Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)=[O:14])[CH3:11]>CN1C(=O)CCC1>[CH2:10]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COc1ccnc(Cl)n1
Solvent: CN1CCCC1=O
Product: CCOC(=O)N1CCC(Nc2nccc(OC)n2)CC1
Yield: 42 %

Procedure:
A mixture of 2-chloro-4-methoxy-pyrimidine (3.64 g, 25.21 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid ethyl ester (4.34 g, 25.21 mmol, 1.0 equiv; commercially available) in anhydrous NMP (32 mL) was heated by microwave irradiation to 200° C. for 15 min. The organic phase was concentrated under reduced pressure and the residue extracted with ethyl acetate (3×50 mL) from a solution of 1 M NaOH (100 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) providing 2.93 g (42%) of the title compound. MS (ISP): 281.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:20][C:21]([CH3:27])=[CH:22][C:23]=1[C:24]([OH:26])=[O:25])=O>>[CH3:27][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1cc(C(=O)O)c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (34 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-fluoro-5-iodobenzoic acid (Aldrich, 5.27 g, 19.8 mmol) in CH2Cl2 (35.0 mL) was added oxalyl chloride (14.9 mL, 29.7 mmol, 1M solution in CH2Cl2) followed by 2 drops of DMF via syringe. Gas evolution was initiated and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 2-fluoro-5-iodobenzoyl chloride which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC=Cc2ccc(Cl)cc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(OCCCc2ccc(Cl)cc2)CC1
Yield: 40.6 %

