Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:18][CH2:19][OH:20])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:18][CH2:19][O:20][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCCO)cc2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(N4CCCC4)cc(C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.2 %

Procedure:
To a cooled (0° C.) solution of of 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethanol (425 mg, 1.56 mmol) in dichloromethane (20 mL) was added triethylamine (0.9 mL, 6.49 mmol) and tosyl chloride (1115 mg, 5.85 mmol). The reaction mixture was stirred 22 h at room temperature. An aqueous solution of NaHCO3 was added. After separation, the organic layer was washed with brine. The brown gum was triturated with diethylether. After filtration, the solid was dried in a high vacuum to give 520 mg (78.1%) of toluene-4-sulfonic acid 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethyl ester as a light yellow solid. ISP mass spectrum, m/e: 427.5 (M+1 calculated for C23H26N2O4S: 427.5).
Reaction SMILES: Br[C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1.C1C=CC=CC=1.[Li]CCCC.[CH:29](=[O:31])[CH3:30]>C1COCC1.CCCCCC>[Cl:8][C:5]1[C:4]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:3]=2[C:2]([CH:29]([OH:31])[CH3:30])=[CH:7][N:6]=1
Reactant: CC=O
Reactant: Clc1ncc(Br)c2sc(-c3ccccc3)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(O)c1cnc(Cl)c2cc(-c3ccccc3)sc12
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
7-bromo-4-chloro-2-phenyl-thieno[3,2-c]pyridine 95 (130 mg, 0.40 mmol) was azeotroped to dryness from benzene and dissolved in THF (11 mL). Upon cooling to −78° C., the solution was treated dropwise with n-BuLi (168 μl of a 2.5 M solution in hexane, 0.42 mmol). After 2 min, acetaldehyde (50 μl, 0.89 mmol) was added and the resultant solution was stirred at −78° C. for 1 h. After this time, the reaction mixture was warmed to 0° C., quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by silica gel column chromatography (eluent: hexane:EtOAc, 4:1) to give 96. 1H NMR (400 MHz, CDCl3) δ: 1.68 (d, J=6.5 Hz, 3H), 2.29 (bd, 1H), 5.22–5.29 (m, 1H), 7.38–7.49 (m, 3H), 7.69 (s, 1H), 7.73–7.78 (m, 2H), 8.13 (s, 1H). MS (EI) m/z (M+H+) 290.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:13]([CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Clc1ccc(OCCBr)cc1
Product: CN(C)CCOc1ccc(Cl)cc1
Yield: 61 %

Procedure:
The title compound was prepared in 61% yield (26% SM recovered) by essentially following the procedure outlined in Example 34, Part A from 2-bromoethyl 4-chlorophenyl ether and dimethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25].N1CCCCC1.C(O)(=O)C>C(O)(C)C.O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)=[CH:18][C:17]=1[C:24]([F:25])([F:26])[F:27]
Reactant: COC(=O)CC(=O)c1ccccc1O
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)C1C(=O)c2ccccc2OC1c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 200 mg, 1.03 mmol) and 4-chloro-3-(trifluoromethyl)benzaldehyde (148 μL, 1.03 mmol) in isopropanol (4.0 mL) was treated with piperidine (10 μL, 103 μmol) and acetic acid (5.9 μL, 103 μmol) and heated to reflux for 16.5 h. After this time, water (2.0 mL) was added and the solution was slowly cooled to rt, whereupon crystals formed. After standing at rt, the mixture was cooled on ice, and the resulting crystals were collected by filtration and dried to provide methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate as a white crystalline solid (204 mg, 51%). A second crop (47 mg) was obtained from the mother liquor, raising the total yield to 63%. The NMR indicated predominantly the enolic form. 1H NMR (500 MHz, CDCl3) δ ppm 3.79 (s, 3 H) 6.24 (s, 1 H) 6.82 (d, J=8.2 Hz, 1 H) 7.00 (t, J=7.7 Hz, 1 H) 7.31 (t, J=6.9 Hz, 1 H) 7.42 (m, 2 H) 7.70 (m, 2 H) 12.27 (br. s, 1 H). Mass spectrum m/z 407.19, 409.18 (M+Na)+.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)=[NH:4].N1C=CC=CC=1.C(C(CCCC)[CH2:44][O:45]C(Cl)=O)C>CN(C)C=O>[O:45]=[C:44]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[CH:22]=[C:21]4[C:17]([CH2:18][CH2:19][N:20]4[S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=3)=[O:13])=[CH:7][CH:6]=2)[NH:4]1
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=N)NO)cc3)cc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide (254 mg, 0.51 mmol) in dimethylformamide (3.5 ml) was treated with pyridine (0.04 ml, 1 equiv.) and the mixture was cooled to 0° C. Chloroformic acid 2-ethylhexyl ester (98 mg, 0.51 mmol, 1 equiv.) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, then quenched with water. The slurry was extracted three times with ethyl acetate. The combined organic layers were dried with Na2SO4 and the solvent was evaporated. The crude compound was suspended in xylene and heated at reflux for 2 hours. After cooling to room temperature, the solid was filtered and dried under high vacuum, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide as a white solid, 114 mg (43%). MS (ISP): m/e=525.2 (M−H), δH (300 MHz; d6-DMSO) 10.31 (1H, s), 7.55-7.80 (8H, m), 7.28 (1H, d), 7.16 (1H, d), 4.04 (2H, t), 3.60 (3H, s), 3.06 (2H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[Br:13]Br>C(O)(=O)C>[Br:13][C:9]1[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(Br)c2c(c1)C(=O)C(=O)N2
Temperature: 25 °C

