Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C@@H:17]3[C@H:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:21]([C:23](OCC)=[O:24])=[N:22][N:16]3[C:15]=2[CH:34]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C@@H:17]3[C@H:20]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:21]([C:23]([N:4]([O:3][CH3:2])[CH3:5])=[O:24])=[N:22][N:16]3[C:15]=2[CH:34]=1
Reactant: CCOC(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The HCl salt of N-methoxy-N-methylamine (4.47 g, 15.3 mmol) in anhydrous CH2Cl2 was cooled to −10° C. and treated with Me3Al (22.9 mL, 2.0M in hexanes, 45.8 mmol) and stirred 30 min. Trans-ethyl 8-fluoro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxylate (5-4, 5.2 g, 15.3 mmol) was added as a solution in CH2Cl2 and the reaction was warmed to 25° C. for 1 h. Upon completion, the reaction was carefully quenched by the addition of 0.5 N tartaric acid, and stirred an additional 30 min. The solution was extracted with CH2Cl2, dried with MgSO4, filtered and concentrated under reduced pressure to give trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-5). This material was used crude in the subsequent transformation. MS (M+H+, C19H18FN3O3) 356.3 found 356.4 required. 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), 7.19 (dd, J=8.9, 2.9 Hz, 1H), 6.86 (dd, J=9.2, 5.2 Hz, 1H), 6.64 (app dt, J=8.2, 3.1 Hz, 1H), 4.51 (d, J=5.1 Hz, 1H), 4.28 (dd, J=10.7, 2.6 Hz, 1H), 4.08 (ddd, J=10.7, 5.2, 3.6 Hz, 1H), 3.79 (s, 3H), 3.57 (t, J=10.7 Hz, 1H), 3.29 (s, 3H).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C@H:4]13.C1C(=O)N([Br:30])C(=O)C1.O.CCOC(C)=O>CN(C=O)C>[Br:30][C:9]1[CH:1]=[C:2]2[C:6]3=[C:7]([CH2:10][CH2:11][N:5]3[C@@H:4]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:3]23)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CC3
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a solution of tert-butyl(±)-cis-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.576 g, 1.92 mmol) in DMF (4 mL) at 0° C., freshly recrystalized NBS (0.375 g, 2.1 mmol) was added as a solution in DMF (4 mL). The reaction was stirred at 0° C. for 20 min, after which it was warmed to RT. The reaction was stirred at RT for 0.5 h. Water (10 mL) and EtOAc (10 mL) were added. The layers were separated, and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried. Concentration afforded a crude brown oil. The crude product was purified by column chromatography (MeOH/CH2Cl2). Tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (550 mg, 75%) was isolated as a brown amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.06 (s, 1H), 7.02 (s, 1H), 3.70–3.90 (m, 1H), 3.50–3.70 (m, 1H), 3.00–3.45 (m, 6H), 2.70–2.90 (m, 2H), 1.70–1.90 (m, 2H), 1.48 (s, 9H) ppm.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14][C@@H:13]1[CH2:26][OH:27])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14][C@@H:13]1[CH:26]=[O:27])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add sulfur trioxide pyridine complex (0.27 g, 1.7 mmol) in dimethylsulfoxide (0.95 mL, 13.0 mmol) to (2R, 5R)-5-Benzyloxy-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 0.84 mmol) in triethylamine (0.70 mL, 5.0 mmol) at 10° C. and stir at room temperature for 30 minutes. Quench with water and extract with diethyl ether. Combine the organic layers, wash with 5% aqueous citric acid followed by saturated aqueous sodium chloride, dry over magnesium sulfate and concentrate. The residue may be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:11][CH2:12][OH:13].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=1>O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:22][CH2:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[N:6]2[CH2:11][CH2:12][OH:13]
Reactant: NCc1cccnc1
Reactant: Nc1ncnc2c1nc(Br)n2CCO
Solvent: O
Product: Nc1ncnc2c1nc(NCc1cccnc1)n2CCO
Temperature: 150 °C
Yield: 86.9 %

