Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:38])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][CH:37]=1)[CH2:20][N:21]([CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)C(=O)OC(C)(C)C)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:38])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:37]=[CH:36][CH:35]=[C:19]([CH2:20][NH:21][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of tert-butyl 3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (450 mg, crude) in DCM (6 mL) was added TFA (6 mL). The mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was purified by prep-HPLC to give the title product (200 mg, 54.9%). 1H NMR (CD3OD, 400 MHz): δ 8.08 (s, 1H), 8.00-7.89 (m, 1H), 7.81-7.68 (m, 1H), 7.58 (s, 1H), 7.39-7.15 (m, 4H), 4.75-4.47 (m, 2H), 4.46-4.39 (m, 1H), 4.34 (s, 2H), 4.05 (dd, J=11.6, 3.6 Hz, 2H), 3.98-3.70 (brs, 1H), 3.62-3.55 (m, 2H), 3.55-3.45 (m, 4H), 3.45-3.32 (m, 2H), 3.32-3.06 (m, 2H), 2.22-2.07 (m, 2H), 1.89-1.72 (m, 2H). LCMS (m/z): 424.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:17][O:18][C:5]=2[CH:4]=1)[CH2:14][CH2:13][CH2:12][NH:11][CH:10]3[CH2:15][NH2:16].[CH3:19]OC(OC)N(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:17][O:18][C:5]=2[CH:4]=1)[CH2:14][CH2:13][CH2:12][N:11]1[CH:19]=[N:16][CH2:15][CH:10]31
Reactant: COc1ccc2c(c1)OCC21CCCNC1CN
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)OCC21CCCN2C=NCC21
Temperature: 25 °C

Procedure:
A solution of 31 mmol of 1-(6-methoxyspiro[1-benzofuran-3,3′-piperidin]-2′-yl)methanamine and 31 mmol of N,N-dimethyl formamide dimethylacetal in 50 ml of dichloromethane is heated to reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. The crude title compound is identified on the basis of the Rf value and reacted further without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([CH2:32][O:33][Si](C(C)(C)C)(C)C)[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([CH2:32][OH:33])[CH:19]=2)[CH2:9][O:10][C:11]([CH3:15])([CH3:14])[O:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
Compound 34-4 (11.7 g) was dissolved in 1,4-dioxane (150 ml), 10% palladium carbon (12.0 g) was added, and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere. The inside of the reaction container was displaced with nitrogen, the solution was filtrated, and the filtrate was concentrated. To a solution of the obtained residue in tetrahydrofuran (100 ml) was added 1M tetrabutylammonium fluoride-tetrahydrofuran solution (20 ml) under ice-cooling, and the mixture was stirred for 1.5 hr under ice-cooling. A solution of 1M tetrabutylammonium fluoride-tetrahydrofuran solution (10 ml) was added, and the mixture was further stirred for 4 hr under ice-cooling. Water was added to the reaction mixture, the mixture extracted with ethyl acetate, washed successively with water saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (5.99 g) as a pale-brown oil.
Reaction SMILES: [NH3:1].CO.[I:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]=2[CH:22]=1>O1CCCC1>[NH2:1][C:13]1[CH2:12][N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:9]2[CH:22]=[C:5]([I:4])[CH:6]=[CH:7][C:8]=2[N:14]=1
Reactant: S=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC1=Nc2ccc(I)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
60 ml of 25% aqueous ammonia solution and 30 ml of methanol were added to a suspension of 3.0 g of 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione in 200 ml of tetrahydrofuran. The mixture was stirred at room temperature for 16 h., with the solution which formed being concentrated to about 50 ml in a vacuum. The crystals were filtered off, washed with water, dried, stirred in 25 ml of dioxan at 100° C., cooled and filtered off. There were obtained 2.35 g of 2-amino-7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine of m.p. 228-229° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:11][CH2:10]2)[CH:2]=1
Reactant: c1cncc(C(OC2CCNCC2)c2cccs2)c1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2cccnc2)c2cccs2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(3-pyridyl)-2-thienylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(3-pyridyl)-2-thienylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[CH2:11][NH:12][CH2:13][CH3:14])[CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[CH2:11][N:12]([CH2:13][CH3:14])[CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1
Reactant: CCNCc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(Cc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 22 was coupled with pyridine-3-carboxaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 339.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2
Reactant: Oc1ccccc1
Reactant: OC1CCc2cc(Br)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCC2Oc1ccccc1
Yield: 80.9 %