Procedure:
To a suspension of 8.0 g of 5-methylisatin in 200 ml of acetic acid was added dropwise a solution of 3.3 ml of bromine in 50 ml of acetic acid with stirring at room temperature, and the mixture was heated at 50° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-hexane to obtain 11.4 g of 7-bromo-5-methylisatin having a melting point of 176°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:14][CH2:13][OH:12]
Reactant: O=C1OCCO1
Reactant: COc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(F)cc1OCCO
Yield: 79.8 %

Procedure:
A suspension of 8.75 g of 5-fluoro-2-methoxyphenol, 10.9 g of ethylene carbonate and 8.50 g of potassium carbonate in 12 ml of toluene was refluxed for 2.5 hours. The reaction mixture was diluted with benzene, washed with water, dried and evaporated. The residue was distilled to give 9.15 g of 2-(5-fluoro-2-methoxyphenoxy)ethanol as colorless oil, b.p. 138°-140° C. (8mmHg).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=[O:6].[OH-].[Na+]>>[CH3:1][S:2][CH2:3][C:4]([CH:5]=[O:6])=[CH:5][CH2:4][CH2:3][S:2][CH3:1]
Reactant: CSCCC=O
Agent: [Na+]
Agent: [OH-]
Product: CSCCC=C(C=O)CSC
Temperature: 0 °C

Procedure:
Into a 1 liter reaction flask equipped with mechanical stirrer, 250 ml addition funnel, Y adapter, thermometer and Friedrich condenser is placed 208 grams of methional. The reaction mass is cooled to 0° C and 100 ml of a 0.5 molar solution of sodium hydroxide is added dropwise with stirring. The resulting reaction mass is extracted with three 100 ml portions of methylene chloride and the extracts are combined, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The resulting product was then subjected to vacuum distillation to give the product, boiling point 129° C (1 mm Hg).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4]
Reactant: Nc1ccccc1F
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1F)Nc1ccccc1C(=O)O
Yield: 85.3 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), ortho-fluoroaniline (7.48 mL, 77.5 mmol) and DMF (80 mL) was heated to 75° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with water (60 mL) and dried under high vacuum at 45° C. to yield 7.62 g (85%) of the title compound as an off-white solid; 1H NMR (DMSO-d6) δ 13.54 (broad s, 1H), 12.01 (s, 1H), 8.72 (d, J=8.4, 1H), 7.93 (dd, J=8, J=1.4, 1H), 7.59 (td, J=7.2, J=1.6, 1H), 7.13 (t, J=7.6, 1H), 7.05 (dd, J=11.6, J=8.0, 1H), 6.94 (t, J=7.6, 1H), 6.58 (m, 2H), 6.37 (broad s, 1H), 3.90 (d, J=5.6, 2H); 13C NMR (DMSO-d6) δ 170.30, 169.19, 151.02 (J=238.1), 140.56, 136.00 (J=11.3), 134.20, 131.12, 124.77 (J=3.1), 122.71, 119.35, 116.80 (J=6.8), 114.52 (J=18.2), 111.81 (J=3.1), 48.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]=[CH:6]2.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)C=CCN2
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2ncccc2c1
Yield: 97 %

Procedure:
3-cyano, 4-oxo, 6-methoxy dihydroquinoline was reacted with phosphorus oxychloride in acetonitrile at 85° C. for 5 hr to give 3-cyano, 4-chloro, 6-methoxy quinoline 97% purity by HPLC
Reaction SMILES: S(=O)(=O)(O)O.Br.[C:7]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:24]CCCCCCCCCCCCCCCOCCCCCCCCCCCCCCC(O)=O>C(O)(=O)C>[Br:24][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:22])=[O:23]
Reactant: O=C(O)CCCCCCCCCCCCCCOCCCCCCCCCCCCCCCBr
Reactant: O=C1CCCCCCCCCCCCCCO1
Agent: Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCBr

