Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2.[C:23](=[O:25])=[O:24]>CCCCCC>[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]1=2
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N,N,N′,N′-Tetramethylethylenediamine (38 ml) was dissolved in hexane (300 ml), cooled in an ice-bath and n-butyllithium (100 ml of a 2.5M solution in hexane) added. The mixture was stirred at 0° C. for 15 minutes before adding 2,3-dihydrobenzo[b]furan (30 g) dropwise over 30 minutes. The mixture was allowed to warm to room temperature over 30 minutes, stirred at room temperature for a further 4 hours, poured onto an excess of solid carbon dioxide and left to stand for 3 days by which time the solvent had evaporated off. The residue was partitioned between ethyl acetate (1L) and 4N aqueous hydrochloric acid solution (240 ml), the layers separated and the aqueous layer extracted with ethyl acetate (500 ml). The organic extracts were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was then triturated with diethyl ether to give 2,3-dihydrobenzo[b]furan-7-oic acid as a white solid (21 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][CH2:15]/[CH:16]=[CH:17]/[CH:18]=O)[CH2:7][CH2:6]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28][CH:29]=[CH:30][C:31](=[O:33])[CH3:32]>>[C:31]([C:30]1[CH:16]([CH2:15][CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:17]=[CH:18][N:28]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[CH:29]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)C=CNCc1ccccc1Cl
Reactant: COc1ccc2c(c1)CCC(CC/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CCC1C=CN(Cc3ccccc3Cl)C=C1C(C)=O)C2=O

Procedure:
The title compound 73 is prepared according to the procedure reported in step D of Example 8 with aldehyde 76 (121 mg, 0.47 mmol) and enamine 45 (138 mg, 0.56 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 74 as a yellow oil. (Yield 67.5 mg, 32%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[Na]>[Cl-].[Cl-].[Cl-].[Ti+3].O1CCOCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:2]1[CH:3]3[CH2:9][CH:7]4[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]4)[CH2:4]3)[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na]
Solvent: C1COCCO1
Product: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Yield: 97 %

Procedure:
One (1) part of adamantanone was treated with 1.5 parts of TiCl3 and 4.5 parts Na. Titanium trichloride (2.314 grams, 15.0 mmol) was weighed into a 3-necked flask in an argon glove bag. The flask was cooled over ice, and 25 ml of dry 1,4-dioxane was added with stirring. Small (about 5 mm) chunks of Na metal were added (1.035 grams, 45.0 mmol). The mixture refluxed with stirring under an argon blanket for 45 minutes. No sodium particles were visible. The adamantanone (1.502 grams, 10.0 mmol) was added to the mixture and reflux was continued for 23 additional hours. After cooling, 50 ml of hexanes was added. The product mixture was filtered through Florisil and the filter cake was washed with additional hexanes. NMR analysis of the recovered product revealed essentially pure dimer, with neither unreacted ketone nor byproduct alcohol detected. The dimer, olefin, adamantylideneadamantane was produced in 97% yield.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[OH:11][CH:6]1[CH2:7][CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CCCc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCc2ncccc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
5,6,7,8-Tetrahydro-5-quinolinone, synthesized according to the literature procedure by F. Zymalkowski and H. Rimek, Arch. Pharm. (1961) volume 294, pp. 759-765, (10.0 g, 67.9 mol) was dissolved in MeOH (350 mL) and cooled to 0° C. under an atmosphere of nitrogen. To the solution was added NaBH4 (7.7 g, 0.204 mol) portionwise over 60 minutes. The reaction was stirred at ambient temperature for 24 h. The mixture was concentrated under reduced pressure and partitioned between EtOAc (600 mL) and saturated aqueous NaHCO3 (250 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced presssure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant. 5-Hydroxy 5,6,7,8-tetrahydro-quinoline was obtained as a pale yellow solid (TLC Rf = 0.14 (98:2 CH2Cl2 :MeOH)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of 4-bromophenol (4.56 g, 0.0264 mol), 4-fluorobenzonitrile (0.0264 mol), 18-crown-6 (0.7 g, 0.00264 mol) and 40% potassium fluoride on alumina (10.8 g) in anhydrous acetonitrile (100 mL) was heated at reflux under an atmosphere of nitrogen for twelve hours. It was cooled to ambient temperature, filtered through a Celite pad and concentrated under reduced pressure. The residue was partitioned between diethyl ether (120 mL) and water (100 mL), the organic phase was further washed with saturated solution of potassium chloride in water, dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (3:97) as mobile phase to yield 4-(4-bromophenoxy)benzonitrile (3.7 g, 0.0135 mol) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([F:9])=[CH:7][N:6]=[CH:5][C:4]=1[F:10].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[C:19]2[N:20]([C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=2)[CH:21]=[CH:22][CH:23]=1>CN(C=O)C.O>[F:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:9])[C:3]=1[CH2:2][O:17][C:18]1[C:19]2[N:20]([C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cncc(F)c1CCl
