Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
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: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Yield: 69.4 %

Procedure:
To a stirred solution of 4-tert-butyl-bromobenzene (21.3 g, 0.0999 mol) in THF (30 mL) at −78° C. under nitrogen was added dropwise a 2.1 M solution of n-butyl lithium in hexanes (45 mL, 0.095 mol), and the mixture was stirred for 1.5 hours. To the mixture was added dropwise neat trimethylborate (10.2 mL, 0.090 mol), and the mixture was allowed to slowly warm to room temperature. The mixture was stirred overnight, then quenched by dropwise addition of 1.0 M aqueous hydrochloric acid. Brine was added, and the organic layer was dried (Na2SO4) and rotary evaporated. The residue was crystallized from n-heptane to give 4.65 g of crude 4-tert-butyl-phenyl-boronic acid as white needles. This material was used directly in the next reaction without further characterization. Thus, in a manner similar to Example 12, Step (b), 4-tert-butyl-phenyl-boronic acid (0.4287 g, 0.00241 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (0.5443 g, 0.00200 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.0472 g, 0.0000408 mol) and 2.0 M aqueous sodium carbonate (2.4 mL, 0.0048 mol) in toluene (5 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with toluene then chloroform, 0.50 g. The material was dissolved in diethyl ether, washed with 0.10 M aqueous sodium hydroxide, water and brine. The organics were dried (K2CO3), and rotary evaporated to give 0.45 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 58-62° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (3.07 g), ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (2.04 g), potassium carbonate (1.22 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxylate as colorless crystals (3.20 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: ClCCN1CCCCC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1-(2-chloro-ethyl)-piperidine gave the title compound as white solid. MS: 424.1 (MH+, 2Cl).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH3:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])[CH2:23][CH2:22]1
Reactant: CC1CCC(CC(=O)O)CC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCC(CC(=O)N2CC3CC[C@](C)(C2)C3(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.84 ml was added in a methylene chloride 20 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g, and stirred at 0° C. for 30 min. 4-methylcyclohexyl acetic acid 0.94 g and WSC 1.35 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-methylcyclohexylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.39 g and refluxed for 1 hour. The reaction mixture was cooled, then added water, and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1) to obtain the product.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH3:13][S-:14].[Na+].O>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([CH2:7][S:14][CH3:13])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)oc1CSC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (8.9 g) in tetrahydrofuran (50 mL) was added sodium methanethiolate (2.5 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 10% ethyl acetate/hexane) to give the title compound (6.7 g, 84%) as an oil.
Reaction SMILES: ClC1N2N=C(C)C=C2N=C(NC(=O)[C:14]2C=[CH:18][C:17]([C:20](O)(C)C)=[N:16][CH:15]=2)C=1.N1CC[CH:28](NC(=O)C)[CH2:27][CH2:26]1>CN1C(=O)CCC1>[CH:27]([N:16]([CH2:15][CH3:14])[CH:17]([CH3:18])[CH3:20])([CH3:28])[CH3:26]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)nc3)cc(Cl)n2n1
Reactant: CC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Product: CCN(C(C)C)C(C)C
Yield: 114.3 %

