Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][O:6][C:7](=[O:16])[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[SH2:17]>CO>[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH:9]([SH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC=CC(=O)OC
Reactant: S
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCCC(S)CC(=O)OC
Temperature: 25 °C

Procedure:
A sodium methylate solution is freshly prepared from 0.3 g of sodium and 5 ml of methanol. 10 g of 2-nonenoic acid methyl ester are added to this solution and the mixture is cooled to -70°. After reaching this temperature, 20 ml of hydrogen sulphide are condensed in and the whole batch is transferred into a pre-cooled autoclave. The pressure-vessel is sealed and immediately heated at 50° in an oil-bath for 3 hours. The autoclave is subsequently cooled to room temperature, the excess hydrogen sulphide vented off and the reaction mixture washed with saturated common salt solution and dried. There are obtained 12.4 g of crude product which, after distillation, yields 5.7 g of pure 3-mercaptononanoic acid methyl ester of boiling point 70°/0.2 mm Hg, nD20 1.4602.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:17][F:7])[N:14]=[CH:15][N:16]=1
Reactant: OCc1cc(Cl)ncn1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCc1cc(Cl)ncn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
(Diethylamino)sulphur trifluoride (0.145 mL, 1.096 mmol) was added to DCM (5.5 mL), cooled to −78° C. and treated dropwise with a solution of (6-chloro-4-pyrimidinyl)methanol (Intermediate 25, 132 mg, 0.913 mmol) in DCM (2 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by adding water (5 mL) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-25% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (40 mg);
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][CH2:25]I.O>O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:2][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)CCCCCl)cc1
Reaction time: 0.5 h

Procedure:
1 g (6.9 mmol) of 4-acetylbenzonitrile was dissolved in 8 ml of tetrahydrofuran. 9 ml of lithium bis(trimethylsilyl)amide (1 M solution in hexane) was gradually added to the solution at −70° C. and they were stirred for 30 minutes. 1.43 g (7 mmol) of 1-chloro-3-iodopropane dissolved in 6 ml of tetrahydrofuran was added thereto, and the resultant mixture was stirred at room temperature overnight. The reaction liquid was poured into water. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid and saturated aqueous common salt solution, and then dried over powdery magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel chromatography to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:27][NH:28][CH:29]1[CH2:31][CH2:30]1>>[CH:29]1([N:28]([CH2:27][C:26]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:24]([Cl:23])[CH:25]=2)[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:30][CH2:31]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Clc1ccc(CNC2CC2)cc1Cl
Product: O=C(O)c1ccnc(-c2cn(CCN(Cc3ccc(Cl)c(Cl)c3)C3CC3)cn2)c1
Yield: 7 %

Procedure:
The title compound was prepared in 7% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and (3,4-dichlorobenzyl)cyclopropylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.14 (2H, m), 0.40 (2H, m), 1.85 (1H, m), 2.90 (2H, t, J=6.2 Hz), 3.74 (2H, s), 4.14 (2H, t, J=6.2 Hz), 7.21 (1H, dd, J=8.3 and 1.8 Hz), 7.45-7.56 (3H, m), 7.70 (1H, s), 7.72 (1H, s), 8.26 (1H, s), 8.56 (1H, d). [M+H] Calc'd for C21H20Cl2N4O2, 432. Found, 432.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:38])([F:37])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]OS(C)(=O)=O)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][CH2:29][C:28]#[C:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]([F:18])([F:37])[F:38])=[CH:22][CH:23]=2)=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(F)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(OC(F)(F)F)cc2)c(F)c1

Procedure:
In analogy to the procedure described in example 20A], 2-(3-fluoro-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (example 32E]) and methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) yielded the title compound as brown oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([N:20]2[C:24]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[N:23][N:22]=[N:21]2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:34][O:35][C:36](=[O:57])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[O:48])=[CH:42][CH:41]=1)[NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:34][O:35][C:36](=[O:57])[C@H:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[O:48])=[CH:44][CH:45]=1)[NH:38][C:13]([C:12]1[CH:16]=[CH:17][C:18]([N:20]2[C:24]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[N:23][N:22]=[N:21]2)=[CH:19][C:11]=1[Cl:10])=[O:15]
Reactant: O=C(O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.8 %

Procedure:
In an argon atmosphere, DIPEA (0.102 mL; 0.585 mmol) was added to a stirred solution of 2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]benzoic acid (51 mg; 0.15 mmol), 4-[[(2,6-dichlorophenyl]carbonyl]amino]-L-phenylalanine methyl ester (60 mg; 0.15 mmol) and HBTU (59 mg; 0.1555 mmol) in dimethylformamide (3 mL). The reaction mixture was stirred for 17 hr at room temperature, then was concentrated under reduced pressure. The residual oil was taken up in dichloromethane (25 mL) and washed in turn with 0.5 N HCl (10 mL) and water (10 mL). The aqueous layers were backwashed in turn with dichloromethane. The combined organic layers were dried (Na2SO4) and evaporated to give 85 mg of crude product. This material was crystallized from dichloromethane-diethyl ether to furnish 79 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]phenyl]carbonyl]-L-phenylalanine methyl ester as a colorless solid, mp 155-158° C. FAB HRMS: (C32H26Cl3N7O5) Obs. Mass 694.1158 Calcd. Mass 694.1139 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NN1CCCCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCCCC2)cn1
Yield: 21 %

