Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24]([CH3:27])([CH3:26])O)[CH:5]=[C:6]([O:22][CH3:23])[C:7]=1[O:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([CH3:21])[N:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:24]([CH3:27])=[CH2:26])[CH:5]=[C:6]([O:22][CH3:23])[C:7]=1[O:8][C:9]1[N:10]=[C:11]([CH3:21])[N:12]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:14]=1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(N2CCOCC2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C=C(C)c1cc(Br)c(Oc2nc(C)nc(N3CCOCC3)n2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-4-[[6-methyl-4-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol (1.92 g) in 80 mL of benzene, a small amount of p-toluene sulfonic acid was added. The solution was refluxed under azeotropic conditions for 16 hours. Once cooled to room temperature, the solution was washed with saturated NaHCO3 followed by water. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified on silica gel using a mixture of 1:1 ethyl acetate and hexane to yield 2-[2-bromo-6-methoxy-4-(1-methylethenyl)phenoxy]-4-methyl-6-(4-morpholinyl)-1,3,5-triazine as a colorless compound, mp 63-67° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[S:9][C:10]2[C:16]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]3=[O:28])=[C:15]([F:29])[CH:14]=[C:13]([Cl:30])[C:11]=2[N:12]=1>O1CCCC1>[Cl:30][C:13]1[C:11]2[N:12]=[C:8]([O:4][CH2:1][CH2:2][CH3:3])[S:9][C:10]=2[C:16]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[NH:19][C:18]2=[O:28])=[C:15]([F:29])[CH:14]=1
Reactant: CCCO
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c2nc(Cl)sc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2s1
Reaction time: 0.5 h

Procedure:
108 ml of absolute n-propanol were added dropwise at room temperature to 1.1 g of sodium hydride (97% strength) in 40 ml of absolute tetrahydrofuran. Stirring was carried out for 30 minutes, after which 7.0 g of 3-[2,4-dichloro-6-fluorobenzothiazol-7-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (compound I.4) were slowly added. Stirring was carried out for 12 hours, after which the solvent was distilled off at reduced pressure and the residue was then taken up in water. 10% strength hydrochloric acid was added to the aqueous phase until the resulting pH was from 3 to 4. The precipitate formed was separated off, washed with water and then dried. Yield: 5.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH:5]2[OH:12].I[CH3:14]>ClCCl>[CH3:14][O:6][C:7](=[O:11])[C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[CH:5]=[O:12]
Reactant: O=C1OC(O)c2cc(Cl)ccc21
Reactant: CI
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
A solution of 5-chloro-3-hydroxy-3H-isobenzofuran-1-one (10 g, 54 mmol) and iodomethane (80 g, 560 mmol) in dichloromethane (200 mL) was heated at reflux, then the heating bath was removed. To the above solution was added triethylamine (60 g) at a rate that maintained a brisk reflux. After the addition was completed, the mixture was allowed to cool to room temperature and stirred for 72 h. The mixture was purified by column chromatography to give the title product (1.5 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O-:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O:19][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 61.4 %

Procedure:
To a solution of sodium 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (1.1 g) was added iodomethyl pivalate (0.744 g) under ice-cooling and the resultant mixture was stirred at the same temperature for 10 minutes. After the reaction mixture was added to a stirred mixture of water and ethyl acetate, the separated organic solution was washed in turn with water, saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated in vacuo to give pivaloyloxymethyl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (0.82 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]#[N:17]>C(#N)C.C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CN1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A mixture of 1-methyl piperazine (0.55 mL, 5.0 mmol), potassium carbonate (3.49 g, 25 mmol) and chloroacetonitrile (0.34 mL, 5.6 mmol) in acetonitrile (3 mL) was stirred at room temperature 8 h. The mixture was diluted with diethyl ether and filtered and concentrated to yield the title compound as yellow crystals (536.6 mg, 77% yield). 1H NMR (500 MHz, CDCl3) δ: 3.50 (s, 2H), 2.66 (t, 4H, J=4.58), 2.52 (bs, 4H), 2.33 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: Cc1ccc(F)c(C2CC(=O)CC(=O)C2)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(F)c(C2CC(=O)C=C(N)C2)c1
Yield: 87.1 %

Procedure:
A solution of 5-(2-fluoro-5-methylphenyl)cyclohexane-1,3-dione (1.5 g) and ammonium acetate (1.6 g) in ethanol (23 ml) was refluxed for 20 hours. Under reduced pressure, the solvent was evaporated, and precipitated crystals were washed with water and toluene, and dried to give 1-amino-5-(2-fluoro-5-methylphenyl)cyclohexen-3-one (1.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[O:32][CH:33]=[CH:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[O:32]1[C:31]2[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[CH2:26][C:27]3[N:28]([CH:35]=[CH:36][CH:37]=3)[CH2:29][C:30]=2[CH:34]=[CH:33]1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 1.1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. To the mixture is added 1.1 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-furo-[2,3-e]pyrrolo[1,2-a][1,4]diazepine and the mixture is stirred for 5 hours. The reaction mixture is washed with water, 1N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1>C(O)C.[Pd]>[CH3:1][N:2]([CH3:25])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:24])[C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CN(C)C1CCCN(C(=O)c2ccc(N)cc2)c2ccccc21
Yield: 96 %