Procedure:
A solution of 5-bromo-2,3-dihydro-1H-inden-1-ol (1 g, 4.7 mmol), phenol (835 mg, 8.9 mmol) and triphenylphosphine (1.8 g, 6.9 mmol) in anhydrous tetrahydrofuran (70 mL) was stirred at 0° C. under nitrogen atmosphere. To this mixture was added dropwise diisopropyl azodicarboxylate (1.4 g, 6.9 mmol) over 5 minutes. Until TLC indicated that starting material was consumed, the solvent was evaporated in vacuo and the resulting oil was purified by column chromatography (silica gel, hexane/ethyl acetate=1/1) to give the product 5-bromo-1-phenoxy-2,3-dihydro-1H-indene (1.1 g, 85%) as a white solid. LRMS (M+H+) m/z: calcd 288.01. found 288. 1H NMR (300 MHz, CDCl3): δ 7.46-7.27 (m, 6H), 7.02 (s, 1H), 6.99-6.98 (m, 1H), 5.73-5.70 (m, 1H), 3.14-3.09 (m, 1H), 2.96-2.95 (m, 1H), 2.59-2.54 (m, 1H), 2.27-2.23 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.CCCC(OC)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COC(=O)CCS
Reactant: C[C@@H]1O[C@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCC(=O)OC
Product: C[C@@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3 h

Procedure:
In methanol (25 ml) were dissolved (2S,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1.0 g), methyl 3-mercaptopropionate (3.5 ml) and 28% sodium methoxide-methanol (3.07 g) and the solution was refluxed in an oil bath. After 2 and after 3 hours, methyl 3-methylpropionate (1.75 ml) and 28% sodium methoxide-methanol (1.5 g) were added at each time. The oil bath was removed after heating for 4 hours and the reaction mixture was neutralized with cold 1N hydrochloric acid (32 ml) and extracted with dichloromethane (200 ml). The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:3). The desired fraction was concentrated and the resulting crystals were recrystallized from ethyl acetate-hexane to give (2S,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1 H-1,2,4-triazol-1-yl)-2-butanol (compound 117, 472 mg) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([CH:9](Br)Br)[C:4]=2[CH:3]=1.[NH2:14]/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([CH:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[NH:14][C:15]([CH3:22])=[C:16]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2scc(C(Br)Br)c2c1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1csc2ccc(Br)cc12
Yield: 28.2 %

Procedure:
A mixture of 2.35 g of 5-bromo-3-(dibromomethyl)benzo[b]thiophene and 1.6 g of ethyl 3-aminocrotonate in 4 ml of ethanol was heated to reflux for 14 hours. The mixture was evaporated in vacuo and the residue was purified by chromatography over silica gel to provide 0.8 g of the desired title product, m.p. 68°-70° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:17][CH2:18]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(N1CCN(c3ccccc3C)CC1)C2
Agent: Br
Product: Cc1ccccc1N1CCN(C2CCc3cc(O)ccc3C2)CC1

