Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[CH2:5]([CH:4]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][OH:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCC(CO)CCCCCCCC
Temperature: 210 °C
Reaction time: 3 h

Procedure:
In a stirred reactor consisting of a flask, heating mushroom, water separator, reflux condenser and nitrogen inlet, 1 g (0.015 mol) of potassium hydroxide was added to 500 g (3.2 mol) of decanal (99% by weight) at 20° C., followed by heating to 210° C. The water formed during the reaction was continuously distilled off. After 3 hours, the reaction was terminated, the reaction mixture was cooled to 20° C. and the potassium hydroxide precipitated was filtered off. The resulting clear liquid contained 90% by weight of α,β-unsaturated aldehyde, 4% by weight trimers, 2% by weight esters and 4% by weight unreacted starting aldehyde. The reaction mixture was transferred to an autoclave and hydrogenated for 3 hours at 230° C./250 bar in the presence of a nickel catalyst until there was no further uptake of hydrogen. 90% by weight of the hydrogenation product consisted of 2-octyl dodecanol, 6% by weight of decanol and 4% by weight of trimers. After distillation, the 2-octyl dodecanol was obtained in a purity of 95.7% by weight.
Reaction SMILES: [O:1]=O.[CH:3]1([OH:14])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH:5]([OH:12])[CH:4]1[OH:13]>C1N(CCCS(O)(=O)=O)CCOC1>[O:14]=[CH:3][C@@H:8]([C@H:7]([C@@H:6]([C@@H:5]([C:4]([OH:13])=[O:1])[OH:12])[OH:11])[OH:10])[OH:9]
Reactant: O=O
Reactant: OC1C(O)C(O)C(O)C(O)C1O
Agent: O=S(=O)(O)CCCN1CCOCC1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O

Procedure:
The enzyme reaction was carried out in 0.7 L reactors with temperature, pH, agitation and dissolved oxygen control. A solution of 50 g/L myo-inositol in 50 mM MOPS at pH 6.5 (200 mL) was used in the standard protocol. Temperature was controlled at 15° C. Pure air, air enriched with oxygen or pure oxygen were used to supply enough oxygen for the reaction to proceed. The air was supplied either in the headspace of the reactor or was sparged into the liquid. The formation of glucuronic acid results in a decrease in the pH of the broth. To keep the pH at the desired value, pH 6.5, the acid was neutralized with 4 N NaOH. The enzyme solution was added to reach an initial concentration of 2 g soluble protein/L. The reaction proceeded very fast immediately after the enzyme addition and the rate decayed over time. Different experiments varied the number and/or amount of enzyme additions. The progress of the reaction was followed by HPLC analysis.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([S:15][CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[Br:17][CH2:18][C:19](Br)=[O:20]>C1COCC1.O>[CH3:16][S:15][C:10]1[C:9]([NH:8][C:19](=[O:20])[CH2:18][Br:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CSc1ncccc1N
Reactant: O=C(Br)CBr
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncccc1NC(=O)CBr
Reaction time: 17 h
Yield: 22.5 %

Procedure:
Triethylamine (197 mg, 1.95 mmol) was added to a solution of 3-amino-2-(methylthio)pyridine (248 mg, 1.77 mmol) in THF (5 ml), then a solution of bromoacetyl bromide (428 mg, 2.12 mmol) in THF (1 ml) was dropped thereinto and the mixture was stirred for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated therefrom and the residue was purified by a silica gel column chromatography (developing solvent, hexane:ethyl acetate=5:1) to provide 104 mg (yield 22%) of N-(2-methylthio-3-pyridyl)-2-bromoacetamide as colorless powdery crystals.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=1[O:26][CH3:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N>CO>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=1[O:26][CH3:27])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
Sodium dithionite (1.5 g) was added to a solution of 1-benzyloxy-2-methoxy-5-nitrobenzene (2.5 gm) in a mixture of methanol (20 ml)/aqueous ammonia (4 ml). After stirring for 12 hrs at room temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (75 ml) and water (50 ml). The ethyl acetate layer was washed with water (25 ml), brine solution (25 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography over silica gel eluting with ethyl acetate/hexane (1:1) provided 0.771 g of 1-Benzyloxy-2-methoxy-5-aminobenzene (Yield=35%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(-c2ccnn2C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nccc1-c1ccc(C(=O)O)cc1Br
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To a solution of methyl 3-bromo-4-(1-methyl-1H-pyrazol-5-yl)benzoate (275 mg, 093 mmol) in MeOH (10 mL) was added NaOH solution (2.5 M, 3.72 mL, 9.3 mmol). After 12 h at 25° C., the solution was partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 with 6N HCl solution. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4 and concentrated to afford the title compound as a white solid (230.1 mg, 88%): LC-MS (ES) m/z=282 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[Na+].[Cl-]>CN(C)C=O.C(O)(=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][C:7]=1[O:12][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Reactant: Clc1cnccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(F)c(Oc2cnccn2)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g, 11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH in mineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol) and heated at 80° C. for overnight. One more equivalent of chloropyrazine was added and heated at the same temperature for 10 h. The reaction mixture was poured into a flask containing 150 ml of aqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with sat NaCl (150 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.55 g (50%) of product. MS (ESI+) m/z 263 (M+H)+;
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][CH2:21]2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 4.56 g (12 mmol) [trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester and 29 mL 4N HCl in dioxane was stirred for 6 h at 50° C. evaporated to dryness and used without further purification in the subsequent step. MS (m/e): 254.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc([N+](=O)[O-])c2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(N)c2)C1
Yield: 94.8 %