Procedure:
In ethanol (500 ml) is dispersed 10% Pd-C (5 g), and thereto is added 5-dimethylamino-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (64.1 g), and the mixture is subjected to catalytic reduction at ordinary room temperature under atmospheric pressure. After reduction, 10% Pd-C is removed by filtration, and the filtrate is concentrated under reduced pressure to give 5-dimethylamino-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (56.1 g) as white powder, mp. 120°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl.C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)CC1CC(=O)c2ccc(F)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)/C=C1\CC(=O)c2ccc(F)cc21
Temperature: 120 °C
Yield: 109.7 %

Procedure:
A mixture of 2-(6-fluoro-3-oxo-1-indanyl)acetamide (0.750 g, 0.0036 mol), N-bromosuccinimide (0.750 g, 0.0042 mol, Aldrich), benzoyl peroxide (0.270 g, 0.0011 mol, Aldrich) in tetrachloromethane (37 ml) and benzene (37 ml) was stirred while heating with an oil bath at 120° C. for 20 min. This reaction was combined with a similarly run reaction (except 0.0024 mol scale). The solution was slurried with Silica Gel 60 and the volatiles were removed by spin evaporation in vacuo. This silica gel was then applied to a column of Silica Gel 60 (51×450 mm) wet with dichloromethane and the product was removed by elution with methanol:dichloromethane (3:97). After the volatiles were removed from the combined fractions containing product by spin evaporation in vacuo, the residue was recrystallized from methanol to give 0.81 g (58%) of (E)-2-(6-fluoro-3-oxo-1-indanylidene)acetamide: m.p., 235° C. (dec.):
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N5CCN(C(C)=O)CC5)c4)sc4c3CCCC4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCN(S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)O)cc5)cc3)CCCC4)c2)CC1
Yield: 39.4 %

Procedure:
A mixture of 300 mg of methyl 4-{2-[4-({[2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 1.5 mL of a 1.0 M aqueous sodium hydroxide solution, and 3.0 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure and the residue was neutralized with 1.0 M hydrochloric acid. Then, the precipitate was collected by filtration and the obtained solid was purified by silica gel column chromatography (methanol-chloroform) to obtain 116 mg of 4-{2-[4-({[2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a colorless crystal.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[C:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([N:34]1[CH2:39][CH2:38][N:37]([CH2:18][C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)[CH2:36][C:35]1=[O:40])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)N1CCNCC1=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.39 mmol), 1-tert-butylpiperazin-2-one (0.072 g, 0.46 mmol) and 4 Å molecular sieves (0.4 g) in DCE (5 mL) was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (0.163 g, 0.77 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to give 577 as a white solid (0.178 g, 87%). LCMS (Method I): RT=3.59 min, [M+H]+ 532.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.98 (m, 1 H), 7.65-7.60 (m, 1 H), 7.26-7.21 (m, 2 H), 4.50-3.95 (m, 5 H), 3.83-3.79 (m, 6 H), 3.78 (m, 4 H), 3.27 (q, J=7.4 Hz, 2 H), 3.08 (s, 2 H), 2.69-2.64 (m, 2 H), 1.36 (s, 9 H), 1.34 (t, J=7.4 Hz, 3 H)
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH2:9]1)=O)C.[NH2:29][C:30]1[CH:34]=[CH:33][NH:32][N:31]=1>ClCCl>[OH:28][C:4]1[N:31]2[N:32]=[CH:33][CH:34]=[C:30]2[N:29]=[C:6]([CH:8]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:11]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:10][CH2:9]2)[CH:5]=1
Reactant: CCOC(=O)CC(=O)C1CCC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1cc[nH]n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CN1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
Di-tert-butyl 5-(3-ethoxy-3-oxopropanoyl)piperidine-1,2-dicarboxylate (18.79 mmol, 7.5 g) and 3-amino-1H-pyrazole (15.0 mmol, 1.25 g) were mixed and heated neat at 100° C. for 16 hours. The resulting residue is dissolved in dichloromethane (100 mL) and concentrated in vacuo to remove water formed during cyclization. LC-MS: 419 [M+H]. This solid is taken forward without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][C:29]=1[F:42])[CH2:2][CH2:3][CH3:4].C([Sn](=O)CCCC)CCC.[N:53]([Si](C)(C)C)=[N+:54]=[N-:55].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:55][N:54]=[N:53][N:41]=2)=[CH:30][C:29]=1[F:42])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12

Procedure:
A mixture of 4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile (0.76 g), dibutyltin oxide (0.17 g), azidotrimethylsilane (4.60 g) and toluene (15 mL) was refluxed overnight. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the residue in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3 mL) at room temperature, and the mixture was refluxed for 3 hr. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.58 g, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>C1COCC1>[OH:16][CH2:15][C:14]([NH:13][C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[S:12])([CH3:18])[CH3:17]
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=S)Nc1ccc([N+](=O)[O-])cc1
Yield: 66.2 %

