Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH:4]1([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH:2]=[CH:3]1
Reactant: ClC1CC(COCc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C1=CC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
[[(3-Chlorocyclobutyl)methoxy]methyl]benzene (82 g, 0.39 mole) in 390 ml of dry dimethylsulfoxide was slowly added to a solution of potassium t-butoxide (132 g, 1.17 mole) in 390 ml of dry dimethylsulfoxide in a water-bath at 18° C. under a dry argon atmosphere. After stirring for 1 hour at room temperature, the reaction mixture was poured into 1600 ml of water and extracted with ether (3×1000 ml). The ether extracts were back-extracted with water (4×2000 ml) and the ether extract was then dried over sodium sulfate. The ether was removed in vacuo and the crude product was purified on a Merck silica column, eluting the column with 5% ethyl acetate-hexane. Appropriate fractions were combined and the solvents removed in vacuo yielding 60.0 g of the title compound as a colorless liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
Indole-5-boronic acid (0.111 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (50-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.049 g in 50% yield.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][C:14]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[CH2:15][N:16]=2)=[CH:8][C:7]=1[Br:29])(=O)C.C[O-].[Na+]>CO.COC(C)(C)C>[Br:29][C:7]1[CH:8]=[C:9]([C:12]2[CH2:13][C:14]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:18])([F:19])[F:20])[CH2:15][N:16]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzyl acetate (1.1 g) in methanol (20 ml) was added sodium methoxide (0.1 g), and the solution was stirred for 1 hour at room temperature. The reaction mixture was returned to room temperature and then diluted with t-butyl methyl ether, washed with water and a saturated aqueous brine and subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain {2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]phenyl}methanol (0.95 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:44][C:45]1[CH:49]=[C:48]([Sn](C)(C)C)[S:47][N:46]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:48]2[S:47][N:46]=[C:45]([CH3:44])[CH:49]=2)=[CH:7][N:6]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Cc1cc([Sn](C)(C)C)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(F)c(F)c2)sn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
5-chloro-2,3-difluoropyridine (0.069 ml, 0.67 mmol), X-Phos (0.045 g, 0.094 mmol) and palladium (II) acetate (0.011 g, 0.047 mmol) were combined in 1,4-dioxane (0.2 M, 3.4 mL). To the reaction vessel was added 3-methyl-5-(trimethylstannyl)isothiazole (0.53 g, 2.0 mmol) and, after purging with argon, the reaction was stirred at 100° C. for 2 h and then concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting first with 100% EtOAc followed by 20% EtOAc in hexanes-isocratic) to yield 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine (0.139 g, 98% yield) as a yellow solid. 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine was converted to the title compound using a procedure similar to 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine.
Reaction SMILES: [I:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1I
Yield: 95 %

Procedure:
A mixture of 2-iodo-3-nitrobenzoic acid (31.0 g, 106 mmol) and concentrated sulfuric acid (24.9 mL, 317 mmol) in methanol (600 mL) was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure and the residue was extracted with methylene chloride. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (chloroform/hexane) to give the title compound (31.0 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(N(CC)CC)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:10])[CH:12]=1
Reactant: CCCCCC(=O)Cl
Reactant: CC(Nc1ccc(Cl)cc1)c1cccnc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCC(=O)N(c1ccc(Cl)cc1)C(C)c1cccnc1

Procedure:
To a stirred solution of 7.5 g. of N-(4-chlorophenyl)-[1-(3-pyridyl)ethyl]amine in 200 ml. of toluene containing 5.0 g. of triethylamine were added dropwise over thirty minutes 4.5 g. of hexanoyl chloride. Following the complete addition, the solid precipitate which had formed was removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure. The product thus formed was chromatographed over a silica gel column to provide, after removal of the solvent from the appropriate factions, 650 mg. of N-[1-(3-pyridyl)ethyl]-N-(4-chlorophenyl)hexanamide. Oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]#[N:25])=[CH:12][N:13]=[C:14]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([OH:22])[CH:18]([F:23])[CH2:17]4)[C:5]=3[C:4]=2[CH:3]=1.OO.C(=O)([O-])[O-:29].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]([NH2:25])=[O:29])=[CH:12][N:13]=[C:14]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([OH:22])[CH:18]([F:23])[CH2:17]4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cnc(NC2CCC(O)C(F)C2)c2c1[nH]c1ccc(F)cc12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cnc(NC2CCC(O)C(F)C2)c2c1[nH]c1ccc(F)cc12
Temperature: 70 °C

