oxalic acid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.O=S(Cl)[Cl:17]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCCCCBr

Procedure:
A solution of 11-bromoundecanoic acid (10.00 g, 37.7 mmol) dissolved in CH2Cl2 (30 mL) was slowly added to a solution of SOCl2 (7.0 mL, 94.0 mmol) in CH2Cl2 (25 mL). The mixture was refluxed for 5 h, then concentrated in vacuo to give 11-bromoundecanoyl chloride, which was used without further purification: 1H NMR (CDCl3) δ 1.26 (bs, (CH2)5, 10 H), 1.34 (m, CH2CH2CH2Br, 2 H), 1.67 (m, CH2CH2COCl, 2 H), 1.81 (m, CH2CH2Br, 2 H), 2.85 (t, CH2COCl, J=7.2 Hz, 2 H), 3.36 (t, CH2Br, J=6.8 Hz, 2 H); 13C NMR (CDCl3) δ 24.89 (CH2CH2COCl), 27.95 (CH2CH2CH2Br), 28.21, 28.52, 28.84, 29.02, and 29.12 ((CH2)5), 32.64 (CH2CH2Br), 33.80 (CH2Br), 46.92 (CH2COCl), 173.47 (COCl).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH2:30][CH3:31]>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:33]1[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=[C:32]1[CH2:29][CH2:30][CH3:31])=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CCCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-propylbenzimidazole were reacted to give 233. LCMS m/z: 533.3 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]1[O:21][C:20](=[O:22])[CH:19]([C:23](OCC)=O)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].BrC[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[O:22]=[C:20]1[O:21][C@@H:17]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][CH:19]1[CH2:23][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:38][CH:39]=1
Reactant: CCOC(=O)C1C[C@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Reactant: BrCc1ccc(-c2ccccn2)cc1
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CC(Cc2ccc(-c3ccccn3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
A solution of the product from Example 107A (13.3 g, 35.27 mmol) in ethanol (140 mL) at 0° C. was treated with a solution of NaOEt (14.9 mL, 21% in ethanol) and solid 2-[4-(bromomethyl)phenyl]pyridine (12.05 g, 48.59 mmol), stirred at 25° C. for 16 hours, treated with a solution of LiOH monohydrate (8.9 g, 212.11 mmol) in water (35 mL), stirred at 25° C. for 5 hours, cooled to 0° C., adjusted to pH 5 by addition of 10% citric acid and then partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (1 L) was heated at reflux for 16 hours, cooled and concentrated to give the title compound (10.55 g, 63% yield), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:4][CH:3]=1.[CH3:16]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([O:13][CH3:16])=[O:12])=[O:7])=[CH:14][CH:15]=1
Reactant: COC(C)(C)OC
Reactant: O=C(c1ccc(Br)cc1)[C@H]1C[C@H]1C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a solution of cis-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (10.6 g, 36.63 mmol) in MeOH (250 mL) was added 2,2-dimethoxypropane (9.54 g, 91.59 mmol) and HCl (4.0 M in dioxane, 3.50 mL). The resulting solution was stirred at 40° C. for 3 days, and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 15 to 25% ethyl acetate in hexanes to afford methyl cis-2-(4-bromobenzoyl)-cyclopropanecarboxylate (10.34 g, 99%). 1H NMR (400 MHz, CD2Cl2) δ 1.39 (m, 1H), 1.82 (m, 1H), 2.34 (m, 1H), 2.77 (m, 1H), 3.54 (s, 3H), 7.65 (m, 2H), 7.89 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C([O:12][CH:13]=[C:14]([C:20]([O-])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([OH:12])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1O
Yield: 74.8 %

Procedure:
To ethanol (30 ml) were added 4-fluorophenylhydrazine (7.75 g) and ethyl ethoxymethylenemalonate (2.5 g), and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (2.5 g), melting point: 127–128° C.
Reaction SMILES: [Zn](C)[CH3:2].[CH:4](=[O:13])/[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:6]=[CH:5][C@@H:4]([OH:13])[CH3:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Zn]C
Reactant: O=C/C=C\c1ccccc1
Product: C[C@H](O)C=Cc1ccccc1
Yield: 91 %