Procedure:
A solution of 4-nitro-phenyl-isothiocyanate (4 g, 22.2 mmol) and 2-amino-2-methyl-propan-1-ol (1.9 g, 21.3 mmol) in THF was stirred overnight at r.t. The solvent was evaporated to give a residue which was triturated with ether to give 1-(2-hydroxy-1,1-dimethyl-ethyl)-3-(4-nitro-phenyl)-thiourea (3.8 g, 66%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:3][CH:4]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)S(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Product: CC(C)S(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(isopropylsulfonyl)-3-nitropyridine (Step D of Example 22) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:11])[N:5]([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=1.[H][H]>CO.[Rh]>[CH3:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[NH:3]1
Reactant: [H][H]
Reactant: Cc1cn(CC(N)=O)c(=O)[nH]1
Agent: [Rh]
Solvent: CO
Product: CC1CN(CC(N)=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
1.6 g of Rh/C are added to a solution of 7.8 g of (4-methyl-2-oxo-1,3-dihydroimidazol-1-yl)acetamide in 80 ml of methanol and the reaction mixture is treated with hydrogen at 3 bar. After 30 minutes, 1.13 litres of hydrogen have been taken up and the reaction has ceased. The reaction mixture is then filtered over Celite and concentrated by evaporation. The residue is dissolved in methylene chloride, magnesium sulfate is added thereto, followed by filtration over Celite and concentration by evaporation. The residue is stirred with ether. The crystals are filtered off with suction and dried in vacuo at 60°. 7.3 g of the title compound having a melting point of 124°-127 are thus obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)[NH:10][CH2:9][CH2:8][CH:7]2[C:17]([OH:19])=[O:18])(=[O:3])N.[OH-:20].[Na+]>>[NH:10]1[C:11]2[C:6](=[CH:5][C:4]([C:1]([OH:20])=[O:3])=[CH:13][C:12]=2[C:14]([OH:16])=[O:15])[CH:7]([C:17]([OH:19])=[O:18])[CH2:8][CH2:9]1
Reactant: NC(=O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CCN2
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CCN2
Yield: 72.9 %

Procedure:
A solution of 6-carbamoyl-1,2,3,4-tetrahydroquinoline-4,8-dicarboxylic acid (1.77 g) in 10% aqueous sodium hydroxide solution (20 ml) was refluxed for 10 hours and after cooling, adjusted to pH 1. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.29 g, 72.9%) which was recrystallized from ethanol to white crystals, mp 240° C.-241° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:10])([CH3:9])[CH2:6][C:7]#[CH:8].CN(C)C=O.N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([O:10][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][C:7]#[CH:8]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(C)(O)CCCCl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(C)(CCCCl)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 7-chloro-4-hydroxy-4-methyl-1-heptyne in 80 ml. of dimethylformamide at 0° C., is added 43.8 g. (0.644 moles) of imidazole and 35.02 g. (0.322 moles of) chlorotrimethylsilane. The mixture is stirred at room temperature for 45 minutes, poured into water and extracted with hexane. The hexane solution is washed with dilute sodium bicarbonate solution, dried over magnesium sulfate and the solvent removed leaving an orange liquid. This liquid is distilled giving the desired product in the fraction boiling at 83°-88° C., 1.5 mm. as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:25])[CH2:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[C:16]([O:23][CH3:24])[CH:15]=2)=[C:5]([O:26][CH2:27][C:28]([O:30]C)=[O:29])[C:4]=1[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35].[OH-].[K+].Cl>CO>[C:28]([CH2:27][O:26][C:5]1[C:4]([CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:11](=[O:25])[CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[C:16]([O:23][CH3:24])[CH:15]=1)([OH:30])=[O:29]
Reactant: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1cc(OC)c(O)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
Then, 1.5 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone was dissolved in 15 ml of methanol, and 8.6 ml of a 5% solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 20 minutes. Then, the reaction mixture was made weakly acidic by addition of dilute hydrochloric acid, the solvent was removed from the mixture by distillation, and the residue was crystallized from ethyl acetate/diethyl ether/hexane to obtain 1.0 g (yield=68%) of 1-(2-carboxymethoxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone in the form of a white cotton-like crystal.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C1(C)C=CC=CC=1>[CH:7](=[N:13][CH2:12][CH2:11][N:10]([CH3:14])[CH3:9])[C:3]1[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=1
Reactant: CN(C)CCN
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: CN(C)CCN=Cc1cccnc1
Reaction time: 2 h
Yield: 101.8 %

Procedure:
Nicotinealdehyde (2.16 ml, 22.9 mmol) and N,N-dimethylethylenediamine (2.51 ml, 22.9 mmol) were added to toluene (100 ml) and the mixture was subjected to azeotropic dehydration for 2 hours. After cooling, solvent was distilled off to obtain N-nicotinylidene-N',N'-dimethylethylenediamine (4.13 g, yield 102%).