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cncc3F)cccn12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At RT, 1.86 g of 4-(chloromethyl)-3,5-difluoropyridine (Example 115A, 9.1 mmol, 2.0 equivalent) and 4.44 g of caesium carbonate (13.6 mmol, 3 equivalent) were added to 1.0 g of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 3A, 4.54 mmol, 1.0 equivalent) in 100 ml of DMF, and the mixture was stirred at 60° C. for 1 h. The mixture was then diluted with 500 ml of water and extracted twice with in each case 300 ml of ethyl acetate. The combined organic phases were washed with 400 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. The residue obtained was purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 7:1 to 1:1). This gave 900 mg (54% of theory) and 200 mg (13% of theory; purity about 85%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26].C(OCC)(=O)C>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH:18][C:28]([NH:27][C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([CH3:19])[CH:21]=3)=[O:29])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: Nc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-3H-benzimidazol-5-ylamine (100 mg, 360 μmol) in THF (5 mL) was added 3,4-dimethylphenylisocyanate (51 μL, 54 mg., 360 μmols) and the mixture was stirred at ambient temperature for 18 h then was poured into ethyl acetate and extracted with water. The organic layer was dried, filtered, and solvent removed under reduced pressure to leave crude product that was purified by chromatography using a 50-90% gradient of heptane/ethyl acetate to give 1-[2-(2,6-dichlorophenyl)-3H-benzimidazol-5-yl]-3-(3,4-dimethylphenyl)-urea. 1H NMR (DMSO-d6, 400 MHz): δ 12.69 (s, broad, 1H), 8.69 (s, broad, 1H), 8.48 (s, 1H), 7.95 (s, broad, 1H), 7.67 (d, J=7.7 Hz, 2H), 7.60 (m, 2H), 7.26 (s, 1H), 7.20 (d, J=7.7 Hz, 1H) 7.03 (d, J=8.0 Hz, 2H), 2.20 (s, 3H), 2.16 (s, 3H); MS (m/z) 425.1 (M+1); Retention time=1.35 min (Method 10); High Resolution MS (M+1): theory 425.0936, measured 425.0951.
Reaction SMILES: Br[CH:2]=[C:3]([CH3:5])[CH3:4].[Mg].[CH3:7][C:8]1[C:9]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([C:9]1[C:8]([CH3:7])=[CH:13][CH:12]=[CH:11][N:10]=1)([OH:15])[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CBr
Reactant: COc1ccccc1C(=O)c1ncccc1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)(C=C(C)C)c1ncccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
9.23 g of 1-bromo-2-methylprop-1-ene were added dropwise to 2.5 g of magnesium turnings covered with tetrahydrofuran while heating. 7.76 g of 2-methoxyphenyl 3-methyl-2-pyridyl ketone were added while heating to reflux. After 4 hours the mixture was allowed to cool to room temperature. Saturated ammonium chloride solution was added and the resulting mixture was extracted with diethyl ether. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 5.75 g of 1-(2-methoxyphenyl)-3-methyl-1-(3-methyl-2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:29])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[CH:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]([C:10]([O:12]CC)=[O:11])[CH3:9].[OH-].[Na+]>CO>[CH3:1][NH:2][C:3](=[O:29])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[CH:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH:8]([C:10]([OH:12])=[O:11])[CH3:9]
Reactant: CCOC(=O)C(C)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(C)C(=O)O

Procedure:
N-[3-(Ethoxycarbonyl)-2-(2-methylpropyl)butanoyl]-O-methyl-L-tyrosine N-Methylamide (2.0 g., 0.0051 mol.) was hydrolysed upon the addition of 0.1M sodium hydroxide solution (6 mls., 0.006 mol.) in methanol (30 mls.). The solvent was removed by evaporation in vacuo and the resulting gum washed with diethyl ether (2×25 mls.). The gum was acidified with 0.1M hydrochloric acid solution and the mixture was extracted with dichloromethane (2×50 mls.). The combined extracts were dried over anhydrous sodium sulfate and the solvent was removed by evaporation in vacuo to yield N-[3-carboxy-2-(2-methylpropyl)butanoyl]-O-methyl-L-tyrosine N-methylamide as a mixture of isomers as an off-white solid (1.9 g., 0.0052 mol.).
