Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])C3C=CC=C(CC(=O)C)C=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH2:35]([O:42][C:43]1[CH:44]=[CH:45][C:46]([C@@H:54]([O:70][Si:71]([C:74]([CH3:77])([CH3:76])[CH3:75])([CH3:73])[CH3:72])[CH2:55][NH:56][C:57]([CH3:69])([CH3:68])[CH2:58][C:59]2[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=2)C(O)=O)=[C:47]2[C:52]=1[NH:51][C:50](=[O:53])[CH:49]=[CH:48]2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]1[CH:44]=[CH:45][C:46]([C@@H:54]([O:70][Si:71]([C:74]([CH3:76])([CH3:77])[CH3:75])([CH3:72])[CH3:73])[CH2:55][NH:56][C:57]([CH3:69])([CH3:68])[CH2:58][C:59]2[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=2)[C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:33][CH3:34])=[O:32])=[C:47]2[C:52]=1[NH:51][C:50](=[O:53])[CH:49]=[CH:48]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using Intermediate 50 in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C51H68N7O5Si+ 886.5. found m/z=886.5 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[CH:1]1([CH2:6][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(=O)C2CCCC2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CC2CCCC2)cc1OC
Yield: 98.7 %

Procedure:
A suspension of cyclopentyl(3,4-dimethoxyphenyl)methanone (10.8 g, 0.046 mol), wet Pd/C (1 g) in 10 ml of acetic acid and 10 ml of ethyl acetate was put in an autoclave at 60° C. with 20 bars of hydrogen during 24 hours. Filtration over Celite® and concentration gave 10 g of pale brown oil. This oil was purified by vacuum distillation (100-120° C., 0.02 mbar) through a short path to give 7.1 g (70%) of a colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([F:29])=[CH:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Temperature: 80 °C
Yield: 83.8 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.16 g, 10 mmol), 2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (2.67 g, 12 mmol), Cs2CO3 (6.50 g, 20 mmol) Pd(dppf)Cl2 (730 mg, 1.0 mmol) and CH3CN—H2O (1 1, 40 mL) were added in a 50 mL of sealed tube, and the mixture was heated at 80° C. for 60 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC to give 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.0 g, yield: 84%). 1HNMR (DMSO-d6, 400 MHz): δ8.68 (s, 1H), 8.43 (t, J=4.8 Hz, 2H), 8.12-8.01 (m, 1H), 8.00-7.92 (m, 1H), 7.84 (t, J=2.8 Hz, 1H), 7.58-7.50 (m, 2H), 7.26 (s, 2H), 4.39 (s, 2H), 3.24 (s, 2H), 2.23 (s, 3H). ESI-MS: m/z=478 [M+H+]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+].Cl>C(C(C)=O)C.CCO.C(Cl)Cl>[N:34]1([CH2:33][CH2:32][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[N:9]=3)=[CH:4][CH:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(O)cc3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(OCCN4CCCC4)cc3)n2)cc1
Yield: 62.4 %

