Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>CN(C=O)C>[CH3:22][S:21][C:17]1[N:18]=[C:19]([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:20]=[CH:15][N:16]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ccnc2-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Phenylimidazole (1-2, 50 g, 347 mmol) was dissolved in 400 ml DMF and the resulting solution was cooled to 0° C. Sodium hydride (8.32 g of solid NaH, plus 13.9 g of a 60% dispersion in mineral oil, 347 mmol) was added and the mixture was stirred for 10 minutes. 4-Chloro-2-(methylthio)pyrimidine (1-1, 55.7 g, 347 mmol) was then added over 2 minutes. The reaction was then heated to 100° C. After stirring overnight the reaction was partitioned between water and EtOAc. The organic phase was washed 2× with water, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (eluting with 50:50 to 70:30 EtOAc/Hexane) afforded 2-(methylthio)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine.
Reaction SMILES: [Na].[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH2:21]([C:25]1[C:26](=[O:34])[CH2:27][C:28]([CH3:33])([CH3:32])[CH2:29][C:30]=1[CH3:31])[CH2:22][CH2:23][CH3:24].C([O-])(=O)C.[NH4+]>C(O)C.C(OCC)(=O)C>[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:31][C:30]2[CH2:29][C:28]([CH3:32])([CH3:33])[CH2:27][C:26](=[O:34])[C:25]=2[CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1=C(C)CC(C)(C)CC1=O
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCC1=C(C=Cc2ccc(N(CCCC)CCCC)cc2OC)CC(C)(C)CC1=O
Temperature: 60 °C
Yield: 10.6 %

Procedure:
0.3 g (13.0 mmol) of sodium was dissolved in 15 ml of ethanol. Next, 2.63 g (10.0 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 2.22 g (11.0 mmol) of 2-butyl-3,5,5-trimethyl-2-cyclohexenone were dissolved in 5 ml of ethanol and added to the mixture. To this mixture, 0.36 g of ammonium acetate was added and the mixture was stirred with heating at 60° C. for 22 hours. To the mixture, 100 ml of ethyl acetate was added. Washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 465 mg of a dark red oily matter (yield: 10.6%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:20][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC1(C)CC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-(trifluoromethyl)phenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C18H15F3O+H+, 305.11478; found (ESI, [M+H]+), 305.1145.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.CN.[NH2:49][CH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([NH:49][CH:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:26])=[CH:28][CH:29]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCOCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml) HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and methylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min, 4-Aminotetrahydropyran (0.106 g, 1.04 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.050 g, 20%.). M.P.: 202-205° C., 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.99 (m, 4H), 7.85 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 4.04 (m, 1H), 3.89 (d, J=9.7 Hz, 2H), 3.39 (t, J=10.0 Hz. 2H), 1.78 (d, J=10.5 Hz, 2H), 1.63 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([OH:16])[C:13]([Cl:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:18]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:24]3[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]3)[C:13]([Cl:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cc(O)c(Cl)cc2c1C
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2c1C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
The above prepared 5-chloro-6-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.700 g, 2.75 mmol) was dissolved in 12 mL of THF and treated successively at −10° C. with 1-isopropyl-piperidin-4-ol (0.551 g, 1.4 eq.), triphenylphosphine (1.001 g, 1.4 eq.) and DIAD (0.755 mL, 1.4 eq.), and the mixture then kept at ambient temperature for another 4 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98), produced 0.990 g of the title compound as light yellow gum.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.CCCCCC>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OC)nc3)oc2C)C2CCCCC2)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1388 mg) which is a synthetic intermediate in Example 133 was dissolved in ethanol-hexane (6:4, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (6:4, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 29 min were collected, and concentrated. The obtained amorphous compound (681 mg) was dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL), 1N lithium hydroxide (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (601 mg, 94%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][O:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][N:33]=1>>[CH3:30][O:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=2)[N:33]=1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1n[nH]c2ccccc12
Product: COc1nn(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)c2ccccc12

Procedure:
2-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (0.1 g) was reacted with 3-methoxy-1H-indazole via General Procedure I for Buchwald coupling give 16.4 mg 234 following reverse phase purification. MS (Q1) 507.2 (M)+
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25.5 %

