Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[N:27][C:28]=3[NH2:30])[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=2)=[CH:17][C:16]=1[O:38][CH3:39]>ClCCl.N1C=CC=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[C:16]([O:38][CH3:39])[CH:17]=3)[C:29]=12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
4-(Trifluoromethyl)-1-benzenecarbonyl chloride (35 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more 4-(trifluoromethyl)-1-benzenecarbonyl chloride (18 mg, 0.086 mmol) was added. 2 hours later, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide (85 mg, 95%). 1H NMR (CDCl3) δ 2.10 (m, 2H), 2.37-2.59 (m, 7H), 3.15 (m, 2H), 4.02 (s, 3H), 4.83 (m, 1H), 5.68 (s, 2H), 7.34 (m, 2H), 7.80 (d, J=8.21 Hz, 2H), 8.04 (d, J=8.10 Hz, 2H), 8.38 (s, 1H), 8.67 (m, 2H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=526.3, Rt=1.93 min.
Reaction SMILES: C(OC(N1CCC(C([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]4[NH:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[N:30]=4)[CH:23]=3)[CH2:18][CH2:17]2)=O)CC1)=O)(C)(C)C.CC[O:40][CH2:41][CH3:42]>C(Cl)Cl>[NH:33]1[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=[C:29]1[C:24]1[CH:23]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:42]3([CH:41]=[O:40])[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]3)[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Reactant: CCOCC
Solvent: ClCCl
Product: O=CC1(N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CCNCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a solution of 4-{4-[3-(1H-Benzoimidazol-2-yl)-4-fluoro-phenyl]-piperazine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.16 mmol) in DCM (1 mL) 2M HCl in Et2O (3.0 mL) was added and the resulting suspension was stirred at room temperature for 3 days. The reaction was concentrated under reduced pressure, water (8 mL) was added and the solution was concentrated under reduced pressure. The solid was purified by preparative HPLC. HPLC fractions were neutralized with K2CO3 and concentrated. DCM (5 mL) and water (5 mL) were added, organic phase was separated and concentrated to give 44 mg of the title compound (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.C(N(CC)CC)C.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH2:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19]
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: COCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
1-Chloro-2-fluoro-3-nitrobenzene (2.85 mmol, 0.500 g) was added to an oven dried 50 mL round-bottomed flask equipped for stifling under nitrogen. Dichlormethane (10 mL) and triethylamine (3.13 mmol, 0.437 mL) were added and the resultant solution was cooled to 0° C. with an ice-bath. 3-Methoxypropan-1-amine (2.85 mmol, 0.292 mL) was then added drop-wise via syringe and the resultant solution was stirred at 0° C. for 1 hr. The ice-bath was removed and the reaction was allowed to warm to room temperature and stirred for 16 hr. The reaction solution was poured into water and extracted twice with dichloromethane (50 mL). The organic layer was collected and water was subsequently removed with anhydrous Na2SO4 and the suspension was filtered. The filtrate was collected, concentrated, and dried in-vacuo affording an orange oil, which was then purified by chromatography on slica gel (10-70% ethyl aetate/hexanes) to afford 2-chloro-N-(3-methoxypropyl)-6-nitroaniline (30A) as a yellow solid (2.23 mmol, 0.542 g, 78% yield). ESI-MS: m/z 245.3 (M+H)+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]=1)[CH3:5])=[N+]=[N-]>[Pd].CCOC(C)=O>[C:15]1([N:7]2[C:8]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[N:14]=[C:6]2[CH:4]([NH2:1])[CH3:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(N=[N+]=[N-])c1nc2cnccc2n1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(N)c1nc2cnccc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
