Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[C:4](=N)[NH:5][C:6]2=[NH:14].[O:16]=[C:17]1[NH:21][C:20](=[S:22])[CH2:19][S:18]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH:14]=[C:6]1[C:7]2[C:3](=[C:2]([Cl:1])[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]=2[Cl:13])[C:4](=[C:19]2[S:18][C:17](=[O:16])[NH:21][C:20]2=[S:22])[NH:5]1
Reactant: N=C1NC(=N)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: O=C1NC(=S)CS1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N=C1NC(=C2SC(=O)NC2=S)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 25 °C

Procedure:
To a mixture of 14.1 parts of 4,5,6,7-tetrachloro-1,3-diiminoisoindoline, 6.7 parts of 2-oxo-4-thioxothiazolidine and 10.0 parts of freshly prepared, ground anhydrous sodium acetate, there was added 157 parts of glacial acetic acid. The resulting slurry was heated at reflux under a continuous flow of nitrogen for approximately one hour. The reaction solution was cooled to room temperature, sealed under an atmosphere of nitrogen and set aside for about sixty hours. The solid which separated on standing was collected by filtration at room temperature, washed five times, each with 21.0 parts glacial acetic acid and then a total of eight times, each with 20.0 parts distilled water. The water-wet pulp was stirred with 90.0 parts of 28 percent aqueous ammonia, filtered to remove any insolubles and the product reprecipitated by adjusting the pH of the solution to 6.0 by the addition of 99.2 parts of 6N hydrochloric acid solution. The solid was collected by filtration, washed with 3000 parts of water and air dried at 60° C. to obtain 1-imino-4,5,6,7-tetrachloro-3-(2-oxo-4-thioxo-5-thiazolidinylidene)isoindoline as a brown powder which did not melt up to 340° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14].Cl>CN(C)C=O>[CH2:4]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:15])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCCCCO
Reactant: CCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 4.2 g) and then 12 ml of 1-bromopentane were added to a solution of 10 g of 1,5-pentanediol in 150 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 min. 3% hydrochloric acid was added to the reaction solution. After extraction with ether, the organic layer was dried and cencentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2) to obtain 6 g of the intended product.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: NS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-aminophenylmethane sulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.1 (d,1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.2 (d, 1H), 6.9 (s, 2H), 4.2 (s, 2H); APCI−MS m/z 387 (M+H)+.
Reaction SMILES: OCC(CO)(CO)CO.[C:10]([O:13][CH2:14][C:15]([CH2:26][O:27]C(=O)C)([CH2:21][O:22]C(=O)C)[CH2:16][O:17]C(=O)C)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CCOCC>CC(C)=O>[C:10]([O:13][CH2:14][C:15]([CH2:26][OH:27])([CH2:21][OH:22])[CH2:16][OH:17])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC(COC(C)=O)(COC(C)=O)COC(C)=O
Agent: O=C([O-])[O-]
Agent: OCC(CO)(CO)CO
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)OCC(CO)(CO)CO
Yield: 129.1 %

Procedure:
Pentaerythritol (9.5 grams, 0.07 mol), 7.0 grams (0.02 mol) of pentaerythritol tetraacetate and 500 mg of potassium carbonate were heated for 12 hours at 180° C. A light brown solution resulted which was boiled for 15 minutes in 50 ml of acetone and the resulting precipitate was filtered off. The filtrate was concentrated and passed through a plug of silica gel using acetone as a solvent. The mixture was purified by flash chromatography (1:1, CHCl3 :acetone) to yield a product of Rf =0.1. Addition of 25 ml of ether caused the product to solidify, yielding 4.6 grams of pentaerythritol monoacetate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]2[CH2:27][C@@H:26]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)=[O:20])[N:10]=[N:9]1.C(OCC)(=O)C.[ClH:53]>C(OCC)(=O)C>[ClH:53].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]2[CH2:27][C@@H:26]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:25][NH:24][CH2:23]2)=[O:20])[N:10]=[N:9]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nnn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (85 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object product (70 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2].CI.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH3:25])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2ccc(OC)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCc1c(C(=O)OCC)cc(OC)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 64 h
Yield: 78.7 %

