Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][CH2:12][CH2:13][OH:14])([CH3:10])([CH3:9])[CH3:8].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:24][O:23]2)[CH:19]=[CH:20][CH:21]=1>C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:23])[CH2:24][O:14][CH2:13][CH2:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OCCO
Reactant: Clc1cccc(C2CO2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OCCOCC(O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5.1 g of potassium tert-butoxide was added to 105 ml of ethylene glycol mono-tert-butyl ether. The mixture was heated to 80° C. Thereto was dropwise added 35.0 g of 2-(3-chlorophenyl)oxirane over 1 hour. The mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 100 ml of ice water and 100 ml of ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to further distillation under reduced pressure to obtain 37.7 g of colorless oily 1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol having a boiling point of 140°-146° C./0.9 mmHg.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=1)[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:7]=1.[OH-].[Li+].C1COCC1.O>CO>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:10][C:6]([CH2:5][CH:4]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=3)[C:3]([OH:43])=[O:2])=[N:7]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(OC)cc2)n1)c1cn(COCC[Si](C)(C)C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nc(CC(C(=O)O)c3cn(COCC[Si](C)(C)C)c4ccccc34)cc2-c2ccc(C)cc2)cc1
Yield: 89.7 %

Procedure:
The title compound was synthesized by Method 2 from 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid methyl ester (Example 69, 0.19 g, 0.32 mmol), lithium hydroxide (40 mg, 0.96 mmol), THF (1.25 mL), water (0.43 mL) and MeOH (0.43 mL), giving 167 mg (89%) of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid. HPLC: Rt=3.66 (Method B). MS (ES+): mass calculated for C34H39N3O4Si, 581.27; m/z found 582.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.64 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.45 (s, 1H), 7.19-7.04 (m, 6H), 7.01 (d,J=8.2 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.33 (s, 1H), 5.52 (s, 2H), 4.21 (m, 1H), 3.76 (s, 3H), 3.41 (m, 2H), 3.07 (dd, J=6.3, 14.3 Hz, 1H), 2.27 (s, 3H), 0.75 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]([F:24])([F:23])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)[OH:10].[NH2:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[C:28]([Cl:33])[N:27]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:33][C:28]1[CH:29]=[C:30]([O:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[C:8]([F:7])([F:23])[F:24])[N:31]=[C:26]([NH2:25])[N:27]=1
Reactant: Cn1cc(-c2ccccc2C(O)C(F)(F)F)cn1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cn1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Cs2CO3 (325 mg, 1.0 mmol) was added to a solution of 2,2,2-trifluoro-1-[2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethanol (60 mg, 0.2 mmol) in 10 ml of anhydrous THF, and the mixture was stirred for 20 minutes. 2-Amino-4,6-dichloro-pyrimidine (32 mg, 0.2 mmol) was added, and then the reaction mixture was heated at 110° C. until the reaction was complete. After cooling, 5 ml of water was added, and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to afford 70 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (yield: 92%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(=O)(=O)(O)[OH:19].O.[Cr](O)(O)(=O)=O>C(O)(=O)C.CC(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:19])[C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Agent: O=[Cr](=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(=O)c1cc2c(nc1C)CCCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.8 %

