Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)CCC(C)=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].N1C=CC=CC=1.NC(N)=S.C[OH:42]>C(Cl)Cl>[CH3:19][O:18][C:17]1[C:16]([CH3:20])=[C:15]2[C:11]([C:12](=[O:21])[O:13][CH2:14]2)=[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:9]=1[CH2:8][CH:7]=[O:42]
Reactant: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: CO
Agent: NC(N)=S
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH2Cl2 (10 mL) and pyridine (50 μL, 0.618 mmol) was cooled to −70° C. using a dry ice/acetone bath according to the procedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through the reaction via a gas dispersion tube until the reaction became blue in color (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for another 15 minutes, by which time the blue color had disappeared. To this solution at −70° C. was added thiourea (75.7 mg, 0.994 mmol) in one portion, and the cooling bath was removed. The reaction was allowed to warm to room temperature and stirred for 15 hours. The reaction was worked up by filtration to remove solid thiourea S-dioxide, and then partitioned between CH2Cl2 and water. The organic layer was removed. The aqueous layer was washed with CH2Cl2 one more time and the organic extracts were combined. The organic layer was washed with aqueous 1N HCl, saturated NaHCO3 and brine. The organic extracts were dried in vacuo and the residue was purified to by silica gel chromatography to afford 357 mg (75%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ −0.01 (s, 9H), 1.05-1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J=1 Hz) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH3:10][CH:4]([CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)CCBr
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)CCN1CCCCC1
Temperature: 60 °C

Procedure:
10.5 g. (0.05 mole) of ethyl γ-bromo-α-methylbutyrate is combined with 17.0 g. (0.20 mole) of piperidine and 100 ml. of benzene, stirred for 16 hours at room temperature and heated at 60° C. for 4 hours. The reaction mixture is cooled and the colorless solid which appeared is removed by filtration. The mother liquor is concentrated to give ethyl α-methyl-γ-piperidinobutyrate as a mobile yellow liquid which distills (b.p. 78° at 0.25 mm.) as 6.7 g. (63%) of colorless liquid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:55][C:56]1[CH:61]=[C:60]([Cl:62])[CH:59]=[CH:58][C:57]=1[C:63](=[O:66])[CH2:64][CH3:65]>C(Cl)Cl.CO>[Br:1][CH:64]([CH3:65])[C:63]([C:57]1[CH:58]=[CH:59][C:60]([Cl:62])=[CH:61][C:56]=1[Cl:55])=[O:66]
Reactant: [Br-]
Reactant: CCC(=O)c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reaction time: 24 h

Procedure:
17.4 g of tetra-butylammonium tribromide are added, at room temperature, to 7 g of 1-(2,4-dichlorophenyl)-1-propanone dissolved in a mixture of 420 ml of methylene chloride and 140 mi of methanol. After 24 hours, the reaction medium is evaporated to dryness under vacuum. The residue is taken up in water and extracted with ethyl acetate, and the organic phase is dried over sodium sulphate. The solvent is evaporated off under vacuum and the product is then purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N:26](OC(C)(C)C)=[O:27].Cl>C(O)(C)(C)C.C(OCC)C>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][C:11](=[N:26][OH:27])[C:10](=[O:13])[CH:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)ON=O
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1=NO
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
A solution of 10.1 g of 4,4-diphenylcyclohex-2-enone in 60 cm3 of tert-butanol is added to a solution of 6.5 g of potassium tert-butoxide in 50 cm3 of tert-butanol at a temperature in the region of 30° C. After stirring for about 15 minutes at a temperature in the region of 30° C., this solution is added dropwise to 14 cm3 of tert-butyl nitrite. The reaction mixture is stirred at a temperature in the region of 20° C. for 2 hours. 100 cm3 of aqueous 3 M hydrochloric acid solution and 100 cm3 of diethyl ether are then added to the preceding mixture at a temperature in the region of 20° C. After separation of the phases by settling, the aqueous phase is extracted with 100 cm3 of diethyl ether. The combined organic phases are washed with three times 100 cm3 of saturated aqueous sodium bicarbonate solution and then with 100 cm3 of saturated aqueous sodium chloride solution, and then dried over magnesium sulphate, filtered and concentrated. After concentrating to dryness under reduced pressure (13 kPa), the residue is purified by flash chromatography on a column of silica (eluent: cyclohexane/ethyl acetate (80/20 by volume)]. 2.23 g of 5,5-diphenylcyclohex-3-ene-1,2-dione 1-oxime are thus obtained in the form of a yellow foam, which is used without further modification for subsequent syntheses and the characteristics of which are as follows:
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][NH:24][CH2:23][CH2:22]2)=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([CH2:2][CH:3]1[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]1)[CH2:23][CH2:22]2)=[O:16]
Reactant: BrCC1COc2ccccc2O1
Reactant: COC(=O)c1cccc2c1CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1CN(CC1COc3ccccc3O1)CC2
Temperature: 140 °C

