Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:15]1[CH2:14][CH2:13][CH:12]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[O:11])[CH2:17][CH2:16]1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc2c(c1)CCO2)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Temperature: 85 °C
Yield: 41.5 %

Procedure:
To a solution of (2,3-dihydro-benzofuran-5-yl)-piperidin-4-yl-methanone (0.30 g, 1.30 mmol) in acetonitrile (10 mL) was added ethyl 2-bromoacetate (0.26 g, 1.6 mmol) and triethylamine (0.66 g, 6.5 mmol). The mixture was heated at 85° C. overnight, the solvent was evaporated under reduced pressure and purified via flash column chromatography (ethyl acetate:heptane) to provide desired product as a white solid (0.18 g, 0.54 mmol). MS (ESI) m/z 317.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.22 min.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[CH3:26])[N+:13]([O-])=[C:14]3[CH3:17])=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:30]>ClCCl>[F:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C:12]2[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[N:8]=[CH:9]3)=[C:14]([CH2:17][OH:30])[N:13]=2)[CH:24]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C)[n+]1[O-]
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a slurry of 7-(cyclopropanecarboxamido)-3-(5-fluoro-2-methylphenyl)-1-methyl-2,6-naphthyridine 2-oxide (100 mg, 0.3 mmol) in dichloromethane (3 mL) was added trifluoroacetic anhydride (0.08 mL, 0.57 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (50 mg, 50%). 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.31 (s, 1H), 8.89 (s, 1H), 8.06 (s, 1H), 7.43-7.33 (m, 2H), 7.19 (td, J=8.4, 2.6 Hz, 1H), 5.43 (t, J=5.4 Hz, 1H), 5.00 (d, J=5.4 Hz, 2H), 2.38 (s, 3H), 2.09 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=4.553 min, M+H+=352.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].O[N:39]1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:39])=[O:31])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 65 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (09.13 g, 65.0%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH:15]=O>>[F:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH2:15][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(F)c1
Product: COc1ccc(CNc2cccc([N+](=O)[O-])c2C)c(F)c1

Procedure:
2-Methyl-3-nitroaniline and 2-fluoro-4-methoxy-benzaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][CH2:32][C@H:33]([OH:46])[C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36](S(C)(=O)=O)[C:35]=4N)[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:7]=1)C.[OH-:48].[Na+].Cl>CO>[OH:46][C@H:33]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([NH:24][S:21]([CH3:18])(=[O:22])=[O:48])[CH:35]=1)[CH2:32][NH:31][CH2:30][CH:27]1[CH2:28][CH2:29][N:24]([S:21]([C:18]2[CH:17]=[CH:16][C:15]([N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([CH2:5][C:4]([OH:3])=[O:47])=[CH:7]3)=[CH:20][CH:19]=2)(=[O:22])=[O:23])[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1cn(-c2ccc(S(=O)(=O)N3CCC(CNC[C@H](O)c4ccc(O)c(S(C)(=O)=O)c4N)CC3)cc2)c2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(-n4cc(CC(=O)O)c5ccccc54)cc3)CC2)ccc1O

Procedure:
A solution of {1-[4-(4-{[(2R)-2-hydroxy-2-(4-hydroxy-3-methane-sulfonyl-amino-phenyl)-ethylamino]-methyl}-piperidine-1-sulfonyl)-phenyl]-1H-indol-3-yl}-acetic acid ethyl ester (0.154 g, 0.225 mmol) and 0.67 mL of 1N NaOH in 10 mL methanol was heated at reflux overnight. On cooling the reaction was neutralized with 0.67 mL of 1N HCl. The reaction mixture was concentrated in vacuo and triturated with H2O. The solids were filtered and dried (high vacuum) to give 0.070 g of the title compound as an off white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C: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)=[CH:3][CH:2]=1.[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[NH:11][C:10]3=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1ccc(N2CCOCC2)cc1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-morpholin-4-yl-benzaldehyde to give the title compound.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:9][CH:8]=[C:7]([C:10]2[CH:22]=[CH:21][C:13]3[NH:14][C:15](=[O:20])[O:16][C:17]([CH3:19])([CH3:18])[C:12]=3[CH:11]=2)[CH:6]=1)C.Cl>C1COCC1>[CH3:18][C:17]1([CH3:19])[O:16][C:15](=[O:20])[NH:14][C:13]2[CH:21]=[CH:22][C:10]([C:7]3[CH:6]=[C:5]([CH:4]=[O:3])[O:9][CH:8]=3)=[CH:11][C:12]1=2
Reactant: CCOC(OCC)c1cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)co1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C=O)c3)cc21