Procedure:
In a 2 ml microwave vial was placed N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(2-hydroxypropan-2-yl)nicotinamide (11C, 75 mg, 0.21 mmol) and N-(piperidin-4-yl)acetamide (31 mg, 0.21 mmol). To the sealed vial was then added NMP (1 ml) and then N,N-diisopropylethylamine (0.042 ml, 0.24 mmol) to give a dark yellow solution. The mixture was then heated in the microwave at 100° C. for 10 minutes. After cooling to room temperature, the crude product mixture was purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled product (77 mg, 79% yield) as an off white powder. 1H NMR (DMSO-d6) δ: 11.07 (s, 1H), 9.00 (dd, J=2.4, 0.9 Hz, 1H), 8.33 (dd, J=8.3, 2.3 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.75 (dd, J=8.3, 0.8 Hz, 1H), 7.26 (s, 1H), 6.11 (d, J=0.5 Hz, 1H), 4.28 (br. s., 2H), 3.76-3.90 (m, 2H), 3.11-3.21 (m, 2H), 2.32 (s, 4H), 1.80-1.90 (m, 3H), 1.76 (s, 3H), 1.51 (d, J=8.8 Hz, 3H), 1.41 (s, 6H); ESI-MS: m/z 452.3 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[N:6]=1)=[N+]=[N-]>CO.[Pd]>[OH:14][C:11]([C:7]1[N:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][CH:8]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(O)c1cccc(CN=[N+]=[N-])n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1cccc(CN)n1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
2-Azidomethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.88 g, 30.6 mmol) was dissolved in methanol (100 mL) and palladium (5% w/w on carbon) added. The suspension was gently agitated under a hydrogen atmosphere overnight, filtered though celite and concentrated to dryness to give 4.61 g (90%) of the amine as a colorless oil; NMR δH (400 MHz, CDCl3) 7.63 (1H, t, J 7.8 Hz), 7.19 (1H, d, J 7.8 Hz), 7.12 (1H, d, J 7.6 Hz), 3.93 (2H, s), 1.49 (6H, s); LC-MS Retention time 0.42 min, (M+H)+ 167.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:6]([CH:12]([OH:14])[CH3:13])[O:7]2.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:14][C@@H:12]([C:6]1[O:7][C:8]2[C:3]([C:4](=[O:22])[C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[CH3:13])(=[O:33])=[O:32]
Reactant: CC(O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OS(C)(=O)=O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of (+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one (0.800 g, 2.63 mmol) in dichloromethane (16 ml) and triethylamine (1.10 ml, 7.91 mmol), methanesulphonyl chloride (0.400 ml, 5.27 mmol) is added stirred at room temperature for 2 h. The reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated to afford the title compound as brown solid which is used as such in next step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([Br:3])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
NaH (761 mg, 19.83 mmol) was added portion wise to 2-bromo-4-hydroxypyridine (3 g, 17.24 mmol) in DMF (50 mL) at 0° C. under Ar(g). Then the reaction mixture was stirred at it for 10 min after which it was again cooled down at 0° C. and benzyl bromide (2.15 mL, 18.10 mmol) was added. The reaction was stirred at it for 4 h, after which it was poured onto brine (200 mL) and EtOAc (200 mL) was added. The phases were separated and the organic phase was dried over MgSO4, filtered and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 80:20) to furnish I as a white solid (2.331 g, 51%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.C[O:18][C:19]([NH:21][NH2:22])=[S:20]>C1(C)C=CC=CC=1>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]2[CH2:2][S:20][C:19](=[O:18])[NH:21][N:22]=2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(C=CC(=O)CCl)cc1
Reactant: COC(=S)NN
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C=CC2=NNC(=O)SC2)cc1

Procedure:
A mixture containing 4.0 g of 1-chloro-4-(4-acetamidophenyl)-2-oxo-3-butene (J. Org. Chem., 28, 2446, 1963) and 2.3 g of hydrazinecarbothioic acid O-methylester in 150 ml of toluene was refluxed for 3 h. The crystals were filtered and washed with toluene. Yield 3.0 g (65%), mp. 235°-240° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[C:42]4[C:37](=[N:38][CH:39]=[CH:40][CH:41]=4)[NH:36][C:35]3=[O:43])[CH2:30][CH2:29]2)=[O:27])[CH2:18][CH2:17]1.[CH:44]1([C:47](Cl)=O)[CH2:46][CH2:45]1>ClCCl>[CH:44]1([C:47]2[N:21]3[CH2:22][C@H:16]([C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=4[F:8])[CH2:17][CH2:18][C@@H:19]([NH:25][C:26]([N:28]4[CH2:29][CH2:30][CH:31]([N:34]5[C:42]6[C:37](=[N:38][CH:39]=[CH:40][CH:41]=6)[NH:36][C:35]5=[O:43])[CH2:32][CH2:33]4)=[O:27])[C:20]3=[N:23][N:24]=2)[CH2:46][CH2:45]1
Reactant: O=C(Cl)C1CC1
Reactant: NN=C1NC[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3CC3)nnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 45 °C
Reaction time: 20 h
Yield: 88.1 %

Procedure:
Triethylamine (20 μL, 0.142 mmol) was added to a solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (59 mg, 0.118 mmol) and cyclopropanecarbonyl chloride (11 μL, 0.124 mmol) in dichloromethane (1 mL) and the mixture heated to 45° C. After 20 h, the reaction was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the title compound (57 mg). MS 549.2524 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N+:7]([O-:16])=[CH:6][C:5]=2[N:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2cnccc2s1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c[n+]([O-])ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methyl-thiazolo[4,5-c]pyridine (2.3 g, 15.3 mmol) was dissolved in 150 ml chloroform and 3-chloroperoxybenzoic acid (4.15 g, 16.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then evaporated. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired product was obtained as a white solid (2.1 g, 83%), MS: m/e=167.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[O:19][C:7]([CH:8]=[C:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[NH:10][C:9]2=[CH:8][C:7]2[O:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Nc1cccc2c1=NC(=Cc1ccc([N+](=O)[O-])o1)N=2
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1cccc2c1NC(=Cc1ccc([N+](=O)[O-])o1)N2C(=O)Nc1cccc(Cl)c1
Yield: 65.6 %