Procedure:
A solution of 1-butyl-4-hydroxy-7-methoxy-2-naphthalenecarboxylic acid ethyl ester (6.5 g) and methyl iodide (7 mL) in acetone (65 mL) containing potassium carbonate (5 g) was stirred at room temperature for 64 hours. After the reaction mixture was filtered, the filtrate was concentrated to dryness and the residue was partitioned between dichloromethane (150 mL) and water (100 mL). The dried (MgSO4) organic layer was evaporated and the residual material crystallized from 2-propanol to yield 5.35 g of 1-butyl-4,7-dimethoxy-2-naphthalenecarboxylic acid ethyl ester, mp 44°-45° C. Anal. Calcd for C19H24O3 : C, 72.13; H, 7.64 Found: C, 72.03; H, 7.78
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[N:13]([CH3:22])[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21].[CH3:24][O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>CN(C=O)C>[CH3:24][O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:11]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:13]([CH3:22])[C:12]1=[O:23]
Reactant: Cn1c(-c2ccccc2F)c(-c2ccccc2F)[nH]c1=O
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2F)c(-c2ccccc2F)n(C)c1=O

Procedure:
The product is produced as described in example 1 from 0.63 of NaH (80% suspension in mineral oil), 5.9 g of 4.5-bis-(2-fluorophenyl)-1-methyl-4-imidazolin-2-one, 40 cc. of DMF, 5.0 g of 8-bromo caprylic methyl ester and 0.63 g of NaJ.
Reaction SMILES: [Cl:1][C:2]([Cl:22])([Cl:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]([Cl:17])([Cl:16])[Cl:15].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]([Cl:21])([Cl:22])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:25])[O:26][CH2:27][CH3:28])=[CH:9][C:8]=1[C:14]([Cl:15])([Cl:16])[Cl:17]
Reactant: Nc1ccc(Oc2cccc(C(Cl)(Cl)Cl)c2)c(C(Cl)(Cl)Cl)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2cccc(C(Cl)(Cl)Cl)c2)c(C(Cl)(Cl)Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-[3-(Trichloromethyl)phenoxy]-3-(trichloromethyl)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-[3-(trichloromethyl)phenoxy]-3-(trichloromethyl)phenyl]carbamate.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20](O)=[O:21])[CH2:15][CH2:14]1>>[CH3:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)=[O:21])[CH2:15][CH2:14]1
Reactant: Nc1cccc2ncccc12
Reactant: CC1CCC(CC(=O)O)CC1
Product: CC1CCC(CC(=O)Nc2cccc3ncccc23)CC1
Yield: 17.2 %

Procedure:
Prepared according to the method of example 18, using 5-quinolinamine (250 mg) and 4-methyl-cyclohexaneacetic acid (270 mg). Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) followed by recrystallisation from methanol/ethyl acetate gave the title compound as a colourless solid (84 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:4]=2[CH:3]=1.BrC1C=CC([N:25]([C:32]2[CH:37]=[CH:36][CH:35]=CC=2)[C:26]2C=CC=CC=2)=CC=1>>[Br:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:2]([C:35]4[N:25]([CH3:26])[CH:32]=[CH:37][CH:36]=4)=[CH:3][C:4]=3[C:5]2([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3cccn3C)cc21

Procedure:
The compound of the present example was synthesized by the same method as described in example 1, except that 3.80 parts of 2,7-dibromo-9,9-diethyl-9H-fluorene (21) was used to substitute 4-bromo-N,N-diphenylaniline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23]([CH3:31])C(=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33](C)C=O.C(OCC)(=O)C.Cl>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[ClH:1].[CH3:31][NH:23][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([C:32]#[N:33])=[N:7][CH:6]=2)(=[O:9])=[O:10])[CH:12]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(Cl)nc2)c1)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C#N)nc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Under an argon atmosphere, a mixture of tert-butyl {[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg), zinc (II) cyanide (51 mg), tetrakis(triphenylphosphine)palladium (50 mg) and N,N-dimethylformamide (4 mL) was stirred at 100° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give an oil. The obtained oil was dissolved in ethyl acetate (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol to give the title compound (yield 57 mg, 68%).
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=O)[NH:2]1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:19])[NH:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NS(=O)(=O)c2cscc21
Solvent: c1ccncc1
Solvent: O
Product: O=S1(=O)NC(=S)c2cscc21
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 40 %

