Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([O:23][CH3:24])[C:11]([CH3:25])=[C:10]2[C:6]=1[C:7](=[O:26])[O:8][CH2:9]2)(=[O:3])[NH2:2].C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C1COCC1>[C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][C:19]([O:21][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:20])=[C:12]([O:23][CH3:24])[C:11]([CH3:25])=[C:10]2[C:6]=1[C:7](=[O:26])[O:8][CH2:9]2)(=[O:3])[NH2:2]
Reactant: COc1c(C)c2c(c(OC(N)=O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: OCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(OC(N)=O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Reaction time: 6 h

Procedure:
To 1.0 g of E-6-(1,3-dihydro-4-carbamoyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid dissolved in 20 ml of dry THF is added 0.59 g of dicyclohexylcarbodiimide and 0.037 g of N-(2-hydroxyethyl)morpholine. The mixture is left at room temperature for 6 hours, then evaporated to dryness. The residue is chromatographed on silica gel, eluting with 50:1 dichloromethane:methanol, to give morpholinoethyl E-6-(1,3-dihydro-4-carbamoyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.
Reaction SMILES: [Br:1][C:2]1[S:13][C:5]2=[N:6][C:7]([Cl:12])=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=1.[CH3:14][Mg]Cl>C1COCC1>[Br:1][C:2]1[S:13][C:5]2=[N:6][C:7]([Cl:12])=[C:8]([CH:10]([OH:11])[CH3:14])[CH:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1cc2cc(Br)sc2nc1Cl
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2cc(Br)sc2nc1Cl
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-6-chlorothieno[2,3-b]pyridine-5-carbaldehyde (2.4 g, 8.7 mmol) (Meth-Cohn, O. Narine B. Tetrahedron Lett., 1978, 2045) in THF (50 mL) at −20° C. was added methylmagnesiumchloride (3.04 mL of 3N in THF, 9.1 mmol) dropwise. The reaction was stirred at −20° C. for 45 minutes and then quenched with 25 mL NH4Cl (sat) and 25 mL of water. The reaction was diluted with ether and the layers were separated. The organic layer was washed with brine and concentrated. Purification by column chromatography afforded 1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethanol. LC/MS (M+1, found=293.8). 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.30 (s, 1H), 5.32 (qd, J=6.3, 2.7 Hz, 1H), 2.19 (br s, 1H), 1.55 (d, J=6.3 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:17]([O:16][C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1csc(N2CC[C@H](O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(N2CC[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of (3S)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (4.1 g, 16.9 mmol) (obtained as described in Reference Example 20(3)) in dimethylformamide (120 ml) were added t-butyldiphenylsilyl chloride (8.8 ml, 33.8 mmol) and imidazole (2.3 g, 33.8 mmol) in an ice bath, and then the reaction mixture was brought to room temperature in 10 minutes, and stirred for overnight. After checking the completion of the reaction, ethanol (1.18 ml) was added thereto in an ice bath, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→1:1) as the eluant to afford (3S)-3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (7.60 g, yield 94%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:7](I)[CH:6]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:17])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][Cl:25])[CH:6]=1
Reactant: COC(=O)Nc1ccc(OC(=O)OC)cc1I
Reactant: C#CCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(OC(=O)OC)cc1C#CCCCCl
Temperature: 70 °C

