Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:19][OH:20])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].[C:23]([O:40]C)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[OH:1][CH:2]([CH2:19][OH:20])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Reactant: CCCCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-tetradecylamine (1.0 g, 0.0035 moles) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum. Methyl palmitate (1.036 g, 0.0038 mole) was heated to melt and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.77 g). The waxy solid was recrystalized from hot hexane (yield=0.33 g).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[CH3:12][NH:13][CH2:14][CH:15]=[O:16]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH:15]=[O:16])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: CNCC=O
Reactant: C=CCc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(C)CC=O)s1

Procedure:
A mixture of 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16](OC(C)(C)C)=[O:17].[O-]CC.[Na+]>CCO.O>[OH:17][N:16]=[C:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: O=C(Cc1cccnc1)c1ccccc1
Reactant: CC(C)(C)ON=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(C(=NO)c1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of 1-phenyl-2-(pyridine-3-yl)ethanone (0.494 g, 2.505 mmol) in EtOH (36.8 mL) at room temperature was added tert-butyl nitrite (0.586 mL, 4.93 mmol) dropwise followed by sodium ethoxide (0.435 g, 2.55 mmol). The reaction was stirred at room temperature overnight. Upon completion, the solvent was evaporated to give a yellow oil. This oil was then diluted with H2O (25 mL), extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (0.214 g). LCMS m/z=227.4 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (355 mg, 1.17 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (223 mg, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336 mg, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively-with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (333 mg, 61%).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=O)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[N:5]1)([CH3:3])[CH3:2].Br.Br.[NH2:23][CH2:24][C:25]([NH2:27])=[NH:26].C[O-].[Na+].O>CO.CCOC(C)=O>[NH2:27][C:25]1[N:26]=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:23][CH:24]=1
Reactant: N=C(N)CN
Reactant: CC(C)n1nc(C(=O)C(=O)c2ccccc2)ccc1=O
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)n1nc(-c2nc(N)cnc2-c2ccccc2)ccc1=O
Reaction time: 1.5 h
Yield: 7.6 %

Procedure:
A mixture of 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione (300 mg), aminoacetamidine dihydrobromide (259 mg) and sodium methoxide (238 mg) in MeOH (3 ml) was stirred for 1.5 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6-(6-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (25.6 mg) as white powder.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][CH2:4][C:3]([OH:18])=[O:2])[O:10]1
Reactant: COC(=O)CCC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O)cc2c1C(CCC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 3-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)propionic acid methyl ester (0.190 g, 0.76 mmol) in THF (4 mL) and H2O (2 mL) was added LiOH (0.146 g, 6.08 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated and purified by silica gel flash column chromatography to give 3-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propionic acid (0.110 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.00 (s, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 2.30-2.10 (m, 6H), 1.50 (m, 1H). MS (ESI) m/z: 235 [M−1]−. HPLC purity: 99.06% (220 nm), 98.87% (Maxplot).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]4[C:18](I)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C([Mg]Cl)(C)C.[Cl-].[NH4+]>ClCCl.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:27])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cc(Cl)cnc43)CC2)ccc1Cl
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)Cn3ncc4cc(Cl)cnc43)CC2)ccc1Cl
Temperature: 25 °C
Yield: 32.2 %

Procedure:
To a solution of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-5-chloro-pyrazolo[3,4-b]pyridine-1-yl)-ethanone (0.037 mmol, 1 eq.) in 1.5 mL of dichloromethane under a nitrogen atmosphere cooled to −40° C., was added dropwise, 30 μl of 2.0 M solution of isopropyl magnesium chloride (0.056 mmol, 1.5 eq.) in THF. The resultant mixture was for 30 minutes at −40° C. followed by dropwise addition of an ammonium chloride aqueous (aq) solution at low temperature. The reaction solution was warmed to rt, diluted with 200 mL of EtOAc, washed with 50 mL of water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by HPLC to provide 5-mg final product: 1H NMR (400 MHz, CDCl3) δ 8.44 (d, 1H), 8.05(m, 1H), 7.23 (d, 1H), 6.50 (d, 1H), 6.43 (dd, 1H), 5.42 (s, 2H), 3.89 (s, 3H), 3.76 (m, 4H), 3.20 (m, 4H). LCMS observed for (M+H)+: 421.1.
Reaction SMILES: C(OC1C=C(C=C(OCC)C=1F)CN1CCC([NH:14][C:15](=O)[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([NH:23][CH3:24])=[N:18][CH:17]=2)CC1)C.[CH3:33][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI>C1COCC1>[CH3:33][N:23]([CH3:24])[C:19]1[C:20]([CH3:22])=[CH:21][C:16]([C:15]#[N:14])=[CH:17][N:18]=1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cnc(NC)c(C)c3)CC2)cc(OCC)c1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C#N)cnc1N(C)C

