Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[N+:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C[O-].[Na+]>C(O)C>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:20]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]=2[OH:10])=[O:22])=[CH:23][CH:24]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccccc1S
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1sc2ccccc2c1O

Procedure:
In a similar manner to Example 58, a mixture of methyl thiosalicylate (2.76 g), 4-nitrophenacyl bromide (4.0 g), sodium methoxide (1.94 g) and ethanol (200 ml) gave 2-(4-nitrobenzoyl)-3-hydroxybenzo[b]thiophene of which 2.25 g was reacted with hydrazine hydrate (6 ml) in a similar manner to Example 58, to give 3-(4-aminophenyl)-1H-[1]benzothieno[3,2-c]pyrazole, m.p. 113-115° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cccs1
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: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cccs2)cc1
Temperature: 85 °C
Yield: 77.8 %

Procedure:
To a stirred degassed solution of 4-bromobenzaldehyde (371 mg, 2.00 mmol) and thiophene-2-boronic acid (287 mg, 2.24 mmol) in DME/THF (5 mL, 4:1) were added a 2 M Na2CO3 solution (3.0 mL) and Pd(PPh3)4 (110 mg, 0.095 mmol). The reaction mixture was flushed with argon and maintained under argon while being heated at 85° C. over 2 days. The mixture was then cooled and diluted with EtOAc (35 mL) and water (30 mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography on silica gel (Hexanes/EtOAc, 4:1) afforded the title compound (293 mg, 78%) as a yellow solid. 1H NMR (CDCl3) δ 7.14 (dd, 1H, J=5.1, 3.6 Hz), 7.40 (dd, 1H, J=5.1, 0.9 Hz), 7.46 (dd, 1H, J=3.6, 0.9 Hz), 7.76 (d, 2H, J=8.4 Hz), 7.88 (d, 2H, J=8.4 Hz), 10.00 (s, 1H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:19]
Reactant: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2O)c1ccccc1
Yield: 74.6 %

Procedure:
To a solution of (2R,5R)-6-(benzyloxy)-7-oxo-N′-(phenylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 182 (0.33 g, 0.88 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5R)-6-hydroxy-7-oxo-N′-(phenylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 183 (0.19 g, 89%) as a colorless foam.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Br[CH:14]([C:16]1[C:21]([Cl:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[F:24])[CH3:15]>>[Cl:22][C:21]1[C:20]([F:23])=[CH:19][CH:18]=[C:17]([F:24])[C:16]=1[CH:14]([N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2)[CH3:15]
Reactant: CC(Br)c1c(F)ccc(F)c1Cl
Reactant: O=C1CNc2ncc(I)cc2N1
Product: CC(c1c(F)ccc(F)c1Cl)N1C(=O)CNc2ncc(I)cc21
Yield: 11 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (2.935 g) was treated with 2-(1-bromoethyl)-3-chloro-1,4-difluorobenzene (Preparation 3) as in General Procedure 1 to give the title compound as an orange solid (11% yield). LCMS: m/z=449.86 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.79 (3H, m), 2.73 (1H, s), 2.89 (1H, s), 5.76 (1H, m), 6.96 (1H, s), 7.29 (1H, m), 7.43 (1H, m), 7.62 (1H, s), 7.83 (1H, m).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][CH:17]([CH3:23])[C:18]#[C:19][C:20](O)=[O:21].[CH2:24]([NH2:36])[CH2:25][C:26]1[CH:35]=[CH:34][C:31]([O:32][CH3:33])=[C:28]([O:29][CH3:30])[CH:27]=1>O1CCCC1>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:36][C:20](=[O:21])[C:19]#[C:18][CH:17]([CH3:23])[CH3:16])[CH:35]=[CH:34][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(C)C#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)C#CC(C)C)cc1OC
Temperature: 22.5 °C
Reaction time: 48 h
Yield: 62.9 %

