Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([OH:7])([CH3:6])[CH2:4][NH3+:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:9])([F:8])[C:3]([OH:7])([CH3:6])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:15]
Reactant: CC(O)(C[NH3+])C(F)(F)F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture comprising 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-ammonium (0.9 g), phthalic anhydride (1.039 g) and DIPEA (2.188 ml) in chloroform (30 ml) was heated at 70° C. for 5 hours. After cooling to RT, the mixture was washed with water and passed through a phase separator. The organic phase was reduced to dryness. The crude product was purified by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc removed to give the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.92 (2H, m), 7.85 (2H, m), 3.95 (2H, m), 1.36 (3H, s).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:17][CH:18]=2)[S:10][C:11]=1[CH3:12])[CH3:6])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[N:15]=[CH:14][C:13]([C:9]2[S:10][C:11]([CH3:12])=[C:7]([CH:5]([CH3:6])[CH2:4][OH:3])[N:8]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(C)c1nc(-c2ccc(-c3ccccc3F)nc2)sc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(-c3ccccc3F)nc2)nc1C(C)CO
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propionic acid ethyl ester (2.6 g, 7.03 mmol) in THF (15 mL) is added LiAlH4 (1.0 M in THF, 7.1 mL, 7.1 mmol) at 0–5° C., and then stirred for 2 h. The reaction is then quenched by water and 5 N NaOH, diluted with THF and filtered through a pad of celite. The filtrate is concentrated and purified by column yielding 1.8 g of the product.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[OH-:5].[Na+]>>[S:1]([O-:4])([O-:3])=[O:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: [OH-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=S(=O)([O-])[O-]

Procedure:
FOr oxidation down to 1 g Na2S per liter black liquor, the black liquor consmues 39 liters of air per liter black liquor, while sulphite from soap splitting reduces the air demand to 18 liter per liter black liquor. For these points the alkalinity values of the black liquors are 4.5 g NaOH/liter and 8.0 g NaOH/liter, respectively. Alkali useful for the neutralization of the sulphite solution is thus produced by the reaction between sulphite and sulphide while sulphate from conventional sulphuric splitting solution is not at all capable of oxidizing the sulphide or to react with any other sulphur compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:10]([C:14]1[NH:15][C:16]([Cl:21])=[C:17]([CH:19]=O)[N:18]=1)[CH2:11][CH2:12][CH3:13].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:10]([C:14]1[NH:18][C:17]([CH2:19][NH:1][C:2]2[N:3]=[CH:4][NH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[C:16]([Cl:21])[N:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CCCCc1nc(C=O)c(Cl)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(CNc2nc[nH]c2C(N)=O)[nH]1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
A reaction mixture of 4-amino-5-imidazolecarboxamide (0.50 g, 3.96 mmol), 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde (0.89 g, 4.76 mmol), and NaCNBH3 (0.25 g, 3.96 mmol) in methanol (5 mL) was stirred at r.t. over night. Acetic acid (0.24 g, 3.96 mmol) was added and the mixture was heated at 50° C. for 5 h. The mixture was concentrated in vacuo and dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.30 g (26%) of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][N:11]=3)[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23]([O:25]C)=[O:24])=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:27])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][N:11]=3)[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:27])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1
Temperature: 80 °C

Procedure:
To a suspension of methyl 2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxylate, (EXAMPLE 148), (0.35 g, 0.906 mmol) in ethanol (5 mL) was added sodium hydroxide 1.0 N solution (2.72 mL, 2.72 mmol). The reaction mixture was heated to 80° C. for 1 h and concentrated. The residue was diluted with water and the pH of the resulting solution adjusted to 6 by the addition of 1N HCl (3.1 mL) solution. The precipitate formed was filtered and dried under high vacuum to give the title compound 2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxylic acid (0.300 g, 0.806 mmol, 89% yield). m/z: 373.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 12.50 (br. s., 1 H), 8.18-8.51 (m, 1 H), 7.79-8.15 (m, 2 H), 7.35-7.66 (m, 1 H), 5.14 (quin, J=8.26 Hz, 1 H), 4.38 (br. s., 1 H), 3.16-3.31 (m, 2 H), 2.97 (tt, J=7.02, 3.64 Hz, 1 H), 2.31-2.47 (m, 2 H), 0.94-1.13 (m, 4 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:29]([O:37][C:38](=[O:41])[CH2:39][NH2:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:29]([O:37][C:38]([CH2:39][NH:40][C:15]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:17])=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCOC(=O)CN
Reactant: O=C(O)c1ncccc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCOC(=O)CNC(=O)c1ncccc1OCc1ccccc1