Procedure:
A mixture of 0.387 g (1.5 mmol) 6-amino-8-bromo-9-(2-hydroxyethyl)-9H-purine and 0.456 3-picolylamine (4.2 mmol) was heated to 150° C. under an argon atmosphere. After completion of the reaction (˜5 hours) the reaction mixture was diluted with water leading to the precipitation of the product. The precipitate was isolated, washed with water and diethylether to give 0.372 g (87%) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]12[CH2:14][NH:13][CH2:12][CH:11]1[CH2:10][O:9][NH:8]2.Cl[C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([F:24])=[C:18]([CH3:25])[N:17]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:24][C:19]1[C:20]([O:22][CH3:23])=[N:21][C:16]([N:13]2[CH2:12][CH:11]3[C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)([NH:8][O:9][CH2:10]3)[CH2:14]2)=[N:17][C:18]=1[CH3:25]
Reactant: COc1nc(Cl)nc(C)c1F
Reactant: c1cnc(C23CNCC2CON3)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1nc(N2CC3CONC3(c3cnccn3)C2)nc(C)c1F
Temperature: 110 °C
Yield: 38.4 %

Procedure:
To a stirred solution of 6a-pyrazin-2-yl-1,3,3a,4,5,6-hexahydropyrrolo[3,4-c]isoxazole (1.4 g, 7.28 mmol) in 1,4-dioxane (30 mL) is added 2-chloro-5-fluoro-4-methoxy-6-methyl-pyrimidine (5.14 g, 29.13 mmol) and diisopropylethylamine (5.7 mL, 32.77 mmol). The resulting solution is heated at 110° C. for 4 hours. The reaction is cooled and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (0.93 g, 38%). ES/MS (m/e): 333 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14](C(=O)C(F)(F)F)[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[F:1][C:2]1[C:7]2[N:8]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:9]3[C:10]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2n1-c1c(F)cccc1OC21CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2n1-c1c(F)cccc1OC21CCNCC1

Procedure:
To a solution of 9′-fluoro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (170 mg, 0.45 mmol) dissolved in MeOH (2.7 mL) was added K2CO3 (130 mg, 0.94 mmol) in one portion at rt. The reaction was monitored by LCMS until no starting material remained. Water was added (10 mL), and the organic solvent removed under vacuum. The product was extracted with dichloromethane (3×30 mL), the organic phases were combined, dried with sodium sulfate, filtered, concentrated to a white solid, which was used directly in next step without further purification (104 mg, 82%). ESI-MS m/z calc. 283.1. found 284.1 (M+1)+; Retention time 0.94 minutes (3 min run).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16]([O:18][C:19](=O)[C:14]=12)=[O:17])([O-:12])=[O:11]>C(O)(=O)C>[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:14]=1[C:19](=[O:18])[N:1]([CH:2]([CH2:3][C:4](=[O:6])[NH2:5])[C:7]([OH:9])=[O:8])[C:16]2=[O:17])([O-:12])=[O:11]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: NC(=O)CC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
A mixture of asparagine (10 mmol) and 3-nitrophthalic anhydride (10 mmol) in 15 ml of acetic acid is heated to reflux. The cooled reaction mixture is concentrated and the residue purified to afford 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-3-carbamoylpropanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)Cl

Procedure:
A suspension of 4-bromo-2-methylbenzoic acid (4.9 g, 22.8 mmol) in dichloromethane containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (2.4 mL, 27.5 mol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes and then evaporated to dryness in vacuo to provide the crude 4-bromo-2-methylbenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>>[CH2:11]([N:10]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:23][N+:20]([O-:22])=[O:21])=[CH:3][C:2]=1[Cl:1])[CH2:13][CH3:14])[CH3:12]
Reactant: C[N+](=O)[O-]
Reactant: CCN(CC)c1ccc(C=O)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Yield: 39 %

Procedure:
A solution was prepared by dissolving 34 grams (0.16 mol) of 3-chloro-4-(N,N-diethyl)aminobenzaldehyde in 150 ml of nitromethane, and added with 5 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 16 grams of red crystal was obtained. The yield was 39%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]([CH:20]=[O:21])[CH:17]=[CH:16][CH:15]=1>O1CCCC1.CCCCCC.O.C(OCC)(=O)C>[Cl:13][C:14]1[N:19]=[C:18]([CH:20]([OH:21])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccccn1
Reactant: O=Cc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OC(Cc1ccccn1)c1cccc(Cl)n1
Reaction time: 0.83 h
Yield: 30.6 %