Procedure:
As described for example 2b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using N-aminopiperidine instead of N-aminomorpholine to the title compound (27 mg, 21%) which was obtained as a white solid. MS: m/e=393.2 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)O
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)C(C)(C)C)ccc32)n1)c1ccccc1
Yield: 29 %

Procedure:
In a procedure analogous to example 44, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and pivalic acid (12 mg, 0.11 mmol) furnished the product (12 mg, 29%) after chromatography.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19].Cl>>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CBr
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CC(C)CN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)piperidine and i-butylbromide; m.p. 212° C. (HCl); MS m/z (rel. intensity, 70 eV) 295 (M+, 1), 252 (80), 129 (40), 115 (50), 70 (bp)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C:15]([CH3:22])([C:18]([O:20]C)=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C:15]([CH3:22])([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)CCc2onc(-c3ccc(Cl)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)CCc2onc(-c3ccc(Cl)cc3)c2CC1
Temperature: 20 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
1 g (3.12 mmol) of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-4H-cyclohept[d]isoxazole-6-carboxylate was dissolved in 60 ml of methanol and a solution of 0.8 g of potassium hydroxide in 4 ml of water was added. The mixture was stirred at 20° C. for 48 hours and then at 50° C. for 6 hours. The methanol was removed by evaporation. Water was added and the mixture was acidified with 2N hydrochloric acid. The mixture was extracted three times with diethyl ether and the extracts were washed with sodium chloride solution and dried over magnesium sulfate. Evaporation and crystallization of the residue from ethyl acetate/hexane gave 0.594 g of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 163° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH2:19]([OH:22])[CH2:20][CH3:21]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:22][CH2:19][CH2:20][CH3:21])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: CCCO
Product: CCCOC(=O)c1csnc1-c1cccc(C(F)(F)F)c1
Yield: 100.5 %

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride and 4 g (0.0667 mol) of 1-propanol was heated on a steam bath for 1 hour and was concentrated under vacuum to 70° (0.5 torr) to give 3.17 g of clear oil, nD20.8 =1.5261, infrared (film) 5.80μ.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (140 mg, 60% in mineral oil, 3.5 mmol) in anhydrous DMF (10 mL) was added 2-chloro-1H-benzoimidazole (460 mg, 3 mmol) at 0° C. The reaction mixture which resulted was allowed to warm to rt and stir at rt for 30 min then was cooled to 0° C. and (2-Chloromethoxy-ethyl)trimethyl-silane was added to this mixture at 0° C. After warming to rt, the mixture was allowed to stir at rt for 16 h. and then was poured onto 100 mL ice-water solution. This solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (20 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product, which was purified by silica gel flash chromatography to afford the title product (660 mg, 80%); 1H NMR (400 MHz, CDCl3); δ 0.03 (s, 9H), 0.89-0.97 (m, 2H), 3.56-3.64 (m, 2H), 5.57 (s, 2H), 7.26-7.35 (m, 2H), 7.45-7.48 (m, 1H), 7.69-7.72 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:7][C:6]([NH:21][C:22]([C:24]2[N:25]=[C:26]([CH:29]3[CH2:31][CH2:30]3)[O:27][CH:28]=2)=[O:23])=[C:5]([N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])[CH2:34][CH2:33]2)[CH:4]=1.[Br-].[Mg+2].[Br-]>N1C=CC=CC=1>[OH:2][C:3]1[C:8]([C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:7][C:6]([NH:21][C:22]([C:24]2[N:25]=[C:26]([CH:29]3[CH2:30][CH2:31]3)[O:27][CH:28]=2)=[O:23])=[C:5]([N:32]2[CH2:33][CH2:34][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])[CH2:36][CH2:37]2)[CH:4]=1
Reactant: COc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: c1ccncc1
Product: Cc1ccccc1N1CCN(c2cc(O)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To a solution of 2-cyclopropyl-oxazole-4-carboxylic acid [4-methoxy-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 2c (40.0 mg, 0.067 mmol) in pyridine (5.0 mL) was added magnesium bromide (49.0 mg, 0.268 mmol). The reaction was stirred at 130° C. for 16 h. Cooled, concentrated and the crude 2d was dissolved in methanol/water mixture and purified on preparative HPLC using methanol/water as eluent.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[C:18]([O:26][CH2:27][O:28][CH3:29])[CH:17]=2)=[CH:10][CH:9]=1)=O)C.[NH2:31][NH2:32]>CCO>[CH3:29][O:28][CH2:27][O:26][C:18]1[CH:17]=[C:16]([CH:15]=[CH:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH2:5][C:4](=[O:3])[N:31]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:32]=3)=[CH:13][CH:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][O:24][CH3:25]
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1ccc(C=Cc2ccc(OCOC)c(OCOC)c2)cc1
Solvent: CCO
Product: COCOc1ccc(C=Cc2ccc(C3=NN(c4ccccc4)C(=O)C3)cc2)cc1OCOC