A mixture of 2-(1-azidoethyl)-1-phenyl-1H-imidazo[4,5-c]pyridine (0.40 g, 1.50 mmol) and 10% palladium on carbon (0.10 g) in EtOAc (20 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure and 20° C. for 16 h. The catalyst was removed by filtration, the filtrate concentrated in vacuo, and the resulting residue purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound as a white solid (0.194 g, 54%). LCMS (method J): Rt 0.26 min, [M+H]+ 239.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1.[Br:12][C:13]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][NH:17]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:12][C:13]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1
Reactant: Cc1cnc(CBr)c(C)c1C
Reactant: Nc1nc(Br)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cn2cnc3c(Br)nc(N)nc32)c(C)c1C

Procedure:
The compound was obtained by reacting 2-bromomethyl-3,4,5-trimethyl-pyridine (see example 117) with 6-bromo-9H-purin-2-ylamine in the presence of K2CO3 in DMF for 0.5 h at 50° C. as described in the general procedure 1.1. HPLC Rt: 4.045 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 7.85 (s, 1H), 5.37 (s, 2H), 5.10 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[NH2:9][C:7]1[S:8][C:4]2[C:5](=[C:10]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:11]=[C:2]([F:1])[CH:3]=2)[N:6]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: O=S(=O)(O)Cl
Product: Nc1nc2c(S(=O)(=O)Cl)cc(F)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
6-fluorobenzo[d]thiazol-2-amine (1 g, 5.95 mol) was added dropwise to chlorosulfonic acid (5.0 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (50% PE/EtOAc) afforded 200 mg of title compound. LC-MS: m/z 266.7 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)[N:13]2[CH:29]=[CH:30][N:31]=[C:12]2[CH:11]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[CH:20]=3)[N:13]3[CH:29]=[CH:30][N:31]=[C:12]3[CH:11]=2)[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 25 °C
Yield: 26.9 %

Procedure:
To a flask charged with 4-methyl-1H-imidazole (0.117 g, 1.43 mmol) and 1 mL of N,N-dimethylformamide was added sodium hydride (60% in oil dispersion) (0.0514 g, 1.29 mmol) at 0° C. with stirring. The reaction mixture was then placed under nitrogen and allowed to warm to ambient temperature and stirred for 30 minutes. To the reaction was added 7-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation G; 0.100 g, 0.286 mmol) and argon was bubbled through the reaction for 5 minutes. The reaction was sealed and heated to 100° C. The reaction was diluted with dichloromethane (50 mL) and 5 mL of aqueous saturated sodium bicarbonate was added. The reaction mixture was stirred for 20 minutes, then concentrated to dryness under reduced pressure at 50° C. and dried on high vacuum overnight. The crude material was taken up in 1:1 ethyl acetate: dichloromethane with 5% methanol (100 mL) and sonicated for 1 hour. This suspension was filtered, the cake was washed with EtOAc (50 mL) and the rinse was then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 1% methanol in dichloromethane containing 0.5% ammonium hydroxide to obtain 7-(4-methyl-1H-imidazol-1-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.053 g, 0.077 mmol, 27% yield). MS (apci) m/z=396.2 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:47][C:48]([NH:50][C@H:51]([C:56](OC2C=CC([N+]([O-])=O)=CC=2)=[O:57])[CH2:52][C:53]([NH2:55])=[O:54])=[O:49])=[CH:42][CH:41]=1>CN(C)C=O>[NH:50]([C:48]([O:47][CH2:46][C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1)=[O:49])[C@H:51]([C:56]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:57])[CH2:52][C:53](=[O:54])[NH2:55]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
5.4 g of H-Lys(BOC)-Phe-His-OMe (compare Example 1) and 4.5 g of Z-Asn-ONP in 20 ml of dimethylformamide are stirred for 20 hours at room temperature. The peptide derivative is precipitated by adding ethyl acetate, filtered off and washed with ether. After recrystallisation from methanol the product melts at 182°-183° C. In a thin layer chromatogram Rf100 = 0.57 (on silica gel). [α]D20 = -28° (c = 1 in dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[F:19][C:20]1[CH:21]=[C:22]([CH3:30])[CH:23]=[C:24]2[C:29]=1[NH:28][CH2:27][CH2:26][CH2:25]2.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:28]1[C:29]2[C:24](=[CH:23][C:22]([CH3:30])=[CH:21][C:20]=2[F:19])[CH2:25][CH2:26][CH2:27]1)=[O:9]
