Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]1[CH:32]=[C:31]([C:33]([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][CH:44]=[CH:45][C:36]2=3)=[O:34])[CH:30]=[CH:29][C:9]=1[CH2:10][NH:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[F:24])[N:17]([CH2:25][C:26]#[N:27])[C:16](=[O:28])[CH2:15]1)=[O:13]>CN(C=O)C>[CH3:7][C:8]1[CH:32]=[C:31]([C:33]([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][CH:44]=[CH:45][C:36]2=3)=[O:34])[CH:30]=[CH:29][C:9]=1[CH2:10][NH:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[F:24])[N:17]([CH2:25][C:26]2[NH:27][N:3]=[N:2][N:1]=2)[C:16](=[O:28])[CH2:15]1)=[O:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC#N)c2cccc(F)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(Cc2nnn[nH]2)c2cccc(F)c21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Sodium azide (78 mg, 1.2 mmol) and ammonium chloride (21 mg, 0.40 mmol) were added to a solution of 4-cyanomethyl-8-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylamide from Example 13 (210 mg, 0.40 mmol) in DMF (5 ml) and the mixture was stirred at 100° C. for 18 h. The mixture was cooled and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant CHCl3 100% to CHCl3:methanol;triethylamine 97:2:1 to CHCl3:methanol;triethylamine 94:4:2). The product was partitioned between chloroform and potassium hydrogen sulphate, separated and the organic phase was dried and evaporated in vacuo; yield 33 mg, 15%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[NH:11][CH2:12][CH2:13][N:14]=1.C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30].O>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[N:11]([C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[CH2:12][CH2:13][N:14]=1
Reactant: CCc1cc2c(s1)NCCN=C2c1ccccc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccccc1Cl
Product: Cl

Procedure:
To a solution of 32 g of 5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine in 100 ml of tetrahydrofuran is added 12.5 g of triethylamine, and then to this solution is added dropwise a solution of 13.2 g of dimethylcarbamoyl chloride in 30 ml of tetrahydrofuran with stirring. The whole mixture is stirred under reflux for 6 hours. After cooling, the reaction solution is transferred to water, and extracted with ethyl acetate. After the organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-dimethylcarbamoyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 240°-241° C with decomposition.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([C:14](=O)[CH3:15])[C:9](OCC)=[O:10].[NH2:17][C:18]([NH2:20])=[S:19]>O1CCCC1.C(O)C>[CH3:7][C:8]1[C:9](=[O:10])[NH:17][C:18](=[S:19])[NH:20][C:14]=1[CH3:15]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: NC(N)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1[nH]c(=S)[nH]c(=O)c1C
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a stirred solution of potassium tert-butoxide (15.71 g, 0.140 mol) in tetrahydrofuran (200 mL) was added a solution of ethyl 2-methyl-3-oxobutanoate (20.0 g, 0.14 mol) and thiourea (10.55 g, 0.14 mol) in dry ethanol (150 mL). The resulting mixture was refluxed for 15 minutes and cooled down to ambient temperature. The formed precipitate was collected by filtration, washed with tetrahydrofuran (200 mL), and dissolved in water (200 mL). Acetic acid (100 mL) was added in to the resulting solution. The formed precipitate was collected by filtration and dried to yield 17 g (78.5%) of the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 3H) 2.09 (s, 3H) 12.19 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6](Cl)(=[O:8])=[O:7])=[CH:2]1.[NH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[Br:17]>>[Br:17][C:12]1[C:13]([CH3:16])=[N:14][O:15][C:11]=1[NH:10][S:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:8])=[O:7]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccsc1
Product: Cc1noc(NS(=O)(=O)c2ccsc2)c1Br
Yield: 22 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 from thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole in 22% yield. Purification by column chromatography using 10% MeOH/CHCl3 as eluent gave a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C@@H:27]2[CH2:26][CH2:25][C@H:24]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:12]=[N:13][C:14]([O:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:15][CH:16]=4)=[N:9]3)[CH2:29][CH2:28]2)[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 4-[4-amino-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclo-hexanone (Intermediate AI) (0.90 g, 0.0022 mol), N-methylpiperazine (0.676 g, 0.0067 mol) and acetic acid (0.405 g, 0.0067 mol) in 1,2-dichloroethane (40 mL) was stirred for 10 min and sodium triacetoxyborohydride (0.62 g, 0.0029 mol) was added at once. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 24 hours and sodium triacetoxyborohydride (0.30 g, 0.0014 mol) was added. The mixture was stirred for another 48 hours, the solvent removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate solution (80 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer further extracted with dichloromethane twice (50 mL). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to yield a yellow oil. The compound was further purified by flash chromatography on silica gel using dichloromethane/triethylamine/methanol (89:10:1) as a mobile phase to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AJ): TLC (dichloromethane/triethylamine=9:1) Rf 0.29 and trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: TLC (dichloromethane/triethylamine=9:1) Rf 0.14.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1F.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:14]([O:21][C:9]1[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[Cl:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Cl)c1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 15.43 g (0.275 moles) portion of solid (pellets) potassium hydroxide was added to a solution of 43.89 g (0.25 moles) of 3-chloro-4-fluoro nitrobenzene and 32.34 ml (33.79 grams, 0.373 moles) of benzyl alcohol in 220 ml of acetonitrile. The reaction was vigorously stirred with a mechanical stirrer overnight. The resulting solid was filtered. Concentration of the filtrate gave a second crop, which was also filtered. On standing more solid came out of this filtrate. This mixture was treated with ether, and the solid filtered. All solids were washed thoroughly with water, and combined to give 49.71 g of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5].[O:6]1[CH2:16][C:7]1([CH3:17])[CH:8]1C[CH2:12][CH:11]([CH3:14])[CH:10](O)[CH2:9]1.C(O)(=O)C>CO>[CH3:1][O:2][CH2:16][C:7]([OH:6])([CH3:17])[CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH:4]1[OH:5]
Reactant: C[O-]
Reactant: CO
Reactant: CC1CCC(C2(C)CO2)CC1O
Agent: [Na+]
Solvent: CC(=O)O
Product: COCC(C)(O)C1CCC(C)CC1O
Yield: 75.1 %