Procedure:
10 g of 1,2,3,4-tetrahydro-6-methoxy-2-[4-(2-methylphenyl)-1-piperazinyl]-naphthalene are suspended in 200 ml of 47% aqueous hydrogen bromide and refluxed under a nitrogen atmosphere for 3 hours. The hydrogen bromide is finally evaporated off and the product which is in the form of the hydrobromide is converted to the free base form, with IN aqueous sodium bicarbonate solution/methylene chloride, and recrystallised from acetonitrile. The title compound is obtained as a compact residue. M.P. 177°-179°. Hydrochloride salt form: M.P. 304°-306°.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:9]=2[CH:37]=1)=[O:3].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:1][C:2]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:9]=2[CH:37]=1)=[O:3]
Reactant: CCCCc1nc2ccc(NC(N)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(N)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-aminocarbonylamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.Cl.C[C:8]1[S:9][CH2:10][CH2:11][N:12]=1.C[O-].[Na+]>C(O)C>[OH:1][CH:2]1[CH2:5][N:4]([C:8]2[S:9][CH2:10][CH2:11][N:12]=2)[CH2:3]1
Reactant: OC1CNC1
Reactant: CC1=NCCS1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: OC1CN(C2=NCCS2)C1
Yield: 57.2 %

Procedure:
To a solution of 109 mg of 3-hydroxyazetidine.HCl [Compound (1)] in 5 ml of ethanol was added a mixture of 133 mg of 2-methylthiazoline [Compound (2)] and sodium methoxide, and the reaction mixture was refluxed for 8 hours. After removal of the solvent under reduced pressure, the resulting residue was dissolved in chloroform and washed with 50% aqueous potassium carbonate solution. The solvent was removed under reduced pressure to give 119 mg (81.5%) of 3-hydroxy-1-(thiazolin-2-yl)azetidine [Compound (3)] as a crystaline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:39][C:35]1[CH:36]=[N:37][CH:38]=[C:33]([N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH:34]=1)=[C:3]([CH3:26])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCC[C@@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCC[C@@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (R)-tert-butyl 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidine-2-carboxylate (350 mg, 0.91 mmol) and 5-morpholinopyridin-3-amine in toluene to give (R)-tert-butyl 1-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)pyrrolidine-2-carboxylate. 1H NMR (CDCl3) δ ppm 7.90 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=2.2 Hz), 7.10 (1H, ddd, J=10.3, 2.4, 1.2 Hz), 6.85 (1H, d, J=12.5 Hz), 6.66 (1H, ddd, J=14.0, 8.9, 2.5 Hz), 6.61 (1H, t, J=2.3 Hz), 4.68 (1H, t, J=7.0 Hz), 3.77-3.90 (5H, m), 3.56-3.68 (1H, m), 3.12-3.21 (4H, m), 2.23-2.39 (1H, m), 2.13-2.21 (1H, m), 2.12 (3H, s), 1.90-2.07 (2H, m), 1.44 (9H, s). Mass Spectrum (ESI) m/e=526.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:16][CH2:17][C:18](O)=[O:19])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([N:16]1[CH2:17][C:18](=[O:19])[N:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]1=[S:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNCC(=O)O
Reactant: Cc1cccc(Cl)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN1CC(=O)N(c2c(C)cccc2Cl)C1=S
Yield: 36.6 %

Procedure:
The title compound was prepared by the procedure described in Example 11 using 6.5 g of 2-chloro-6-methylphenyl-isothiocyanate, 8.5 g of N-butyl glycine, 10.0 g of triethyl amine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (3.85 g) as a light pink solid, m.p. 97°-100° C. Anal. Calcd. for. C14H17Cl N2O S : C, 56.65; H, 5.77; N, 9.44. Found: C, 56.45; H, 5.67; N, 9.33. Mass spectrum (+FAB, [M+H]+) m/z 297.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[C:19](=[C:21]([CH3:23])[CH3:22])[CH3:20].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:19]([CH3:20])=[C:21]([CH3:23])[CH3:22])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC(C)=C(C)Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)=C(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (577 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from 2-bromo-3-methyl-2-butene (1.73 mL), a small iodine flake, and magnesium powder (347 mg) in THF (5 mL). The resulting mixture was stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as an off-white solid.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:4]1[NH:5]2.[C:17]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[CH3:17][C:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C@H:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:4]1[NH:5]2
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(c1)CC1Nc3ccccc3C21
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cc1cccc2c1[C@H]1c3ccccc3C[C@H]1N2
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A mixture of 0.6 g (0.00289 mol) of 5,5a, 6,10b-tetrahydroindeno[2,1-b]indole, 0.9 g (0.00723 mol) of K2CO3 and 1.03 g (0.00723 mol) of methyl iodide in 10 ml of acetonitrile was stirred for over the night at room temperature. The resulting mixture was filtered and evaporated. The resulting residue was dissolved in ether and then washed twice with water. Drying (Na2SO4) and evaporation gave 0.25 g (39%) of the title compound. 1H NMR (CDCl3) δ, 2.78 (3H, s), 3.2 (2H, d), 4.3 (1H, m) 4.66 (1H, d), 6.37 (1H, d), 6.68(1H, t), 7.06 (1H, t), 7.13-7.18 (2H, m),7.22-7.26 (1H, m) 7.3-7.37 (2H, m).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[C:61]=1[C:62](Cl)=[O:63]>>[Cl:59][C:60]1[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:63]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3)cc2C1=O
Yield: 78 %