Reactant: Cc1cc(F)c2c(c1)CCCN2
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)c2c(c1)CCCN2C(=O)c1ccccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-benzoic acid (51.0 mg, 0.18 mmol, 1.0 equiv; Example 110, Step 1) in dichloromethane (2 mL) was added 8-fluoro-6-methyl-1,2,3,4-tetrahydro-quinoline (35.7 mg, 0.22 mmol, 1.2 equiv; [CAS RN 954260-80-1]), triethylamine (36.5 mg, 50 μL, 0.36 mmol, 2.0 equiv; [CAS RN 121-44-8]) and 2-chloro-1-methylpyridinium iodide (57.8 mg, 0.22 mmol, 1.2 equiv; [CAS RN 14338-32-0]). The reaction mixture was stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 20.7 mg (27%) of the title compound. MS (ISP): 430.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[NH:11][C:10]3[C:13]4[C:18]([CH2:19][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH3:3])[CH3:2].O1CCN(B)CC1.Cl.[OH-].[Na+]>O1CCOCC1>[CH:1]([C:4]1[C:12]2[NH:11][C@@H:10]3[C:13]4[C:18]([CH2:19][C@@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc2c3c([nH]c12)-c1ccccc1C3
Agent: BN1CCOCC1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)c1cccc2c1N[C@@H]1c3ccccc3C[C@H]21
Yield: 70.8 %

Procedure:
To a solution of 4.95 g (0.020 mol) of 5.10-dihydro-6-isopropylindeno[1,2-b]indole and 8.08 g (0.080 mol) of morpholino borane in 25 ml of dioxane was added dropwise 7 ml of conc. hydrochloric acid. The mixture was refluxed for 30 minutes, cooled to room temperature whereupon 20 ml of 6M hydrochloric acid was added. The mixture was refluxed for 15. After cooling the mixture was alkalinized by addition of aqueous sodium hydroxide and extracted three times with ether. Drying (MgSO4) and evaporation gave a crude product which was purified by column chromatography on silica gel using methylene chloride/light petroleum (20/80) as eluent. Thus 3.53 g (71%) of the title compound was obtained. 1H NMR(CDCl3) δ: 1.19 (3H,d), 1.29 (3H, d), 2.84 (1 h,dq), 3,26 (1H,dd), 3.56 (1H,dd), 4,24 (1H,td), 5.31 (1H,d), 6.79 (1H,dd), 6.97 (1H, d), 7.05-7.09 (1H,m), 7,28-7,21 (3H,m), 7.36-7,40 (1H,m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[CH3:28][N:29]([CH3:30])[CH2:27][CH:25]([C:21]1[CH:20]=[C:19]([NH:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:24]=[CH:23][CH:22]=1)[OH:26]
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 33% dimethylamine in ethanol, a mixture of regioisomers was obtained. Reverse-phase HPLC was used to purify the mixture and the title compound was obtained as a pale orange powder. 1H NMR (300 MHz, CDCl3): δ 2.70 (6H, s), 3.05-3.10 (2H, m), 5.05 (1H, bd), 6.80-6.95 (2H, m), 7.00-7.22 (3H, m), 7.25-7.35 (2H, m), 7.49 (2H, d, J=8 Hz) and 7.87 (2H, d, J=8 Hz).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[CH3:33][C@H:34]1[CH2:39][O:38][CH2:37][C@H:36]([CH3:40])[N:35]1[CH2:41][C:42]#[C:43][CH2:44]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:44][C:43]#[C:42][CH2:41][N:35]2[C@@H:36]([CH3:40])[CH2:37][O:38][CH2:39][C@@H:34]2[CH3:33])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: C[C@H]1COC[C@H](C)N1CC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1COC[C@H](C)N1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine (0.20 g), (3S, 5S)-3,5-dimethyl-4-(4-chloro-2-butynyl)morpholine (0.11 g) and potassium carbonate (0.31 g) in N,N-dimethylformamide (4 ml) was stirred at 60° C. for 3 hours. After cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 3% of methanol in ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3,5-dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazine. It was dissolved in ethyl acetate and the solution was added 4N hydrogen chloride in ethyl acetate. The mixture was evaporated in vacuo and the residue was triturated with isopropyl ether to give (2R)-1-[3,5-bis-trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3,5-dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazine dihydrochloride (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1noc(-c2cccc(Cl)c2)n1
