Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([F:7])=[CH:9][CH:10]=2)=[O:13])=[CH:5][CH:6]=1
Reactant: Cc1cccs1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccc(F)cc2)s1
Reaction time: 4 h

Procedure:
To a stirred mixture of 29.5 parts of 2-methylthiophene, 39.65 parts of p-fluorobenzoyl chloride and 280 parts of methylene chloride are added portionwise 40 parts of aluminium chloride while keeping the temperature at 20° C (water-bath). Upon completion, stirring is continued for 4 hours at room temperature. The reaction mixture is poured onto crushed ice and 50 parts of hydrochloric acid, while stirring vigorously. The layers are separated and the aqueous phase is washed with chloroform. The organic layers are dried and evaporated. The residue is taken up in benzene and the latter is evaporated again. The residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from ethanol at -20° C, yielding p-fluorophenyl 5-methyl-2-thienyl ketone; mp. 68° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH2:16]([C:19]1[CH:20]=[N:21][C:22](Cl)=[N:23][CH:24]=1)[CH2:17][CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]3[N:23]=[CH:24][C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][N:21]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: CCCc1cnc(Cl)nc1
Product: CCCc1cnc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-Bromo-N-(5-propylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 5-propyl-2-chloropyrimidine (0.5 mL) in a similar manner as described above to give 5 mg (5%) of a yellow solid. 1H-NMR (DMSO-d6): δ 10.86 (s, 1H), 8.17 (s, 2H), 7.53 (s, 1H), 7.30 (d, 1H), 7.22 (d, 1H), 7.10 (d, 1H), 5.30-5.23 (m, 1H), 2.63-2.56 (m, 2H), 2.36 (t, 2H), 2.06-1.96 (m, 2H), 1.84-1.73 (m, 2H), 1.56-1.47 (m, 2H), 0.88 (t, 3H); MS m/z (M−1) 383, 385.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:30][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a suspension of methoxymethyltriphenylphosphonium chloride (6.366 g, 18.5 mmol) in dry tetrahydrofuran (50 ml) under argon atmosphere at −78° C. slowly (ca. for 5 minutes) a 2.46 N solution of potassium tert-butoxide in tetrahydrofuran (8.2 ml, 20.2 mmol) was added and the reaction mixture was stirred at this temperature for 1 hour. A solution of methyl 4-formylbenzoate (6a) (2.531 g, 15.4 mmol) in tetrahydrofuran (10 ml) was added to the reaction mixture and the resultant suspension was stirred at −78° C. for 30 minutes. The cooling bath was removed and the reaction mixture was stirred for 30 minutes allowing warming up to room temperature. The mixture was partitioned between benzene (150 ml) and water (150 ml), and the organic layer was washed successively with water (150 ml), brine (50 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (100 g) with toluene-triethylamine (100:0.25) as eluent to give the title compound (2.696 g, 91%) as a mixture of E and Z isomers (ca. 95:5). (E)-(7a): 1H NMR (CDCl3, HMDSO) δ: 3.67 (3H, s); 3.86 (3H, s); 5.81 (1H, d, J=13.5 Hz); 7.14 (1H, d, J=13.5 Hz); 7.25 (2H, d, J=8.5 Hz); 7.89 (2H, d, J=8.5 Hz). A small additional singlet at 3.80 ppm and 2 doublets at 5.23 (d, J=7.6 Hz); 6.22 ppm (d, J=7.6 Hz) in the 1H NMR spectrum of 7a was attributed to minor amounts (ca. 5%) of (Z)-(7a) isomer present in the product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CCN(CC)CC.[CH3:20][O:21][C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][O:21][C:22]([N:8]1[CH2:7][CH2:6][C:5]2[N:4]=[C:3]([Cl:2])[CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:23]
Reactant: Clc1ccc2c(n1)CCNC2
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2nc(Cl)ccc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (1.54 g, 7.5 mmol) in DCM (25 mL) was added Et3N (3.1 mL, 22 mmol). After the addition and stirring at room temperature for 5 min, the solution was cooled to 0° C., followed by the addition of methylchloroformate (0.85 mL, 11 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. It was then washed with satd. aq. NaHCO3 solution and brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 40 g, 30% EtOAc in hexane) then afforded the tile compound (1.53 g, 90%) as a white solid. MS: 227.3 (M+H+).
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:17]=[CH:16][C:9]([CH:10]=[CH:11][S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][S:12]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Reactant: CC(=N)N
Product: CC(=N)NS(=O)(=O)C=Cc1ccc(Cl)cc1