Procedure:
A mixture of tert-butyl 4-[3-(4-chlorophenyl)-2-propenyloxy]piperidine-1-carboxylate (0.37 g, 1.05 mmol) prepared in Reference example 112 and platinum oxide (37 mg) in ethanol (10 ml), was stirred at room temperature under atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford tert-butyl 4-[3-(4-chlorophenyl)propoxy]piperidine-1-carboxylate (0.151 g, yield 40%) as a yellow oil.
Reaction SMILES: [Li+].[I-].[CH3:3][CH:4]([CH:6]=[O:7])[CH3:5].Br[CH:9]([CH3:20])[C:10](=[O:19])[C:11]([CH3:18])([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14]>C1COCC1>[OH:7][CH:6]([CH:4]([CH3:5])[CH3:3])[CH:9]([CH3:20])[C:10](=[O:19])[C:11]([CH3:18])([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14]
Reactant: CC(C)C=O
Reactant: COC(OC)C(C)(C)C(=O)C(C)Br
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(C)(C)C(=O)C(C)C(O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 298 mg (2.42 mmol) CrCl2 and 29 mg (0.22 mmol) LiI in 6.0 mL abs. THF were added 100 μl (1.1 mmol) isobutyric aldehyde and 253 mg (1.0 mmol) 4-bromo-1,1-dimethoxy-2,2-dimethyl-pentan-3-one (225). After stirring at ambient temperature for one hour the brown solution was quenched with 5.0 mL brine. The aqueous phase was extracted three times with 5.0 mL of a diethylether-pentane mixture (5:1). The organic layers were combined, washed with conc. NH4Cl solution (3×5.0 mL), dried over MgSO4, filtrated and concentrated in vacuo. The remaining colourless oil (206 mg) was purified via flash chromatography (column dimensions: 3.5×20.0 cm, ethyl acetate/petroleum ether=1:8).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1>CO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][CH:3]=1
Reactant: CCC(CC)Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CC)Nc1nc(Cl)ccc1N
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a room-temperature solution containing 6-chloro-3-nitro-N-(pentan-3-yl)pyridin-2-amine (1.8 g, 7.4 mmol) in MeOH (10 mL) and EtOAc (10 mL) was added SnCl2 dihydrate (10.0 g, 44.3 mmol). After 3 h, the reaction mixture was concentrated in vacuo and then re-dissolved in EtOAc and water. After stirring overnight, the layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (25%-50% EtOAc/Hexanes) provided the title compound as a white solid (940 mg, 57%). m/z=223.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH:14]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCB(CC)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=Cc1cccc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
3-Bromobenzaldehyde (5 g, 27 mmol), diethyl (pyridin-3-yl)borane (3.97 g, 27 mmol) and potassium carbonate (11 g, 81 mmol) were dissolved in ethylene glycol dimethyl ether and water (40 ml, 2:1) and degassed under N2 then heated at 80° C. for 18 h after addition of tetrakis(triphenylphosphine)palladium(0) (0.2 g). The reaction was then diluted with ethyl acetate and water (200 ml, 1:1) and passed through a hyflo filter plug, the separated organic phase was washed with brine, dried (MgSO4) and evaporated to dryness. Purified on SiO2 eluting with 25-50% ethyl acetate-hexane to afford the title compound (3.6 g, 73%). MS (ES+) m/e 184 [MH]+.
Reaction SMILES: [N:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:3]1([NH2:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=NN1CCCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 14.7 mmol) in THF (40 mL) was added dropwise under N2 to a suspension of LAH (0.56 g, 14.7 mmol) in THF (10 mL) cooled with an ice-bath such that the temperature did not rise above 15° C. The mixture was stirred at room temperature for 1 h, quenched with saturated Rochelle's salt solution (15 mL) and extracted with ether (3×20 mL). The organic layer was dried (Na2SO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:4) gave 2,3,4,5-tetrahydro-1H-1-benzazepinamine (1.63 g, 68%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ 1.50–1.72 (m, 2H), 1.78–1.92 (m, 2H), 2.70–2.82 (m, 2H), 3.180–3.22 (m, 2H), 3.78 (br, 2H), 6.91 (td, J=7.3, 1.5 Hz, 1H), 7.10 (dd, J=1.1, 7.4 Hz, 1H), 7.21 (td, J=8.0, 1.4 Hz, 1H), 7.28 (dd, J=1.4, 8.0 Hz, 1H) ppm.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])[CH2:2]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])[N:14]=1.C(N(CC)CC)C>C(Cl)Cl>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])[N:14]=[C:13]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([CH:9]2[CH2:10][CH2:11]2)=[O:8])[CH2:2]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: O=C(N[C@@H]1CCNC1)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A mixture of N-((R)-pyrrolidin-3-yl)cyclopropanecarboxamide (250 mg, 0.86 mmol), 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.86 mmol) and triethylamine (0.240 mL, 1.72 mmol) in CH2Cl2 (10 mL) was stirred at room temperature. The reaction was complete after one hour. The reaction was quenched with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 gave N-((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide (230 mg, 68%). LC/MS: m/z 393.3 (M+H)+ at 2.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.42-8.46 (m, 2H), 8.03 (dd, J=10.5, 2.6 Hz, 1H), 7.88-7.92 (m, 1H), 7.74-7.79 (m, 1H), 7.35-7.39 (m, 1H), 6.92-6.96 (m, 2H), 4.44-4.47 (m, 1H), 4.01-4.28 (m, 3H), 3.83-3.87 (m, 1H), 2.20-2.28 (m, 1H), 1.99-2.06 (m, 1H), 1.51-1.57 (m, 1H), 0.63-0.73 (m, 4H).
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]4=[O:24])=[CH:14][CH:13]=3)[C:7](=[O:25])[C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:4]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(O)(=O)C>C(Cl)Cl>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([N:5]2[C:6]3[C:7](=[O:25])[N:8]([C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]5=[O:24])=[CH:14][CH:13]=4)[CH2:9][CH2:10][C:11]=3[C:3]([CH3:2])=[N:4]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(-n2nc(CO)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To 3-hydroxymethyl-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (65 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added triethylsilane (0.1 mL) and TFA (0.05 mL). After 2 h more triethylsilane (0.2 mL) and TFA (0.1 mL) were added and the reaction was stirred for 72 h. The reaction was not proceeding so the solvents were stripped and replaced with acetic acid (10 mL), triethylsilane (0.5 mL), and TFA (0.1 mL). The reaction was heated 24 h at 80° C. Mass spectra indicated only the acetyl product formed. The solvents were removed. The acetyl group was removed by stirring with LiOH (0.1 g) in THF/H2O for 3 h. The reaction was quenched with 1N HCl, extracted with EtOAc, and dried (MgSO4) to recover the alcohol. To the alcohol in CHCl3 was added PBr3 and the reaction was stirred 24 h. The reaction was quenched with ice water, extracted with CHCl3, and dried (Na2SO4). To the crude bromide were added activated Zn (80 mg) and acetic acid (10 mL) and heated to 120° C. for 24 h. The product was purified by silica gel chromatography using 0-3% MeOH in CH2Cl2 and recrystallized from CH3CN/H2O to afford 22 mg (35%); Mass Spec (M+H)+ 427.3.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](F)[CH:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)[CH:2]=[CH2:3].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O.CO>[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C(=O)OCC)c(=O)c2ccc(F)cc21
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCn1cc(C(=O)OCC)c(=O)c2ccc(N3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
A solution of ethyl 1-allyl-7-fluoro-4-quinolone-3-carboxylate (390 mg, 1.41 mmol) and piperazine (1.22 g, 14.1 mmol) in dry N,N-dimethylformamide was heated for 7 hours at 110° C., then stirred at room temperature for 2 days. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel using dichloromethane:methanol (gradient from 98:2 to 85:15) as eluent affording 300 mg (62% yield) of ethyl 1-allyl-4-oxo-7-(4-piperazinyl)quinoline-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Br:8].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:8][C:7]1[CH:6]=[N:5][N:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3](=[O:9])[C:2]=1[Br:1]
Reactant: O=c1[nH]ncc(Br)c1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc(Br)c(Br)c1=O
Yield: 110.8 %