Procedure:
5-Methyl-6-methylamino-nicotinonitrile (example 121, 0.345 g, 2.34 mmol) was dissolved in 3.2 ml of abs. THF and treated at 0° C. with sodium hexamethyldisilazide-solution (1M in THF, 7.03 ml, 3.0 eq.) and, after 5 Min., 4 eq. of methyl iodide (0.58 ml). The mixture was allowed to react for 1 h at room temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=7/3) yielded 0.330 g of the title compound as off-white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:37])[CH2:33][C:34](=O)[CH3:35])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:33]2[CH:21]([C:20]3[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)[NH:12][C:10](=[O:11])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=3)[C:34]=2[CH3:35])=[O:37])=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC1=C(C(=O)c2ccc(Br)cc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4.23 g (20.74 mmol) N-[3-(trifluoromethyl)phenyl]urea, 2.72 g (20.74 mmol) 4-cyanobenzaldehyde, 5.00 g (20.74 mmol) 1-(4-bromophenyl)butane-1,3-dione and 6.5 g polyphosphoric acid ethyl ester are suspended in 50 ml of tetrahydrofuran. The mixture is stirred at reflux for 20 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:2]([CH:13]=[CH2:14])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)ccc1NC(C)=O
Temperature: 95 °C
Yield: 63.9 %

Procedure:
To a stirred solution of N-(2-bromo-4-chloro-phenyl)-acetamide (2 g, 8 mmol) in toluene (20 mL) was added tributyl(vinyl)tin (3.05 mL, 10.5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (1.41 g, 2 mmol). The reaction mixture was heated at 95° C. for 1 hour, and the solvent removed in vacuo. The residue obtained was purified by flash chromatography eluting with 20% ethyl acetate/CH2Cl2 to give N-(4-Chloro-2-vinyl-phenyl)-acetamide (1 g, 64%). HPLC: Rt=2.16 min. m/z=196 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([C:39]([CH3:41])=[CH2:40])=[CH:27][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:44]I>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([C:39]([CH3:41])=[CH2:40])=[CH:27][C:10]=1[C:11]([N:13]([CH3:44])[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][CH:19]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: C=C(C)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N(C)c2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 118.5 %

Procedure:
2,4-Bis-benzyloxy-5-isopropenyl-N-(4-morpholin-4-ylmethyl-phenyl)-benzamide (0.1 g, 0.18 mmol) [Method A2 from (2,4-bis-benzyloxy-5-isopropenyl)-benzoic acid (Preparation B5) and 4-morpholin-4-yl-methyl-phenylamine] were dissolved in DMF (1 ml) and treated with 60% NaH in mineral oil (11 mg, 1.6 eq) and the reaction mixture was stirred for 15 minutes followed by the addition of methyl iodide (26 mg, 0.18 mmol). The reaction mixture was then stirred for 1 hour at room temperature, and subsequently diluted with EtOAc and water. The organic phase was separated, washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a solid (0.12 g). MS: [M+H]+ 563
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(OCC)=O)=NC(OCC)=O.O[C:26]1[CH:42]=[CH:41][C:29]2[CH2:30][CH:31]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:32](=[O:35])[NH:33][CH2:34][C:28]=2[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:26]1[CH:42]=[CH:41][C:29]2[CH2:30][CH:31]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:32](=[O:35])[NH:33][CH2:34][C:28]=2[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC1Cc2ccc(O)cc2CNC1=O
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CC1Cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2CNC1=O
Reaction time: 18 h
Yield: 67.7 %

Procedure:
A solution of 3-[(tert-butoxycarbonyl)amino]-1-propanol (0.14 g, 0.8 mmol) and diethyl azodicarboxylate (0.13 mL, 0.8 mmole) in anhydrous DMF (2 mL) was added dropwise to a solution of methyl (±)-8-hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.10 g, 0.4 mmole) and triphenylphosphine (0.21 g, 0.8 mmol) in anhydrous DMF (1.4 mL) and dry THF (2 mL) at RT under argon. The resulting solution was stirred for 18 hr, then was concentrated under vacuum. Silica gel chromatography (1%-3% MeOH/CH2Cl2) gave the title compound (0.11 g): MS (ES) m/e 407.3 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C@H:5]([CH3:9])[CH2:6][S:7][CH3:8])[CH:3]=O.[C-:10]#[N:11].[K+].Cl.[CH3:14][NH2:15].O>CO>[OH:1][C@H:2]([C@H:5]([CH3:9])[CH2:6][S:7][CH3:8])[CH:3]([NH:15][CH3:14])[C:10]#[N:11]
Reactant: CSC[C@@H](C)[C@@H](O)C=O
Reactant: CN
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNC(C#N)[C@H](O)[C@H](C)CSC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (G) was dissolved in methanol (120 ml.) and the stirred solution treated sequentially with potassium cyanide (1.82g., 0.028m), methylamine hydrochloride (2.03g., 0.03m.), and water (20 ml.). The sides of the flask were rinsed down with an additional 5 ml of methanol, the mixture covered with a nitrogen atmosphere and allowed to stir overnight at room temperature. The mixture was then concentrated in vacuo to a slurry. This was distributed between methylene chloride (300 ml.) and water (400 ml.), separated, and the aqueous layer re-extracted 2x with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated to yield compound (H) as a waxy solid (3.lg.). It was used directly in the next step.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16][CH2:17]C.ICCC>>[CH2:15]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCCI
Product: CCCC1c2ccccc2-c2ccccc21

