Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:14]([O-])=O)[N:10]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:9][CH2:8][CH2:7]2)[CH3:2].[H][H]>CO.[Pd]>[CH3:21][N:19]([CH2:18][C:17]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[C:13]([NH2:14])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1)=[O:22])[CH3:20]
Reactant: [H][H]
Reactant: CCOc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2
Agent: [Pd]
Solvent: CO
Product: CCOc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Reaction time: 16 h
Yield: 54.5 %

Procedure:
A solution of {2-[6-(ethyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethyl}dimethylamine (5.8 g, 18.87 mmol) in degassed methanol (50.0 mL) was added to a suspension of 10% Pd/C (3.0 g, 16.36 mmol) in degassed methanol (5 mL) and maintained under a 50 psi hydrogen gas with rapid stirring for 16 hours. The suspension was purged with nitrogen, filtered through celite, all volatiles removed, and the resulting residue was purified by flash column chromatography to afford 1-[(dimethylamino)acetyl]-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (2.85 g, 63%) as a viscous yellow liquid which solidified upon standing for 10 hours. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.80 (s, 1 H), 6.55 (s, 1 H), 4.52 (s, 2 H), 3.95 (q, J=6.89 Hz, 2 H), 3.61 (t, J=6.02 Hz, 2 H), 3.15 (s, 2 H), 2.55 (t, J=6.52 Hz 2 H), 2.20 (s, 6 H), 1.73-1.86 (m, 2 H), 1.32 (t, J=7.02 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH2:10][CH3:11].O>C1COCC1>[CH2:10]([N:5]1[C:6]([CH:7]=[O:8])=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH3:11]
Reactant: Cc1nc[nH]c1C=O
Reactant: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCn1cnc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol), and iodoethane (3.4 mL, 45.4 mmol). The mixture was stirred at room temperature overnight. Water (50 mL) was added before the THF was evaporated. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-1% MeOH/DCM), affording 1-ethyl-4-methyl-1H-imidazole-5-carbaldehyde (806 mg, 13% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7]2=[N:9][C:10]([CH2:12][CH3:13])=[CH:11][C:6]2=[C:5]([Cl:14])[N:4]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.[H-].[Na+]>O1CCCC1>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:14])[C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=3)[C:7]=2[N:8]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
A solution of 300 mg (1.31 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 10 mL of tetrahydrofuran (THF) was added to a 0° C. slurry of 377 mg (1.97 mmol) of 3-fluorobenzyl bromide and 55 mg (2.30 mmol) of sodium hydride in 10 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by the addition of 15 mL of brine. The organic phase was dried with sodium sulfate and concentrated to an oil. The product precipitated upon addition of hexanes to provide 384 mg (87%) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine as a light tan solid. nmr (300 MHz, CDCl3) δ1.11 (t, 3H), 2.58 (s, 3H), 2.59 (q, 2H), 5.39 (s, 2H), 6.29 (s, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 6.96 (dt, 1H), 7.26 (dt, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[O:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29](Cl)=[O:30])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>O1CCCC1>[O:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([N:10]3[CH2:11][CH2:12][N:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)=[O:30])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: O=C(Cl)c1ccc2c(c1)CCO2
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc2c(c1)CCO2)N1CCN(c2ncccn2)CC1
Temperature: 60 °C
Yield: 77.6 %

Procedure:
To a solution of 8.2 g of 1-(2-pyrimidinyl)-piperazine and 5g of anhydrous triethylamine in 200 ml of anhydrous tetrahydrofuran, there were added dropwise a solution of 9.1 g of 5-coumaranyl carboxylic acid chloride in 20 ml of tetrahydrofuran. After the completion of the addition, the reaction mixture was heated at 60° C for 2 hours, then the so-formed precipitate was suction-filtered off. The filtrate was evaporated under reduced pressure and the crystalline residue was washed with water then recrystallized in 70 ml of ethanol. There were obtained 12 g of 1-(5-coumaranyl carbonyl)-4-(2-pyrimidinyl) piperazine, melting (K) at 149°-150° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH2:17])[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH2:17])[N:14]=[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Nc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Nc1nc2c(c(-c3ccccc3Cl)n1)CN(Cc1ccccc1)CC2
Temperature: 95 °C
Yield: 61.2 %