Procedure:
Into a solution of a 28% sodium methylate-methanol solution (19.2 g; 0.1mol) in methanol (22ml) was added dropwise a solution of 8,9-epoxy-p-menthan-2-ol (17 g; 0.1 mol) in methanol (10 ml) with heating under reflux for over one hour. Upon completion, the resultant mixture was stirred at the same temperature for 3 hours for reaction. After cooling, glacial acetic acid (6.6 g; 0.11 mol) was added dropwise to the mixture for neutralizing the alkali. The oil layer which had been separated by adding chilled water was extracted with toluene, washed with brine until neutral, dried over anhydrous magnesium sulfate and concentrated under a low vacuum while recovering the toluene to give a crude product (17 g). The crude product was distilled under a high vacuum at a boiling point of 114° to 150° C./0.9 mm Hg to give the title compound (5) (15.2 g) (Theoretical yield: 75%). Analytical results on the title compound are given below.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]1([C@H:9]([NH2:31])[C:10]([N:12]2[CH2:16][C:15]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])=[CH:14][C@H:13]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][CH2:2][C:3]([NH:31][C@@H:9]([CH:6]1[CH2:8][CH2:7]1)[C:10]([N:12]1[CH2:16][C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][C@H:13]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:11])=[O:4]
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reaction time: 0.5 h

Procedure:
Bromoacetyl bromide (49 μL, 0.56 mmol, 1.1 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 181 mg, 0.511 mmol, 1 equiv) and N,N-diisopropylethylamine (107 μL, 0.613 mmol, 1.20 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was allowed to stir for 30 minutes. The reaction mixture was partitioned between water (70 mL) and dichloromethane (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-bromo-N-{(1S)-1-cyclopropyl-2-[(2S) (2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}acetamide (25-1) as a pink foam. LRMS m/z (M+H) 477.3 found, 477.1 required.
Reaction SMILES: C(C[C:4]1[CH:5]=[CH:6][C:7]2[O:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][C:8]=2[CH:17]=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19]>Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9][C:8]3[CH:17]=[C:4]([CH2:19][C:18]([OH:21])=[O:20])[CH:5]=[CH:6][C:7]=3[O:16][C:11]=12
Reactant: CC(=O)O
Reactant: N#CCc1ccc2c(c1)Cc1cccnc1O2
Agent: Cl
Product: O=C(O)Cc1ccc2c(c1)Cc1cccnc1O2