Procedure:
38.2 g (280 mmol) of isobutyl chloroformate were added dropwise at 0 to 5° C., as well as 28.3 g (280 mmol) of N-methylmorpholine at 5 to 15° C., to a solution of 28.4 g (254 mmol) of 4-methyl-2-pentynoic acid (ex. 3) in 100 ml of tetrahydrofuran (THF). 46 g (254 mmol) of homoveratrylamine were subsequently added dropwise while cooling with ice and the mixture was allowed to stir at 20 to 25° C. for 48 hours. The reaction solution was then concentrated and the residue was poured into water/10% hydrochloric acid solution and extracted with MTBE. After drying, distilling off the volatile components and chromatographing on silica gel (cyclohexane:MTBE [3:1]), 44 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-methylbenzylamine (17 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 20 mg of the title compound as a colorless solid.
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C(N(CC)CC)C.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:3]2[C:4](=[O:6])[CH2:5][O:1][C:2]2=[O:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1COC(=O)N1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 1,3-oxazolidine-2,4-dione (60.7 g, 0.600 mol) and triethylamine (60.7 g, 0.600 mol) in methylene chloride (500 mL) was added triphenylmethyl chloride (167.3 g, 0.600 mol). After 30 minutes, the thick white solid was collected by vacuum filtration, washed with water (2 L) and dried in a vacuum desicator to give the title compound (201.4 g, 96%). A portion was recrystallized from chloroform to give white plates: mp 216°-218° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1.CCOCC>[C:16]([O:15][C:13]([NH:12][CH:4]([CH:3]([OH:20])[CH:2]([NH:1][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccccc2)C(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
The resultant compound of Example 11 (0.05 mmol) in 2 ml of pyridine was cooled to 0° C. and treated with 0.05 mmol of p-toluenesulfonyl chloride. After 2 h, the solution was diluted with ether, washed sequentially with 1N HCl, aqueous NaHCO3, and saturated brine, dried over MgSO4, and concentrated. Silica gel chromatography gave the desired compound.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[C:15]1[N:16]=[C:17]([C:28](OCC)=[O:29])[N:18]([CH3:27])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1>>[CH:1]1([NH:6][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15]([C:9]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=3[Cl:7])[N:16]=2)=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Product: Cn1c(C(=O)NC2CCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Step B (Method B), but using neat cyclopentylamine (1.5 mL), ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (30 mg, 0.073 mmol) was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)=[N:11]1.[C:49]([NH:52][C:53]1[CH:54]=[N:55][NH:56][CH:57]=1)(=[O:51])[CH3:50]>C(OCC)(=O)C>[C:49]([NH:52][C:53]1[CH:54]=[N:55][N:56]([CH:13]2[C:14](=[O:15])[N:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=3[Cl:9])[N:11]=[C:12]2[NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)[CH:57]=1)(=[O:51])[CH3:50]
Reactant: CC(=O)Nc1cn[nH]c1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Br)c1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cc(NC(C)=O)cn2)c1
Temperature: 100 °C

Procedure:
17.8 g of 1-(2,4,6-trichlorophenyl)-3-{3-[2-(2,4-di-tert-amylphenoxy)butyramido]benzamido}-4-bromo-5-oxo-2-pyrazoline and 10 g of 4-acetamidopyrazole were well mixed in a mortar and heated at 100° C. for 2 hours. To the reaction mixture, 200 cc of ethyl acetate was added and the mixture was washed several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and ethyl acetate, 12.1 g of Coupler (1) was obtained. The melting point of the coupler was 135° to 141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](OC2C=CC=CC=2)=[N:37][C:38]#[N:39])=[CH:31][CH:30]=1>CC#N>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:36](=[N:37][C:38]#[N:39])[O:35][C:32]2[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Temperature: 40 °C

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.50 g, 1.26mmol) and diphenyl cyanocarbonimidate (0.60 g, 2.51 mmol) were combined in MeCN (5 mL) and stirred at 40° C. until no starting material was seen by analytical LCMS. The mixture was concentrated and purified by silica gel chromatography (10-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.O>ClCCl>[CH:4]1([CH:8]=[O:10])[CH2:3][CH2:5][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:8][CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=CC1CCCCCCCCCCCC1
Yield: 60 %