Procedure:
6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-ylamine (1.92 g., 7 mmoles) and 2-chlorophenylboronic acid (1.09 g., 7 mmoles) were mixed and stirred in a mixture of acetonitrile and water (50:50, 32 mls); anhydrous potassium carbonate (1.93 g., 14 mmoles) was then added to the stirred reaction mixture under nitrogen. Pd(PPh3)4 (0.2 g.) was then added to the reaction mixture which was stirred and heated at 95° C. for 3 hours also under nitrogen. The reaction mixture was then allowed to cool to room temperature and a beige solid formed. This suspension was quenched with water (150 mls) and the solid filtered and washed with water (100 mls) dried in a vacuum desiccator. The product was then eluted through a ‘silica plug’ in ethyl acetate, after evaporation the solid was slurried in ether to give, after filtering and drying a white solid (1.5 g., 61.2% yield). LC-MS (retention 2.65 mins, mass 351 M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:16])[CH3:15])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:16])[CH3:15])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)ccc1C(=O)O

Procedure:
A reaction mixture prepared by dissolving 575 mg of 4-nitro-N-acetyl-anthranilic acid in 200 ml of ethyl acetate and by mixing the resultant solution with 100 mg of a 10% Pd-C catalyst was stirred at room temperature in a hydrogen gas atmosphere for 4 hours. Then, the reaction mixture was filtered through a Celite filter to remove the catalyst, and the catalyst was washed with ethyl acetate. The total amount of the filtrate was collected and concentrated under a reduced a silica gel column chromatography. A final product consisting of 4-amino-N-acetyl-anthranilic acid was obtained in an amount of 450 mg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]=1[OH:13])[CH:8]=[O:9]
Reactant: BrBr
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=O)cc(Br)c1O
Reaction time: 3 h

Procedure:
To 3-tert-butyl-4-hydroxybenzaldehyde (3 gm) in acetic acid (30 ml) was added dropwise bromine (1.5 ml). The mixture was stirred at 25° for 3 hours and the solvent removed in vacuo. Recrystallisation of the residue from aqueous ethanol gave 3-bromo-5-tert-butyl-4-hydroxybenzaldehyde (3.2 gm) m.p. 126°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:22][C@@H:21]([O:23][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH2:20][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C([C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1)N1CCCC1
Product: COc1ccc(O[C@H]2C[C@@H](C(=O)N3CCCC3)N(C(=O)OCc3ccccc3)C2)cc1

Procedure:
By repeating the process of Example 2(a) above but using N-(N-benzyloxycarbonyl-trans-4-hydroxy-L-prolyl)pyrrolidine in place of N-[N-(4-phenylbutanoyl)-trans-4-hydroxy-L-prolyl]pyrrolidine and 4-methoxyphenol in place of phenol, N-[N-benzyloxycarbonyl-cis-4-(4-methoxyphenoxy)-L-prolyl]pyrrolidine (SUAM 14491) was obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1([Br:12])[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:11].I[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[C:18]([O:17][C:15]([CH2:14][N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:4]([Br:12])([Br:3])[C:5]1=[O:11])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1NCCCCC1(Br)Br
Reactant: CC(C)(C)OC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCCCC(Br)(Br)C1=O

Procedure:
To a suspension of 300 mg of sodium hydride in 25 ml THF add a solution of 2.71 g of 3,3-dibromoperhydroazepin-2-one [R. Wineman et al., J. Am. Chem. Soc., 80, 6233 (1958)] and 2.50 g of t-butyl iodoacetate in 25 ml THF, carrying out the operation under N2. Stir the reaction at room temperature for several hours, quench with aqueous NaHSO3, isolate the organic phase, dry and concentrate in vacuo to obtain 1-t-butoxycarbonylmethyl-3,3-dibromoperhydroazepin-2-one.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.Br[CH2:30][C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[CH3:39])=O>>[CH3:39][C:38]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:31]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:30]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: Cl
Product: Cc1ccncc1-c1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 67 mg (0.269 mmol) of 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrochloride were reacted according to the General Method 3. Yield: 13 mg (12% of theory).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH:45][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7](=[O:25])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOCCOc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOCCOc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Yield: 22 %