Procedure:
To a solution of tert-butyl [(3R)-1-(3-nitrobenzyl)-3-pyrrolidinyl]carbamate (750 mg) in ethanol (5.6 mL) and H2O (1.9 mL) was added NH4Cl (62.4 mg) and Fe (391 mg), which was stirred under reflux for 1 hour. The resultant was filtered and evaporated in vacuo. The residue was washed water and brine. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo to give tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (645 mg) as a brown oil.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([S:17][C:7]=2[CH:6]=[C:5]([O:19]C)[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.Cl.N1C=CC=CC=1.Cl>>[OH:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([S:17][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: COc1cc(OC)c2c(c1)SC1(CCCCC1)CC2=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CC2(CCCCC2)Sc2cc(O)cc(O)c21
Yield: 96.5 %

Procedure:
A mixture of 5,7-Dimethoxyspiro[2H-1-benzothiin -2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 78) (0.526 g, 1.80 mmol) and pyridine hydrochloride (4 g, 34.6 mmol) is heated at 205°-210° C. for 50 minutes with stirring under nitrogen gas. After cooling, dilute HCl is added to the mixture. The mixture is extracted with diethyl ether. The extract is washed with saturated brine, dried, and the solvent is removed. The residue is placed on a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:9) to obtain the title compound as a crystalline solid (0.459 g, 96%). Recrystallization from diethyl ether gives a product having a melting point of 160°-162° C.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl.C(O)C>C(OCC)(=O)C>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([NH:13][C:11]1[CH:10]=[C:9]([O:22][C:23]([F:25])([F:26])[F:24])[CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6]2)(=[O:15])=[O:16]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixed solution of ethyl 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (105 mg), 6N hydrochloric acid (4 mL) and ethanol (4 mL) was stirred at 80° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were suspended in dichloromethane (10 mL), and thionyl chloride (0.20 mL) and N,N-dimethylformamide (1 drop) were added. The mixture was stirred at 50° C. for 2 hr. Ethanol (2 mL) and triethylamine (1 mL) were added to the reaction solution, and the mixture was stirred at 50° C. for 2 hr. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8), and the obtained oil was crystallized from diethyl ether-hexane to give the title compound (41 mg, yield 43%) as colorless crystals. melting point 192-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[C:11](=O)[NH:10][C:9]3=O)=[C:4]([F:16])[CH:3]=1.B(F)(F)F.CCOCC.S(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[C:4]([F:16])[CH:3]=1
Reactant: O=C1NC(=O)C2(c3ccc(Br)cc3F)CC12
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: Fc1cc(Br)ccc1C12CNCC1C2

Procedure:
To a solution of 1-(4-bromo-2-fluoro-phenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (2.5 g, 8.8 mmol) in THF (20 mL) were added BF3.OEt2 (1.8 mL, 1.8 mmol) and BH3.Me2S (11.0 mL, 22.0 mmol) at r.t. The reaction mixture was refluxed for 3 h and progress of the reaction was monitored by TLC. On completion, the reaction mixture was quenched with 20% HCl (10 mL) and solvent evaporated, residue was washed with diethylether (10 mL). The aqueous layer was neutralized with sodium carbonate and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The title compound was obtained as brown liquid in crude form (1.22 g, 54%) and was as such used in the next step.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]([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)[CH2:9][NH:10]C(=O)OC(C)(C)C)[C:2]([CH3:5])([CH3:4])[CH3:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:6][CH2:7][C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][NH2:10])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CNCC(CNC(=O)OC(C)(C)C)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CNCC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared by treating a solution of the crude tert-butyl 3-(neopentylamino)-2,2-diphenylpropylcarbamate (0.055 g) in dichloromethane (5 mL) with trifluoroacetic acid (1 mL) at 23° C. for 30 minutes. The reaction was concentrated to dryness and the residue was used as such in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:11](=[O:21])[C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:13][C:6]3=[CH:5][C:4]=2[CH:3]=1.[OH-:22].[Na+]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:13][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:20])[C:11]([OH:21])=[O:22])=[CH:5]2
Reactant: CC1(c2ccccc2)Sc2cc3cc(O)ccc3n2C1=O
Reactant: [OH-]
Agent: [Na+]
Product: CC(Sc1cc2cc(O)ccc2[nH]1)(C(=O)O)c1ccccc1
Yield: 71 %