Procedure:
1.1 g (5 mmol) of 3-benzyloxypyridine-2-carboxylic acid were condensed with glycine 1-octyl ester tosylate in analogy with Example 147. 1.3 g of the title compound were obtained, without column chromatography, as a pale brown oil, 1H NMR (DMSO): δ=5.24 (s, CH2 -benzyl).
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]1[C@@H:14]([CH2:15][F:16])[CH2:13][N:12]([C:17]2[C:26]([O:27][CH3:28])=[C:25]3[C:20]([C:21](=[O:35])[C:22]([C:32]([OH:34])=[O:33])=[CH:23][N:24]3[CH:29]3[CH2:31][CH2:30]3)=[CH:19][C:18]=2[F:36])[CH2:11]1)=O)(C)(C)C>O>[NH2:9][C@H:10]1[C@@H:14]([CH2:15][F:16])[CH2:13][N:12]([C:17]2[C:26]([O:27][CH3:28])=[C:25]3[C:20]([C:21](=[O:35])[C:22]([C:32]([OH:34])=[O:33])=[CH:23][N:24]3[CH:29]3[CH2:31][CH2:30]3)=[CH:19][C:18]=2[F:36])[CH2:11]1
Reactant: COc1c(N2C[C@H](CF)[C@H](NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: O
Product: COc1c(N2C[C@H](CF)[C@H](N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to 7-[3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline -3-carboxylic acid (140 mg, 0.28 mmol) which was cooled in an ice bath, and the mixture was stirred for 30 minutes at the same temperature. The reaction solution was diluted with water (50 ml) and washed with chloroform (50 ml×3) and then, while cooling in an ice bath, the aqueous layer was alkalified with 50% sodium hydroxide aqueous solution. The aqueous layer was washed with dichloromethane (50 ml×3), adjusted to pH 7.4 with concentrated hydrochloric acid and 1N hydrochloric acid and then extracted with chloroform (100 ml×3). The organic layer was dried over sodium sulfate, the solvent was evaporated, and the thus obtained residue was purified by its recrystallization from a 28% aqueous ammonia-ethanol mixed solvent to give 94 mg (85%) of the title compound in the form of light yellow crystals.
Reaction SMILES: [OH-].[Na+].CO.[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([C:23]([O:25]C)=[O:24])=[CH:20][CH:19]=3)=[CH:14][C:13]=2[C:27]#[N:28])[CH:9]=[CH:10][CH:11]=1.Cl>O1CCCC1>[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=3)=[CH:14][C:13]=2[C:27]#[N:28])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3cccc(N)c3)c(C#N)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2ccc(C(=O)O)s2)ccc1-c1cccc(N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.2 ml of aqueous 1 M sodium hydroxide solution was added to a methanol (0.25 ml)/tetrahydrofuran (0.25 ml) solution of methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate, followed by stirring overnight at 60° C. 1 M hydrochloric acid was added to the reaction liquid to make it acidic, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC [elution through column: SunFire (registered trademark) C18 5 μm, 19 mm×100 mm, solvent: MeOH/aqueous 0.1% formic acid solution 10/90 for 1 minute, ratio change to 95/5, taking 8 minutes, and further elution with 95/5 for 3 minutes, flow rate: 25 mL/min), thereby obtaining 2.5 mg of 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][OH:11])[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:4]2[CH:5]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7]([CH2:9][CH2:10][OH:11])=[CH:8][C:3]2=[O:2])=[CH:23][CH:24]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1ccc(-c2cnc(OC)cc2CCO)cc1
Product: COc1ccc(-c2cn(Cc3ccc(Cl)cc3)c(=O)cc2CCO)cc1
Yield: 35.5 %

