Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[Cl:12])[CH:7]=O)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>C(Cl)Cl>[Cl:12][C:11]1[CH:10]=[CH:9][C:6](/[CH:7]=[C:21](/[N+:18]([O-:20])=[O:19])\[CH3:22])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: C/C(=C\c1ccc(Cl)c([N+](=O)[O-])c1)[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A stirred mixture of 3-Nitro-4-chlorobenzaldehyde (10 g, 53.89 mmol), ammonium acetate (1.39 g, 18 mmol) and nitroethane (31.3 ml, 432 mmol) is heated at reflux (80° C.) overnight. After cooling to room temperature the reaction mixture is concentrated if vacuo to give a solid which is dissolved in DCM (200 ml) and washed with water (3×200 ml), followed by brine (200 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an orange solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][NH:37][C:32](=[O:34])[C:31]1[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 83.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) were combined to give 45 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3>[Pd]>[N:7]1[C:8]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=2)=[CH:9][N:10]2[C:6]=1[C:5]1[CH:24]=[CH:25][CH:2]=[CH:3][C:4]=1[O:13][CH2:12][CH2:11]2
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A solution of [5-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol (67 mg, 0.17 mmol) in IMS was degassed then treated with Pd/C (10% wt. 120 mg) before being stirred at RT under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Celite®, washing with DCM, the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 7% methanol in DCM) to give 315 as a white solid (13 mg, 24%). LCMS: RT=3.79 min, [M+H]+=326. 1H NMR 400 MHz (DMSO-d) δ: 8.42 (1H, dd, J=8.03, 1.74 Hz), 7.91 (1H, s), 7.33 (1H, ddd, J=8.16, 7.12, 1.77 Hz), 7.16-7.16 (1H, m), 7.06 (1H, dd, J=8.18, 1.21 Hz), 5.86 (1H, t, J=6.61 Hz), 5.21 (1H, t, J=6.03 Hz), 4.52 (4H, q, J=5.81 Hz), 4.42 (2H, d, J=6.00 Hz), 1.48 (6H, d, J=6.61 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:11][C@@H:12]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:8][CH2:13][C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:11])=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1F
Reactant: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Product: C[C@@H](COc1ncc(Br)cc1F)N1C(=O)c2ccccc2C1=O

Procedure:
Using 5-bromo-3-fluoropyridin-2-ol and 2-((2S)-1-hydroxypropan-2-yl)-1H-isoindole-1,3(2H)-dione, and in the same manner as in Step C of Example 1, the title compound was obtained.
Reaction SMILES: [Li+].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[O:16][C@@H:15]([C:17]([Cl:20])([Cl:19])[Cl:18])[N:14]2[CH2:21][CH2:22][CH2:23][C@:13]12[CH:24]=O>C1COCC1>[Cl:18][C:17]([Cl:20])([Cl:19])[C@H:15]1[N:14]2[CH2:21][CH2:22][CH2:23][C@:13]2([CH:24]=[CH2:2])[C:12](=[O:11])[O:16]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C[C@]12CCCN1[C@H](C(Cl)(Cl)Cl)OC2=O
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C[C@]12CCCN1[C@H](C(Cl)(Cl)Cl)OC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
The solution of CH3P(Ph)3Br (268 mg, 0.736 mmol) in anhydrous THF (5 mL) was cooled to −78° C. under N2. LiHMDS (1 M in THF, 0.69 mL) was added dropwise via syringe. The mixture was stirred at 0° C. for 1 h then cooled down to −78° C. again. To it, was added the reactant carbaldehyde 155b (125 mg, 0.46 mmol) in anhydrous THF (5 mL) at −78° C. dropwise. The mixture was stirred at −78° C. to RT over 2 h period, then RT for 2 h. Reaction was monitored by TLC. After completion, the reaction was quenched by adding sat'd NH4Cl. It was extracted with EtOAc twice, washed with brine. The organic layer was dried through (Na2SO4), and concentrated; the residue was purified by CombiFlash on silica gel column using EtOAC/Hexane as eluents to give (3S,7aS)-3-(trichloromethyl)-7a-vinyltetrahydropyrrolo[1,2-c]oxazol-1(3H)-one 30 mg, 24%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH2:38][CH3:39])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH2:38][CH3:39])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OCC)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(OCC)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (544 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (466 mg, yield: 90%) This was recrystallized from ethanol-hexane. Melting point: 105–106° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17]C3C=NC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(F)c2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=355.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:16]3[CH:17]=[CH:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=3)=[CH:34][CH:33]=2)[CH:6]=1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Product: COC(=O)Cc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccccc12