Procedure:
51.2 g of 2-(5-nitro-furfurylidene)-amino-benzimidazole are dissolved in a mixture of 120 ml of chloroform and 80 ml of dimethylformamide, whereupon 30.6 g (0.2 moles) of 3-chlorophenyl-isocyanate are slowly added. The crystalline reaction mixture is stirred at room temperature for 7 hours while a mixture of 40 ml of dimethylformamide and 60 ml of chloroform are added. The precipitated crystals are filtered off, washed with 100 ml of chloroform and dried in vacuo at 40° C. to 60° C. Thus 54 g of 1-(3'-chlorophenyl-carbamoyl)-2-(5-nitro-furfurylidene)-amino-benzimidazole are obtained. Mp.: 210°-212° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C(=O)C(c2cc(Br)ccc2O)c2ccccc21
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one (2.22 g, 5.64 mmol) in dichloromethane (10.0 mL) were added trifluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) at ambient temperature. The reaction mixture was stirred at 50° C. for 15 hrs and concentrated in vacuo to dryness to give the title compound: MS (ES+) m/z 374 (M+1), 376 (M+1).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10](O)=O.[CH3:14][NH:15][C:16]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:15]([CH3:14])[C:16]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=[CH:24][C:25]=2[N:26]=1
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Reactant: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Product: COC(=O)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12

Procedure:
The title compound was prepared from mesityleneacetic acid and methyl 2-(methylamino)-3-nitrobenzoate in the similar method described in Reference Example 5.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([OH:14])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 65 °C
Yield: 52 %

Procedure:
70 g (0.39 mol) of 4-fluoro-3-trifluoromethylaniline, prepared according to G.C. Finger and colleagues, Journal of Med. Chem., 7, (1964), 572, are added a little at a time, while stirring, to 500 ml of a 2.5 N solution of sulphuric acid heated to a temperature of 65° C. The solution obtained is cooled to 0° C and 27 g of sodium nitrite dissolved in 45 ml of water are added whilst continuing the stirring and ensuring that the temperature does not exceed +5° C. After the end of the addition, the mixture is stirred for a further hour, during which it becomes perfectly clear. Thereafter, whilst carrying out a steam distillation, the cold solution of the diazonium salt is introduced dropwise into a mixture of 56g of copper sulphate, 21 g of urea, 70 ml of water and 2 ml of concentrated sulphuric acid. The speed of addition is regulated so that the phenol formed is immediately carried away. The distillate is cooled and is extracted repeatedly with ether. The ether solutions are combined and dried, the solvent is driven off and the residue is rectified. 37 g (yield: 52%) of 4-fluoro-3-trifluoromethyl-phenol, distilling at 84° C under 15 mm, are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][OH:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2].CC(C)=O>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH:21]=[O:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCO)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CC=O)cc12
Reaction time: 4 h
Yield: 50.3 %

Procedure:
300 mg of 6-(3-hydroxy-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is suspended in 25 ml of chloroform and 25 ml of acetone and mixed with 1.4 g of manganese dioxide. After stirring for 4 h, manganese dioxide is added again in an amount of 0.4 g. After standing overnight, 0.4 g of manganese dioxide is added again and the mixture is stirred for 8 h. Then it is filtered and the manganese dioxide is extracted in an Soxhlet extractor under acetone. After consolidating the filtrates, 150 mg of 6-(3-oxo-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[OH:1])[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: COc1ccc(C(OC)C(=O)O)c(O)c1
Reactant: N#Cc1ccc(CN)cc1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(O)c1

Procedure:
(RS)-(2-Hydroxy-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide. Orange amorphous solid. MS 327.3 ([M+H]+)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[C:29]([C:38](O)=[O:39])=[CH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:29]4[C:28]([O:27][CH3:26])=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1cc2ccccc2cc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc5ccccc5cc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-methoxynaphthalene-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To 2,4-difluoro-phenylamine (1, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 140.0 mmol) and benzyl chloroformate (2, 11.9 mL, 83.4 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and potassium bisulfate solution. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from hexanes to give the desired compound (3, 15.6 g, 85%).