Procedure:
Carbonic acid 3-iodo-4-methoxycarbonylamino-phenyl ester methyl ester (28.0 g, 79.75 mmol) was dissolved in acetonitrile (350 mL). Triethylamine (22.2mL, 160 mmol), Copper (I) iodide (300 mg, 1.58 mmol), bis(triphenylphosphine)palladium (II) chloride (1.12 g, 1.6 mmol) and 5-chloro-1-pentyne (10.0 mL, 95.54 mmol) were added and the mixture heated 3 h at 70° C. The reaction was cooled and partitioned between ethyl acetate (100 mL) and IM pH4 phosphate buffer (100 mL). The phases were separated, the aqueous phase extracted with ethyl acetate and the combined organic phases washed with 10% sodium thiosulfate solution, brine, dried over sodium sulfate and evaporated. The orange/brown residue (23.5 g, 90%) was used without further purification. (A small sample was purified by column chromatography on silica gel (5:1 hexane/ethyl acetate) for analytical purposes). ISP-MS: m/e=326.3 ([M−H]+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1.O>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][C:19]=1[N+:24]([O-:26])=[O:25]
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3[N+](=O)[O-])c2cc1OC
Temperature: 180 °C
Reaction time: 23 h
Yield: 27.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.15 g) and 4-methyl-2-nitrophenol (1.52 g) were suspended in o-dichlorobenzene (7 ml), and the suspension was stirred at 180° C. for 23 hr. The reaction solution was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (480 mg, yield 27%).
Reaction SMILES: C(O[K])CCC.[C:7]([C:11]1([C:17]([O:19]CC)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O>[C:7]([C:11]1([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)C1(C(C)(C)C)CCCCC1
Agent: CCCCO[K]
Solvent: CS(C)=O
Product: CC(C)(C)C1(C(=O)O)CCCCC1

Procedure:
BuOK in 300 cm3 of anhydrous dimethylsulfoxide and 15.5 g of ethyl 1-tert-butyl-cyclohexyl-carboxylate were heated for 7 hours at 110° C. The mixture was then poured on ice. By acidification with dilute HCl the tert-butyl-cyclohexyl-carboxylic acid was precipitated.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1([OH:33])[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1.[O:34]1CCC[CH2:35]1>O>[F:31][C:29]([F:32])([F:30])[C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=1)[C:17]([N:14]1[CH2:15][CH2:16][C:11]2([O:33][C:35](=[O:34])[NH:1][CH2:2][CH:3]2[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=2)[CH2:12][CH2:13]1)=[O:18]
Reactant: C1CCOC1
Reactant: NCC(c1cccc(Cl)c1)C1(O)CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: O
Product: O=C1NCC(c2cccc(Cl)c2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)O1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 1.48 g (3 mmol) {4-[2-amino-1-(3-chloro-phenyl)-ethyl]-4-hydroxy-piperidin-1-yl}-(3,5-bis-trifluoromethyl-phenyl)-methanone in 30 ml of tetrahydrofuran 1.46 g (9 mmol)1,1′-carbonyl-diimidazole was added and the mixture was stirred over night at room temperature under argon. Water (15 ml) was added, the organic layer was separated, washed twice with a solution of hydrochloric acid (1 M), dried and evaporated. The residue was purified by flash column chromatography (SiO2, ethyl acetate) to yield 1.08 g (69%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-methoxyaniline were reacted to yield N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.67 (d, 1H, J=4.8 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.67 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.83 (d, 2H, J=8.7 Hz), 3.83 (s, 3H), 3.81 (s, 3H); LCMS: ret. time: 22.53 min.; purity: 100%; MS (m/e): 341 (MH+).
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:23])[CH2:4]2)[O:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl.CCOCC>[CH2:25]1[CH2:1][O:2][C:3]2([CH2:20][CH:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:23])[CH2:4]2)[O:24]1
Reactant: C[C@H]1CC2(C[C@@H]3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1CC2(C[C@@H]3CC[C@@H]4[C@H](CC[C@]5(C)C(=O)CC[C@@H]45)[C@@]13C)OCCO2
Yield: 94 %

Procedure:
23 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17β-ol is agitated for 1 hour at room temperature in 230 ml of dichloromethane with 20 g of pyridinium chlorochromate in the presence of 20 g of sodium acetate. The reaction solution is then diluted with ether, filtered off from the insoluble proportions, and the filtrate is washed with water. After drying and evaporation, 21.5 g of 3,3-ethylenedioxy-1-methyl-5α-androstan-17-one is obtained as the crude product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:17])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)cnc2ccc(F)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)cnc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinoxalinone (2.4 g, 11.77 mmol) in 1,4-dioxane (140 ml) and water (250 ml) was treated with osmium tetroxide (4% solution in water; 14.5 ml) and sodium periodate (11.9 g) and the mixture was stirred at rt for 1.5 hours. It was evaporated to dryness onto silica gel and chromatographed on a 300 g silica gel column, eluting with 1:1 ethyl acetate-hexane then ethyl acetate. The early fractions gave (7-fluoro-2-oxo-1(2H)-quinoxalinyl)acetaldehyde which was triturated with ether/DCM 3:1 to give product (1.56 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])=[CH:19][CH:18]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 36 h
Yield: 86.5 %