Procedure:
Reaction of acetamidine with 4-chlorostyrylsulfonyl chloride according to the above procedure affords N-[(4-CHLOROSTYRYL)-SULFONYL]ACETAMIDINE, m.p. 161°-163° C., crystallized from ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:18][C:19]=3[CH:25]=2)=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 29 mg, 0.13 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 3, 50 mg, 0.13 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The crude product was dissolved in dimethylformamide (2 mL) and water was added (2 mL). After storage at 4° C. overnight, the resulting precipitate was filtered off, washed with water and dried to obtain a yellow solid (27 mg, 48 μmol, 37%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]=; Rt=4.14 min.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>O.C(O)(=O)C>[N:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:2]([NH2:3])=[O:1])=[CH:11][CH:10]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: N#C[O-]
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A solution of sodium cyanate (0.26 g) in water (30 ml) was added over 10 minutes to a stirred solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.50 g) in a mixture of acetic acid (20 ml) and water (30 ml). The solution was stirred for 2 hours, allowed to stand for 18 hours and then evaporated. The residue was triturated with water and filtered. The solid was crystallised from N,N-dimethylformamide to give the title compound (0.27 g), m.p. above 250° C. Found: C,64.17; H,6.42; N,23.32. C16H19N5O requires: C,64.62; H,6.44; N,23.55%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH2:30])[CH3:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][CH3:32])[CH2:24][CH3:25])[N:7]=1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CCN(CC)CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (1.59 g, 4.47 mmol) in dichloromethane (89.4 mL) were added N,N-diethyl-1,3-propanediamine (0.845 mL, 5.36 mol) and triethylamine (1.26 uL, 8.94 mmol). The mixture was stirred at rt overnight. Some white precipitate was formed during the reaction. Filtration followed by wash with ethyl acetate/dichoromethane/methnol afforded the title compound (1.028 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:21][C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25])[CH:5]=[CH:6][C:7]=1[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH3:28]>CO>[NH2:28]/[C:24](/[CH3:25])=[CH:23]\[C:22]([NH:21][C:4]1[CH:5]=[CH:6][C:7]([N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: N
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1Cl
Solvent: CO
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of N-(3-chloro-4-(dihexylamino)phenyl)-3-oxobutanamide (3.94 g, 10 mmol), MeOH (50 mL) and ammonia (50 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound as black oil (3.94 g, 100%).
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)=[C:12]1[C:33]([O:35]CC)=[O:34])([O:3]CC)=[O:2].C(COC1C=C(OC)C=CC=1CN1C2C(=CC(O)=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O)(OCC)=O.[H-].[Na+].ICCC>CN(C=O)C>[C:1]([CH2:6][O:7][C:8]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)=[C:12]1[C:33]([OH:35])=[O:34])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)OCC)n2Cc1ccc(OC)cc1OCC(=O)OCC
Agent: CCOC(=O)COc1cc(OC)ccc1Cn1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)O)n2Cc1ccc(OC)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethyl 1-(2-Carboethoxymethoxy-4-methoxybenzyl)-3-(3,4-methlenedioxyphenyl)-5-(prop-1-yloxy)indole-2-carboxylate. To a solution of ethyl 1-(2-carboethoxymethoxy-4-methoxybenzyl)-5-hydroxy-3-(3,4-methylenedioxyphenyl)indole-2-carboxylate (175 mg, 0.30 mmol) in DMF stirred at ice bath temperature under an argon atmosphere was added a slurry of NaH (11 mg of 80% oil dispersion, 0.36 mmol, oil removed by pentane wash) in DMF (1 mL). After 15 min at ice bath temperature, 1-iodopropane (0.255 g, 1.5 mmol) was added and the ice bath was removed. The reaction mixture was stirred an additional 30 min at room temperature then partitioned between 3N HCl (25 mL) and EtOAc (75 mL). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo and the resulting solid crystallized from EtOH to afford the title compound (83 mg 47%); m.p. 89°-91° C.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([Br:9])[C:6](=[O:10])[O:5][C:3]1=[O:4].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:9][CH:7]([CH2:8][CH:2]([Br:1])[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4])[C:6]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: O=C1OC(=O)C(Br)CC1Br
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C(Br)CC(Br)C(=O)OCc1ccccc1
Yield: 100.2 %

Procedure:
2.18 g (8 mmol) of 2,4-dibromoglutaric anhydride, 2.1 ml (20 mmol) of benzyl alcohol, and 2 ml of benzene are stirred for 1.5 hours at room temperature. 76 mg (0.4 mmol) of p-toluenesulfonic acid monohydrate and 8 ml of benzene are added, and the solution is refluxed under a Dean-Stark trap for 2 hours. Filtration over silica gel and evaporation yields 3.77 g (100%) of dibenzyl 2,4-dibromoglutarate as a colourless oil. 1H NMR (CDl3): δ7.37 (br. s., 10H), 5.21 (narrow AB system, 4H, J=12.5); dl isomer: δ4.55 (dd, 2H, J=6.5, 7.5), 2.69 (dd, 2H, J=6.5, 7.5); meso isomer: δ4.42 (t, 2H, J=7.5), 2.90 (dt, 1H, J=7.5 (t), 14.5 (d)), 2.66 (dt, 1H, J=7.5 (t), 14.5 (d)); dl/meso=6:1. IR (neat): 3034, 1740, 1499, 1456, 1385, 1273, 1154, 750, 696 cm-1.
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCCCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCC)C(=O)OCC
Yield: 89.1 %