Procedure:
The present reaction can be carried out in the presence of acetic acid and can be performed by using acetic acid as a solvent. As described in the above Non-patent Document 11, when concentrated sulfuric acid-hydrogen bromide acid is used and 15-pentadecanolide is reacted, for example, 15-(15-bromopentadecyloxy)pentadecanoic acid, which is difficult to get separated from the target compound 15-bromopentadecanoic acid, is produced as a byproduct. As a result, it becomes difficult to obtain highly pure 15-bromopentadecanoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)=[O:12])=[CH:3][CH:2]=1.[N:29]1([C:35]2[N:42]=[CH:41][CH:40]=[CH:39][C:36]=2[C:37]#[N:38])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[C:37]([C:36]1[C:35]([N:29]2[CH2:30][CH2:31][N:32]([C:19]([C:18]3[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=3)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[NH:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:21])[CH2:33][CH2:34]2)=[N:42][CH:41]=[CH:40][CH:39]=1)#[N:38]
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Product: N#Cc1cccnc1N1CCN(C(=O)c2cccc(CONC(=O)c3ccccc3NCc3ccncc3)c2)CC1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and 2(1-piperazinyl)-nicotinonitrile (Emka-chemie). 1H-NMR (DMSO-d6) δ 11.5 (bs, 1H), 8.48 (m, 2H), 8.43 (dd, 1H), 8.10 (dd, 1H), 7.89 (bt, 1H), 7.60-7.53 (m, 2H), 7.50 (t, 1H), 7.44 (dt, 1H), 7.38 (dd, 1H), 7.30 (m, 2H), 7.16 (m, 1H), 6.97 (dd, 1H), 6.54 (m, 1H), 6.49 (bd, 1H), 5.00 (s, 2H), 4.46 (d, 2H), 4.00-3.36 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:18][N:19]([CH3:29])[NH:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C3=NNN(C)N3)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.116 g, 0.331 mmol, prepared in example E-242 in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.015 g, 0.364 mmol, 60% in mineral oil). Let stir for 20 min, then add methyl iodide (0.022 mL, 0.364 mmol) and let stir for 3 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×30 mL). Combine the organic layers and wash with brine (2×30 mL), aqueous NH4Cl (1×30 mL), aqueous NaHCO3 (1×30 mL) and water (1×30 mL). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Separate the two regioisomeric products via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes) and concentrate under reduced pressure the purified fractions. Place the residue under vacuum to provide the title compound as a white solid (0.015 g); mass spectrum (m/e): 365.09 (M+H)
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:31][C:25]3([OH:32])[CH2:26][C:27]([OH:30])([CH2:29][C:23]([OH:33])([CH2:24]3)[CH2:22]1)[CH2:28]2)([OH:20])=[O:19]>>[C:18]([C:21]12[CH2:22][C:23]3([OH:33])[CH2:24][C:25]([O:32][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:26][C:27]([OH:30])([CH2:29]3)[CH2:28]1)[CH2:31]2)([OH:20])=[O:19]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: O=C(O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3(O)CC(O)(C1)CC(C(=O)O)(C3)C2
Yield: 81 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1-carboxy-3,5,7-trihydroxyadamantane was used instead of the 1-carboxy-3,5-dihydroxyadamantane, and, as a result, a 1-carboxy-3,5-dihydroxy-7-acryloyloxyadamantane (yield: 81%, white solid) was produced.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:19])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:19][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2ccccn2)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ccccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 7 h
Yield: 20.7 %

Procedure:
Dimethyl sulfoxide (1.5 ml) was added to 5,6-dimethyl-[2,2′]-bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (101 mg), and cesium carbonate (147 mg), and the mixture was stirred at 130° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (12 mg, yield 20%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc(Oc2ccc(-c3nc(-c4ccccc4)c(-c4ccccc4)o3)cc2)cc1
Yield: 97.9 %

Procedure:
A mixture containing one gram (3.2 mmoles) of 4,5-diphenyl-2-(p-fluorophenyl)-1,3-oxazole, 1.2 g (12 mmoles) of phenol, 2 g (14.5 mmoles) of anhydrous potassium carbonate and 10 ml of N-methylpyrrolidone (hereinafter NMP) is stirred and refluxed under nitrogen atmosphere for 40 minutes when gas chromatograph analysis indicates the disappearance of the starting material and the formation of a new compound. The reaction mixture is cooled, diluted with 30 ml of water, and stirred for 30 minutes. The colorless precipitate is filtered and recrystallized from 95 percent ethanol. The title compound (1.22 g, 99 percent yield) is recovered. The product has a melting point of 125° C.-126° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:14])[C:5]1([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Cl>CN(C)C=O.Cl.CCOCC>[CH3:3][N:4]([CH3:14])[C:5]1([C:11]([NH:13][C:17]2[C:16]([Cl:15])=[C:23]([Cl:24])[CH:22]=[CH:21][C:18]=2[CH3:19])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C1(C(N)=O)CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(Cl)c1NC(=O)C1(N(C)C)CCCCC1
Reaction time: 2 h