Procedure:
The compound of example 129 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,6-dichloro benzoyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].N#N.Br[CH2:24][CH2:25][CH2:26][OH:27]>C1OCCOCCOCCOCCOCCOC1.CC(C)=O>[OH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([C:10](=[O:12])[CH3:11])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Reactant: OCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)cc(OC)c1OCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
1-(4-hydroxy-3,5-dimethoxyphenyl)ethanone (3.0 g, 15.3 mmol), 18-crown-6 (0.0606 g, 0.229 mmol) and potassium carbonate (2.74 g, 19.9 mmol) were taken in a two neck round bottom flask equipped with a stir bar. The flask was vacuumed and refilled with N2 three times. Acetone (30 mL) was added through syringe and needle. The mixture was stirred at room temperature for 30 minutes, followed by addition of 1-bromo-3-propanol (1.6 mL, 18.3 mmol). The mixture was refluxed for 24 hours and then filtered. Acetone was removed under vacuum to yield the crude product (3.8 g) which was used in the next step without purification. Purification can be performed by column chromatography (30% ethyl acetate and 70% hexane) to get pure product (1.64 g): 1H NMR (300 MHz, DMSO-d6) δ ppm 1.76 (t, J=6.44 Hz, 2H) 2.55 (s, 3H) 3.54 (d, J=5.27 Hz, 2 H) 3.82 (s, 6 H) 4.01 (q, J=7.03 Hz, 2 H) 7.22 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][C@@H:43]([NH2:46])[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:47])[NH:39][CH:40]1[CH2:41][CH2:42][CH:43]([NH:46][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:31])[CH2:44][CH2:45]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
{4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-cyclohexyl}-carbamic acid tert-butyl ester was prepared starting from intermediate M and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester. MS calcd. for C28H34ClN4O4 [(M+H)+] 525.2, obsd. 525.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[N:4]=[C:5]([S:34][CH3:35])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:16].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52]Cl>O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:36])[N:4]=[C:5]([S:34][CH3:35])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])[C:8]=1[F:16]
Reactant: CN(C)CCCl
Reactant: CCc1cc(O)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(OCCN(C)C)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a mixture of {2-[4-bromo-3-(t-butoxycarbonylaminomethyl)phenylimino]-2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-1-methylsulfanylethylidene}carbamic acid methyl ester (542 mg) and DMF (21.6 mL) there were added potassium carbonate (257 mg) and 2-dimethylaminoethyl chloride hydrochloride (268 mg) at 0° C. in that order, under a nitrogen atmosphere. The mixture was stirred for 4 hours at 0° C., and then potassium carbonate (257 mg) and 2-dimethylaminoethyl chloride hydrochloride (268 mg) were again added in that order, stirring was continued for 4 hours at 0° C., and potassium carbonate (257 mg) and 2-dimethylaminoethyl chloride hydrochloride (268 mg) were added. The mixture was stirred overnight at room temperature, and then ethyl acetate (200 mL) and water (100 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (100 mL) and once with saturated aqueous sodium chloride (100 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate system) to obtain the target compound (242 mg) as a colorless solid.