Procedure:
50.2 g of 2-picoline was dissolved in 1363 ml of tetrahydrofuran and 237.2 ml of a 2.5M solution of n-butyllithium in hexane was added to the obtained solution at -50° C. in a nitrogen stream. The obtained mixture was stirred at that temperature for 50 minutes, followed by the addition thereto of a solution of 76.2 g of 6-chloro-2-pyridinecarbaldehyde in 1363 ml of tetrahydrofuran at -50° C. The obtained mixture was stirred at that temperature for 30 minutes and brought to 0° C. at room temperature. Water was added to the resulting mixture to terminate the reaction. Ethyl acetate and water were added to the obtained mixture to conduct extraction. The ethyl acetate phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (with a hexane/ethyl acetate (2:1) mixture) to give 38.7 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:20])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[CH:10]=2)[NH:5][C:4](=[O:21])[CH2:3]1.[C:22](O)(=O)[CH3:23]>>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:20])[CH:8]=[C:9]([N:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:19]=[C:22]3[CH3:23])[CH:10]=2)[NH:5][C:4](=[O:21])[CH2:3]1
Reactant: Cc1cc(Nc2ccccc2N)cc2c1NC(=O)CC2C
Reactant: CC(=O)O
Product: Cc1cc(-n2c(C)nc3ccccc32)cc2c1NC(=O)CC2C

Procedure:
3,4-Dihydro-4,8-dimethyl-6-[(N-2-aminophenyl)-amino]-2-(1H)-quinolone (0.39 g) was added with stirring to glacial acetic acid (3 cm3) and the mixture heated under reflux for 5 hours. Solvent was evaporated in vacuo and the residue partitioned between saturated sodium carbonate solution (40 cm3) and dichloromethane (50 cm3). The aqueous phase was separated and re-extracted with dichloromethane (2×50 cm3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution with methanol:chloroform, 1:100 by volume followed by combination and evaporation at appropriate fractions gave a solid which was triturated with diethyl ether to afford the title compound, m.p. 248°-252°, (0.11 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35](O)=[O:36])[CH:30]=[CH:31][C:32]=1[F:33].CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(F)c(F)c4)c3)c2c1
Yield: 11 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 3,4-difluorophenylacetic acid (0.12 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 25 mg (10% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.52–7.3 (m, 4H), 7.2 (m, 1H), 3.7 (s, 2H); ES-MS (m/z) 407 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]#[N:24])[CH:18]=[CH:19][CH:20]=1)=O.N1CCCCC1.O>C(Cl)(Cl)Cl>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:13][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22][C:23]#[N:24])[CH:16]=1
Reactant: N#CC=Cc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(C=CC#N)c2)c(=O)o1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of 5.24 g of 3-acetyl-4-hydroxy-6-methyl-2H -pyran-2-one, 4.90 g of 3-(3-formylphenyl)-2-propenenitrile and 1.92 g of piperidine in 40 ml of chloroform was heated under refluxing for 35 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooling to room temperature, the reaction mixture washed successively with 10% hydrochloric acid, and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. Precipitated crystals were filtered, and the crystals were subjected to silica gel column chromatography to obtain 4.05 g of 4-hydroxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a)] as a pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]#[N:15].C(O)(=O)C>C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]#[N:15])=[C:2]([F:1])[CH:7]=1
Reactant: N#CCCCc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#CCCCc1ccc(N)cc1F
Temperature: 21 °C
Yield: 80.5 %

Procedure:
A solution of compound 4-(2-Fluoro-4-nitrophenyl)butanenitrile (72) (47 mg, 0.23 mmol), Fe (78 mg, 1.40 mmol) and acetic acid (1 mL) in ethyl acetate (3 mL) was heated under reflux for 2 h. The reaction mixture was allowed to cool to 21° C. and then filtered. The organic layer was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give desired 4-(4-Amino-2-fluorophenyl)butanenitrile (71) (33 mg, 83%): 1H NMR δ 6.98-7.01 (m, 1H), 6.46-6.52 (m, 2H), 2.70 (t, 2H, J=7.6 Hz) 2.32 (t, 2H, J=7.2 Hz) 1.89-1.98 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]3)=[N:16][CH:15]=2)[C:3]=1[CH3:21]
Reactant: OC1CCNC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCC(O)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C
Reaction time: 1.6 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (2.5 mL) was added 3-pyrrolidinol (0.029 mL, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 120° C. and stirring continued for 1.6 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)pyrrolidin-3-ol as a yellow solid. Mass Spectrum (ESI) m/e=376.1 (M+1).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.C([O:21]C(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[O:21]1[CH2:3][CH2:4][CH:1]([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:2]1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: O=C(O)c1cc2c(OCC3CCOC3)cccc2[nH]1