Procedure:
A solution of 3-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-3-oxo-propionic acid ethyl ester (400 mg) and hydrazine (excess) in EtOH (30 mL) was stirred at 90° C. for 5 hours. Evaporation and purification by flash chromatography eluted with 5-10% MeOH in DCM gave 5-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro-pyrazol-3-one as a yellow oil (260 mg). 1H NMR (CDCl3, 300 MHz): 7.95 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.40-7.00(m, 7H), 6.90 (d, 1H), 6.58 (d, J=12.0 Hz, 1H), 6.50 (d, J=12.0 Hz, 1H) 5.21, 5.07(2s, 4H, MOM), 3.78(s, 2H), 33.51, 3.41 (2s, 6H, MOM) ppm. 13C NMR (CDCl3, 75 MHz 170.65, 154.82, 147.23, 147.15, 140.38, 138.53, 131.56, 129.84, 129.68, 129.29, 128.88, 126.17, 125.69, 123.72, 119.42, 117.83, 116.67, 56.69, 56.52, 40.03 ppm. MS: 459 (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([F:43])[CH:37]=2)([C:33](O)=[O:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:30]2([C:33]([N:16]3[CH2:15][CH2:14][N:13]([C:11]4[C:12]5[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=5[N:8]=[CH:9][N:10]=4)[CH2:18][CH2:17]3)=[O:34])[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:32][CH2:31]2)=[CH:37][C:38]=1[F:43]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)c(F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)c(F)c5)CCN(C(=O)OC(C)(C)C)CC4)CC3)c21
Reaction time: 4 h
Yield: 22.9 %

Procedure:
(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (35.0 mg, 0.114 mmol) and 1-(tert -butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid (40.8 mg, 0.114 mmol) were dissolved in DCM (1.1 mL) and treated with DIEA (0.0595 ml, 0.342 mmol) at ambient temperature. The mixture was allowed to homogenize before the HBTU (47.5 mg, 0.125 mmol) was added in one lot. The reaction was allowed to stir for four hours to completion by LCMS analysis of the crude. The reaction was diluted with DCM, washed with diluted NaHCO3 solution, washed with water, washed with brine, and separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 5% methanol in ethyl acetate) to afford the pure tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylate (15.0 mg, 22.9% yield) as a pale yellow oil. MS (APCI+) [M+H]+574; Rf: 2.92.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2]
Reactant: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1OCC
Temperature: 65 °C
Reaction time: 20 h
Yield: 24.1 %

Procedure:
Into a solution of methyl 7-[[3-ethoxy-4-(propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.76 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (3.0 ml), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[3-ethoxy-4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (178 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2NN=[N:24][N:23]=2)=[CH:18][CH:17]=1.N1C=CC=CC=1>O>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:24][N:23]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc(-c2nnn[nH]2)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Yield: 3487.1 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (1.39 g), 5-(4-trifluoromethylphenyl)-1H-tetrazol (1.50 g) and pyridine (30 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration and purified by silica gel column chromatography (hexane:tetrahydrofuran=1:9, volume ratio) to give methyl 4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1. 85 g, yield 76%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 216–217° C.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([OH:21])[CH:10]=3.Cl.[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28]Cl)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([O:21][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH3:31])[CH2:23][CH3:24])[CH:10]=3)[CH3:24]
Reactant: Oc1ccc2c(c1)-c1ccc(O)c3cccc-2c13
Reactant: CCN(CC)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCCOc1ccc2c(c1)-c1ccc(OCCCN(CC)CC)c3cccc-2c13

Procedure:
To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 27.9 g (0.15 mole) of 3-diethylaminopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-diethylaminopropoxy)-fluoranthene which is converted to the dihydrochloride salt with ethereal HCl and recrystallized from methanolbutanone, M.P. 235°-236.5°C.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]([F:31])([F:30])[C:23]#[C:24][C:25](OCC)=[O:26]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:25](=[O:26])[CH:24]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Solvent: CCO
Product: O=c1cc(C(F)(F)F)n2c(n1)OC(COc1ccc(C3CCCCC3)cc1)C2
Temperature: 170 °C
Yield: 25.3 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (165 mg, 0.602 mmol) in ethanol (6 mL) was added ethyl 4,4,4-trifluoro-2-butynoate (100 mg, 0.602 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 30 mins. Solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-10% EtOH/CH2Cl2) to afford 60 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-trifluoromethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as an off-white solid.