Procedure:
To a stirred mixture of 3 g of zinc dust, 50 ml of anhydrous tetrahydrofuran and 2.66 g of dibromomethane, was added dropwise a solution of 2.13 g of anhydrous titanium tetrachloride in 5 ml of dichloromethane. After 15 minutes, to the resulting solution was added dropwise a solution of 2 g of cyclotridecanone in 8 ml of anhydrous tetrahydrofuran. The mixture was allowed to react at room temperature for 12 hours. The reaction mixture was diluted with 50 ml of pentane, admixed with 100 ml of 1-M hydrochloric acid, and intermixed by shaking. The organic layer was washed successively with water, dilute aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, then dried, and concentrated to yield methylenecyclotridecane. To a solution of this substance in 40 ml of anhydrous dichloromethane, after having been cooled to -15° C., was added dropwise with stirring a solution of 2.64 g of m-chloroperbenzoic acid in 40 ml of anhydrous dichloromethane. After 3 hours of reaction, the organic layer was washed successively with 10-% sodium sulfite solution, 7-% sodium hydrogencarbonate solution, and saturated sodium chloride solution, then dried and concentrated under reduced pressure. The residue was purified by the silica gel chromatography [developed with a petroleum ether-ethyl acetate (20:1) mixture] to yield 2.04 g (95% yield based on the ketone compound) of an epoxide. To a solution of the epoxide in anhydrous dichloromethane, after having been cooled to -18° C., was added dropwise a borontrifluoride-ether complex. After completion of the addition, water was added to the reaction mixture. The organic layer was separated, then concentrated, and purified by the silica gel chromatography to yield only cyclotridecanecarbaldehyde in a yield of 60-70%.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N+:4]=1[O-:12].[CH2:13]([OH:16])[CH2:14][CH3:15]>>[CH3:2][C:3]1[CH:8]=[C:7]([O:16][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][N+:4]=1[O-:12]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CCCO
Agent: [Na]
Product: CCCOc1cc[n+]([O-])c(C)c1

Procedure:
To a solution of sodium n-propoxide solution prepared by dissolving sodium (1.7 g) in n-propanol (200 ml) was added to a hot solution of 2-methyl-4-nitropyridine-1-oxide (5.2 g) in n-propanol (210 ml). The mixture was stirred for ten minutes, then n-propanol was evaporated off. To the residue was added chloroform under ice-cooling, and insoluble materials were removed by means of celite filtration. From the resultant solution was removed chloroform by evaporation. The residue was subjected to a silica-gel column chromatography, followed by elution with 10% methanol-chloroform to yield 2-methyl-4-propoxypyridine-1-oxide (4.7 g) as an oily substance.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:5]3[CH2:4][CH2:3][CH2:2][S:1](=[O:11])(=[O:10])[CH2:8][CH2:7][C:6]=3[C:15]=2[CH:14]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCCS(=O)(=O)CCC1
Solvent: CC(=O)O
Product: O=S1(=O)CCCc2[nH]c3ccc(Br)cc3c2CC1

Procedure:
A mixture of 14.1g (0.08 mole) of 1-thiacyclooctane-5-one 1,1-dioxide and 16.1g (0.086 mole) of p-bromophenylhydrazine in 125 ml of glacial acetic acid is treated according to the procedure in Example 2. There is obtained 14.2g (54%) of a buff solid, m.p. 280° C., dec. Recrystallization from dimethylformamide-methanol gives 11.5g (44%) of an analytical sample, m.p. 283° C., dec.
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[Cl:18])=O.[OH-].[Na+]>C(O)C>[Cl:18][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[CH:10]=[CH:11][C:6]=1[OH:5]
Reactant: CC(C)(C)C(=O)Oc1ccc(Cn2nccn2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Cn2nccn2)cc1Cl