Procedure:
A solution of 11.5 g of 7-cyanomethyl-5H-[1]benzopyrano[2,3-b]-pyridine in a mixture of 60 ml of acetic acid and 25 ml of concentrated hydrochloric acid is heated under reflux for 24 hours. After concentration, water is added to the residue, and further 10% sodium hydroxide solution is added to dissolve the residue. An insoluble material is removed by extraction with chloroform. The aqueous layer is made acid with acetic acid, and the resulting crystalline precipitate is filtered off. The crystals are recrystallized from dioxane to give 8.5 g of 5H-[1]benzopyrano[2,3-b]-pyridin-7-yl-acetic acid as white needles melting at 218°C.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([CH:21]=[O:29])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:25][CH:26]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1cc(OC)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methoxy-2-vinylbenzoate (0.16 g) in a mixed solvent of acetone (2.20 mL)-acetonitrile (2.20 mL)-water (2.20 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.48 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.16 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:10]=2[N:11]=1.[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(=[O:31])=[O:30])=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(=[O:31])=[O:30])=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]4[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)[C:10]=3[N:11]=2)=[CH:24][N:23]=1
Reactant: COc1ccc(Nc2ncnc3ccc(Cl)nc23)cn1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)cn1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A mixture of 6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 22) (0.040 g, 0.139 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.066 g, 0.153 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.011 g, 0.014 mmol) and 1 N aq. sodium bicarbonate (0.278 ml, 0.278 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(6-methoxypyridin-3-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.024 g, 31%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)(C)C>[OH:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][S:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: O=C(CSCc1ccncc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC(CSCc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Under a nitrogen atmosphere, alpha-(4-picolylthio)acetophenone (852 mg., 3.5 mmoles) was dissolved in 8.75 ml. of isopropyl alcohol. Sodium borohydride (54 mg., 1.4 mmoles, 1.6 equiv.) was added. After stirring for 0.5 hour at room temperature, the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled somewhat and then evaporated to an oil. With stirring, hydrochloric acid (4 N, 10 ml.) was added slowly to the oil, so as to control heating and foaming. Once addition was complete and there was no evidence of gas evolution, the acid solution was made strongly basic with 20% sodium hydroxide. The oil which precipiated was extracted into chloroform. The chloroform was back-washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and concentrated to an oil (0.87 g.) which crystallized to a waxy solid on standing. The solid was triturated with ether and filtered to yield crude product (0.61 g.). Recrystallization from ethyl acetate gave purified 4-(2-hydroxy-2-phenylethylthiomethyl)pyridine [0.42 g.; m.p. 116.5°- 119° C. (incomplete); ir (KBr): 3.17, 5.1-5.8, 6.22, 6.88, 9.49, 12.25, 13.88 and 14.25μ; mass spectra: m/e calcd.: 245, found: 245; pnmr/CDCl3 /TMS/δ: 8.73-8.37 (m, 2H), 7.57-7.10 (m, 7H), 4.75 (t, 1H), 3.63 (s, 2H), 3.10 (s, 1H, exchanges with D2O) and 2.72 (d, 2H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[O:21]C)=[O:10].B(Cl)(Cl)Cl.O.CCO>C(Cl)Cl>[Cl:23][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[OH:21])=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OC)c1OC
Agent: ClB(Cl)Cl
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(O)c1OC

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3,4-trimethoxy-phenyl)-ethanone from preparation 2 (20 g, 56 mmol) was dissolved in DCM (75 mL) under argon. BCl3 (95 mL of a 1M solution in DCM) was added slowly at room temperature for 2 hours. Water (50 mL) was added slowly followed by EtOH (200 mL). The white precipitate was filtered and re-crystallised from EtOH. 2-(3,5-Dichloro-pyridin-4-yl)-1-(2-hydroxy-3,4-dimethoxy-phenyl)-ethanone was obtained as a white solid. 1H NMR (CDCl3) δ=11.92 (1H, s), 8.54 (2H, s), 7.68 (1H, d), 6.60 (1H, d), 4.67 (2H, s), 3.98 (3H, s), 3.90 (3H, s). Yield 14.2 g (74%)
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[C:3]1([C:9]2[CH:10]=[N:11][N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2cn[nH]c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2ccccc2)cn1
Reaction time: 1 h

Procedure:
To a slurry of 3.0g (0.075 mol) of sodium hydride in 30 mL of DMF at room temperature was added 10g (0.069 mol) of 4-phenyl-1H-pyrazole of example 1. The mixture was stirred 1 hr and 7.8 mL (0.07 mol) of ethyl bromoacetate was added with cooling. The reaction was stirred 3 hr at room temperature, briefly at 100° C. and was poured onto ice. The product was filtered off, rinsed with water, dried, and washed with hexane to yield 14.0g of ethyl 4-phenyl-1H-pyrazole-1-acetate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(Cl)Cl.CCOC(C)=O>[S:6]1[CH:7]=[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]2)[N:4]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1cscn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Temperature: 35 °C
Reaction time: 5 h
Yield: 19.2 %

