Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=1.ClC(OCC)=O.[CH:27]([NH:30][CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C(N(CC)CC)C>[CH3:28][CH:27]([N:30]([CH:31]([CH3:33])[CH3:32])[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH3:29]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1)C(C)C
Yield: 23.2 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 1.31 g of di-isopropylamine in 100 ml of chlorofom. 0.85 g of N,N-di(1-methyl ethyl) 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 161° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[CH2:14][CH2:13][N:12]=[C:11]2SC)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([N:17]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:10]3[CH2:14][CH2:13][N:12]=[C:11]23)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NN1CCCCC1
Reactant: CSC1=NCCN1C(=O)c1cccnc1Cl
Product: O=C1c2cccnc2N(N2CCCCC2)C2=NCCN12
Temperature: 160 °C
Yield: 54.1 %

Procedure:
A mixture of 10.0 g (39.1 mmoles) of the product of Example 12 and 11.4 g (0.1114 mole) of 1-aminopiperidine was heated at 160° C. for 1 hour. The mixture was concentrated by Kugelrohr distillation and the residue was partitioned between methylene chloride and water. The organic layer was dried (sodium sulfate) and concentrated to a small volume. The resulting crystals were collected to give 5.74 g of 2,10-dihydro-10-(1-piperidinyl)imidazo[1,2-a]pyrido[2,3-d]pyrimidin-5(3H)-one. Melting point 206°-207° C. Total yield 54%.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:13]=[C:12]([CH3:23])[CH:11]=1)(=O)C.[ClH:24]>CO>[ClH:24].[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][C:12]([CH3:23])=[N:13]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2nc(C)cc2NC2=NCCN2C(C)=O)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-n2nc(C)cc2NC2=NCCN2)cc1

Procedure:
1-Acetyl-2[1-(4-methoxyphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (13.1 g.) was treated with HCl in methanol as described in Example II to give 7.9 g. of product as the HCl salt, mp 197°-198°.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>O1CCOCC1>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:23]3[CH:24]=[C:19]([NH2:18])[CH:20]=[CH:21][CH:22]=3)[C:6]=2[N:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Clc1ncc2scc(Br)c2n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.2 %

Procedure:
7-Bromo-2-chlorothieno[3,2-d]pyrimidine (3.645 g, 14.61 mmol) was dissolved in dioxane (44 mL) and 2.0 N sodium carbonate (22 mL, 43.83 mmol) and 3-aminophenylboronic acid (2 g, 14.61 mmol) were added. After flowing nitrogen to the mixture solution for 10 minutes, Pd2(PPh3)Cl2 (615 mg, 0.88 mmol) and t-ButylXphos (558 mg, mmol) were added. The reaction mixture solution was stirred at 90° C. for 6 hours and filtered with celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was concentrated by drying with magnesium sulfate. Purification by chromatography (20% ethyl acetate/hexane) yielded the target compound (2.8 g, 73% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([CH:28]1[CH2:33][CH2:32][CH:31](OS(C)(=O)=O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].ClCCl>C(O)(C)(C)C.CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C@H:31]3[CH2:32][CH2:33][C@H:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:29][CH2:30]3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc21
Temperature: 100 °C

Procedure:
A mixture of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.6 g, 2.6 mmol) in tert-butyl alcohol (8 ml) and 2-butanone (4 mL) was added cesium carbonate (2.5 g, 7.7 mmol) followed by methanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.9 g, 7.7 mmol). The mixture was heated in a sealed vial at 100° C. over night to form precipitate. The mixture was treated with dichloromethane and the precipitate was filtered off and the solvent was concentrated. The residue was purified with a silica gel column eluted with ethyl acetate in hexanes from 0 to 30% to give precipitate (0.96 g, yield: 100%). ESI-MS: 373.30 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 83.1 %

Procedure:
A mixture of 7-(2-chlorophenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (0.20 g), aminoguanidine hydrochloride (0.081 g), concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and ethanol (20 ml) was refluxed for 13.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(2-chlorophenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 86) (0.11 g) as colorless crystals.
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][CH:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([C:24]([CH3:26])=[O:25])=[CH:19][C:18]=1[Cl:27].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:27][C:18]1[C:17]([CH3:16])=[CH:22][C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:20]([C:24](=[O:25])[CH3:26])[CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(Cl)cc3C(C)=O)c2cc1OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-chloro-2-hydroxy-4-methylacetophenone (248 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (71 mg, yield 45%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=3)=[O:11])=[N:30][C:29]=2[CH:31]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 476 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(O)C(C)C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)C(C)C)c1
Reaction time: 8 h