Procedure:
Sodium hydride (0.8 g., 50% dispersion in oil) was added to a solution of 1-dimethylaminocyclohexane carboxamide (2 g.) in dimethylformamide (40 ml.) and the mixture stirred for 2 hrs. A solution of 3,4-dichlorobenzyl chloride (2.4 g.) in dimethylformamide (10 ml.) was added dropwise and the resulting mixture stirred overnight. The mixture was filtered and the filtrate evaporated to dryness. Petrol (80/100 ) was added, the mixture boiled, and the solid filtered off. The filtrate was decolourised with activated charcoal and evaporated to dryness to leave a colourless oil. The oil was dissolved in 2N hydrochloric acid and washed with benzene (4 × 200 ml.). The aqueous phase was basified (2N NaOH) and extracted with benzene (4 × 200 ml.). The benzene extracts were washed with water, (4 × 200 ml.) dried (Na2SO4) and evaporated to leave a colourless oil (2.1 g.), shown by T.L.C. (silica/ether) to consist of three components. The oil was dissolved in the minimum of ether and chromatographed on a column of silica (50 × 2.0 cms.) eluting with ether (11 × 100 ml. fractions). Fractions 3 - 11 were combined, evaporated to dryness and rechromatographed as above. Combination and evaporation of the appropriate fractions afforded a white crystalline solid (1.315 g., 35%). Recrystallisation from 40/60 petrol afforded 1-dimethylamino-N-[3,4-dichlorotolyl]-cyclohexane carboxamide as white needles (0.846 g.) m.p. 82°-83°c. A second crop (0.091g.) melted at 78°-83°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:23]([C:25]1[CH:26]=[C:27]2[C:33]3([CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:32][N:31]([C:46]3[C:47]4[C@H:54]([CH3:55])[CH2:53][CH2:52][C:48]=4[N:49]=[CH:50][N:51]=3)[C:28]2=[CH:29][CH:30]=1)=[O:24].CC(O)C>C1COCC1.O>[F:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:23]([C:25]1[CH:26]=[C:27]2[C:33]3([CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:32][N:31]([C:46]3[C:47]4[C@H:54]([CH3:55])[CH2:53][CH2:52][C:48]=4[N:49]=[CH:50][N:51]=3)[C:28]2=[CH:29][CH:30]=1)=[O:24]
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)c1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C(=O)c5cccc(F)c5)ccc43)c21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 42.8 %

Procedure:
To a solution of 1-bromo-3-fluorobenzene (0.066 ml, 0.59 mmol) in THF (0.3 mL) was added dropwise n-BuLi in hexane (0.23 ml, 0.52 mmol) at about −78° C. under nitrogen. After being stirred at about −78° C. for about 20 minutes, a solution of (R)-tert-butyl 5-(methoxy(methyl)carbamoyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.050 g, 0.099 mmol) in THF (0.2 mL) was added dropwise to the reaction mixture at about −78° C. After 2 hours, i-PrOH (0.090 ml, 1.2 mmol) and water (2.0 mL) were added to the mixture, and the cold bath was removed. The mixture was stirred at about room temperature for about 20 minutes. The mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The crude residue was purified by column chromatography (1-3% MeOH/DCM) to yield (R)-tert-butyl 5-(3-fluorobenzoyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.023 g, 43%). LCMS (APCI+) m/z 543.3 [M+H]+; Rt=4.49 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21].O>ClCCl>[Br:18][CH2:19][C:20]([NH:9][C:6]1[N:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(C(F)(F)F)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(C(F)(F)F)nn1
Reaction time: 1.5 h

Procedure:
6-Trifluoromethyl-pyridazin-3-ylamine (0.042 g) (prepared by a procedure similar to that described in WO2007048779) was dissolved in dichloromethane (40 mL) and stirred with potassium carbonate (0.214 g). 2-Bromoacetyl bromide (0.12 mL) was added and stirring continued for 1.5 hours. Water (0.24 mL) was added and the reaction mixture was stirred for 1.5 hours after which water (40 mL) was added and the reaction mixture stirred for a further 1.5 hours. The dichloromethane was separated, dried (MgSO4) and evaporated to afford the sub-titled compound as a white solid (0.053 g).