Procedure:
The 2-(4-hydroxyphenyl)-3,6-bis(4-methoxyphenyl)pyridine (2.3 g, 6 mmol), N-(2-chloroethyl)pyrrolidine hydrochloride (1.1 g, 6 mmol), and powdered K2CO3 (4.1 g, 30 mmol) were stirred in 250 mL methyl ethyl ketone and refluxed 18 h. The TLC (EtOH/ CH2Cl2, 1:4) of the reaction mixture indicated some starting material remained, so more N-(2-chloroethyl)pyrrolidine hydrochloride (0.3 g, 1.6 mmol) and K2 CO3 (2 g, 15 mmol) were added and reaction mixture refluxed an additional 18 h. The reaction mixture was worked up, concentrated, and the residue was dissolved in 25 mL MeOH, treated with 5 mL HCl/ MeOH at 0° C., and concentrated. The residue was recrystallised from MeOH/ Et2O to give 1.8 g (58% yield) of product as the HCl salt: mp 230°-231° C.; 1H NMR (CDCl3) d 1.61 (bs, 2H, pyrrolidine), 2.10-2.26 (comp, 4H, pyrrolidine), 2.90-3.10 (bs, 2H, pyrrolidine), 3.48 (bs, 2H, NCH2), 3.84 (s, 3H, ArOCH3), 3.88 (s, 3H, ArOCH3), 4.10-4.14 (m, 2H, OCH2), 6.78-6.81 (d, 2H, J=9 Hz, ArH), 6.86-6.89 (d, 2H, J=9 Hz, ArH), 7.00-7.03 (d, 2H, J=9 Hz, ArH), 7.14-7.16 (d, 2H, J=9 Hz, ArH), 7.44-7.46 (d, 2H, J=9 Hz, ArH), 7.66-7.73 (m, 2H, ArH), 8.07-8.10 (d, 2H, J=9 Hz, ArH); MS(FD) 480(M+). Anal. Calcd for C31H32N2O3HCl: C, 72.01; H, 6.43; N, 5.42. Found: C, 72.02; H, 6.65; N, 5.24.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si]([C:29]#[C:30][C:31]1[CH:32]=[C:33]([C:37]2([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)(C(C)C)C(C)C)(C)C>C1COCC1.O.CCOC(C)=O>[C:30]([C:31]1[CH:32]=[C:33]([C:37]2([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)#[CH:29]
Reactant: CC(C)[Si](C#Cc1cccc(C2(C(N)=O)CC2)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(C2(C(N)=O)CC2)c1
Reaction time: 0.25 h

Procedure:
A 1.0 M TBAF solution in THF (10.5 mL, 10.5 mmol) was added to a solution of 1-(3-((triisopropylsilyl)ethynyl)phenyl)cyclopropanecarboxamide A59 (1.20 g, 3.50 mmol) in THF (50 mL) and stirred for 15 minutes. The mixture was diluted with water (200 mL) and EtOAc (200 mL) before the organic fraction was separated and washed with 0.5 M citric acid solution (200 mL), water (200 mL), brine (50 mL) and dried (Na2SO4). The volatiles were removed in vacuo and the resulting solid was suspended in cyclohexane (50 mL) and sonicated for 10 minutes. The solid was collected by filtration and dried to give the title compound A60 as a tan solid (386 mg, 59%). LCMS-A: rt 5.635 min; m/z 186.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:9][C:10]([N:12]1[CH:16]=[CH:15]N=[CH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CNC[C@@H:20]([C@H:22]([C@@H:24]([C@@H:26](CO)[OH:27])[OH:25])[OH:23])[OH:21].C[OH:31]>>[CH2:1]([NH:9][C:10]([N:12]([CH3:13])[CH2:16][C@@H:15]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26][OH:27])[OH:25])[OH:23])[OH:21])[OH:31])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)n1ccnc1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Product: CCCCCCCCNC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3 h
Yield: 55 %

Procedure:
47 g of 1-N-(octylaminocarbonyl)imidazole and 42 g of N-methyl-D-glucamine were suspended in 300 cm3 of methanol under an inert atmosphere. The reaction mixture was maintained at reflux with stirring for 3 hours. Cooling was carried out with an ice bath and then the precipitate is filtered off. It was recrystallized from 300 cm3 of ethanol. 40 g (55% yield) of N-octylaminocarbonyl-N-methyl-D-glucamine were obtained in the form of a white powder.
Reaction SMILES: O1CCOCC1.[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21](=[O:26])[C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[K+]>C(O)C>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:27])[CH2:20][C:21](=[O:26])[C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)C(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 20 ml of ethanol and 2.4 ml of dioxane there was suspended 1.15 g (4 mMol) of the ester product prepared in Step B above. There was then added 3 ml of 2 N potassium hydroxide, whereupon a precipitate formed. The reaction mixture was stirred overnight at room temperature. The mixture was evaporated to dryness, an then water was added, whereupon most of the solid dissolved. The mixture was then made acidic to pH 1.0 using 6 N hydrochloric acid. A white solid was obtained which was filtered off, washed with water and dried. The solid was crystallized from benzene to give product, m.p. 140°-142° C. Analysis:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:27]=2[CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:34][CH2:35][N:36]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([C:10]5[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=5[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=4[N+:20]([O-:22])=[O:21])[CH2:37][CH2:38]3)[C:27]=2[CH:26]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1OCc2ccc(Cl)cc2N1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccc(Cl)cc43)CC2)c([N+](=O)[O-])c1