Procedure:
According to Scheme 30 Step 3: The title compound was prepared from 2-(2-methoxy-5-(4-methoxyphenyl)pyridin-4-yl)ethanol (1 eq, 0.62 mmol, 0.16 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 0.93 mmol, 0.19 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 19 hours under 90° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 98/2 as eluent afford 1-(4-chlorobenzyl)-4-(2-hydroxyethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.22 mmol, 82 mg, 36%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:30]=3)[N:13]([CH3:28])[C:14]=2[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])=[CH:6][CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH2:35]([C:31]1[CH:30]=[C:29]([C:12]2[N:13]([CH3:28])[C:14]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[CH2:21][CH2:22]3)=[O:16])=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=3)[N:11]=2)[CH:34]=[CH:33][CH:32]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCc1cccc(-c2nc(-c3ccc(C(=O)OC)cc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCc1cccc(-c2nc(-c3ccc(C(=O)O)cc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Temperature: 50 °C
Reaction time: 10 h
Yield: 88.7 %

Procedure:
To a solution of 0.15 g (0.27 mmol) of 4-[2-(3-hexyl-phenyl)-1-methyl-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-imidazol-4-yl]-benzoic acid methyl ester (example 10) in 10 ml of THF/MeOH 1:1 was added drop by drop 0.67 ml (0.67 mmol) of lithium hydroxide solution (1 molar in water) and the reaction mixture was heated up to 50° C. After 10 hours, the solvents were evaporated and the residue poured into crashed ice, acidified with HCl (25% in water) and extracted twice with CH2Cl2/2-propanol 4:1; the organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.13 g (89%) of the title compound as light brown solid. MS: 541.2 ([M-H]−).
Reaction SMILES: [Li+].[Cl-].[C:3]([O:7][C:8](=[O:23])[NH:9][CH2:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:14]([NH2:21])=[C:13](I)[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:24](C([Sn])=C(CCCC)CCCC)[CH2:25]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:3]([O:7][C:8](=[O:23])[NH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH2:25])[C:14]([NH2:21])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NCc1cc(I)c(N)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1N

Procedure:
Pd(PPh3)4 (0.06 eq, 0.014 mmol, 16.64 mg) and LiCl (2.8 eq, 0.67 mmol, 28.49 mg) were added into DMF. (4-Amino-3-iodo-5-trifluoromethylbenzyl)carbamic acid tert-butyl ester (100 mg, 0.24 mmol) and tributylvinyltin (1.5 eq, 0.36 mmol, 105.37 μl) were added into the reaction mixture. The reaction mixture was stirred for 12 ha in reflux. The reaction mixture was purified according to step 4 of Example 8 to give a title product, yellow syrup (51.5 mg, 67.87%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)(O)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC1CCC(O)(c2cccc(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC1=CCC(c2cccc(F)c2)CC1
Temperature: 30 °C
Yield: 93.6 %

Procedure:
The compound (10) (80.0 g), p-toluenesulfonic acid (2.4 g) and toluene (250 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture obtained was cooled to 30° C., and then water (500 ml) and toluene (900 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation into an organic phase was carried out. The organic phase obtained was fractionated, washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and dried, giving 70.3 g of 4-heptyl-1-(3-fluorophenyl)-3-cyclohexene (11). The yield based on the compound (11) was 94.0%.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([OH:22])[CH:24]=3)[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(N2CCNCC2)cc1O
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(O)c3)CC2)c(OC)nc1C