Procedure:
8-Cyclopentyl-6-(2-ethoxy-ethoxy)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.2 mL of a 0.46 M solution in toluene, 0.552 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.307 g, 1.1 mmol) were combined in toluene under nitrogen and heated to 110° C. After 4 h the toluene was replaced by xylenes (1 mL) and heating was continued under reflux overnight. After cooling to room temperature the crude reaction mixture was dissolved in CH2Cl2 and washed with saturated aqueous ammonium chloride solution then with brine. The organic layer was dired (MgSO4), filtered and evaporated to dryness. Chromotagraphy on silica gel eluting with 5% CH3OH in CH2Cl2 followed by a second chromatography step eluting with ethyl acetate provided 4-{6-[8-cyclopentyl-6-(2-ethoxy-ethoxy)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 22%) as a yellow solid. MS (APCI); M++1: Calc'd, 580.32. Found 580.2. 1H NMR: 68 (400 MHz, DMSO) 8.50 (s, 1H), 8.26 (d, J=9 Hz, 1H), 7.94 (d, J=3 Hz, 1H), 7.39 (dd, J=3, 9 Hz, 1H), 6.78 (s, 1H), 5.89-5.98 (m, 1H), 4.15 (t, J=5 Hz, 2H), 3.86 (t, J=5 Hz, 2H), 3.56-3.62 (m, 6H), 3.09 (br t, J=5 Hz, 4H), 2.29-2.33 (m, 2H), 2.07-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.63-1.69 (m, 2H), 1.47 (s, 9H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1C(C2C=C[N+:25]([O-:28])=[CH:24][CH:23]=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[N+:25]1([O-:28])[CH:5]=[CH:3][C:2]([CH:1]=[O:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc[n+]([O-])cc1
Agent: N
Solvent: CCO
Product: O=Cc1cc[n+]([O-])cc1

Procedure:
Analogously to the process described in Example 1 there is obtained from 12.3 g of pyridine-4-carboxaldehyde-1-oxide, 25.7 ml of ethyl acetoacetate and 10 ml of 30% aqueous ammonia in 20 ml of absolute ethanol, 2,6-dimethyl-4-(1-oxido-4-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which, after recrystallisation from 100 ml of isopropanol, melts at 229°-231°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]#[CH:10].C(NCC)C>C(=O)(O)[O-].[Na+]>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]#[C:9][CH2:8][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1ccccn1
Reactant: C#CCOCCCCCCNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCNCC
Product: C(#Cc1ccccn1)COCCCCCCNCc1ccccc1
Reaction time: 18 h
Yield: 73.5 %

Procedure:
A mixture of 2-bromopyridine (2.0 g), N-[6-[(2-propynyl)oxy]hexyl]benzenemethanamine (3.2 g), BTPC (0.07 g), cuprous iodide (0.007 g), and diethylamine (20 ml) was stirred under nitrogen for 18 h, treated with aqueous sodium bicarbonate (1M, 50 ml), and extracted with diethyl ether (2×100 ml). The dried extract was evaporated and the residue was purified by FCC eluting with diethyl ether to give the title compound as a yellow oil (3.0 g), t.l.c. (diethyl ether) Rf 0.05.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2)[CH3:7].[I:17]I>O.C(O)C>[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[I:17])[CH3:7]
Reactant: II
Reactant: CCc1cccc2cn[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cccc2c(I)n[nH]c12
Yield: 48.2 %