Procedure:
Methyl 2-[(4-chloro-3-nitrophenyl)carbonyl]benzoate (0.5 g), the product from step (ii) (0.47 g) and triethylamine (0.5 ml) in N,N-dimethylformamide (2.5 ml) were heated at 60° C. overnight. The mixture was evaporated under reduced pressure and the residue purified by chromatography eluting with 25% ethyl acetate/toluene. Yield 0.7 g of a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:26])[O:12][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1.[H-].[Na+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][Br:38]>CN(C)C=O>[Br:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:26])[O:12][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4ccccc4CBr)c4ccccc34)C(=O)OC2=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 17.1 %

Procedure:
A suspension of 3-(indol-3-yl)-4-(1-methyl-indol-3-yl)-furan-2,5-dione (1.0 g, 3 mmol) and sodium hydride (154 mg, 3.5 mmol, 55-60% dispersion in oil) in dimethylformamide (20 mL) was stirred and cooled to 0° C., under a stream of nitrogen. After 35 min the solution was transferred to a dropping funnel and added slowly, over 40 min, to a solution of 1,2-bis-bromomethyl-benzene (3.8 g, 14.5 mmol) in dimethylformamide (6 mL). The resulting solution was stirred for 1 h at room temperature under a stream of nitrogen. The reaction was quenched by adding NaHCO3 (aq), and extracted with ethyl acetate. The organic phase was washed with several portions of water and dried (MgSO4). Evaporation followed by chromatography on silica (ethyl acetate:heptane, 3:7) afforded 270 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=4[N:28]=3)[C:14]2=[O:29])[CH2:9][CH2:8]1)=[O:4].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][N:25]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:24][CH2:23][C:22]=4[N:28]=3)[C:14]2=[O:29])[CH2:11][CH2:12]1)=[O:4]
Reactant: COC(=O)CC[C@H]1CC[C@H](N2CCN(c3cnc4c(n3)CCNCC4)C2=O)CC1
Reactant: ClCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC[C@H]1CC[C@H](N2CCN(c3cnc4c(n3)CCN(Cc3ccccc3)CC4)C2=O)CC1

Procedure:
1.5 g of 1-[trans-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]-3-(6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)imidazolidin-2-one, 480 mg of benzyl chloride, 520 mg of N-ethyldiisopropylamine and 100 mg of sodium iodide are heated under reflux in 20 ml of acetonitrile for 1 hour. The mixture is cooled, and the solid is filtered off with suction and purified by chromatography on an alumina column with methylene chloride/methanol (99:1).
Reaction SMILES: Br.[F:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[C:12]2=[NH:29])=[CH:5][CH:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:46][C:47]1[CH:59]=[CH:58][CH:57]=[CH:56][C:48]=1[CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>ClCCCl>[Cl:46][C:47]1[CH:59]=[CH:58][CH:57]=[CH:56][C:48]=1[CH2:49][N:50]1[CH2:51][CH2:52][N:53]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:11]([CH2:10][CH2:9][CH2:8][O:7][C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:31][CH:30]=4)[C:12]3=[NH:29])=[CH:28][CH:27]=2)[CH2:54][CH2:55]1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(C=O)cc1
Reactant: Clc1ccccc1CN1CCNCC1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(CN2CCN(Cc3ccccc3Cl)CC2)cc1
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a mixture of 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde, hydrobromide salt (0.39 g, 0.81 mmol) and sodium triacetoxyborohydride (0.322 g, 1.52 mmol) in 1,2-dichloroethane (5 ml) at rt was added 1-(2-chloro-benzyl)-piperazine (0.20 g, 0.95 mmol). The reaction was stirred for 8 h and then washed with a saturated solution of NaHCO3, H2O, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by chromatography provided 1-{4-[4-(2-chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (90 mg, 19%). HPLC-MS 598 [M+1]+, 300.
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>C1COCC1.O>[N:29]1([C:27](=[O:28])[CH2:26][O:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@@H:5]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH2:4][CH2:3]2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CO[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)c2ccccc21)N1CCOCC1
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A solution of Intermediate 32a (115 mg, 0.39 mmol) in dry THF (4 mL) was added NaH (60% in mineral oil, 23 mg, 0.59 mmol) at RT and stirred for 15 min. 4-(Chloroacetyl)morpholine (56 μL, 0.43 mmol) was then added and the mixture heated at reflux for 3.5 h. After cooling, the dark brown mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% MeOH in DCM, to give the title compound as light brown foam (103 mg, 62%). LCMS (Method 3): Rt 3.44 min, m/z 443 [MNa+].
Reaction SMILES: [C:1]([C:3]1(O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].ClCCl>[CH3:2][C:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C#CC1(O)CCCCC1
Reactant: Nc1ccccc1
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: ClCCl
Product: CC1=Nc2ccccc2C12CCCCC2
Temperature: 120 °C
Reaction time: 12 h
Yield: 1.2 %