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield: 59% Example 53
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[O:12]=[C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:17]2[CH2:29][CH2:30][C:31](=[O:32])[C:16]=2[CH:15]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=2[S:41][CH3:42])[NH:14]1.C([O-])(O)=O.[Na+]>ClCCl>[O:12]=[C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:17]2[CH2:29][CH2:30][C:31](=[O:32])[C:16]=2[CH:15]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=2[S:41]([CH3:42])=[O:6])[NH:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2

Procedure:
meta-Chloroperoxybenzoic acid (77%, 390 mg, 1.74 mmol) is added at room temperature to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylthio)benzonitrile (example 16, 776 mg, 1.75 mmol) in dichloromethane, and the mixture is stirred for 30 min Saturated aqueous NaHCO3 solution is added, and the mixture is extracted with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate. Yield: 527 mg; ESI mass spectrum [M+H]+=460; Retention time HPLC: 0.48 min (early eluting diastereomer), 0.49 (late eluting diastereomer) (X012_S01).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)[OH:4])#[CH:2].[OH:28][C:29]1[CH:38]=[C:37](I)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32]>>[OH:28][C:29]1[CH:38]=[C:37]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:6]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: C#CC(O)c1cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c1
Reactant: COC(=O)c1ccc(I)cc1O
Product: COC(=O)c1ccc(C#CC(O)c2cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c2)cc1O

Procedure:
In a similar manner to Example 1(d), by reaction of 6.7 g (17.3 mmol) of α-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol with 4.8 g (17.3 mmol) of methyl 2-hydroxy-4-iodobenzoate, 8.5 g (91%) of the expected ester are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[NH3:25].CO>>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:25])=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cc1F
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of methyl 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate (25 mg, 0.071 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) was heated at 90° C. in a sealed tube overnight. After evaporating the mixture to dryness, the residue was used directly in next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
440 mg (1.5 mmol) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 15 ml CH2Cl2 were treated with 0.15 ml (1.8 mmol) methane sulfonyl chloride and 0.63 ml (4.5 mmol) triethyl amine at 0° C. for 10 min. The solution was stirred at RT for 2 h and was diluted with CH2Cl2. The organic phase was extracted with 1M HCl and water, and dried over Na2SO4. Evaporation yielded 400 mg (71%) Methanesulfonic acid 5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as light yellow viscous oil, MS: 372 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21](=[O:26])[CH2:22][N+:23]([O-:25])=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C@@H:21]([OH:26])[CH2:22][N+:23]([O-:25])=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)C[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@@H](O)C[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 11.3 g (30.8 mmol) of benzyl 2(S)-tert-butoxycarbonylamino-5-nitro-4-oxopentanoate in 300 ml of tetrahydrofuran is cooled to −78° C., 30.8 ml of a 1M solution of L-Selectrideo in tetrahydrofuran are added dropwise, and the mixture is stirred at −78° C. for 1 h. After warming to RT, a saturated ammonium chloride solution is cautiously added to the solution. The reaction solution is concentrated, and the residue is taken up in water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated. The crude product is prepurified on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 10/1), and the collected fractions are concentrated and stirred with cyclohexane/ethyl acetate 5/1. The remaining crystals are collected by suction filtration and dried. 2.34 g (21% of theory) of the desired diastereomer are obtained. Chromatographic separation of the mother liquor on Lichrospher Diol 10 μm (mobile phase: ethanol/isohexane 5/95) results in a further 0.8 g (6.7% of theory) of the product.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]>CC(C)=O>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC(C)=O
Product: O=C(O)C(Sc1nc2ccccc2[nH]1)c1ccccc1
Yield: 92 %

Procedure:
An acetone solution of 13.5 g (0.09M) of 2-mercaptobenzimidazole and 19.4 g (0.09M) of α-bromophenylacetic acid containing 10 ml glacial acetic acid is heated for 3 hours. The solid HBr salt upon removal of the solvent is disproportionated by stirring in 1 L of water. The crude material is recrystallied from aqueous acetone. The recrystallized material weighs 24.0 g (92% yield) and melts at 187°-8° C. dec.