Procedure:
Benzyl chloroformate (5.5 g) was added to a suspension of 5-aminosalicylic acid (4.6 g) in dry pyridine (25 ml) at 0° C. during a period of 5 minutes. The mixture was allowed to warm to 25° C. and was stirred for 20 hours, and was then poured into a mixture of ice (100 g) and concentrated hydrochloric acid (50 ml). The solid that precipitated was then filtered off and dissolved in ethanol (50 ml) and treated with a little charcoal. The mixture was filtered and the filtrate was evaporated to dryness to give 5-benzyloxycarbonylaminosalicylic acid (2.2 g), m.p. 222°-224° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)CC1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (105 mg, 92%), MS (ISP) m/z=457.4 [(M+H)+], mp 233° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]=3[CH3:23])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:28][C:19]1[C:20](=[O:21])[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[C:16]([CH3:23])[NH:17][C:18]=1[CH3:22]
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A mixture of 3-(4-(4-trifluoromethoxyphenoxy)phenyl)-2,6-dimethylpyridin-4(1H)-one (0.37 g) and N-chlorosuccinimide (0.16 g) in chloroform was stirred at room temperature for 3 days. The precipitate was filtered off and recrystallised from DMF to afford the title compound (0.1 g), m.p. 298°-302°, NMR δH (d6 -DMSO) 7.35-7.5 (2H, m), 7.1-7.3 (4H, m), 7-7.1 (2H, m), 2.38 (3H, s), 2.1 (3H, s).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])=[CH:24][CH:25]=1
Reactant: Cc1ccc(I)cc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Product: Cc1ccc(N2c3nc(N4CCOCC4)cc(=O)n3CC[C@H]2C(F)(F)F)cc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 100 mg of 1-iodo-4-methylbenzene. After purification by silica chromatography (eluent: CH2Cl2/MeOH 98/02), 23 mg of (8S)-9-(4-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a cream solid, the characteristics of which are the following:
Reaction SMILES: C(=O)(O)O.ClC(Cl)C.C([N:16]1[CH2:20][C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C@@H:18]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:17]1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Si:32]([O:31][CH2:30][C@@H:18]1[C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[CH2:20][NH:16][CH2:17]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
1-Chloroethyl chloride carbonate was added to 4 ml of a 1,2-dichloroethane solution of 390 mg of (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(4-nitrophenyl)pyrrolidine under cooling with ice bath, and this was warmed up to room temperature and stirred for 2Hours. This was again cooled in an ice bath, mixed with saturated sodium carbonate aqueous solution, warmed up to room temperature and stirred for 30 minutes. This was extracted twice with chloroform, and the combined organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The oily residue was dissolved in 4 ml of methanol and heated under reflux for 5Hours. After concentration under a reduced pressure, the residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 290 mg of (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(4-nitrophenyl)pyrrolidine as an orange oily substance.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([NH:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:11][C:19](=[O:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(C(=O)NCc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
N-benzyl mandelic amide 100 g is suspended in 250 ml of acetic anhydride and the mixture is heated to 60 degrees C. After all the solid materials have been dissolved in acetic anhydride concentrated sulfuric acid 0.5 ml is added to the solution. Acetylation takes place instantly with exothermic reaction and the reaction mixture turns reddish in color. After the initial exothermic reaction has subsided the mixture is heated to 90-100 degrees C. for 5 hours to complete the acetylation. The reaction mixture is then evaporated at 70-80 degrees C. in vacuum to remove acetic acid, water and the like. The residue is mixed with 300 ml of chloroform. The chloroform layer is washed with 300 ml of 5% aqueous sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. On evaporation of chloroform solution crystalline product 113 g is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([NH2:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:21][C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1ccco1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccco1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.27 mmol) and Furfuryl amine (31 mg, 0.32 mmol). The title compound was obtained as a solid (45 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.34 (1H, m), 8.99 (2H, m), 8.48 (1H, s), 7.58 (1H, m), 6.39 (1H, m), 6.29 (1H, m), 4.39 (2H, m). MS m/z: 428.04, 429.99 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Br)cn1
Temperature: 70 °C
Yield: 57.3 %

Procedure:
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. for 1 hour and then allowed to cool to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a pale yellow volatile oil (2.5 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.87 (dd, 1H), 6.81 (d, 1H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:13]\[OH:14])/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[C:21](OC(=O)C)(=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>CCOCC>[C:21]([O:14]/[N:13]=[C:5](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])\[C:4]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([Cl:1])[C:3]=1[OH:20])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(/C(=N\OC(C)=O)c2ccccc2F)c(O)c1Cl

Procedure:
E-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone oxime (18.1 g) is warmed at 60° C. for 30 minutes with 9 ml of acetic anhydride. The reaction mixture is distributed between ether and 10% NaHCO3 and washed with 10% NaHCO3 until the washes remained basic. Drying, evaporation and trituration with hexane gives E-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 125°-128° C.
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36]>C1COCC1>[CH3:36][C:35]([CH3:37])=[CH:34][CH2:33][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (120.0 g, 0.412 mol) in THF (400 ml) cooled at −78° C. was added dropwise 270 mL of sodium bis(trimethylsilyl)amide solution (1M solution in THF from Aldrich, cat #:245585) over 2 h. The mixture was stirred at −78° C. for additional 1 h. Then 1-bromo-3-methylbut-2-ene (Aldrich cat #: 249904) (71 mL, 0.62 mol) was added slowly over 1 h. The mixture was stirred at −78° C. for 30 min, and allowed to warm to r.t. and stirred for an additional 3 h. The reaction mixture was quenched with 1N HCl aq. solution. Most of THF was removed under reduced pressure. The residue was extracted with ethyl acetate. The combined extracts were washed with sat. aq. NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on a silica gel column with 10˜20% ethyl acetate in hexane to yield the desired product (140 g, 94%). LC/MS: m/e=332.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:12]([CH:11]=[C:7]([C:8]([Cl:20])=[O:9])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)Cl)cc(C(C)(C)C)c1

Procedure:
A mixture of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (9.18 g, 38.9 mmol, prepared by the method of Carter et. al., WO2005021500A1), thionyl chloride (75 mL) and 1 drop of DMF in toluene (200 mL) was heated at reflux for 2 h, cooled and concentrated. The residue was azeotroped with toluene (3×50 mL) and dried under high vacuum to give the title compound as an off-white waxy solid (9.9 g, quantitative yield).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]1([CH:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)[C:24]([OH:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C@@H:51](O)[CH2:50]2>C1COCC1>[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C@@H:51]([O:25][C:24](=[O:26])[CH:23]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:36])([F:37])[F:38])[CH:29]=1)[CH2:50]2
Reactant: O=C(O)C(Nc1cccc(OC(F)(F)F)c1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(OC(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
PS-DCC (920 mg, 1.15 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL). Phenyl-(3-trifluoromethoxy-phenylamino)-acetic acid hydrochloride (I40) (200 mg, 0.57 mmol) and HOBT (176 mg, 1.15 mmol) are added, followed by (R)-quinuclidin-3-ol (219 mg, 1.73 mmol) and the mixture is shaken for 16 hours at RT. PS-DCC is filtered off and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed with water, sat. NaHCO3, water and brine. The organic phase is dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (206 mg, 85% yield, mixture of diastereoisomers).