Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.CO[CH:38]1[CH2:42][CH2:41][CH:40](OC)O1>>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH2:21][CH2:20]3)[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[O:7])=[CH:34][CH:35]=2)[CH:38]=[CH:42][CH:41]=[CH:40]1
Reactant: COC1CCC(OC)O1
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(-n3cccc3)cc2)c1
Yield: 78 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (238.1 mg, 0.50 mmol) and 2,5-dimethoxytetrahydrofuran (0.066 ml, 0.50 mmol), the procedure of Inventive Example 149 was repeated to obtain 205.0 mg (78.0%) of the title compound in a light brown amorphous form.
Reaction SMILES: [C:1]([O:11]CC(N)CC)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]>O>[C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCC(N)COC(=O)[C@H](O)c1ccccc1
Solvent: O
Product: O=C(O)[C@H](O)c1ccccc1
Yield: 87.4 %

Procedure:
A portion of the (-)-2-amino-1butanol D-(-)-mandelate wet cake 155 grams "as is" -90.3% pure; 0.58 mole) from resolution A is dissolved in the mother liquor plus water washes from (D) at 50°-55° C. and the solution is distilled under vacuum to remove 41 mls of methanol and water. The concentrated solution is then treated with 37% hydrochloric acid (60 mls) and processed as described in (D) to obtain 77 grams of D-(-)-mandelic acid (87.4% of theoretical; m.p. 130°-132° C.; [α]D25° =-152.9° (C=2, H2O)).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1([C:17](=O)[CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C.ClCCl.CO.N>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:18]2[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(CCCN1CCCCC1)c1ccccc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: Brc1ccc2[nH]c(-c3ccccc3)c(CCN3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
4-Bromophenylhydrazine hydrochloride (1.45 g, 6.5 mmol) and 1-phenyl-4-(1-piperidinyl)butan-1-one (1.50 g, 6.5 mmol) were dissolved in ethanol (10 ml) and stirred at 25° C. for 4 hours. The solid was filtered and washed with ethanol and ether. The white product was dissolved in trifluoroacetic acid (10 ml) and heated at 70° C. for 2 hours. The reaction mixture was basified with saturated potassium carbonate solution and extracted into ethyl acetate. The organic phase was washed with brine, dried (sodium sulphate) and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane-methanol-ammonia (98:2:0.2) as eluent yielded the title compound (0.51 g, 20%) as a white solid. Oxalate salt, white crystals, mp 121-122° C. (from methanol/ether) (Found: C, 58.07; H, 5.23; N, 6.01. C21H23BrN2. C2H2O4. 0.1H2O requires C, 58.14; H, 5.35; N, 5.90%); δH (360 MHz, dG-DMSO) 1.5-1.6 (2H, m, piperidine H-4), 1.7-1.8 (4H, m, piperidine H-3), 3.1-3.3 (8H, m, CH2), 7.2 (1H, dd, J 2 and 8, indole H-6), 7.3 (1H, d, J 8, indole H-7), 7.4 (1H, t, J 7, Ar H-4), 7.5 (2H, t, J 7, Ar H-3), 7.6 (2H, d, J 7, Ar H-2), 7.8 (1H, ds, J 2, indole H-4), 11.6 (1H, br s, indole NH); m/z (ES+) 383 ( M++H).
Reaction SMILES: [OH2:1].[O-:2][CH2:3][CH2:4][CH2:5]C.[O-:7][CH2:8][CH2:9]CC.[O-][CH2:13]CCC.[O-]CCCC.[Ti+4:22].CC(O)(CCC)CCO>C(O)CCC>[C:8]([O:7][CH:4]([CH3:5])[CH2:3][O:2][CH3:13])(=[O:1])[CH3:9].[Ti:22]
Reactant: CCCC[O-]
Reactant: [Ti+4]
Reactant: O
Agent: CCCC(C)(O)CCO
Solvent: CCCCO
Product: COCC(C)OC(C)=O
Product: [Ti]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-butanol (BOH) solution (500 g) of deionized water (27 g) was agitated with BOH solution (500 g) of a titanium tetrabutoxide (340 g) and dropped at room temperature for 2 hours. 3-methyl-1,3-hexanediol (132 g) was added to a solution obtained and agitated at room temperature for 30 minutes. After the solution was concentrated under reduced pressure at 40° C., it was heated to 60° C. and heating was continued under reduced pressure to generate no distillate. Then, propylene glycol methyl ether acetate (PGMEA) (1,200 g) was added thereto and heated under reduced pressure at 50° C. until no BOH was distilled to obtain a PGMEA solution of a titanium-containing compound [A-III] (1,000 g) (compound concentration: 22%). The molecular weight (Mw) of the compound measured in terms of polystyrene was 1,250.
Reaction SMILES: [CH2:1]=[CH2:2].[H][H].[CH2:5]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH2:17][NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1>>[CH2:1]([N:18]([CH2:17][CH2:16][O:15][C:10]1[C:9]2[C:14](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:13]=[CH:12][CH:11]=1)[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[CH3:2]
Reactant: O=C(O)c1ccc(NCCOc2cccc3c2CCCC3)cc1
Reactant: [H][H]
Reactant: C=C
Product: CCN(CCOc1cccc2ccccc12)c1ccc(C(=O)O)cc1