Procedure:
To a stirred solution of 8-fluoro-1-[(3-fluoro-4-hydroxycyclohexyl)amino]-5H-pyrido[4,3-b]indole-4-carbonitrile (72 mg, 0.21 mmol) in DMSO were added hydrogen peroxide (30%, 0.18 mL, 2.10 mmol) and potassium carbonate (157 mg, 1.14 mmol). The reaction mixture was heated to 70° C. for 4 h, cooled to room temperature, filtered, and purified by prep-HPLC to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 8.48 (s, 1H); 7.92 (dd, 1H); 7.57 (dd, 1H); 7.16 (dt, 1H); 4.35-4.52 (m, 2H); 3.71 (m, 1H); 1.46-2.55 (series of m, 6H). LRMS (APCI) calc'd for (C18H18F2N4O2) [M+H]+, 361.1. found 361.0.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:12]=1
Reactant: Nc1ccc(I)cc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: Nc1ccc(C2=Cc3ccccc3C2)cc1

Procedure:
20 ml of triethylamine, 2.2 g (20 mmol) of indene, 4.38 g (20 mmol) of para-amino-iodo-benzene and 0.134 g (0.6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. After that all triethylamine was removed under reduced pressure. The residue was treated with 80 ml of 15% HCl. Forming precipitate was separated and washed with dichloromethane. The resulting substance was treated with the mixture 50 ml of dichloromethane and 50 ml of 5% KOH in water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yield of product was 21%.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[F:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23]>>[F:12][C:13]1[C:18]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=2)=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1ccc(CBr)cc1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(CBr)cc1
Yield: 56.4 %

Procedure:
Starting from 4-(bromomethyl)benzoic acid (5.0 g, 23.25 mmol) and pentafluorophenol (4.3 g, 23.25 mmol), applying the same procedure described in Preparation 2, 4-(bromomethyl)benzoic acid pentafluorophenyl ester (5.0 g, 56%) was obtained as an off white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][C:9]=2[N:10]=1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[Br:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
2-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (890 mg) was dissolved in dichloromethane (2 ml), and to the solution trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. Precipitated solid materials were collected by filtration to obtain the title compound (867 mg) as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([C:21]([C:23]3[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:25][C:24]=3[CH3:41])=[O:22])[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:42])[C:14]=3[NH:13][C:12]=2[CH:43]=1>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([C:21]([C:23]3[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:34][CH2:33]4)=[CH:25][C:24]=3[CH3:41])=[O:22])[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:42])[C:14]=3[NH:13][C:12]=2[CH:43]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(CNC(=O)CCC2CCNCC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(CCC(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of propionyl chloride (0.46 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=577.4
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[C:8]#[N:9])[CH2:3][CH2:2]1.C(O)([C:18](F)([F:20])[F:19])=O.O(C(C)(C)C)O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:19][CH:18]([F:20])[C:13]1[N:12]=[CH:11][C:10]([CH:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:8]#[N:9])=[CH:15][N:14]=1
Reactant: N#CC(c1cncnc1)N1CCOCC1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC(c1cnc(C(F)F)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
To a solution of 2-morpholino-2-(pyrimidin-5-yl)acetonitrile (1.03 g, 5.04 mmol) and DFMS (4 g, 13.61 mmol) in DCM (40 mL) and H2O (16 mL) at room temperature was added CF3COOH (575 mg, 5.04 mmol) followed by slow addition of 2-hydroperoxy-2-methylpropane (3.24 g, 70% solution in H2O) with vigorous stirring. The reaction mixture was stirred at room temperature overnight. The reaction mixture was portioned between DCM (50 mL) and saturated NaHCO3 solution (50 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by Prep-TLC (Petroleum ether:EtOAc=10:1˜2:1) to give 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile (150 mg, yield: 11.7%). 1H NMR (CDCl3 400 MHz): δ9.01 (d, J=10.0 Hz, 2H), 6.67 (t, J=54.4 Hz, 1H), 4.91 (s, 1H), 3.95-3.62 (m, 4H), 2.81-2.46 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
Periodinane (26.9 g, 63.5 mmol) was added to a solution of 1-tert-butoxycarbonyl-piperidine-4-methanol (10.5 g, 48.8 mmol) in methylene chloride (200 mL) and the mixture was stirred for 90 min. Diethyl ether was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 300 mL). The organic layer was washed with 0.5 M NaOH and brine, dried and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 8:2) gave 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (8.5 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([CH3:21])[C:10](=[O:20])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:26]([C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[CH3:23])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10](=[O:20])[C:9]=1[CH3:21]
Reactant: Cc1ccccc1N
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccccc1-n1c(-c2ccccc2)cc(=O)c(C)c1-c1ccccc1Cl

Procedure:
In 500 ml of xylene were dissolved 37.7 g (0.012 mole) of 1-(2-chlorophenyl)-2-methyl-5-phenyl-1,3,5-pentanetrione, 38.6 g (0.36 mole) of 2-methylaniline, 22.8 g (0.12 mole) of para-toluenesulfonic acid and 30 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 8 hours. After cooling, solid matter was filtered off and the organic layer was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. After washing the organic layer further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). As result, two atrop-isomers of 2-(2-chlorophenyl)-3-methyl-1-(2-methylphenyl)-6-phenyl-4(1H)-pyridinone, namely, Compound 338 and Compound 339 were obtained in yields of 1.2 g and 8.0 g, respectively. Their melting points were 227°-229° C. and 222°-225° C., respectively.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O.N1CCC[CH2:16]1.COC(OC)N(C)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[CH:1]=[CH:16][NH:12]2
Reactant: C1CCNC1
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2[nH]ccc12
Temperature: 60 °C
Yield: 57.2 %