Procedure:
Methyl 1H-pyrrole-2-carboxylate (330 mg, 2.64 mmol) was dissolved in anhydrous DMF (8 mL). Solid K2CO3 (547 mg, 3.96 mmol) was added, followed by the addition of 1-chloro-4-(chloromethyl)benzene (638 mg, 3.96 mmol). The reaction was permitted to stir at 60° C. for 36 h, at which time the reaction was allowed to cool to rt. Water was added and the resulting precipitate was isolated over a filter, and dried under high vacuum overnight to give 570 mg of the title compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:19](=[O:27])[CH2:18]3)=[C:13]([F:28])[CH:12]=2)[CH2:6]1)=[N+]=[N-].[C:29](OCC)(=[O:31])[CH3:30]>>[F:28][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][NH:1][C:29](=[O:31])[CH3:30])[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:19](=[O:27])[CH2:18]1
Reactant: COCCN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Reactant: CCOC(C)=O
Product: COCCN1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R)-5-Azidomethyl-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one (750 mg) was dissolved in ethyl acetate (15 ml), and the solution purged with argon. Palladium (10% on carbon, 150 mg) was added, followed by acetic anhydride (0.36 ml) and the mixture stirred at ambient temperature under hydrogen confined in a balloon for 2 hours. The mixture was filtered through celite, evaporated to dryness, and chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated, to give N-(5S)-[3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (228 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CO[CH:13](OC)[CH2:14]Br>O1CCOCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]2[CH:13]=[CH:14][N:1]=[C:2]2[CH:7]=1
Reactant: COC(CBr)OC
Reactant: CSc1nc(N)cc(Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(Cl)cc2nccn12

Procedure:
75 g (427 mmol) of 4-amino-6-chloro-2-(methylthio)pyrimidine are dissolved in 3000 ml of dioxane and 750 ml of water. 101.05 g (597.81 mmol) of bromoacetaldehyde dimethyl acetal are added, and the mixture is heated under reflux for 24 h. After the reaction is complete, the dioxane is removed in vacuo and the aqueous suspension is suspended in THF, filtered with suction and washed with some THF. Drying of the solid at 40° C. under high vacuum results in 56.5 g (66% of theory) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[NH:5][CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[NH:5][CH:6]1[CH2:9][C:8]2([CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)NC1CC2(CCN(c3ccc(C=C(C)C)cn3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)NC1CC2(CCN(c3ccc(CC(C)C)cn3)CC2)C1
Yield: 99.2 %

Procedure:
0.05 g (0.45 mmol) of palladium-on-charcoal is added to a solution of 0.37 g (1.08 mmol) of ethyl{7-[5-(2-methylpropenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate obtained in the preceding step, in 15 mL of methanol. The reaction medium is placed in a Parr flask under a hydrogen atmosphere (10 psi) at room temperature for 2 hours. The resulting mixture is filtered through a Büchner funnel and the filtrate is then concentrated under reduced pressure. 0.37 g of expected product is thus obtained in the form of a yellow wax.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:32]I>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:32])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
Add 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (16.03 g; 1.00 equiv; 38.77 mmoles) in 40 mL of dimethyl sulfoxide to a solution of potassium hydroxide (1.5 equiv; 58.16 mmoles; 3.26 g) in 200 mL of dimethyl sulfoxide. After 5 min at room temperature, add methyl iodide (1.1 equiv; 42.65 mmoles; 2.66 mL) in one portion. Stir at room temperature for two hours, then pour the mixture into ice water. Filter the solid, wash with water, and dry under reduced pressure. Triturate the solid in hot heptane, filter and dried under reduced pressure to give 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (8.7 g; 52.49% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH2:19][O:20][CH3:21])[NH:12][C:11](=[O:22])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+]>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH2:19][O:20][CH3:21])[NH:12][C:11](=[O:22])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCC1=C(C(=O)OC)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Yield: 90 %