Procedure:
The compound according to claim 2 wherein Y is ethylene, R is hydrogen and X is 1,2,3,4-tetrahydro-5-naphthyl; p-{[2-(1,2,3,4-tetrahydro-5-naphthyloxy)ethyl]amino}benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:32][C:33]1[N:34]=[CH:35][C:36]([CH2:39][NH2:40])=[N:37][CH:38]=1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:40]([CH2:39][C:36]3[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][N:37]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: Cc1cnc(CN)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(Cc3cnc(C)cn3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 251.5 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1-(5-methylpyrazin-2-yl)methanamine (1 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (0.73 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.82 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12](=[O:18])[N:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12](=[O:18])[N:13]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccn(O)c1=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccn(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of (1-hydroxy-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester (1.5 g, 5.76 mmol) from Step C and K2CO3 (1.59 g, 11.5 mmol) in dry DMF (15 mL) was added benzyl bromide (0.82 mL, 6.91 mmol). The reaction mixture was stirred at room temperature for 2 h and diluted with water. The usual work-up (EtOAc extraction) and purification by chromatography (silica gel, 25% EtOAc/hexanes) gave the desired product. MS 351 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:10](C)[CH:9]=[C:8]([Cl:26])[C:3]=1[C:4]([O:6]C)=O.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].[CH2:32]1COCC1>>[Cl:26][C:8]1[CH:9]=[CH:10][C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]2[C:3]=1[C:4](=[O:6])[N:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:32]2
Reactant: C1CCOC1
Reactant: CC(C)(C)N
Reactant: COC(=O)c1c(Cl)cc(C)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1Br
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3c2CN(C(C)(C)C)C3=O)c1=O
Reaction time: 18 h

Procedure:
A solution of 0.50 gram (0.0011 mole) of methyl 2-bromo-methyl-6-chloro-3-[1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl]benzoate and 0.18 gram (0.0025 mole) of tert.-butylamine in 50 mL of THF was stirred at ambient temperature for about 18 hours. After this time, TLC analysis of the reaction mixture indicated little reaction had taken place. The reaction mixture was warmed to reflux where it stirred for an additional 18 hours, then it was concentrated under reduced pressure to a residue. The residue was taken up in methylene chloride and washed in turn with water and an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of EtOAc and hexane as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 0.36 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 52.4 %

Procedure:
A mixture of 2.00 g (0.0066 mole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 1.655 g (0.0099 mole) of 4-amino-3-methoxybenzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.500 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:13][C:12]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:11][C:10]=1[C:30]1[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:26]([CH3:29])([CH3:27])[CH3:28])[CH:11]=[C:10]([C:30]3[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=3)[C:9]=2[OH:8])=[CH:18][CH:19]=1
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(C=Cc2ccc([N+](=O)[O-])cc2)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(N)cc2)c1O
Reaction time: 8 h
Yield: 65.8 %