Procedure:
This compound was prepared from indole-3-acetic acid methyl ester (J.C.S., 2581, 1955) and 4-(quinolin-2-ylmethoxy)benzyl chloride (example 1a) by the method described in Example 1b, part i.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]3[O:27][CH2:26]3)[C:20](OC)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CCN(CC)CC.[CH2:40]([SH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]3[CH2:24][CH:25]([CH2:26][S:47][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[O:27][C:20]3=[O:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CSCc4ccccc4)OC3=O)cc2)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.5 g, 1.28 mmol) in benzene (3 mL), NaHCO3 (0.32 g, 3.84 mmol) and Et3N (0.23 mL, 1.6 mmol) at room temperature is added slowly benzyl mercaptan (0.62 mL, 4.99 mmol). The reaction mixture is heated at 70° C. for 3 h, and stirred two days at room temperature. The resulting mixture is diluted with water, and then the mixture is extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with hexane/EtOAc (4:1) to give the desired product.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([CH2:31][NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNCc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Yield: 81 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.49 g, 1.71 mmol), diisopropylethylamine (0.70 ml, 4.12 mmol) and ethyl 3-(methylamino)propionate hydrochloride (I-159) (0.32 g, 1.91 mmol) were dissolved in dichloromethane (15 ml). After heated under reflux for 3 hours, this was diluted with dichloromethane. After washed with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70; 1), then again purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) to obtain the entitled compound (0.53 g, 81%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Mg]Br)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[CH2:20][N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([OH:27])[CH2:23][CH2:22][N:21]([CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[C:17]([O:16][CH3:15])[CH:18]=3)[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Reactant: Clc1ccc(I)cc1Cl
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To 3,4-dichloro-1-iodobenzene (9.00 g, 41.0 mmol) in tetrahydrofuran (80 mL) at room temperature, was added isopropylmagnesium bromide (40.5 mL of a 2.0 M solution in THF, 82.0 mmol) dropwise. After 2 h, a solution of 1-(3-methoxybenzyl)piperidin-4-one (9.0 g, 41.0 mmol) from Step B above in tetrahydrofuran (10 mL) was added dropwise at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 2 h. After 1 h, the reaction mixture was quenched with saturated ammonium chloride (5 mL). The mixture was diluted with ethyl acetate (50 mL) and washed with saturated ammonium chloride (80 mL), water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (dichloromethane to 10% ethyl acetate in dichloromethane) gave 4-(3,4-dichlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (13.0, 86%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.62 (d, J=2.0 Hz, 1H), 7.43-7.38 (m, 1H), 7.36-7.30 (m, 1H), 7.25-7.21 (m, 1H), 6.96-6.90 (m, 2H), 6.84-6.77 (m, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 2.84-2.76 (m, 2H), 2.47-2.37 (m, 2H), 2.10 (dt, J=4.5, 13.1 Hz, 2H), 1.72-1.65 (m, J=11.5 Hz, 2H); ESI MS (m/z) 366 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH3:21])[C:10]3[NH:16][C:15]4[CH:17]=[CH:18][N:19]=[CH:20][C:14]=4[C:11]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[CH3:22]I.O>CN(C)C(=O)C.CCO.CCN(CC)CC.C(Cl)Cl>[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH3:21])[C:10]3[N:16]([CH3:22])[C:15]4[CH:17]=[CH:18][N:19]=[CH:20][C:14]=4[C:11]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CI
Reactant: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccncc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1c2ccnc(Cl)c2cc2c3cnccc3n(C)c12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
50% NaH (90 mg) is added to the solution of 10-chloro-6-methyl-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinoline (400 mg; product known, already published) in N,N-dimethylacetamide (20 ml) cooled to −10° C. The mixture is stirred for 30 min then CH3I (0.11 ml) is introduced and the mixture is stirred again at −10° C. for 2.5 h. Water and CH2Cl2 are added and the organic phase is separated, dried (MgSO4) and dry evaporated. The residue obtained is chromatographed on a silica column by eluting successively with CH2Cl2-EtOH (9:1 v/v) then EtOH-NEt3 (95:5 v/v) to yield respectively 10-chloro-5,6-dimethyl-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinoline (66 mg, 16% yield) and the expected 10-chloro-2,6-dimethyl-2H-pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinoline (138 mg, 32% yield) in the form of yellow microcrystals (point melting>260° C.). NMR in agreement.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=O)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)N1CC2CC2(c2ccccc2)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(CN2CC3CC3(c3ccccc3)C2)cc1

Procedure:
In a similar manner, 3-(p-fluorobenzoyl)-1-phenyl-3-azabicyclo[3.1.0]hexane is reduced by sodium bis(2-methoxyethoxy)aluminum hydride to give 3-(p-fluorobenzyl)-1-phenyl-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[N:28](CC[Si](C)(C)C)[C:27](=[O:38])[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].Cl>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:38])[CH2:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(2-methoxymethylbenzyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (375 mg, 0.679 mmol) in DMF (5 mL) is added CsF (361 mg, 2.37 mmol) and the mixture is stirred at 65° C. for 3 h. The mixture is diluted with EtOAc and water then is acidified with 1N HCl. The organic phase is washed with 1N HCl, water and brine. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure to give the title compound as a foam.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:22])[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6](C(O)=O)=[CH:5]2)[CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:22])[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1C(=O)CCN2C1CC1
Yield: 89.2 %