Procedure:
To a mixture of 5.6 g. (0.03 mole) of thieno[3,4-d]isothiazol-3(2H)-one 1,1-dioxide* in 50 ml. of dry pyridine is added 5.6 g. (0.016 mole) of phosphorus pentasulfide portionwise over 3 minutes. The viscous mixture is slowly heated in an oil bath under an atmosphere of nitrogen. The temperature of the oil bath is slowly increased to 80° C. after 30 minutes. The temperature of the oil bath is then kept at 80° C. for 25 minutes, the internal temperature reading 63° C. The solution is cooled to 50° C. and is added dropwise over 5 minutes to 200 ml. of water and cooled in an ice bath. The precipitate which forms is collected and discarded. The filtrate is cooled in ice and acidified with concentrated hydrochloric acid to pH 1. The precipitate which forms is collected to yield 40% of material. In another expeirment, a sample is recrystallized from water to obtain an analytical sample, m.p. 196°-8° C. (dec.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14](=O)[C:9]2[C:10]([CH3:13])=[CH:11][O:12][C:8]=2[CH2:7]1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl>C(O)C>[ClH:22].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15]/[C:14](=[N:21]\[NH:20][C:17]([NH2:19])=[NH:18])/[C:9]2[C:10]([CH3:13])=[CH:11][O:12][C:8]=2[CH2:7]1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccco1)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccco1)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of 6-(2-furyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.22 g) and aminoguanidine hydrochloride (113 mg) were ethanol (20 ml) and 6N hydrochloric acid (0.088 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-furyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 47) (0.22 g).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15](C)[C:16](=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>CO>[CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][CH3:16])[CH2:13][CH2:14]2)=[CH:7][N:8]=1
Reactant: CN(C)c1ccc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)cn1
Solvent: CO
Product: CNC1CCN(c2ccc(N(C)C)nc2)CC1
Reaction time: 3 h
Yield: 94 %

Procedure:
Benzyl 1-(6-(dimethylamino)pyridin-3-yl)piperidin-4-yl(methyl)carbamate (400 mg, 1.086 mmol, 1.0 eq.) was dissolved in MeOH (10 ml) and degassed with argon. Pd(OH)2 (200 mg) was then added and hydrogenation was carried out for 3 hours. After monitoring by TLC, the reaction mixture was filtered over Celite, the filtrate was concentrated under reduced pressure and the crude product was used in the next stage without being purified further. Yield: 94% (240 mg, 1.0212 mmol)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:24])([CH3:23])[C:16]([NH:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1.[OH-].[K+].[CH3:27]I>CS(C)=O>[CH2:19]([NH:18][C:16](=[O:17])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]([CH2:2][O:1][CH3:27])[N:8]=2)=[CH:14][CH:13]=1)([CH3:23])[CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cncc(CO)n2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1cncc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
2-(4-(6-(Hydroxymethyl)pyrazin-2-yl)phenyl)-N-isobutyl-2-methylpropanamide (example 29a) (37 mg, 0113 mmol) in DMSO (1 mL) was added under argon to a solution of KOH (9.5 mg, 0.169 mmol) in DMSO (1 mL) and the mixture was stirred for 5 min then cooled to 0° C. MeI (7.7 μL, 0.124 mmol) in DMSO (1 mL) was added dropwise and the mixture was stirred at room temperature for 20 min. The reaction was quenched with water (100 μL) and the product was purified by RP HPLC (water-acetonitrile) to give 19 mg (50%) of the product. 1H NMR (400 MHz, dMSO): δ 0.73-0.75 (d, 6H), 1.49 (s, 6H), 1.68-1.71 (m, 1H), 2.83-2.86 (m, 2H), 3.37 (s, 3H), 4.63 (s, 2H), 7.37 (t, 1H), 7.45-7.48 (d, 2H), 8.07-8.09 (d, 2H), 8.60 (s, 1H), 9.16 (s, 1H); MS+H (342).
Reaction SMILES: C[Mg]Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)([C:17]#N)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>C1COCC1>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)([CH3:17])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN1CCN(C2(C#N)CCN(Cc3ccccc3)CC2)CC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCN(C2(C)CCN(Cc3ccccc3)CC2)CC1
Reaction time: 2 h