Yield: 49.4 %

Procedure:
12.1 g (53.9 mmol) 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol an 1.60 g Novozyme 435® are taken up under Ar in toluene (750 mL). After addition of 5.0 mL (54.2 mmol) vinyl acetate the reaction was run at r.t. o.n., followed by filtration over celite and washing with DCM. The filtrate was purified over silica using DCM neat, followed by EA/Hep=1/1, yielding 7.1 g (49%) of the title compound. 1H NMR: 8.13 (t, 1 H), 8.01 (d, 1 H), 7.55 (d, 1 H), 7.47 (t, 1 H), 6.07 (q, 1 H), 2.15 (s, 3 H), 1.69 (d, 3 H)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][N:4]=1.N1C2C(=CC=CC=2)C=[C:15]([CH:23]=[O:24])C=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:15][CH:23]=[O:24])=[CH:5][N:4]=1
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Reactant: O=Cc1cnc2ccccc2c1
Product: O=CC=Cc1cnc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 7 by substituting 2-trifluoromethyl-5-pyrimidinecarboxaldehyde (prepared as described in WO0066566) for the 3-quinolinecarboxaldehyde of Reference Example 7. MS 203 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12](N(OC)C)=[O:13])=[CH:10][CH:9]=1>>[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Product: O=C(c1ccc(Br)cc1)c1nccs1
Yield: 98 %

Procedure:
The title compound was prepared from 2-bromothiazole and 4-bromo-N-methoxy-N-methylbenzamide following the general method of Method 1. The crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate, 7:3, as the eluent affording 0.52 g (98% yield) of the title compound as a yellow crystals: mp 74-75° C.; 1H NMR (400 MHz, CDCl3) δ 8.32 (m, 2 H), 8.02 (d, J=3.0 Hz, 1 H), 7.67 (d, J=3.0 Hz, 1 H), 7.60 (m, 2 H); 13C NMR (100.5 MHz, CDCl3) δ 183.4, 167.9, 145.3, 134.2, 133.0, 132.2, 129.6, 127.0; MS (TSP) m/z 268, 279 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23].Cl[CH2:25][C:26]1[NH:27][C:28](=[O:36])[C:29]2[CH2:35][O:34][CH2:33][CH2:32][C:30]=2[N:31]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:19][CH2:18][N:17]([CH2:25][C:26]4[NH:27][C:28](=[O:36])[C:29]5[CH2:35][O:34][CH2:33][CH2:32][C:30]=5[N:31]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1C
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN([C@H]3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1C
Temperature: 70 °C
Yield: 79 %

Procedure:
To a solution of (R)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.79 mmol, 250 mg) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.87 mmol, 174 mg) in THF (10 mL) was added sodium hydride (60%, 2.77 mmol, 111 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 100 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (300 mg). Chiral resolution of 2-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (300 mg) via chiral SFC chromatography on a AS-H column (60 g/min, 21×250 mm) eluting 40% IPA/0.2% DEA/CO2 (v/v) afforded 77 mg of pure material. HRMS calculated for C26H32N4O5=480.5687. found (ESI, [M+H]+) 481.2455. 1H NMR (400 MHz, MeOD) δ ppm 1.69-1.90 (m, 4H) 2.10-2.20 (m, 1H) 2.20-2.31 (m, 4H) 2.48-2.58 (m, 1H) 2.59-2.65 (m, 2H) 2.77-2.88 (m, 1H) 2.90-3.06 (m, 1H) 3.10-3.20 (m, 1H) 3.32-3.42 (m, 3H) 3.46-3.54 (m, 2H) 3.63 (t, J=8.53 Hz, 1H) 3.88-3.94 (m, 5H) 4.39 (s, 2H) 4.47 (s, 2H) 6.99 (d, J=8.53 Hz, 1H) 7.77 (s, 1H) 7.87 (dd, J=8.53, 2.01 Hz, 1H), analytical RP-HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.731 min.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH:9]=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:8][CH2:9][C@@H:10]([OH:12])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 2.0 g (9.33 mmol) of (1S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enol (Curran, et al. Tetrahedron 1997, 53, 1983-2004) in 10 mL of ethyl acetate was treated with 66 mg of 20% palladium hydroxide on activated carbon and the mixture was stirred overnight under a hydrogen atmosphere (1 atm) at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to give 2.0 g of the title compound (32). Rt=1.72 min (Method C). Detected mass: 217.2 (M+H+).