Procedure:
Dissolve 5-(1-hydroxy-2-methyl-propyl)-N-methyl-N-propyl-isophthalamic acid methyl ester (70 mg, 0.23 mmol) in dichloromethane (3 mL) and add Dess-Martin periodinane (174 mg, 0.41 mmol) at room temperature. Stir the mixture overnight and quench with 10% aqueous sodium bisulfite solution. Extract the organic layer, wash with saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7](SC)[CH2:8][O:9][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([NH:22][CH2:21][CH:20]([O:23][CH3:24])[O:19][CH3:18])[CH2:8][O:9][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1c(N)ccc2c1OCC(SC)=N2
Reactant: COC(CN)OC
Solvent: CCO
Product: COC(=O)c1c(N)ccc2c1OCC(NCC(OC)OC)=N2
Yield: 115.1 %

Procedure:
A solution of methyl 7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate (Intermediate 28, 0.645 g) and aminoacetaldehyde dimethylacetal (0.403 g) in ethanol (15 mL) was heated to reflux for 4 days. After cooling, the mixture was concentrated in vacuo to give methyl 7-amino-3-(2,2-dimethoxyethylamino)-2H-benzo[1,4]oxazine-8-carboxylate (0.910 g) as a brown oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([NH:10][CH2:11][CH3:12])=[NH:9])[N:5]=[CH:4]1)[CH3:2].CCN(C(C)C)C(C)C.Cl[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24]>C(Cl)Cl>[CH2:11]([NH:10][C:8](=[N:9][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24])[N:6]1[CH2:7][CH:3]([CH2:1][CH3:2])[CH:4]=[N:5]1)[CH3:12]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCNC(=N)N1CC(CC)C=N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc(C(=O)O)c1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
Under N2 atmosphere, 1.0 g 4,N-diethyl-4,5-dihydro-pyrazole-1-carboxamidine was dissolved in 15 mL dry DCM, and 1.14 mL DiPEA and 1.31 g of 3-(chlorosulfonyl)benzoic acid were added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by flash chromatography (first column with DCM/MeOH/acetic acid 84:15:1; second column with DCM/MeOH/NH4OH 84:15:1) to yield 0.08 g (4%) of an off-white powder. 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.4 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H), 1.38-1.62 (m, 2H), 3.02-3.18 (m, 1H), 3.27-3.62 (m, 3H), 3.89-4.17 (m, 1H), 6.94 (s, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 8.49 (s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][C:35](Br)=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:38][N:39](C)C=O>C(OCC)(=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([C:38]#[N:39])[CH:34]=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C#N)ccc21
Temperature: 25 °C
Yield: 51 %

Procedure:
Purge with nitrogen, a solution of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.074 g, 0.124 mmol) and zinc cyamide (0.014 g, 0.124 mmol) in N,N-dimethylformamide (2 mL) in a 10 mL microwave vial. Add tetrakis(triphenylphosphine)palladium (0) (0.0043 g, 0.0037 mmol) and irradiate the mixture at 175° C. for 0.5 h (60-80 Watts). Add a second portion of zinc cyamide (0.014 g, 0.124 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.0043 g, 0.0037 mmol) and continue irradiating for 8 min. Cool the mixture to room temperature and dilute with ethyl acetate (35 mL) and wash with water (3×25 mL) and brine (25 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a crushable white foam (0.034 g, 51%): ESI MS 542 (M+H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:47])[CH:33]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:47])[CH:33]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C(Cc1ccccc1)c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(C(Cc1ccccc1)c1ccccc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
340 mg (0.535 mmol) of (2R*,4S*)-2-benzyl-1-(2,3-diphenylpropionyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 81 mg (2.14 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR46## is obtained as mixture of diastereomers in the form of white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.37, FD-MS: M+ =539.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C.CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:25]2[C:26]3[CH2:27][CH2:28][N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC#N
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 4-tert-butylbenzenamine (0.312 mL, 1.98 mmol) and 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.467 g, 1.80 mmol), prepared as described in Example 1.B. in acetonitile (2 mL) was heated in a sealed tube at 170° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for five min. Upon cooling to room temperature, a precipitate formed. The mixture was diluted with hexane (5 mL) and the precipitate was collected by filtration to give 0.576 g of the title compound as a tan solid.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[O:17][C@H:18]([CH3:23])[C:19]([O:21]C)=[O:20])([CH3:6])([CH3:5])[CH3:4].Cl>O.O1CCCC1>[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:10]=[CH:9][C:8]=1[O:17][C@H:18]([CH3:23])[C:19]([OH:21])=[O:20])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 5.98 mg (11 mmol) of potassium hydroxide in water (75 mL) and tetrahydrofuran (75 mL) was added 3.34 mg (10 mmol) of methyl (2R)-2-(2,4-di-t-butylphenyloxy)propanate (17). The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was acidified to pH 2 with concentrated hydrochloric acid and the resulting solution was extracted with diethyl ether (3×200 mL). The combined extracts were washed with an aqueous saturated sodium chloride solution (1×300 mL) and dried (MgSO4). Filtration and concentration afforded a thick crude oil. Purification by precipitation from hexane at -78° C. afforded 2.65 g (83%) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoic acid (18) as a white crystalline material: 1H NMR (CDCl3) δ1.29 (s, 9 H), 1.42 (s, 9 H), 1.68-1.70 (d, 3 H), 4.77-4.85 9q, 1 H), 6.58-6.61 (d, 1 H), 7.11-7.15 (d, 1 H), 7.34 (s, 1 H); 13C NMR (CDCl3) δ177.2, 153.5, 143.3, 137.3, 124.4, 123.3, 110.7, 71.4, 35.0, 34.3, 31.6, 30.0, 18.5.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C([O:8][C:9]([C:11]1[N:12]([CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH2:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[O:32])[C:22]2=O)[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1)=O)C.C(O)(=O)C>O>[C:37]1([S:34]([NH:33][C:31]([CH2:30][C:27]2[C:28]3[CH2:29][C:21]4[N:12]5[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:11]5[C:9](=[O:8])[NH:5][C:22]=4[C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:32])(=[O:35])=[O:36])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1cn(C2Cc3c(CC(=O)NS(=O)(=O)c4ccccc4)cccc3C2=O)c(C(=O)OCC)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)NS(=O)(=O)c2ccccc2)c1C3
Temperature: 0 °C
Yield: 48 %