Procedure:
1-Cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (8.0 g) is added to methanol (450 ml), and thereto is added gradually sodium borohydride (3.4 g) with stirring under ice cooling. The mixture is stirred at room temperature for one hour. After the reaction is finished, the reaction mixture is adjusted to about pH 1 with conc. hydrochloric acid and then refluxed for 30 minutes, and thereafter methanol is distilled off under reduced pressure. To the resulting residue is added water, and the mixture is made weakly alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer is dried over sodium sulfate, and chloroform is distilled off. The resulting residue is purified with silica gel column chromatography (eluent, chloroform → chloroform : methanol =50 : 1) ane then recrystallized from diethyl ether to give 1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (6.3 g) as yellow prisms, m.p. 98°-100° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[C:39]#[C:40][C:41]1[CH:42]=[C:43]([CH:47](O)[CH2:48][CH3:49])[CH:44]=[CH:45][CH:46]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[C:39]#[C:40][C:41]1[CH:42]=[C:43]([CH2:47][CH2:48][CH2:49][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH:44]=[CH:45][CH:46]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(O)c1cccc(C#Cc2c(C)cccc2C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1C#Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triphenylphosphine (0.087 g, 0.33 mmol), phthalimide (0.0.49 g, 0.33 mmol) and (3-((2,6-dimethylphenyl)ethynyl)phenyl)propan-1-ol (12) (0.085 g, 0.32 mmol) were dissolved in anhydrous THF (3 mL) under argon, and the solution was cooled over an ice bath. Diethyl azodicarboxylate (0.052 mL, 0.33 mmol) was added dropwise with rapid stirring, and the resulting mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (6 to 60% EtOAc-hexanes gradient) to yield 2-(3-(3-((2,6-dimethylphenyl)ethynyl)phenyl)propyl)isoindoline-1,3-dione (13) as a white solid. Yield (0.095 g, 75%): 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.89 (m, 4H), 7.42 (s, 1H), 7.13-7.35 (m, 6H), 3.63 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.51 (s, 6H), 1.90-1.97 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[N:9]([N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[C:10](=O)[CH:11]=1.O=P(Cl)(Cl)[Cl:24].CN(C)C1C=CC=CC=1>C(#N)C.C(Cl)(Cl)Cl>[Cl:24][C:10]1[N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:8]2[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccco2)[nH]c2cc(-c3ccccc3)nn12
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Clc1cc(-c2ccco2)nc2cc(-c3ccccc3)nn12
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A mixture of 5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (0.277 g, 1.0 mmol, 1.0 eq), POCl3 (0.613 g, 4.0 mmol, 4.0 eq), N-benzyl-N,N,N-triethylethanaminium chloride (0.456 g, 2.0 mmol, 2.0 eq) and N,N-dimethylaniline (0.121 g, 1.0 mmol, 1.0 eq) in acetonitrile (5.0 mL) was heated at 80° C. for 4 hr. The completed reaction was diluted with CHCl3 (20 mL), washed with H2O (10 mL), and the separated organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography (Biotage25 g, EtOAc/Hexane) to afford 7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (0.247 g, 84%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.97-7.94 (m, 2H), 7.56 (m, 1H), 7.43-7.39 (m, 2H), 7.36-7.34 (m, 1H), 7.19 (s, 1H), 7.17 (dd, J=3.5, 0.5 Hz, 1H), 6.97 (s, 1H), 6.54 (dd, J=3.5, 1.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(I)ccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1cc(I)ccc1Cl
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 2-chloro-5-iodobenzoic acid (28 g, 99 mmoles) and toluene (198 mL) was cooled to 0° C. A 1M diisobutyl aluminium hydride (DIBAL) solution in toluene 208 mL, 208 mmol) solution was added drop wise over 20 minutes. The solution was allowed to slowly warm to rt. After 16 h the solution was cooled to 0° C., MeOH and 1M HCl was slowly added (exothermic reaction). The solution became clumpy and was filtered and the clumps washed with EtOAc. The organic phase was then isolated and the aqueous layer washed with EtOAc. The combined organic extracts were then washed with brine, dried (Na2SO4), and concentrated. The product was purified by Biotage chromatography (0%-100% EtOAc/Hexanes) to afford 9.01 g of product as a solid (34%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.85 (d, J=2.02 Hz, 1 H) 7.55 (dd, J=8.34, 2.27 Hz, 1 H) 7.09 (d, J=8.34 Hz, 1 H) 4.74 (s, 2 H) 2.25 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([O:9][CH2:10][C:11]2([CH2:14]Br)[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1.[C-:18]#[N:19].[K+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([O:9][CH2:10][C:11]2([CH2:14][C:18]#[N:19])[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)OCC2(CBr)CC2)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)OCC2(CC#N)CC2)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 17.8 %

Procedure:
261 mg of compound 10a was dissolved in 5 ml ethanol. A solution of 98 mg potassium cyanide in 5 ml water was added and the mixture was stirred at 35° C. for two days. 10 ml of a saturated aqueous sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate. The combined extracts were dried with sodium sulfate and evaporated to give a yellow liquid. Purification with column chromatography (heptane/ethyl acetate 3/1) gave the title compound (38 mg) confirmed by NMR and LC/MS.