Procedure:
4-(Chloromethyl)thiazole (0.500 g, 2.94 mmol, 1 eq) was suspended in DCM (4.6 mL). DIPEA (1.28 mL, 7.35 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (1.200 g, 6.47 mmol, 2.2. eq). The mixture was stirred at 35° C. for 5 h, diluted with EtOAc and washed with H2O and brine. The organic layer was separated, dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound as a clear oil (0.160 g, 19%); 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H, C(CH3)3), 2.47 (br t, J=4.2 Hz, 4H, piperazine N(CH2)2), 3.46 (br t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.75 (s, 2H, NCH2), 7.20 (s, 1H, thiazole 5-H), 8.79 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.80 min—284 [(M+H)+, 100%].
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[N:15]([CH3:20])[C:14](=[O:21])[CH:13]=1>>[NH2:11][C:12]1[C:13]([CH2:14][NH2:15])=[C:1]([C:3]2[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=2)[C:13]2[C:14](=[O:21])[N:15]([CH3:20])[C:16](=[O:19])[N:17]([CH3:18])[C:12]=2[N:11]=1
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: N#Cc1ccc(C=O)cc1
Product: Cn1c(=O)c2c(-c3ccc(CN)cc3)c(CN)c(N)nc2n(C)c1=O

Procedure:
The synthesis of title compounds started from 4-formylbenzonitrile and 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, according to the procedures described in the synthesis of Compound 56. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.06 (s, 3H) 3.53 (s, 3H) 3.56 (d, J=5.56 Hz, 2H) 4.12 (d, J=5.56 Hz, 2H) 7.22 (d, J=7.83 Hz, 2H) 7.49 (m, 4H) 7.92 (br. s., 2H) 8.37 (br. s., 2H) MS [m+H] MS [m+H] calc'd C17H20N6O2 341.38; found 341.4.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].[H][H].C1C=CC=CC=1.CCCCCC>C(O)C.[Ni]>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][OH:21])[CH3:18])[CH3:13])[CH3:8])[CH3:1]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Yield: 81.9 %

Procedure:
Phytol (30.0 g, 0.101 mol) was dissolved in 200 ml of ethanol. A suspension of 1.8 g of Raney-Ni (W-1) in 5 ml of ethanol was added thereto, and hydrogenation was carried out under hydrogen for about 5 hours so that 2405 ml of hydrogen (theoretical volume at 24° C.; 2465 ml) was absorbed. After filtering off the catalyst through a filter paper, the ethanol was evaporated. Yield 29.9 g. Silica gel column chromatography with benzene-hexane (1:1) gave 24.7 g of the title compound (yield 82.3%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14](=O)[CH3:15].[CH3:17][C:18]1[N:19]=[C:20]([C:26]2S[CH:28]=[CH:29][CH:30]=2)S[C:22]=1[C:23](=O)[CH3:24].[NH3:31]>>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]1[CH:15]=[CH:14][C:3]2[C:2](=[CH:28][CH:29]=[C:30]([CH2:26][CH2:20][N:19]3[CH2:24][CH2:23][CH2:22][C@H:18]3[CH3:17])[CH:4]=2)[N:31]=1
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Reactant: N
Reactant: CC(=O)c1c(-c2ccccc2)nn(C)c1Cl
Product: C[C@@H]1CCCN1CCc1ccc2nc(-c3c(-c4ccccc4)nn(C)c3Cl)ccc2c1

Procedure:
The title compound was prepared using the procedure described in Example 1G using 1-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-ethanone for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.15 (d, J=6.10 Hz, 3H), 1.48 (m, 1H), 1.78 (m, 2H), 1.96 (m, 1H), 2.27 (q, J=8.59 Hz, 1H), 2.41 (m, 2H), 3.03 (m, 2H), 3.15 (m, 1H), 3.31 (m, 1H), 3.99 (s, 3H), 7.26 (m, 4H), 7.46 (m, 2H), 7.62 (m, 2H), 8.00 (d, J=8.48 Hz, 1H), 8.05 (d, J=8.14 Hz, 1H); MS (DCI-NH3) [M+H]+ at 431.