Procedure:
4,5-Dibromopyridazin-3(2H)-one (5.0 g, 19.7 mmol) in N,N-dimethylformamide (50 mL) was stirred with ethyl bromoacetate (3.28 g, 29.5 mmol) and potassium carbonate (4.08 g, 29.5 mmol) at 80° C. for 1 hour and 40 minutes. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride three times and with saturated aqueous sodium chloride once, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (7.42 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Nc1cc(F)c(F)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OC(c1nc2cc(F)c(F)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Difluoro-benzene-1,2-diamine (4.98 g; 34.5 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (7.48 g; 51.9 mmoles) were suspended in 6N HCl (8 mL; 48 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.05 g; 72.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a pale orange solid.
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O.[OH:27][CH2:28][CH2:29][CH2:30][NH2:31]>CCOCC>[OH:27][CH2:28][CH2:29][CH2:30][NH:31][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12][C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:26])=[O:25])=[O:24].[OH:27][CH2:28][CH2:29][CH2:30][NH3+:31]
Reactant: O=C(O)CCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: NCCCO
Solvent: CCOCC
Product: O=C([O-])CCCCCCCCC#CC#CCCCCCCCCC(=O)NCCCO
Product: [NH3+]CCCO
Reaction time: 8 h

Procedure:
A mixture of 9.4 g. (0.025 mole, 376.59) of monomethyl ester of 10,12-docosadiynedioic acid and 11.3 g. (0.12 mole, 75.11) of 3-hydroxypropylamine is briefly warmed, then kept overnight at room temperature. The product is slurried with ether, then recrystallized from an ether-ethanol mixture, obtaining a white solid, m.p. 91°-3° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.[H-].[Na+]>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (3.59 g, 24.39 mmol) and 2,6-dichlorobenzyl bromide (7.05 g, 29.39 mmol) in dimethylformamide (20 mL) at 0° C. was added 60% sodium hydride (1.176 g, 29.39 mmol). After stirring at ambient temperature for 16 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium chloride and dried (MgSO4). Purification by flash column chromatography (silica gel, hexane/ethyl acetate) yielded the title compound as an off-white solid (7.38 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16]CC)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c[nH]c(C(=O)O)c1-c1ccc(Cl)cc1
Yield: 95.7 %

Procedure:
To a solution of ethyl 3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate [for synthesis see ACI-02] (2.0 g, 7.58 mmol) in dry THF (26 mL) and MeOH (26 mL) was added aqueous 6 M NaOH (25.3 mL, 152 mol) and the mixture was stirred at reflux for 3 h. The organic solvents were evaporated and the remainder was acidified with aqueous 6 M HCl (30 mL) at 0° C. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated to yield the desired product 1.71 g, 96%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:10][C:9]=2[F:27])=[CH:4][CH2:3]1.C(=O)(O)[O-].[Na+].[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>CC(C)=O.O>[C:33]([O:36][CH2:37][C:38]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:9]([F:27])=[CH:10][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:12][C:13]=2[F:14])=[CH:4][CH2:3]1)=[O:39])(=[O:35])[CH3:34]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCNCC2)c(F)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCC(=O)N1CC=C(c2c(F)cc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.1 %