Procedure:
10 mL methylmagnesium chloride solution (30 mmol, 3 M in THF) were added at RT to a solution of 3.0 g (10.1 mmol) 1-benzyl-4-(4-methyl-piperazin-1-yl)-piperidin-4-carbonitrile in 50 mL dry THF and the reaction mixture was stirred for 2 h. It was combined with saturated NH4Cl solution, stirred for 10 min, extracted exhaustively with diethyl ether and the combined organic phases were dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (Alox, activity stage II-III, gradient DCM/MeOH 100:1 to 50:1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C:15]2[C:16](=[O:56])[N:17]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[F:55])[C:18](=[O:47])[N:19]([CH2:22][C:23]3[N:27]=[CH:26][N:25]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]=3)[C:20]=2[NH2:21])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[F:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][N:17]1[C:16](=[O:56])[C:15]2[NH:14][C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=3)=[N:21][C:20]=2[N:19]([CH2:22][C:23]2[N:27]=[CH:26][N:25]([C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:24]=2)[C:18]1=[O:47]
Reactant: CC(=O)Nc1ccc(CC(=O)Nc2c(N)n(Cc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 50 °C
Yield: 82.1 %

Procedure:
A solution of 2-(4-acetylamino-phenyl)-N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1-(1-trityl-1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (50 mg, 0.06 mmol) in methanol (2.0 mL) was treated with a 10% aqueous sodium hydroxide solution (0.8 mL). The reaction was heated to 50° C. for 8 h. At this time, the reaction was cooled to 0° C., acidified with a 3N aqueous hydrochloric acid solution, filtered, and washed with water to afford N-{4-[1-(2-fluoro-benzyl)-2,6-dioxo-3-(1-trityl-1H-[1,2,4]triazol-3-ylmethyl)-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide (36 mg, 75%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) δ13.45 (broad s, 1H), 9.87 (s, 1H), 7.94 (s, 1H), 7.47–6.89 (m, 23H), 5.21 (s, 2H), 5.07 (s, 2H), 3.95 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.CS[C:25]([NH:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:36]=1)=[CH:26][N+:27]([O-:29])=[O:28].C(OCC)(=O)C.CO>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:25]([NH:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:36]=2)=[CH:26][N+:27]([O-:29])=[O:28])[CH3:16])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN(CCCN)CCC(c1ccc(F)cc1)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: CN(CCCNC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
A mixture of 0.74 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and an equimolar amount of 1-methylthio-1-[3-[3-(piperidinomethyl)phenoxy]propyl]amino-2-nitro-ethene is heated under reflux for 12 hours in 20 ml of acetonitrile. The batch is then freed from solvent and the title compound is isolated in the form of a viscous oil by means of preparative thick-layer chromatography (eluant: ethyl acetate/methanol 9+1, ammoniacal atmosphere); MS (+FAB method): m/z (rel. int.[%])=619 ([M+H]+ 2), 214 (100). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 102° C. with decomposition.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[Cl:21][C:18]1[S:17][C:16]([CH2:15][O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:22])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(OCc2ccc(Cl)s2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2ccc(Cl)s2)c1C(=O)O
Yield: 76.4 %

Procedure:
A solution of 3-(5-chloro-thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (2.3 g, 6.7 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(5-chloro-thiophen-2-ylmethoxy)-phthalic acid as an off-white solid (1.6 g, 76% yield). The product was used in the next step without further purification.