Procedure:
A stirred mixture of one mole equivalent of methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (10.0 g, 32.0 mmol) and lithium hydroxide (2 equivalents, 1.53 g, 64.0 mol) in H2O-THF (2:1, 300 mL) was heated at reflux temperature for 1 h. The reaction mixture was concentrated, dissolved in water, washed with ethyl acetate and acidified (1 N HCl) to pH 3-4 (pH paper). The precipitated product was collected, washed with water and dried under reduced pressure to give the desired product in 90% yield.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:12]2[N:11]3[CH:13]=[CH:14][CH:15]=[C:10]3/[C:9](=[N:16]/[O:17][CH2:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)/[C:8]=2[S:7][CH:6]=1>C(O)C.C(O)(C)C>[CH3:4][C:5]1[C:12]2[N:11]3[CH:13]=[CH:14][CH:15]=[C:10]3/[C:9](=[N:16]/[O:17][CH2:18][CH2:19][NH2:20])/[C:8]=2[S:7][CH:6]=1
Reactant: Cc1csc2c1-n1cccc1/C2=N/OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: Cc1csc2c1-n1cccc1/C2=N/OCCN
Yield: 36.8 %

Procedure:
Add 0.3 ml (6.1 mmol) of hydrazine hydrate to a solution of 0.85 g (2.2 mmol) of (Z)-3-methyl-8-[(2-phthalimido-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole in 50 ml of a mixture of ethanol/isopropanol, 1:1. The reaction mixture is heated to reflux. After refluxing the mixture for 30 minutes, add 0.3 ml of hydrazine hydrate and heat at reflux again for 90 minutes. Add 0.5 ml of hydrazine hydrate during the course of the 90 minutes' refluxing. After cooling the reaction mixture, the precipitate formed is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with diethyl ether and the ethereal phase is washed with water, dried over magnesium sulfate, treated with animal charcoal and concentrated to yield 200 mg of the title product in the form of an oil (base).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[C:30](Cl)(=[O:46])[O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2>O1CCOCC1.O>[CH:44]1[C:45]2[CH:33]([CH2:32][O:31][C:30]([N:12]3[CH2:13][C@H:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10][C@H:11]3[C:14]([OH:16])=[O:15])=[O:46])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To a solution of (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid, TFA (522 mg, 1.557 mmol) in 1,4-dioxane (4 mL) and water (16 mL) was added potassium carbonate (861 mg, 6.23 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (403 mg, 1.557 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water 0.1% TFA buffer) to afford the pure product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylic acid (430 mg, 62.3% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.86-7.76 (m, 2H), 7.71-7.57 (m, 2H), 7.44-7.27 (m, 9H), 4.58-4.50 (m, 2H), 4.49-4.33 (m, 3H), 4.29-4.19 (m, 2H), 3.72-3.49 (m, 2H), 2.49 (br. s., 1H), 2.10 (ddd, J=13.4, 8.2, 4.8 Hz, 1H). ESI-MS (+) m/z=444 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:25]=[CH:26][C:27](=[O:40])[NH:28][C:29]=4[C:30]4[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].[H-].[Na+].[CH3:43]I>CN(C=O)C.[NH4+].[Cl-]>[CH3:43][N:28]1[C:29]([C:30]2[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:2]([CH3:1])([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)[CH:25]=[CH:26][C:27]1=[O:40]
Reactant: CI
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(=O)[nH]c3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(S(C)(=O)=O)cc2)c(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 158 in DMF (0.05M) at 0° C. was added NaH (1.1 eq) followed by MeI (6 eq). The reaction mixture was stirred at rt for 1 h, diluted with NH4Cl solution and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 70:30, then EtOH:EtOAc, 12:88) to afforded the title compound and EXAMPLE 160.