Procedure:
A solution of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (650 mg, 1.64 mM) in acetone (20 ml) and water (10 ml), was treated with sodium bicarbonate (1.38 g, 16.4 mM) and the mixture cooled to 0–4°. Acetoxyacetyl chloride (448 mg, 3.28 mM) was added dropwise and the reaction mixture stirred at 0–4° for 20 minutes before allowing to warm to ambient temperature. After dilution with water the mixture was extracted well with ethyl acetate. The organic phase was separated, dried (sodium sulfate), solvent evaporated, and the residue triturated with diethyl ether to give the desired product (702 mg).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CC1.[Li+].[CH3:25][CH2:26][CH2:27][CH2-:28].[CH2:29]1[O:39][C:32]2([CH2:37][CH2:36]C(=O)[CH2:34][CH2:33]2)[O:31][CH2:30]1>C1COCC1>[C:26]1(=[C:25]2[CH2:36][CH2:37][C:32]3([O:39][CH2:29][CH2:30][O:31]3)[CH2:33][CH2:34]2)[CH2:28][CH2:27]1
Reactant: [CH2-]CCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [Li+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Solvent: C1CCOC1
Product: C1COC2(CCC(=C3CC3)CC2)O1
Temperature: -60 °C
Yield: 53.3 %

Procedure:
Cyclopropyltriphenylphosphonium bromide (10.8 g, 28 mmol) was suspended in dry THF (30 mL) and cooled to −60° C. N-Butyllithium (1.6M in THF, 17 mL, 27 mmol) was added dropwise at −40 to −60° C. The temperature was raised to 20° C. and after 3 hours at this temperature, the reaction mixture was cooled to −60° C. 1,4-Cyclohexane dione mono ethylene ketal (4.0 g, 26 mmol) dissolved in THF (30 mL) was added at −60° C. whereafter the temperature was raised to 20° C. After 16 hours the reaction mixture was diluted with THF (75 mL) filtered through hyflo and concentrated in vacuo. The residue was purified by flash chromatography (4×15 cm column of silica) using heptane and ethyl acetate (4:1) as eluent to give 2.5 g of 8-cyclopropylidene-1,4-dioxa-spiro[4.5]decane (cf Synthetic Communications 21(20), 2015-2023, 1991).
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)[CH3:2].[CH:18]1[C:30]2[NH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2C=C[CH:19]=1>[Cu]=O>[CH:15]1[C:16]2[N:4]([C:1]3[CH:19]=[CH:18][C:30]4[NH:29][C:28]5[C:23]([C:22]=4[CH:2]=3)=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Agent: O=[Cu]
Product: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4ccccc43)cc12
Temperature: 170 °C
Yield: 82.4 %

Procedure:
A mixture of 4.0 g of 9-Acetyl-3-bromocarbazole prepared as described above and 2.8 g of carbazole were stirred together in 30 ml N,N′-dimethylacetamide. To this was added 0.8 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid (5.0 g) was then taken up for further deprotection using 1.2 g KOH with THF (6 ml), methanol (12 ml) and water (12 ml) at reflux temperature. The reaction mixture was then extracted using ethylacetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene:hexane (1:2) as eluent, yielded 3.8 g of 3-(9-carbazolyl)carbazole as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].C([BH3-])#N.[Na+]>O1CCCC1.C(O)(=O)C.C(Cl)(Cl)Cl>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][C:25]([CH2:28][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=Cc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(CN4CCOCC4)cn3)CC2)cc1
Yield: 59.5 %

Procedure:
Morpholine (250 mg, 2.87 mmol) was added to a suspension of 6-[4-(4-nitrophenyl)piperazin-1-yl]pyridine-3-carbaldehyde (750 mg, 2.41 mmol) and sodium cyanoborohydride (454 mg, 7.23 mmol) in a mixture of tetrahydrofuran (10 mL) and acetic acid (0.5 mL) at ambient temperature then heated at reflux for 3 h. The mixture was then concentrated in vacuo to give a gummy solid which was dissolved in chloroform (40 mL), washed with water (2×20 mL), brine (2×15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina using 20-30% of ethyl acetate in petroleum ether afforded 4-[[6-[4-(4-nitrophenyl)piperazin-1-yl]-3-pyridyl]methyl]morpholine (550 mg, 59%).