Reaction SMILES: [Na].[Br-].[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:5])=[O:4].[C:29]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>CS(C)=O>[C:29]1(=[CH:9][CH2:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCCC=C1CCCCCCCCCCC1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
Dry dimethylsulfoxide (50 ml, distilled from calcium hydride) and 24.1 ml (0.06 mole) of the sodium salt of dimethylsulfoxide (2.49 M in dimethylsulfoxide, Fieser and Fieser, "Reagents for Organic Synthesis", 1:310 [1967]) were mixed together and cooled in an ice-water bath. Then 13.29 g (0.03 mole) of (4-carboxybutyl) triphenylphosphonium bromide (Aldrich Chemical Co.) was added thereto and the mixture was stirred for 30 min. Cyclododecanone (3.64 g, 0.02 mole; Aldrich Chemical Co.: Beilstein 7[2],36) was dissolved in 10 ml of dry dimethylsulfoxide and added to the above mixture and the mixture was stirred for 15 hr at room temperature. The resulting mixture was then poured into 500 ml of water. This aqueous mixture was extracted with 900 ml (3×300 ml) of ether-ethyl acetate (1:1 V/V). The aqueous phase was acidified (pH 1 to 2) with 30 ml of concentrated hydrochloric acid. The aqueous phase was then extracted with 900 ml (3×300 ml) of ether-hexane (1:1 V/V). The ether-hexane extract was then dried over anhydrous magnesium sulfate, filtered, and the solvent removed in vacuo. The resultant product was recrystallized from ethanol-water to yield 2.0 g (36.2%) of 5-cyclododecylidenepentanoic acid (mp 70°-72° C.) having the following physical characteristics:
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[C:4]([OH:23])(=[O:22])[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][CH2:18][CH2:19][CH2:20][CH3:21]>O>[C:4]([O-:23])(=[O:22])[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][CH2:18][CH2:19][CH2:20][CH3:21].[Ca+2:2].[C:4]([O-:23])(=[O:22])[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][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
317.5 Kg of calcium hydroxide was charged to a Littleford mixer, followed by addition of 11.3 Kg of water. 606.9 Kg of melted stearic acid was then added with high intensity mixing. Total batch time was 30 minutes with reaction time of approximately 15 to 20 minutes. The analysis of the product showed an ash content of 26.95 percent.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[N:39]1[C:44]2[NH:45][C:46]3[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=3[NH:48][CH2:49][C:43]=2[CH:42]=[CH:41][CH:40]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:48]3[C:47]4[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=4[NH:45][C:44]4[N:39]=[CH:40][CH:41]=[CH:42][C:43]=4[CH2:49]3)=[O:13])=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[N:3]=1
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(C(F)(F)F)c2)n1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Reaction time: 5.5 h
Yield: 58.2 %

Procedure:
To a solution of 4-(3-methyl-1H-pyrazol-1-yl)-2-trifluoromethyl benzoic acid (1.1 g, 4.1 mmole) of Step C, and triethylamine (0.57 mL, 4.1 mmol) in dichloromethane (20 mL) was added 2,4,6-trichlorobenzoyl chloride (0.63 mL, 4.0 mmol). After stirring for 5.5 hours, 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (0.67 g, 3.4 mmol) and 4-dimethylamino pyridine (0.42 g, 3.4 mmol) were added. After stirring for an additional 18 hours, the mixture was poured into saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with hexane-ethyl acetate (gradient from 8:2 to 7:3) provided the title product (0.89 g) as a foam which crystallized by sonication from ethanol-hexane, m.p. 212-214° C. This material was identical to the compound of Example 4, Step C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH:26]1([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)=[O:16])=[N:18]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OC(c1cccc(OCc2ccccc2)c1)c1nn(C2CCCC2)c2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(c1cccc(O)c1)c1nn(C2CCCC2)c2ccccc12