Procedure:
A solution of 6-(5-diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (1.1 g, 3 mmol) was stirred in THF (20 mL) and 2N HCl (2 mL) for 1 hour. The crystalline product was filtered and dried (0.52 g, 69%): mp 262-263° C.; 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 9.65 (s, 1H), 8.59 (s, 1H), 8.04 (s, 1H), 7.65-7.64 (d, 1H, J=1.5 Hz), 7.61-7.60 (d, 1H, J=1.8 Hz), 7.59-7.58 (d, 1H, J=1.8 Hz), 6.94-6.91 (d, 1H, J=8.2 Hz), 1.65 (s, 6H). MS (ESI) m/z 270 [M−H]−.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=3)[CH:34]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)CCCC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CCCC3CCCCC3)ccc2c1
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 3.0 g of 4-cyclohexylbutyric acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture, and the mixture was stirred for 24 hours at room temeprature. The precipitate which was formed upon addition of ethyl ether was collected by filtration, admixed with dimethylformamide. Ethyl ether was added to the filtrate, and the precipitate was collected by filtration. On recrystallization from a dimethylformamide ethyl ether mixture there were obtained 3.2 g of a white powder of 6-amidino-2-naphthyl 4-cyclohexylbutyrate methanesulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][N:19]2[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[C@H:23]([CH3:41])[N:22]([C:42]([CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:43])[C:21]3[CH:50]=[CH:51][CH:52]=[CH:53][C:20]2=3)=[N:10]1)#[N:2].[ClH:54]>O1CCOCC1.CCOCC>[ClH:54].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][N:19]2[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[C@H:23]([CH3:41])[N:22]([C:42]([CH:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[O:43])[C:21]3[CH:50]=[CH:51][CH:52]=[CH:53][C:20]2=3)=[N:10]1)#[N:2]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C
Yield: 81 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-1-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (128 mg, 178 μmol) in 4 M HCl in dioxane (889 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (94.1 mg, 81%) as an off-white solid. MS m/z 620 (MH)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14])#[N:2].[S:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>O1CCCC1>[F:11][CH:10]([F:12])[O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([S:13]([N:19]2[CH2:20][CH2:21][S:17][CH2:18]2)(=[O:15])=[O:14])[C:3]=1[C:1]#[N:2]
Reactant: C1CSCN1
Reactant: N#Cc1c(OC(F)F)cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: N#Cc1c(OC(F)F)cccc1S(=O)(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
54 mg of 2-cyano-3-difluoromethoxy-benzenesulfonyl chloride in 10 ml of tetrahydrofuran are treated with 32 I of thiazolidine and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated in vacuo. Purification by HPLC affords 35 mg of 2-difluoromethoxy-6-(thiazolidine-3-sulfonyl)-benzonitrile.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:6][CH:5]=1.[CH:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:28][N:27]([C@H:37]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[C:38]([O:40]CC2C=CC(OC)=CC=2)=[O:39])[CH2:26]1)=O>>[F:22][C:3]([F:2])([F:21])[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:23][C@@H:25]3[C@@H:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[CH2:28][N:27]([C@H:37]([CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)[C:38]([OH:40])=[O:39])[CH2:26]3)[CH2:15][CH2:14]2)=[O:11])=[CH:19][CH:20]=1
Reactant: O=C(CC1CCNCC1)NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3cccc(F)c3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: O=C(CC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2cccc(F)c2)CC1)NCc1ccc(C(F)(F)F)cc1
Yield: 37.8 %

Procedure:
The title compound was prepared from 4-((N-(4-(trifluoromethyl)benzyl)carbamoyl)methyl)-piperidine hydrochloride (34 mg, 0.1 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (25 mg, 0.06 mmol, Aldehyde 6) according to the method described in Example 1, Step C to give 14 mg (38%) of the title compound. ESI-MS: 618.4 (M+H); HPLC A: 2.30 min.
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>C1COCC1>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:18]1([OH:21])[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: c1cscn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 26 mL, 65 mmol) was dropped slowly into a solution of thiazole (Aldrich, 5.0 g, 59 mmol) in THF (50 mL) at −78° C. over 10 min. The reaction was stirred for additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (9.36 g, 60 mmol) in THF (20 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for additional 2 hours at −78° C. The reaction was then quenched with water solution and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:11]([C:12]([C:23](=[O:35])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([O:33][CH3:34])[CH:25]=3)=[C:13]([CH3:22])[C:14]=2[C:18]([O:20][CH3:21])=[O:19])[CH:10]=1)C1C=CC=CC=1.[H][H]>CN(C)C=O.O1CCCC1.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C:12]2[N:11]3[C:15]([CH:16]=[CH:17][C:9]([OH:8])=[CH:10]3)=[C:14]([C:18]([O:20][CH3:21])=[O:19])[C:13]=2[CH3:22])=[O:35])=[CH:25][C:26]=1[O:33][CH3:34]
Reactant: COC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2cc(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2cc(O)ccc12