Procedure:
step 4—A mixture of 52 (311 mg, 0.630 mmol) and Pd(OH)2 (20% wt. on carbon, 103 mg, 0.146 mmol) in EtOAc (10 mL) and MeOH (10 mL) was stirred under a H2 atmosphere overnight. The catalyst was filtered, and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 25% EtOAc) to afford 156 mg (66%) of 2-[2-(4-amino-phenyl)-ethyl]-4-tert-butyl-6-(2-methoxy-pyridin-3-yl)-phenol (54) as a colorless oil.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[C:14]([SiH2:18][O:19][C:20]([CH3:31])([CH3:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([SiH2:18][O:19][C:20]([CH3:31])([CH3:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH:25][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Cyclopropylcarbonyl chloride (2.88 mL, 31.0 mmol) and Et3N (4.38 mL, 31.0 mmol) were added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) in CH2Cl2 (125 mL). The mixture was stirred for 30 min at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl (2×), with aq. 1M NaOH (2×) and with brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:19) yielded the title compound (6.10 g, 82%). LC-MS: tR=1.09 min; ES+: 395.42.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][CH3:56]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:52]([CH2:53][CH2:54][O:55][CH3:56])[CH2:51][CH2:50][O:49][CH3:48])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: COCCNCCOC
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with bis-(2-methoxy-ethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H55Cl2N6O5 [(M+H)+] 781.3606, observed 781.3603.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[C@@H:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([O:15][C@H:12]1[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][C@@H:11]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1OC(=O)c1ccccc1
Yield: 90.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107a by using the (1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (1.07 g, 3.45 mmol) prepared in Example 161a, triethylamine (2.88 mL, 20.7 mmol), benzoyl chloride (2.00 mL, 17.2 mmol) and dichloromethane (10 mL), to yield the title compound (1.30 g, 91%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([N:35](C(OC(C)(C)C)=O)[CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc(/C=C/c3ccc(N(C)C(=O)OC(C)(C)C)cc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(/C=C/c2ccc(OCCOCCOCCOS(=O)(=O)c3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 mg 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]phenyl}-vinyl]phenoxy}ethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (2c) were dissolved in 2.5 mL dichloromethane. 252 μL trifluoroacetic acid were added and the mixture was stirred for 5 h at room temperature. The solvent was removed under reduced pressure. The crude product was washed with hexane and diethyl ether and dried under reduced pressure 84 mg 2f were obtained as light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:15]([CH2:22][CH:23]1[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]1)[C:16](=O)[C:17]([F:20])([F:19])[F:18].C(=O)([O-])O.[Na+]>C(O)CCC>[Cl:13][C:11]1[N:12]2[C:15]([CH2:22][CH:23]3[CH2:24][CH2:25][C:26]([F:29])([F:30])[CH2:27][CH2:28]3)=[C:16]([C:17]([F:18])([F:20])[F:19])[N:1]=[C:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=1
Reactant: CCOC(=O)c1cc(N)nc(Cl)c1
Reactant: O=C(C(Br)CC1CCC(F)(F)CC1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
Ethyl 2-amino-6-chloroisonicotinate (510 mg, 2.54 mmol) obtained in step 1 was suspended in n-butanol (5.08 mL), and the suspension was stirred overnight at 130° C. after adding 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (821 mg, 2.54 mmol) obtained in step 2 of Example 36, and molecular sieve 4A (510 mg). The reaction mixture was allowed to cool to room temperature, and, after adding a sodium hydrogen carbonate aqueous solution, the mixture was filtered through Celite (registered trademark), and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→2/1), amino silica gel column chromatography (hexane/ethyl acetate=20/1→9/1), and preparative thin-layer chromatography (hexane/ethyl acetate=9/1) to give ethyl 5-chloro-3-{(4,4-difluorocyclohexyl)methyl}-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylate (62.0 mg, yield 5.7%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH:21]([OH:23])[CH3:22]>>[OH:23][CH:21]([CH3:22])[CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: CC(O)CBr
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Agent: Cl
Product: CC(O)CN1CCC(c2cc3ccccc3c(=O)[nH]2)CC1
Yield: 16.1 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (500 mg) and 1-bromo-2-propanol (394 mg), 3-[1-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (87 mg) was obtained.
Reaction SMILES: C1([C:7]([C:19]2[CH:24]=[CH:23]C=[CH:21][CH:20]=2)(C2C=CC=CC=2)[S:8][CH2:9][CH2:10][O:11][CH3:12])C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+].C([O:44][CH:45]1[NH:48]C(=O)C1(CC)CC)(=O)C>ClCCl.CC(C)=O>[CH3:12][O:11][CH2:10][CH2:9][S:8][CH:7]1[NH:48][C:45](=[O:44])[C:19]1([CH2:20][CH3:21])[CH2:24][CH3:23]
Reactant: COCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC1(CC)C(=O)NC1OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(CC)C(=O)NC1SCCOC
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To S-triphenylmethyl 2-methoxyethanethiol (1.37 g, 4.1 mmol) in dichloromethane (30 ml) under nitrogen were added triethylsilane (0.953 g, 1.31 ml, 8.2 mmol) and trifluoroacetic acid (0.632 ml, 0.935 g, 8.2 mmol). The mixture was stirred at room temperature for 16 hours. Acetone (50 ml) was added and the mixture neutralised with 2 M aqueous sodium hydroxide. 1 M Aqueous sodium hydroxide (24 ml, 24 mmol), 4-acetoxy-3,3-diethyl-2-azetidinone (J. Med. Chem., 35, 3745-3754 (1992)) (0.690 g, 6.00 mmol) and acetone (10 ml) were then added and the mixture stirred at room temperature for 23 hours. The solvents were removed in vacuo and to the residue were added water (50 ml) and dichloromethane (50 ml). The organic layer was isolated and the water layer extracted further with dichloromethane (3×30 ml). The 4 organic layers were combined and washed with water (30 ml) and saturated brine (30 ml), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (gradient from petrol/EtOAc, 9:1 to EtOAc) gave the title compound (0.51 g, 63%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][C@@H:18]([CH3:23])[C:19]([F:20])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:33][CH2:32][C:30]2[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: C[C@H](Oc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: COc1cc(CN)on1
Agent: Cl
Product: COc1cc(CNC(=O)c2cnc(O[C@@H](C)C(F)(F)F)c(-c3ccc(Cl)cc3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinic acid (Example AO) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials. MS: 456.1 (M+H)+.