Procedure:
Ethyl methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (2.50 g, 10.1 mmol) was dissolved in acetic acid (7.0 ml), the solution was mixed with concentrated sulfuric acid (1.4 ml), and then 11% acetic acid aqueous solution (4.8 ml) of chromic anhydride (1.41 g, 14.1 mmol) was added thereto at 10 to 15° C. spending about 1 hour. After 6 hours of stirring at room temperature, water was added to the reaction solution to which was subsequently added dropwise 2-propanol at 0° C. to decompose excess chromic acid. The solvent was evaporated under reduced pressure, the thus obtained residue was neutralized with 20% sodium hydroxide aqueous solution at 0° C. and mixed with chloroform, and then the insoluble matter was removed by celite filtration and washed with chloroform. The resulting filtrate was extracted with chloroform, washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (284.7 mg, 10.8%) as colorless oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]=1[CH3:19].[F:24][C:25]([F:42])([F:41])[C:26](=[O:40])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([CH3:30])[CH3:29]>C1COCC1>[F:42][C:25]([F:24])([F:41])[C:26]([CH2:13][C:14]1[O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]=1[CH3:19])([OH:40])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([CH3:30])[CH3:29]
Reactant: Cc1oc2ccccc2c1C
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1oc2ccccc2c1C)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution of diisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. The reaction mixture was cooled to −78° C. and stirred for 15 minutes. A solution of 2,3-dimethylbenzofuran (48 mg, 0.4 mmol) in 2 mL anhydrous THF was added dropwise to this mixture. After the addition, the reaction mixture was stirred for 15 to 30 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) (Example 1) was added as a solution in anhydrous THF (2 mL) in one portion, the cold bath was removed, and the reaction was stirred at room temperature for 12 hours. THF was evaporated under reduced pressure. Water (2 mL) was added to the residue and the mixture was extracted with three 5 mL portions of EtOAc. The extract was dried over magnesium sulfate. After evaporation, the residue was chromatographed on a silica gel column to provide 80 mg of the title compound as an oil.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:29])[CH3:28])(C(C)(C)C)(C)C.CO.Cl.O>O1CCCC1>[OH:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of 4-[(4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (391.7 mg) in tetrahydrofuran (12 mL)-methanol (12 mL) was added 6 mol/L hydrochloric acid (12 mL), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless oil (yield: 203.6 mg, 71%).
Reaction SMILES: ClC1C=CC(C2N(C[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]C(O)=O)=[CH:16][CH:15]=3)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.C1(C[N:45]2[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[N:47]=[C:46]2[C:54]2C=C[CH:57]=[CH:56][C:55]=2CCC2C=CC(OCC(O)=O)=CC=2)CCCCC1.[Br:73][CH2:74][CH2:75]C1CCCCC1>>[Br:73][C:74]1[CH:75]=[CH:57][CH:56]=[CH:55][C:54]=1[C:46]1[N:45]([CH2:21][CH2:20][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:19][CH2:18]2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[N:47]=1
Reactant: BrCCC1CCCCC1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)COc1ccc(CCc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Product: Brc1ccccc1-c1nc2ccccc2n1CCC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 79, intermediate f) and (2-bromo-ethyl)-cyclohexane (CAS Reg. No. 1647-26-3). Light yellow sticky solid (87%). MS (Turbo Spray): m/z=384.2 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10]1)(=[O:3])[CH3:2].Cl.[CH3:20][O:21][NH2:22].O>CN1CCCC1=O>[C:1]([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:22][O:21][CH3:20])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10]1)(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OCCON=C1Oc2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CON=C1C(=NOCCOC(C)=O)Oc2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10 g (0.04 mol) of 2-(3-oxo-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIV-1) and 4.18 g (0.05 mol) of O-methylhydroxylamine hydrochloride are dissolved in 40 ml of N-methyl-2-pyrrolidinone and stirred at 80° C. for 1 hour. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 10.6 g of crude 2-(3-methoxyimino-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIII-1) are obtained, which are chromatographed over silica gel using a mixture of tert-butyl methyl ether and petroleum ether (1:1). 6.9 g (59.1% of theory) of 2-(3-methoxyimino-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIII-1) having a content of 82.15% of stereoisomer A and 13.38% of stereoisomer B are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(OCC)(=O)C.C(Cl)[Cl:31]>>[Cl-:31].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:16][CH2:15][NH2+:14][CH2:13][CH2:12]1
Reactant: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Reactant: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(C2CC[NH2+]CC2)nc2ccccc21
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The above piperidine (50.0 mg, 0.160 mmol) was dissolved in DCM (5 mL) and ethyl acetate (5 mL) and cooled to 0° C. Hydrogen chloride gas was bubbled through the solution for 30 seconds, which was stirred for 30 minutes before warming to ambient temperature. The reaction mixture was concentrated to dryness to afford 4-(1-methyl-1H-benzimidazol-2-yl)piperidinium chloride.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:17]([C:15]2[CH:14]=[C:13]([O:20][CH:21]([CH3:22])[CH3:23])[C:11]3[CH2:12][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][C:10]=3[CH:16]=2)=[O:19])=[N:26]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)Oc1cc(C(=O)O)cc2c1CC(Cc1ccccc1)O2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(Cc1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.6 mmol) in CH2Cl2 (15 mL) were added 1-methyl-1H-pyrazol-3-ylamine (0.16 g, 1.7 mmol), EDCI (0.46 g, 2.4 mmol), HOBt (0.32 g, 2.4 mmol) and N-methylmorphiline (0.81 g, 8 mmol) sequentially. The mixture was stirred at room temperature overnight. The reaction solution was washed with water (5 mL), aq. HCl (1 N, 5 mL) and sat. NaHCO3. The organic phase was dried over Na2SO4 and concentrated to give a yellow oil. The crude oil was purified by prep. HPLC to give the product as a white solid (98.6 mg, 16% yield, TFA salt). 1H NMR (400 MHz, CDCl3): δ 10.71 (s, 1H), 7.58 (s, 1H), 7.30-7.48 (m, 5H), 7.01-7.19 (d, 2H), 6.57 (s, 1H), 5.08 (d, 1H), 4.74 (m, 1H), 3.74 (s, 3H), 2.66 (d, 2H), 2.17 (m, 1H), 1.96 (m, 1 H), 1.28 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.P(Cl)(Cl)(Cl)=O>ClCCCl.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]1[N:15]2[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1
Reactant: COc1ccccc1C(=O)NC(C)c1cnc(Nc2cc(OC)c(OC)c(OC)c2)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccccc1-c1nc(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn12
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a solution of 2-methoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 25) (27 mg, 0.06 mmol) in 1,2-dichloroethane (4 mL) was added phosphorus oxychloride (45 microL, 0.5 mmol). The mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was diluted with DCM (150 mL) and aqueous (saturated) Na2CO3 (25 mL). The aqueous layer was extracted with dichloromethane (DCM) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by reverse-phase HPLC to give 7-(2-methoxyphenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.005 g) as a yellow solid. 1H NMR (CDCl3): δ8.80 (s, 1H), 7.59 (dd J=7.51, 1.65 Hz, 1H), 7.44 (m, 1H), 7.00-7.07 (m, 3H), 6.84 (s, 1H), 3.78 (s, 6H), 3.59 (s, 6H), 2.63 (s, 3H). MS m/z 421 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][CH2:28][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1
Reactant: NC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCN
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C(N)=O)cc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 7.1 %