Procedure:
To a stirred solution of sodium bicarbonate (1.67 g, 19.8 mmol) in water (4.65 mL) and ethanol (9.3 mL) was added 7-ethyl-1H-indazole (771 mg, 5.27 mmol) followed by iodine (1.87 g, 7.38 mmol). After 16 h the reaction mixture was quenched with sodium thiosulfate, diluted with ethyl acetate and washed with water. The organic layer was collected and dried (MgSO4). Purification by chromatography (silica, 5-25% ethyl acetate/hexanes) gave 7-ethyl-3-iodo-1H-indazole (690 mg, 2.54 mmol, 48%) as an off-white solid. MS (M+H)+=272.9; 1H NMR (CDCl3) δ: 7.39 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.1 Hz, 1H), 7.22 (t, J=7.1 Hz, 1H), 2.95 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]12[CH2:15][CH:6]([C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=31)[CH2:5][NH:4][CH2:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>C(O)C>[CH2:24]([N:4]1[CH2:3][CH2:2][CH:1]2[CH2:15][CH:6]([CH:7]([OH:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=32)[CH2:5]1)[CH:23]=[CH2:22]
Reactant: O=C1c2ccccc2C2CCNCC1C2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCN1CCC2CC(C1)C(O)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
20 ml of ethanol was added to 1 g of 2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one and 0.63 g of sodium carbonate, and the mixture was heated and refluxed. Then, 0.72 g of allyl bromide was gradually added to the mixture, and the reaction mixture liquid was heated and refluxed for 5 hours. The mixture was cooled and filtered, and methanol and excessive allyl bromide were distilled from the filtrate. The residue was dissolved in 20 ml of methanol and cooled with ice water, and 0.15 g of sodium boron hydride was gradually added to the solution under agitation. Then, the mixture was agitated at room temperature for 2 hours. Methanol was distilled from the reaction mixture, and 15 ml of water was added to the residue and the mixture was shaken sufficiently. Then, the mixture was extracted with ether and the extract was subjected to distillation to remove ether therefrom. The residue was recrystallized from cyclohexane to obtain 0.9 g of 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4 -benzazonin-7-ol in the form of a white crystal melting at 98° to 100° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].[OH:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=O>O>[O:6]([CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:12]
Reactant: CCCCCCCCCC(=O)O
Reactant: CCCCCC(CO)CCC
Solvent: O
Product: CCCCCCCCCC(=O)OCC(CCC)CCCCC
Yield: 84.1 %

Procedure:
1108.0 g 2-propylheptanol (7 mol) and 1205.9 g capric acid (7 mol) were heated for 6 h to 220° C. on a water separator together with 0.27 g Fascat® 2001 (Sn oxalate: 0.1% by weight, based on the composition as a whole). After the separation of water had stopped, the crude product was distilled in an oil pump vacuum through a 250 mm Vigreux column (T=141-152° C.). 1840.1 g of a colorless oil were obtained: OHV=<0.08, AV=<0.18.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:5]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:11]=2)[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:5]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ncccn1
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ncccn3)ccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To methyl 2-(3-acetyl-5-hydroxy-1H-indazol-1-yl)acetate (1.80 g, 7.25 mmol) in CH3CN (75 mL) was added 2-(chloromethyl)pyrimidine hydrochloride (1.32 g, 7.98 mmol) and Cs2CO3 (5.91 g, 18.13 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was filtered and washed with CH3CN. The solvent was removed under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to 1:3). TLC, Rf (c-hexane/EtOAc 1:3)=0.35; MS (LC/MS): 340.9 [M+H]+, 363.0 [M+Na]+; tR (HPLC conditions e): 3.64 min.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:12](=O)[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1>CO>[O:17]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:12]=[N:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NNC(=O)c1ccccc1O
Reactant: O=Cc1ccco1
Solvent: CO
Product: O=C(NN=Cc1ccco1)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 76.1 g (0.5 mol) of salicylohydrazide and 1 liter of methanol, and 57.6 g (0.6 mol) of furfural was dropwise added thereto in 30 minutes while stirring at room temperature. After heating under reflux for 2 hours, the reaction liquid was cooled down to 20° C. or lower, and crystal was filtered off. The crystal was washed with a small amount of methanol and then dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained. The amount yielded in this reaction was 108.1 g (0.47 mol), and the yield was 93%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26]Br.CCOCC>CC(C)=O>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: BrCc1ccco1
Reactant: Cc1ccc(Nc2nccs2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nccs2)cc1OCc1ccco1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 36 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-methyl-5-(thiazol-2-ylamino)phenol (100 mg, 0.48 mmol) and Cs2CO3 (158 mg, 0.48 mmol) in acetone (4.4 mL) was treated with a freshly prepared solution of 2-furylbromomethane in ether (0.85 mL, 0.44 mmol) at room temperature. After 2 h Cs2CO3 (150 mg, 0.46 mmol) was added and stirred for 5.5 h at rt. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 36% yield (50 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].[CH3:11][N:12](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:11]([C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10])#[N:12]
Reactant: OCc1ccc(Br)c(F)c1
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: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(CO)cc1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of the product from Step I (11.4 g, 55.6 mmol) in 100 mL of DMF was added Zn(CN)2 (3.92 g, 33.4 mmol) and Pd(PPh3)4 (5.1 g, 4.45 mmol). The reaction was stirred at 90° C. overnight, cooled to room temperature, and concentrated in vacuo. Purification of this material by silica gel chromatography (50% EtOAc/hexane) provided the titled product as a light yellow solid.