Procedure:
A mixture of 3 g of 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-di-methylpropanoate, 10 ml of 20% aqueous sodium hydroxide solution and 60 ml of ethanol was heated at reflux for 5 hours. The reaction mixture was then concentrated under reduced pressure, to which water was added, and the mixture was adjusted to pH 6.0 with concentrated hydrochloric acid. This mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 2-chloro-4-(2-2H-1,2,3-triazolylmethyl)phenol.
Reaction SMILES: [Na].Cl[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:9]=2)[N:4]=1.[CH2:20]([OH:23])[CH2:21][CH3:22]>>[N:15]1([CH2:14][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[C:3]([O:23][CH2:20][CH2:21][CH3:22])[CH:12]=[C:11]3[CH3:13])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CCCO
Reactant: Cc1cc(Cl)nc2ccc(Cn3ccnc3)cc12
Agent: [Na]
Product: CCCOc1cc(C)c2cc(Cn3ccnc3)ccc2n1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirred solution of 2 parts of sodium in 24 parts of 1-propanol was added a solution of 3.2 parts of 2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline in 16 parts of 1-propanol at room temperature under nitrogen atmosphere. After stirring for 2 hours at reflux temperature, the mixture was evaporated. The residue was taken up in a potassium carbonate solution and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatograhpy over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.8 parts (31.9%) of 6-(1H-imidazol-1-ylmethyl)-4-methyl-2-propoxyquinoline; mp. 137.9° C. (compound 35).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH2:20]C)[O:17][N:16]=3)[N:4]2[N:3]=1.N1C=CC=C[C:23]=1CO>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[C:19]([CH3:23])=[C:18]([CH3:20])[O:17][N:16]=3)[N:4]2[N:3]=1
Reactant: OCc1ccccn1
Reactant: CCc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1onc(-c2nnc3c4ccccc4c(Cl)nn23)c1C

Procedure:
The title-compound was prepared from 6-chloro-3-(5-ethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine and 2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.6 Hz, Me), 2.93 (2H, q, J=7.5 Hz, CH2), 5.78 (2H, s, CH2O), 6.83 (1H, s, Ar—H), 7.29 (1H, m, Ar—H), 7.75-7.85 (3H, m, 3 of Ar—H), 7.99 (1H, m, Ar—H), 8.33 (1H, d, J=7.8 Hz, Ar—H), 8.64-8.72 (2H, m, Ar—H); MS (ES30) m/e 373 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:24])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Yield: 103.7 %

Procedure:
The product from Example 168a (2.0 g. 6.8 mmol) was treated with oxalyl chloride (9.0 g, 13.6 mmol) and catalytic DMF at 60° C. for 5 h. The excess oxalyl chloride was removed under vacuum. The residue was chased with benzene to give the desired product (2.2 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10]O)[CH:6]=[CH:7][C:8]=1[CH3:9].O=S(Cl)[Cl:14]>C(Cl)Cl>[Cl:14][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CO)ccc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of (3-methoxy-4-methylphenyl)methanol (2.0 g, 13.0 mmol) in dry DCM (20 mL) at 0° C., SOCl2 (3.1 g, 26.0 mmol) was added slowly. The resulting solution was stirred at room temperature for 0.5 h. The mixture was evaporated, and the residue was dissolved in DCM (20 mL). The mixture was washed with saturated NaHCO3 (3×10 mL), dried over Na2SO4 and evaporated to give the title compound as brown oil (2.1 g).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(=O)C.[K+]>C(O)CCC.O>[F:11][C:12]1[C:17]([C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: Fc1ncccc1-c1ncnc2cc[nH]c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.500 g, 3.26 mmol), 2-fluoropyridin-3-ylboronic acid (0.688 g, 4.88 mmol) and potassium acetate (0.959 g, 9.77 mmol) in 1-butanol (25 mL) and water (5 mL) was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2Cl2(PtBu2Ph)2 (0.0243 g, 0.0391 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 60 min. The brown solution was concentrated in vacuo to a solid residue. The residue was treated with 3:1 CHCl3:IPA (100 mL) and water (70 mL). The mixture was sonicated and the layers separated. The aqueous phase was extracted with 3:1 CHCl3:IPA (50 mL). The combined organic extracts were washed with water (3×70 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 0.74 g crude product as a yellow solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 80% to 100% EtOAc in CH2Cl2, to provide 4-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (0.51 g, 73% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 215 [M+H]+.