Procedure:
Fluorene (15.0 g, 90.4 mmol), n-BuLi (48.1 ml, 120 mmol, 2.5 M in hexane), RX=1-iodopropane (20.8 g, 122.3 mmol). 43 was isolated as a yellowish solid (18.6 g, quant.). The analytical data were identical to those found in the literature (A. Mathieu, Bull. Soc. Chim. Fr. 1971, 1526).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].FC(F)(F)C(O)=O.[CH3:35][N:36]1[O:40][NH+:39]([O-:41])[CH:38]=[C:37]1[C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:47]2[CH2:46][CH2:45][N:44]([C:42]([C:37]3[N:36]([CH3:35])[O:40][NH+:39]([O-:41])[CH:38]=3)=[O:43])[CH2:49][CH2:48]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Reactant: CN1O[NH+]([O-])C=C1C(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C(=O)C5=C[NH+]([O-])ON5C)CC4)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
410 mg (1.0 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 10 ml of dichloromethane and cooled to 0° C. 590 mg (2.00 mmol) of 1-(5-methyl-4-furoxanecarbonyl)-piperazine trifluoroacetate and 400 mg of triethylamine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution, 1M hydrochloric acid and water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 448 mg (74%) of a colourless solid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[CH2:11](O)[CH3:12]>>[C:4]([O:6][CH2:11][CH3:12])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C=C\C(=O)[O-]
Reactant: CCO
Product: CCOC(=O)/C=C\C(=O)OCC

Procedure:
In the plant of FIG. 6 maleic anhydride is supplied in line 401 to monoesterification reactor 402, to which is also supplied a stream containing ethanol in line 403. Reactor 402 is also fed by way of line 401 with a recycle stream from line 404 that contains recovered maleic anhydride and diethyl maleate. Monoesterification reactor 402 is provided with a stirrer 405, with a cooling coil 406 (which doubles as a steam heating coil at start up of the plant), and with a vent line 407. Maleic anhydride reacts with ethanol in reactor 402 to produce monoethyl maleate in the absence of a catalyst. The liquid reaction mixture from reactor 402 is discharged in line 408 and pumped by pump 409 to steam heater 410. Upstream from heater 410 it is admixed with two streams comprising further ethanol supplied in lines 411 and 412. The mixed stream flows on in line 413 to a primary esterification reactor 414 which contains a fixed bed of an acidic ion exchange resin, such as Amberlyst 16. Reaction between monoethyl maleate and ethanol to form diethyl maleate takes place in reactor 414.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[BH4-].[Na+]>CO>[OH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:13][CH2:12]1
Reactant: OC1CCNCC1
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(CN2CCC(O)CC2)c1
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
To a solution of 0.2 mol of 3-hydroxybenzaldehyde in 100 ml of methanol, is added a solution of 0.4 mol of 4-hydroxypiperidine in 80 ml of methanol at about 20° C. To the mixture thus obtained 0.2 mol of sodium borohydride is added portionwise and under stirring, at the temperature of 20°-25° C. within about 90 minutes, then the reaction mixture is stirred 4 hours at room temperature and the solvent is evaporated under reduced pressure to dryness. The residue is taken up with ice and acidified with hydrochloric acid. The acid solution is washed twice with 40 ml of ethyl acetate and concentrated ammonium hydroxide is added thereto up to clearly basic reaction. The product which precipitates is filtered and crystallized from 400 ml of water. The product thus obtained melts at 156°-158° C. Yield: 66.8%.
Reaction SMILES: N1C=CC=CC=1.[O:7]([Si:15]([CH3:18])([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O.[CH2:19]([C:21](O)([CH2:52][CH3:53])[C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH2:49][CH3:50])([C:33]2[CH:38]=[CH:37][C:36]([B:39]3[O:43][C:42]([CH3:45])([CH3:44])[C:41]([CH3:47])([CH3:46])[O:40]3)=[C:35]([CH3:48])[CH:34]=2)[CH2:31][CH3:32])=[CH:26][C:25]=1[CH3:51])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:31]([C:30]([C:33]1[CH:38]=[CH:37][C:36]([B:39]2[O:40][C:41]([CH3:46])([CH3:47])[C:42]([CH3:45])([CH3:44])[O:43]2)=[C:35]([CH3:48])[CH:34]=1)([C:27]1[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:21]([CH2:19][CH3:20])([O:7][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:52][CH3:53])=[C:25]([CH3:51])[CH:26]=1)[CH2:49][CH3:50])[CH3:32]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Pyridine (0.116 mL, 1.432 mmol) and trimethylsilyl triflate (0.129 mL, 0.716 mmol) were added to a solution of 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-pentyn-3-ol (Example 125-(2); 175 mg, 0.358 mmol) in dichloromethane (5 mL) at 0° C., and the mixture was stirred for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target compound as a colorless oil (158 mg, 79%).