Procedure:
A solution of 2-methyl-1-nitro-3-(trifluoromethyl)benzene (10.00 g, 48.8 mmol), pyrrolidine (4.44 mL, 53.7 mmol) and dimethylformamide dimethylacetal (19.8 mL, 146 mmol) in DMF (100 mL) was heated at 100° C. for 4 h, cooled and concentrated in vacuo. The residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in THF/MeOH (1:1, 200 mL), and transferred to a 3-necked flask equipped with an overhead stirrer, reflux condenser, and dropping addition funnel. Raney-Ni (Raney® 2800 slurry in water, 10 g) was added in one portion and the entire apparatus was thoroughly flushed with N2. The mixture was heated to 60° C., under N2, and a solution of hydrazine monohydrate (8 mL) in THF/MeOH (1:1, 20 mL) was added dropwise over 1 h. The mixture was heated at 60° C. for 1 h, cooled, and filtered through a pad of Celite®. The filtrate was concentrated in vacuo, the residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (10% HCl, H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 5.17 g of the title compound as a light brown liquid: 1H NMR (300 MHz, methanol-d4) δ 7.61 (d, J=8.2 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.19 (partially resolved dd, J 8.4, 7.5 Hz, 1H), 6.59 (br. s, 1H).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:58])[CH3:57])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:63])[CH3:62])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].[C:86]([O:89]C(=O)C)(=[O:88])[CH3:87].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>O1CCCC1>[CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:57])[CH3:58])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:62])[CH3:63])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].[C:86]([O-:89])(=[O:88])[CH3:87]
Reactant: CC(=O)OC(C)=O
Agent: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)[O-]

Procedure:
To a stirred solution of 3.6 g (30 mmol) of cyclosporin A in 100 ml tetrahydrofuran were added 1.5 equivalents of acetic anhydride, 1.5 equivalents of triethylamine, and 0.3 g of dimethylaminopyridine. The mixture was refluxed for 18 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed sequentially with 1N hydrochloric acid solution, water, dried over MgSO4 and evaporated. The crude product was chromatographed to give a title compound of 3.2 g.
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.O>[CH3:11][C:10]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 200 °C
Yield: 20.7 %

Procedure:
A mixture of 2-nitro-3-methylaniline (Newman, M. S.; Kannan R. J. Org. Chem., 1976, 41, 3356., 1.9 g, 12.4 mmol), 4-bromophenylethyl alcohol (2.5 g, 12.4 mmol), K2CO3 (1.7 g, 12.4 mmol) and CuI (230 mg, 1.24 mmol) was placed in a sealed tube and heated at 200° C. for 2 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 700 mg (21%) of the title compound as an orange oil: 1H-NMR (CDCl3) δ 7.77 (1H, br.s), 7.09–7.45 (6H, m), 6.69 (1H, d, J=6.3 Hz), 3.83 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=6.6 Hz), 2.59 (3H, s).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:20][CH2:21][CH3:22])([C:6]1[N:11]2[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].C.P(CC1C2N(C=C(C(O)=O)N=2)C=CC=1)(O)(O)=O.O1CCOCC1.[Cl:47]Cl>CCOCC>[ClH:47].[CH2:1]([O:3][P:4]([O:20][CH2:21][CH3:22])([C:6]1[N:11]2[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: ClCl
Agent: CCOC(=O)c1cn2c(P(=O)(OCC)OCC)cccc2n1
Agent: O=C(O)c1cn2cccc(CP(=O)(O)O)c2n1
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cl

Procedure:
The product from Example 51 (1.6 g, 4.4 mmol) was dissolved in CH2 Cl2 (30 mL), treated with activated charcoal and filtered. To this filtrate was then added 6N HCl in dioxane (0.9 mL, 4.4 mmol) followed by Et2O (100 mL). The precipitated product was filtered, washed with Et2O, and dried in vacuo.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][NH:12][CH3:13]>>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([N:12]([CH3:13])[CH3:11])[N:9]=1
Reactant: O=Cc1ccc(Cl)nc1Cl
Reactant: CNC
Product: CN(C)c1nc(Cl)ccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
2,6-Dichloronicotinaldehyde (500 mg, 2.84 mmol) was diluted with dimethylamine (3125 μL, 6.25 mmol) and heated to 50° C. After stirring for 3 hours, the reaction was loaded onto a silica gel column and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield 6-chloro-2-(dimethylamino)nicotinaldehyde (155 mg, 0.840 mmol, 29.6% yield).