Procedure:
100 mg of Pd/C (10%) are added to 1.0 g (2.17 mmol) of methyl [6-(benzyloxy)-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate in suspension in 30 mL of dimethylformamide and 30 mL of tetrahydrofuran. The reaction mixture is stirred at 10 bar of hydrogen for 48 hours.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:12]2[CH2:17][CH2:16][N:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: BrCc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccc(Cl)cc2)cc1
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(Cc3ccccc3)CC2)c2ccc(Cl)cc2)cc1
Yield: 92.8 %

Procedure:
Method as described for Example 4, using compound 23 (96 mg) and benzyl bromide (43 mg) provided N,N-diethyl4-(4-chlorophenyl-N-benzyl-piperidin-4-ylidene-methyl)-benzamide (110 mg, 93%):
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:19])=[C:12]2[NH:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][CH2:32][C:33](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:33]([CH2:32][CH2:31][O:30][CH3:29])[N:20]([CH3:21])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCC(=O)Cl
Reactant: CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 6-benzyloxy-N4-methylquinoline-3,4-diamine (7.88 g, 28.2 mmol), prepared as described in Parts A-F of Example 57, in dichloromethane (300 mL) was cooled to 0° C.; triethylamine (4.2 mL, 30.3 mmol) was added. Methoxypropionyl chloride (3.3 mL, 30.6 mmol) was added dropwise over a period of five minutes, and the reaction was stirred at ambient temperature for 90 minutes. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (300 mL) and triethylamine (13 mL) and heated at 75° C. over two nights. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed with deionized water (3×200 mL) and concentrated under reduced pressure. Small volumes of hexanes and dichloromethane were added, and a white precipitate formed, which was isolated by filtration and washed with hexanes to provide 3.76 g of 8-benzyloxy-2-(2-methoxyethyl)-1-methyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]>ClCCl>[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:35]=[CH:36][C:37]([CH:38]=[C:1]([Br:5])[Br:2])=[CH:40][CH:41]=2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](c2ccc(C=C(Br)Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
26.9 g of carbon tetrabromide was dissolved in 82 ml of dichloromethane, and 42.6 g of triphenylphosphine was added at 0° C. or less. Next, 10 g of 4-(trans-4'-propylcyclohexyl)benzaldehyde was dissolved in 41 ml of dichloromethane, which then was added dropwise to the first dichloromethane solution over a period of one hour. The combined solutions were then agitated at room temperature for one hour. After completion of the reaction, the dichloromethane was distilled off, and 500 ml of hexane was added to the residue. The resulting crystals were filtrated and washed with hexane three times. The residue was subjected to recrystallization with hexane to obtain 16 g of 4-(trans-4'-propylcyclohexyl)-β,β-dibromostyrene.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C=C(C=CC=1)C=O>>[CH3:20][O:21][C:6]1[CH:5]=[C:4]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:3]=[CH:8][CH:7]=1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 95 %

Procedure:
According to the preparation of 42, 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) was used to afford 43 (1.7 g, 95.0%) as pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[C:32]([CH3:33])=[N:31][N:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[C:32]([CH3:33])=[N:31][N:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1F
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1F

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.18 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].[I-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:12][C:5]1[N:4]([CH2:3][CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)c2ccccc2C1=O
Reaction time: 16 h

Procedure:
A mixture of 17.0 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole, 18.0 parts of potassium phthalimide, and 2.0 parts of potassium iodide in 240 parts of dimethylformamide is heated in a boiling water bath for 3 hours with stirring. Stirring is then continued for 16 hours at room temperature. The resulting brown mixture is diluted with 870 parts of toluene and the toluene solution is washed with several portions of water. The toluene solution is dried over sodium sulfate and the solvent is evaporated to leave a residue which is digested with cold alcohol. The alcohol solution is then cooled and the precipitate which forms is separated by filtration and recrystallized from ethanol to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]phthalimide melting at about 177° C. This compound has the following formula ##STR6##
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14]C)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][OH:25]>C[O-].[Na+].CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Agent: C[O-]
Agent: [Na+]
Product: COc1nc2c(N)nc(OCCO)nc2n1Cc1ccccc1
Reaction time: 10 h
Yield: 69 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-methoxyethoxyl)purine (130 mg, 0.36 mmol) in methanol (50 ml) was dissolved in 28% sodium methoxide/methanol (3 ml) and the solution was refluxed on heating under stirring for 10 hours. The reaction mixture was concentrated in vacuo to dryness, and to the residue was added saturated brine. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate, followed by removal of the solvent. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (78 mg, yield 69%).