Yield: 22.1 %

Procedure:
A mixture of [3-(benzyloxy)phenyl]-(1-cyclopentyl-1H-indazol-3-yl)methanol (0.11 g, 0.37 mmol.), ammonium formate (0.09 g, 1.17 mmol) and 10% palladium on carbon (0.09 g) in 10 mL ethanol was heated at reflux for 18 hours. The reaction was filtered (celite) and the cake washed with excess ethanol. The filtrate was concentrated in vacuo. The crude product was purified by HPLC [column: silica gel 150×12 mm (Biotage) at 10 mL/min with methyl-t-butyl ether/hexane, gradient elution, 1:9 to 1:1 over 15 min) to give the title compound (0.025 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:26]1([O:25][C:23](=[O:24])[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzyloxyaniline (0.999 g, 5.01 mmol) in DCM (10 mL) was added pyridine (1.22 ml, 15.03 mmol) and phenyl chloroformate (0.68 ml, 5.51 mmol) dropwise (Exotherm!). The reaction was then allowed to stir at room temperature for 2 hours. The reaction mixture was then partitioned between DCM and 1M HCl, extracted twice, combined organics passed through phase separating cartridge and filtrate evaporated to dryness to give an orange solid. This was then triturated in 10% ethyl acetate/hexanes, filtered and dried to give the product, phenyl[3-(benzyloxy)phenyl]carbamate, as beige solid (1.209 g, 3.78 mmol, 75% yield).
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[OH-].[Na+]>C(O)C>[Br:1][C:11]1[C:6]([CH2:5][CH2:4][OH:3])=[CH:7][C:8]([O:12][CH3:13])=[N:9][CH:10]=1
Reactant: BrBr
Reactant: COc1cc(CCO)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CCO)c(Br)cn1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Bromine (2.95 g, 18.4 mmol) was slowly added to a stirred solution of 4-(2-hydroxyethyl)-2-methoxypyridine (1.4 g, 9.2 mmol) in 15 mL of absolute ethanol at 0° C., and the reaction mixture was stirred at this temperature for 30 min. The mixture was neutralized by the addition of 2 N aq. NaOH and extracted with EtOAc (50 mL×3). The organic layers were combined and washed with 5% aq. NaHSO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (4:1) to afford 5-bromo-4-(2-hydroxyethyl)-2-methoxypyridine (1.93 g, 91%). 1H NMR (CDCl3) δ 8.14 (s, 1H), 6.68 (s, 1H), 3.86 (s, 3H), 3.85 (t, 2H, J=6.6 Hz), 3.13 (br s, 1H), 2.90 (t, 2H, J=6.6 Hz); 13C NMR (CDCl3) δ 163.27, 149.24, 148.00, 114.41, 112.60, 60.56, 53.63, 38.34.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1C=CC=CC=1>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH3:30])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N1CCC(OC(=O)c2ccccc2C)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol- 2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1 -(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop- 2-ynyl)-6-(2-methylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=O)[O:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[F:19].[OH-].[Na+].O>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH2:15][OH:14])[C:11]([CH2:12][OH:13])=[CH:17][C:18]=1[F:19]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(F)c(F)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of LiAlH4 (1M in tetrahydrofuran) (11 ml, 11.0 mmol, 2.0 molar equivalents) cooled to −78° C. was added dropwise a solution of 4,5-difluorophtalic anhydrid (1.0 g, 5.4 mmol, 1 molar equivalent) in THF (5 ml). The reaction mixture was allowed to warm up to room temperature and then stirred at 70° C. for 2 hours. To this resulting solution cooled to 0° C. was added a 2M sodium hydroxide solution (5 ml) followed by cold water (5 ml) and THF (10 ml). The reaction mixture was then further extracted with THF (3 times 20 ml). The organic fractions were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give a light yellow solid. Purification by recrystallisation from acetone/hexane gave the title compound as light yellow needles (0.8 g, 85%). 1H NMR (300.13 MHz, DMSO) δ(ppm) 4.47 (d, J=5.30, 4H) 5.26 (t, J=5.30 Hz, 2H) 7.36 (t, J=10.10 Hz, 2H). 19F NMR (282.38 MHz, DMSO) δ(ppm) −142.27 (s).