Procedure:
The product was prepared by General procedure M using 4.5 mg (0.012 mmol) ligand 2, 0.30 mL (0.60 mmol, 2.0 M in hexanes) Me2Zn, 116 μL (0.30 mmol) Ti(OtBu)4, and 19 μL (0.15 mmol) cis-cinnamaldehyde. The crude product was purified by column chromatography on silica (10% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 91% yield (20 mg, 0.14 mmol). 1H NMR (CDCl3, 500 MHz) δ. □ □□ (d, 3H, J=6.2 Hz), 1.66 (br s, 1H), 4.69 (dq, 1H, J=8.5, 6.4 Hz), 5.60 (dd, 1H, J=11.5, 9.3 Hz), 6.40 (d, 1H, J=11.6 Hz), 7.18 (d, 2H, J=7.4 Hz), and 7.25 (t, 3H, J=7.5 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ.23.6, 64.1, 127.2, 128.3, 128.8, 130.0, 135.7, and 136.7 ppm; 1H NMR and 13C NMR spectra for this compound compare with previously reported literature data.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].CS(C)=O.[CH3:20][C:21]1[O:25][N:24]=[C:23]([OH:26])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][C:21]1[O:25][N:24]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[C:23](=[O:26])[CH:22]=1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2oc(C)cc2=O)c([N+](=O)[O-])c1
Reaction time: 10 h
Yield: 58.9 %

Procedure:
After mixing 400 g of ethyl 4-chloro-3-nitrobenzoate, 1.2 liters of dimethyl sulfoxide, 270 g of 5-methyl-3-hydroxyisoxazole, and 292 g of potassium carbonate, the reaction was performed for 10 hours at 60° C. After the reaction was over, the reaction mixture was poured into water and crystals thus deposited were recovered by filtration and recrystallized from ethyl acetate to provide 300.1 g of the desired compound with a yield of 59.0%. The melting point thereof was 122° C. to 123° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:32])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:28][CH:27]([F:29])[CH2:26]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].Cl.C([O-])(O)=O.[Na+]>O.O1CCOCC1>[Cl:32][CH:2]([Cl:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:28][CH:27]([F:29])[CH2:26]3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[OH:7])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CN4CC(F)C4)cc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(CN3CC(F)C3)cc2)cc1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To a slurry of the product of step 1 (875 mg, 1.81 mmol) in water (10 mL) is added 4 N HCl in dioxane (7 mL) and the mixture stirred at room temperature for 24 hours. Reaction is cooled with ice water and basified slowly using solid NaHCO3. The mixture is partitioned between ethylacetate and brine and subsequently extracted with ethyl acetate (3×30 mL). Combined extracts are dried over Na2SO4 and concentrated. Crude product dissolved in ethyl acetate (2 mL), adsorbed on celite and purified on silica gel eluting from 40 to 80% ethyl acetateheptane to give the title compound (560 mg). 1HNMR (400 MHz, DMSO-d6) δ: (1H-NMR) 3.07-3.20 (m, 2H), 3.49-3.61 (m, 2H), 3.66 (s, 2H), 4.14-4.32 (m, 1.5H), 4.36-4.44 (m, 0.5H), 4.54-4.60 (m, 0.5H), 4.65-4.72 (m, 0.5H), 4.85-4.91 (m, 1H), 5.07-5.14 (m, 0.5H), 5.21-5.29 (m, 0.5H), 5.95 (d, 1H, J=4.0 Hz), 6.53 (s, 1H), 7.34 (d, 1H, J=8 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.57-7.63 (m, 4H), 8.61 (d, 1H, J=8 Hz), (m/z (Cl) 443 [M++1].
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=[CH:15][C:16]#N)=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.C(O)=[O:26].Cl>[Ni].O>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:15][CH:16]=[O:26])=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: O=CO
Agent: [Ni]
Agent: Cl
Solvent: O
Product: O=CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
In a 5 mL-volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed under nitrogen atmosphere 314 mg (1.0 mmol) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile (prepared in Example 1), 2.25 mL of formic acid (60 mmol, mol calculated as 100% formic acid), 0.75 mL of water, and 620 mg (5.3 mmol as nickel atom) of water-containing developed Raney-nickel (NDHT-90, nickel content 50 wt. %, available from Kawaken Fine Chemical Co., Ltd.). The content was reacted at 80° C. for 1.5 hours. After the reaction was complete, the content was cooled to room temperature. After addition of 9 mL of water and 9 mL of hydrochloric acid (1 mol/L), the catalyst was removed by filtration using a celite. The celite was washed with two portions of 2-butanol (1 mL) and two portions of toluene (9 mL). The organic portion was dried over anhydrous magnesium sulfate. The dried organic portion was filtered and the filtrate was concentrated under reduced pressure to give 307 mg (yield 91%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enal as yellow solid (purity 97%, in terms of an area percent according to high performance liquid chromatography).
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC(C)(C)C)cc1
Yield: 45.4 %

Procedure:
In a sealed tube, dissolve p-toluenesulfinic acid sodium salt (5.71 g, 32.1 mmol) in DMF (20 mL) and water (10 mL). Add neo-pentyl bromide (6.3 mL, 48 mmol) and tetrabutylammonium iodide (592 mg, 1.60 mmol) and heat the mixture at 145° C. overnight. Cool the reaction to ambient temperature, dilute with water and extract 3 times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (3.3 g, 45%).