Procedure:
A mixture of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinoline-6-carboxamide (300 mg, 0.75 mmol) and propane-1,3-diamine (306 mg, 4.14 mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 120° C. under microwave irradiation. The reaction mixture was purified by preparative HPLC to afford 23.5 mg of the desired product (yield was 7.2%). MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.70-8.69 (d, J=1.6 Hz, 1 H), 8.18-8.15 (m, 1 H), 8.10-8.08 (dd, J=1.2, 7.6 Hz, 1 H), 7.88-7.84 (t, J=6.8 Hz, 2 H), 7.73-7.72 (m, 1 H), 7.60-7.59 (m, 1 H), 6.01 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.64-3.60 (t, J=6.8 Hz, 1 H), 3.11-3.09 (m, 2 H), 2.18-2.09 (m, 2 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C2SC=CN=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.BrC1SC=CN=1.[Cl:40][C:41]1[O:42][C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[N:45]=1>>[ClH:40].[O:42]1[C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[N:45]=[C:41]1[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][C@H:8]([NH:7][CH2:6][C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[O:3][CH3:2])[C@@H:9]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nc2ccccc2o1
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCCNc2nccs2)[C@H]1c1ccccc1
Agent: Brc1nccs1
Agent: Cl
Product: COc1ccccc1CN[C@H]1CCCN(CCCCNc2nc3ccccc3o2)[C@H]1c1ccccc1