Procedure:
4-(Tetrahydro-furan-3-ylmethoxy)-1H-indole-2-carboxylic acid (16b) is synthesized analogous to 16a from 4-(tetrahydro-furan-3-yl)methanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.C(OC([N:33]([CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1)[S:34]([NH2:37])(=[O:36])=[O:35])=O)C=C>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:45]3[CH:44]=[C:41]4[S:42][CH:43]=[C:39]([CH2:38][NH:33][S:34]([NH2:37])(=[O:35])=[O:36])[N+:40]4=[CH:46]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)N(Cc1csc2cncn12)S(N)(=O)=O
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CNS(N)(=O)=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 2.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 91.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 145 mg of 3-[N-allyloxycarbonyl-N-(aminosulfonyl)amino]methyl imidazo[5,1-b]thiazole were used, thereby obtaining 2.8 mg of the title compound.
Reaction SMILES: OC1C=C(CCC(OC)=O)C=CC=1.[CH2:14]([O:18][C:19]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C@@H:33](C(F)(F)F)[CH2:34][C:35]([OH:37])=[O:36])[CH:30]=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[F:50])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:18][C:19]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:30]=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[F:50])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(COc2cccc([C@H](CC(=O)O)C(F)(F)F)c2)ccc1-c1cc(OC)ccc1F
Agent: COC(=O)CCc1cccc(O)c1
Product: CCCCOc1cc(COc2cccc(CCC(=O)O)c2)ccc1-c1cc(OC)ccc1F

Procedure:
Compound 13 was synthesized from methyl 3-(3-hydroxyphenyl)propanoate (available from Aagile Labs Division of Tyger Scientific) and 5.4 by a method analogous to the method used to prepare compound 7. ESI (neg.) m/e: 451.1 (M−H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.22-7.32 (2H, m), 7.01-7.09 (3H, m), 6.82-6.91 (5H, m), 5.08 (2H, s), 4.00 (2H, t, J=6.5 Hz), 3.81 (3H, s), 2.97 (2H, t, J=7.8 Hz), 2.71 (2H, t, J=7.8 Hz), 1.64-1.72 (2H, m), 1.34-1.43 (2H, m), 0.90 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH:4]1[C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=12.[Cl:16][S:17](O)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[Cl:16][S:17]([C:13]1[C:5]2[CH:4]3[CH:3]([O:2][CH3:1])[CH:7]([CH2:8][CH2:9]3)[C:6]=2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)C1CCC2C1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(c(S(=O)(=O)Cl)c1)C1CCC2C1OC
Temperature: 0 °C
Yield: 58 %

Procedure:
A small amount of chloroform was added to 50 g of 3,6-dimethoxybenzonorbornene, and the mixture was stirred with cooling by ice water. Chlorosulfonic acid (65 ml) was slowly added to this. After the mixture was reacted at 0° C. for 1 hour, the reaction solution was poured over ice. It was extracted with diethyl ether. The extract solution was dried over anhydrous sodium sulfate and then the diethyl ether was distilled off, giving 4-chlorosulfonyl-3,6-dimethoxybenzonorbornene. Yield: 58%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C@H:31]([C:45]([OH:48])([CH3:47])[CH3:46])[C:32]([NH:34][NH:35][C:36](=[O:44])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=O)=[C:26]([CH3:49])[C:25]=1[C:50]([F:53])([F:52])[F:51])#[N:23]>C(Cl)Cl.C1COCC1>[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]2[O:44][C:32]([C@H:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[C:25]([C:50]([F:52])([F:51])[F:53])[C:26]=3[CH3:49])[C:45]([OH:48])([CH3:47])[CH3:46])=[N:34][N:35]=2)=[CH:42][CH:41]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)cc3)o2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Reaction time: 0.5 h
Yield: 123.1 %

Procedure:
Triphenylphosphine (766 mg, 2.92 mmol) was dissolved in DCM (100 mL) followed by addition of I2 (741 mg, 2.92 mmol) and TEA (0.81 mL, 5.84 mmol) at 0° C. (R)—N′-(2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (660 mg, 1.46 mmol) in DCM (20 mL) and THF (10 mL) was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred for 30 min. The reaction mixture was then concentrated to furnish a yellow solid (781 mg). The crude material was chromatographed with EtOAc:Hexanes (2:1) to furnish the title compound as a white solid (361 mg, 57%). 1H NMR (500 MHz, Acetone d6, δ in ppm): 7.97-7.94 (m, 2H), 7.49 (d, J=9 Hz, 1H), 7.19-7.14 (m, 2H), 6.81 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.72 (d, J=9 Hz, 1H), 2.35 (s, 3H), 1.50 (s, 3H) and 1.35.