Procedure:
Reaction and post-treatment were carried out according to Reference example 12(a) using 2.16 g of diethyl butylmalonate, 2.44 g of 4-benzyloxybenzyl chloride and 480 mg of sodium hydride (55% oil suspension) to obtain 3.67 g of the desired compound as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(C(F)(F)F)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 109 from tert-butyl (±)cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (63 mg, 0.16 mmol) and 2-chloro-4-(trifluoromethyl)phenylboronic acid (69 mg, 0.32 mmol), after chromatographic purification (35.9 mg, 46%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.69 (s, 1H), 7.51 (bd, 1 H, J=8.0 Hz), 7.42 (d, 1H, J=8.1 Hz), 7.04 (s, 1H), 6.97 (s, 1H), 3.60-3.75 (m, 1H), 3.48-60 (m, 1H), 3.15-3.35 (m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00 (m, 2H), 1.46 (s, 9H) ppm. MS (CI, NH3): 493 (base, M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:39]([O:41][CH2:42][C:43]1[N:44]([CH2:56][C:57]([NH2:60])([CH3:59])[CH3:58])[C:45]2[C:54]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[N:48]=[CH:47][C:46]=2[N:55]=1)[CH3:40]>CN(C=O)C>[CH2:39]([O:41][CH2:42][C:43]1[N:44]([CH2:56][C:57]([NH:60][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:59])[CH3:58])[C:45]2[C:54]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[N:48]=[CH:47][C:46]=2[N:55]=1)[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
6-[(tert-Butoxycarbonyl)amino]hexanoic acid (6.81 g, 29.5 mmol), 1-hydroxybenzotriazole (3.98 g, 29.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (5.66 g, 29.5 mmol) were added to a 0° C. solution of 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylamine (which was prepared by acid-mediated deprotection of tert-butyl 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate, which is described in U.S. Patent Publication No. 2004/0091491, 8.00 g, 26.8 mmol) in DMF (80 mL). The solution was stirred at room temperature overnight. More 6-[(tert-butoxycarbonyl)amino]hexanoic acid and EDC were added and the solution was stirred for an additional hour. The solution was partitioned between aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to provide 3.99 g of tert-butyl 6-({2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-6-oxohexylcarbamate as a foam.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[NH:12][C:11]=2[C:10](=[O:27])[N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:8]1=[O:36].[NH2:38][NH2:39]>CO.O1CCCC1>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:9]1[C:10](=[O:27])[C:11]2[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)=[N:14][C:15]=2[N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH:38][NH2:39])=[O:2])[C:8]1=[O:36]
Reactant: COC(=O)CCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Reactant: NN
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)NN)cc1

Procedure:
Prepared by the reaction of 4-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-butyric acid methyl ester with hydrazine (10 equivalents) in methanol/tetrahydrofuran according to the general procedure of Kramer et al. as described in J. Heterocyclic Chem. 1994, 31, 1439. MS, m/z(M+H)=508.2111.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[N:12]=1.CN(C(ON1[N:33]=[N:32][C:27]2C=[CH:29][CH:30]=[CH:31][C:26]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NN1CCCCC1.O>CN(C=O)C>[N:32]1([NH:33][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:9][C:10]=2[CH3:16])=[O:15])[CH2:29][CH2:30][CH2:31][CH2:26][CH2:27]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)O
Agent: F[B-](F)(F)F
Agent: NN1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)NN1CCCCC1
Reaction time: 0.02 h
Yield: 83.1 %

Procedure:
To 1 g of 2-(2-chloro-phenyl)-5-methyl-1H-imidazole-4-carboxylic acid in 10 ml of DMF was added 1.36 g of TBTU and 3.6 ml of Hünigs' base and the reaction mixture was stirred for 1 minute. Then 0.46 ml of 1-aminopiperidin was added and the reaction mixture was stirred for 1.5 hour at room temperature. After such time the reaction mixture was poured onto 200 ml of water and extracted with ethyl acetate (2×200 ml). The combined organic extracts were then washed with water (2×100 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to yield an oil which crystallized on standing. The residue was then triturated with heptane, the solid was filtered and dried to yield 1.12 g of the title compound, MS (ISP) 319.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([N+:14]([O-])=O)[C:12]=1[CH3:13])[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([NH2:14])[C:12]=1[CH3:13])[C:9]([CH3:17])([CH3:18])[CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: Cc1c2c(c([N+](=O)[O-])c(C)c1[N+](=O)[O-])C(C)(C)CC2
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)c(C)c2c(c1N)C(C)(C)CC2

Procedure:
One hundred seventy-five grams (0.662 mol) of the 5,7-dinitro-1,1,4,6-tetramethylindane thus obtained were dissolved in 500 g of methanol, and after addition of 17.5 g of 5% Pd/C (water content: 50%) to the resultant solution, the mixture was stirred at 50-60° C. for 84 hours in a hydrogen gas atmosphere. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The thus-obtained residue was distilled under reduced pressure to obtain 5,7-diamino-1,1,4,6-tetramethylindane as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccc(C(F)(F)F)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3-trifluoromethyl-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-(trifluoromethyl)benzoyl chloride (131 μl, 0.89 mmol). The title compound was obtained as light brown powder (195 mg, 50%).