Procedure:
3 g of ammonium acetate are added, with stirring, to a solution of 2.1 g of 2-(2,4-diethoxycarbonylimidazol-1-yl)-4-benzenesulphonamidocarbonylmethylindan-1-one and 55 ml of acetic acid. The reaction medium is heated at boiling temperature for 3 hours and then cooled and poured into a mixture of 60 g of ice and 60 ml of distilled water. The suspension thus obtained is filtered on sintered glass, washed twice with 20 ml of water, 10 ml of acetone and dried under reduced pressure at 53° C. 0.92 g of ethyl 9-bezenesulphonamidocarbonylmethyl-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-2-carboxylate is thus obtained in the form of a grey solid melting above 260° C. (Analysis: C24H20N4O6S1 : % calculated C: 58.53, H: 4.09, N: 11.38, S: 6.54; % found C: 58.3, H: 4.1, N: 11.5, S: 6.9).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:35]=[CH:34][CH:33]=1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(Cl)c2)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (43%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7](O)=[O:8].[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH-].[Na+]>ClCCCl>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([C:14]1[CH:13]=[CH:12][C:11]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:16][CH:15]=1)=[O:8]
Reactant: c1ccc(CCCCn2ccnc2)cc1
Reactant: COC(=O)CCC(=O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCC(=O)c1ccc(CCCCn2ccnc2)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
20.3 g of succinic acid methyl ester chloride and then a solution of 27 g of 1-(4-phenylbutyl)-imidazole in 100 ml of 1,2-dichloroethane are added dropwise to a suspension of 59.3 g of aluminium chloride in 200 ml of 1,2-dichloroethane, whilst cooling with ice. The mixture is then stirred at 85° C. for 3 hours. After it has been cooled, the reaction mixture is stirred into a mixture of 165.7 g of ethylenediaminetetraacetic acid and 600 g of ice and is brought to about pH 8 by addition of dilute sodium hydroxide solution. The phases are separated and the organic phase is dried over Na2SO4 and concentrated. The residue is purified by column chromatography (silica gel/chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[C:18]([O:28]C)[CH:19]=[C:20]([C:23]3[CH:24]=[N:25][NH:26][CH:27]=3)[CH:21]=2)[CH:16]=[CH:15]1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[CH:21]=[C:20]([C:23]3[CH:27]=[N:26][NH:25][CH:24]=3)[CH:19]=[C:18]([OH:28])[C:17]=2[CH:16]=[CH:15]1
Reactant: COc1cc(-c2cn[nH]c2)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(O)cc(-c4cn[nH]c4)cc32)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-4-(4-methoxy-6-(1H-pyrazol-4-yl)-1H-indol-1-yl)-2,3-dimethylquinoline (0.1059 g, 0.272 mmol) in DCM (2.7 mL) in ice bath was added 1M BBr3 in DCM (0.82 mL, 0.815 mmol) dropwise. The mixture was stirred at 0° C. for 1 h and at rt. After 26 h, to the mixture was added ice water and the mixture was neutralized with 10N NaOH to pH 9.0. The resulting solid was filtered to give a brown solid. The brown solid was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 1-(6-chloro-2,3-dimethyl-4-quinolinyl)-6-(1H-pyrazol-4-yl)-1H-indol-4-ol as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 12.74 (1H, br. s.), 9.74 (1H, s), 8.08 (1H, d, J=8.8 Hz), 7.94 (1H, br. s.), 7.73 (1H, dd, J=8.9, 2.3 Hz), 7.68 (1H, br. s.), 7.33 (1H, d, J=3.4 Hz), 6.94 (1H, d, J=2.2 Hz), 6.87 (1H, d, J=3.2 Hz), 6.76 (1H, s), 6.47 (1H, s), 2.77 (3H, s), 2.06 (3H, s); Mass Spectrum (ESI) m/e=389.0 (M+1).