Procedure:
The title compound was prepared in a similar manner to the compound of Example 1 by replacing (2S, 3S)-3-(2-methoxybenzyl)amino-2-phenylpiperidine with the corresponding racemate and 2-bromothiazole with 2-chlorobenzoxazole; mp 158°-160° C. (dec.) 1H NMR (CDCl3) 67 1.58 (m, 5H), 1.90 (m, 1H), 2.04 (m, 4H), 2.20 (m, 1H), 2.56 (m, 1H), 2.71 (d, 1H, J=2), 3.25 (m, 1H), 3.38 (m, 5H), 3.57 (d, 1H, J=15), 3.96 (d, 1H, J=15), 6.60 (d, 1H, J=6), 6.76 (t, 1H, J=6), 6.96 (m, 2H), 7.12 (m, 3H), 7.28 (m, 6H). HRMS calc'd for C30H36N4O2 : 484.2838. Found: 484.2844.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:6]=[C:7]([C:11]([CH3:13])=O)[C:8]([O-:10])=[O:9].[CH3:19][O:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24].O.[C:28]1(C)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[C:22]([C:21]([O:20][CH3:19])=[O:26])=[C:23]([CH3:24])[NH:25][C:11]([CH3:13])=[C:7]2[C:8]([O:10][CH3:28])=[O:9])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=C(C(C)=O)C(=O)[O-])cc1OC
Reactant: Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Yield: 63 %

Procedure:
A solution of 5.0 g (18.9 mmol) 2-(3,4-dimethoxybenzylidene)acetoacetate and 2.18 g (18.9 mmol) 3-amino-crotonic acid methyl ester in 100 ml toluene was heated in a Dean-Stark apparatus for water removal, the solvent was distilled off from the reaction mixture, and the residue was purified by column chromatography (SiO2 /CHCl3), giving 4.30 g (63%) of dimethyl 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate as whitish yellow crystals. M.P.: 153.5°-155° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[CH:29]=3)=[C:26]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+]>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:29]=3)=[C:26]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Nc3ccccc3)c2)CC1
Temperature: 120 °C

Procedure:
To a suspension of NaH (130 mg, 3.3 mmol) in DMA (2 mL) was added aniline (0.58 mL, 6.1 mmol) and stirred until bubbling ceased. To this solution was added 1-(1-t-butoxycarbonyl-4-piperidinyl)-4-(4fluorophenyl)-5-(2-chloro-4-pyridinyl)imidazole (0.30 g, 0.66 mmol) and the resulting solution was heated at 120° C. until no evidence of starting material was observed by mass spectroscopy (1-3 days). To the cooled reaction mixture 1M NaOH was added and the resulting mixture extracted three times with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to afford a yellow residue which was chromatographed with 50-80% EtOAc/hexanes. The resulting solid was triturated with Et2O to give the title compound as a light yellow solid; yield 180 mg (53%): ESMS m/z=514 (M+ +H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:29]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.2 %

Procedure:
To a solution of 1G (62 mg, 0.2 mmol) in CH2Cl2 (1 mL) was added pyridine (0.049 mL, 0.6 mmol), followed by addition of benzoyl chloride (42 mg, 0.3 mmol). The resulting mixture was stirred at RT under argon for 6 h, then loaded on a silica gel cartridge (10 g), eluting with EtOAc (25-50%) in hexane to give the title compound as a white solid (72 mg, 88%). m.p. 174-175° C., HPLC: 99% at 3.01 min (retention time, Phenom. Luna C18, 4.6×50 mm elating with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 inn). MS (ES): m/z=418 [M+1]+. Chiral HPLC 100% e.e.; retention time=34.8 min; Conditions: OD (4.6×250 mm); Eluted with 40% isopropanol in hexane at 1 mL/min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.