Procedure:
1-Ethynyl-1-cyclohexanol (1.242 g, 10 mmol), aniline (0.931 g, 10 mmol), Ru3(CO)12 (32.0 mg, 0.05 mmol) and aniline hydrochloride (0.259 g, 2.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 120° C. for 12 hours. After cooling, dichloromethane (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby 2-methyl-3H-indole-3-spiro-1′-cyclohexane (24 mg; 0.12 mmol; yield, 1.2%; purity, 95% or more) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[N:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:48]=[CH:47][C:34]([C:35](OC3C=CC([N+]([O-])=O)=CC=3)=[O:36])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]([C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([C:28]4[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=4)=[CH:48][CH:47]=3)[CH2:17][CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)C1=CNCCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(-c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=CN(C(=O)c2ccc(-c3ccncc3)cc2)CCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
In N,N-dimethylformamide (1 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine (60 mg) and p-nitrophenyl 4-(pyridin-4-yl)benzoate (52 mg) were dissolved, followed by the addition of sodium hydride (60% in oil, 7.20 mg) under ice cooling. The resulting mixture was stirred for 1 hour. Water and ethyl acetate were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate:hexane=2:1), followed by dissolution in ethanol. To the resulting solution, 1N aqueous hydrochloric acid in ethanol was added and the resulting mixture was concentrated, whereby the title compound (58 mg, 60%) was obtained as pale yellow powder.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][OH:21])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([NH:44][C:45](=[N:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])SC)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CCN(C(C)C)C(C)C>CN(C=O)C>[C:49]([NH:48][C:45](=[N:44][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:16]([NH:18][C@H:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][OH:21])=[O:17])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:50]
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N=C(NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Yield: 45.6 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(S)-N-(2-hydroxy-1-phenylethyl)ornithine amide (0.5 g; 1.12 mmol; from step (d) above), N,N'-bis(Cbz)-S-methyl-isothiourea (0.603 g; 1.68 mmol), DiPEA (0.2 mL) and DMF (15 mL), yielding 0.386 g of the sub-title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.Cl.[NH2:42][C:43]1[C:51]([NH2:52])=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([NH2:47])=[O:46].C(O)(C)C>N1C=CC=CC=1.CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3([C:25](=[O:26])[NH:52][C:51]4[CH:50]=[CH:49][CH:48]=[C:44]([C:45](=[O:46])[NH2:47])[C:43]=4[NH2:42])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)CCCCC2)c1N
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 1-(9H-fluoren-9-ylmethoxycarbonyl amino)-cyclohexanecarboxylic acid (0.326 g, 0.9 mmol) in pyridine (1 mL) and DMF (1 ml) was heated to 40° C. for 30 min. Carbonyl diimidazole (0.15 g, 0.9 mmol) was added and the mixture was stirred at 40° C. for 1 hour then treated with 2,3-diamino-benzamide dihydrochloride (prepared as described in WO0026192, 0.2 g, 0.9 mmol). After stirring for 1 hour at room temperature, isopropyl alcohol (3 ml) was added and the solution was cooled overnight at 0° C. The precipitated solid was filtered, dissolved in water (3 ml), treated with 50% aqueous NaOH (0.071 ml) then stirred for 3 hours at room temperature. The mixture was filtered and used immediately in Example 48B.