Procedure:
To the 7-hydroxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3(2H)-one (3.65 g), a 2N sodium hydroxide solution (70 ml) was added, and the mixture was heated and refluxed for 30 minutes. The reaction mixture was allowed to cool, and was washed with ethyl acetate. The water layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and a saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (diluting solvent: chloroform/methanol=4:1), and recrystallized from acetonitrile to give 2.77 g (yield: 71%) of the desired product compound as a brown powder. The melting point was 179.5-181.5° C.
Reaction SMILES: [CH2:1](N(C)CCO)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:14]1>>[CH2:1]([CH2:18][NH:13][CH2:14][CH2:15][N:13]1[CH2:14][CH2:15][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCCc2ccccc2)CC1

Procedure:
The title compound was prepared by mesylation of N-benzyl-N-methyl ethanolamine, which was then reacted with biphenyl-2-ylcarbamic acid piperidin-4-yl ester in an alkylation reaction.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.Cl.C[N:35](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O>[S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:35])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 4-acetyl-benzamide (0.3 g, 1.84 mmol) and 5-(benzo[b]thein-2yl)-2,4-dimethoxybenzaldehyde (0.55 g, 1.84 mmol) in a mixture of N,N-dimethylformamide (7 mL) and methanol (3 mL) was added lithium methoxide (0.14 g, 3.68 mmol). The reaction mixture was allowed to stir at ambient temperature for 9 hours. The resulting precipitate was collected by filtration, washed with methanol, dried in vacuo to obtain the title compound as a yellow solid (5.56 g, 68%). Alternatively, to mixture of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid (Ex-3, 3.0 g, 6.75 mmol), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.81 g, 9.45 mmol), 1-hydroxybenzotriazole hydrate (1.09 g, 8.10 mmol) and ammonium chloride (1.81 g, 33.7 mmol) in N,N-dimethylformamide (60 mL) was added triethylamine (2.4 mL, 16.9 mmol). The reaction mixture was allowed to stir overnight at ambient temperature. Any insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate to 180 mL. The solution of ethyl acetate was washed with a saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give the title compound as a yellow solid (2.82 g, 94%), mp 240–241° C. 1H-NMR (DMSO-d6) δ 8.37 (s, 1H), 8.19 (d, J=7.8 Hz, 2H), 8.12 (d, J=15.3 Hz, 1H), 8.04–7.91 (m, 6H), 7.83 (d, J=7.5 Hz, 1H), 7.55 (s, 1H), 7.36–7.30 (m, 2H), 6.87 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H). MS m/z=444 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].CC(C)([O-])C.[K+].[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:8])=[O:9])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]([CH2:37][O:36][CH2:34][CH3:35])[C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CCOCCl
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCn1c(-c2ccc(Cl)cc2)c(S(=O)(=O)c2ccc(Cl)cc2)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-4-[(p-chlorophenyl)sulfonyl]-2-(trifluoromethyl)pyrrole (0.92 g, 1.84 mmol) and potassium tert-butoxide (0.26 g, 2.21 mmol) in tetrahydrofuran is stirred at room temperature for 5 minutes, treated with a solution of chloromethyl ethyl ether (0.21 g, 2.21 mmol) in tetrahydrofuran, stirred at room temperature overnight, diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid (0.98 g, mp 107°-112° C.).
Reaction SMILES: [CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C@H:16]3[O:21][C:20](=[O:22])[CH2:19][C@H:18]([OH:23])[CH2:17]3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[OH-:31].[Ca+2].[OH-]>O>[CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:31])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([OH:21])=[O:22])=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1C[C@H](O)C[C@@H](/C=C/c2c(C3CC3)nc3ccccc3c2-c2ccc(F)cc2)O1
Reactant: [OH-]
Agent: [Ca+2]
Solvent: O
Product: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
E-6-{2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}-(4R,6S)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (2.0 g), water (20.0 mL), and calcium hydroxide (0.4 g) were added to a reactor. The reaction mixture was stirred at room temperature for 3 hours and then filtered under reduced pressure. The resulting white solid was dried to obtain (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy hept-6-enoic acid 1/2 calcium salt (2.0 g, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][N:24]1[N:28]=[N:27][C:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=O)=[N:25]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([C:26]5[N:27]=[N:28][N:24]([CH3:23])[N:25]=5)[CH:30]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: Cn1nnc(-c2cccc(C=O)c2)n1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nnc(-c2cccc(C=Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)c2)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 565 mg (3.0 mmol) of 3-(2-methyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[{3-(2-methyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H, analogous working-up and digestion in methanol yield 4-(3-chloro-phenylamino)-3-[3-(2-methyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.51 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=8.7; FAB-MS: (M+H)+=433.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]=[C:11]=[O:12].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: O=C=Nc1nc2ccccc2s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzothiazol-2-yl isocyanate dimer prepared in Example, 1 benzene (300 ml) and the dimethyl acetal of 2-methylaminoacetaldehyde (80 grams; 0.67 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about one hour. After this time the mixture is filtered to remove a yellow solid that has formed. The filtrate is then stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-(1-methyl-3-benzothiazol-2-ylureido)-acetaldehyde as an oil.