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.88 mmol) and 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (0.14 g, 0.88 mmol) in DMF (10 ml) was added K2CO3 (0.61 g, 4.41 mmol). The reaction mixture was heated under microwaves at 140° C. for 10 min. Water was then added and the mixture extracted with DCM (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 95:5).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>>[CH3:29][N:30]([CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2)[CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1
Reactant: CNC1CCN(C)CC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)C3CCN(C)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N,1-dimethylpiperidin-4-amine via General Procedure E to give 5.2 mg of 275 following reverse phase purification. MS (Q1) 490.3 (M)+
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:15]=[N:16][N:17]=2)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.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>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([CH:15]=[N:16][N:17]=3)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c2nncn2c1
Reactant: Cc1ccc(B(O)O)cc1
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: CCCO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cn3cnnc23)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 16.9 %

Procedure:
To a solution of tert-butyl 8-chloro[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (1.7 g, 6.7 mmol) in n-propanol (53.6 mL) and water (13.4 mL) were added (4-methylphenyl)boronic acid (1.37 g, 10.1 mmol), tetrakistriphenylphosphinepalladium (0) (0.39 g, 0.34 mmol) and potassium carbonate (2.78 g, 20.1 mmol). The mixture was purged with nitrogen and heated to 85° C. After 18 h, the mixture was cooled to ambient temperature and filtered with Celite. The filtrate was concentrated to remove n-propanol. The aqueous mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol). The product obtained was purified again by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (0.35 g): LC-MS [M+1]=310.2.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][CH:12]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>CO.O>[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][S:13](=[O:2])[CH:12]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCC(O)CCN1C(=O)CSC1CCCCCCC(=O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Temperature: 0 °C

Procedure:
Sodium metaperiodate (0.75 g., 3.5 millimole) is added to a cold (0°-5° C.) solution of 7-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]heptanoic acid (1.24 g., 3.44 millimole) in methanol-water (5:4; v:v; 18 ml.). The resulting mixture is stirred and allowed to slowly warm to 25° C. (as the ice bath melts, etc.) over 16 hours. After removing the precipitated solid via filtration, the filtrate is diluted with cold water and extracted twice with chloroform. The organic extract is washed with saturated aqueous brine, dried over magnesium sulfate, filtered, and evaporated in vacuo leaving an oily residue which is chromatographed on silica gel (20 g.). Elution with chloroform-acetic acid (25:1; v:v) provides the title compound as a viscous, essentially colorless oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([O:42][C:43](=[O:49])[C@H:44]([CH2:46][CH2:47][CH3:48])[NH2:45])C1C=CC=CC=1.C(N1CCOCC1)C>ClCCl.CN(C)C=O>[CH:16]1([C:21]([NH:45][C@H:44]([C:43]([OH:49])=[O:42])[CH2:46][CH2:47][CH3:48])=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCC[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)C1CCCC1)C(=O)O
Temperature: 0 °C

Procedure:
A cool solution of 15 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to a solution of 15 mmoles of cyclopentanecarboxylic acid in dichloromethane, at -5° C. 15 mmoles of norvaline benzyl ester toluenesulfonate salt in dimethylformamide (DMF), which is neutralized with N-ethyl morpholine, is then added. The reaction mixture is stirred at 0° C. initially and then at room temperature until the reaction is completed as judged by TLC. Dicyclohexylurea is removed by filtration and 50 ml of ethyl acetate is added to the filtrate. The organic phase is washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator. The residue is crystalized from isopropanol and hexane.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([CH2:9][CH2:10][CH2:11][N+:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.CO.[BH4-].[Na+]>O>[F:2][C:3]1[CH:25]=[CH:24][C:6]([CH:7]([OH:8])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: Cc1csc(-c2cc[n+](CCCC(=O)c3ccc(F)cc3)cc2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1csc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)n1

Procedure:
To a 0.4 g. portion of 1-(3-p-fluorobenzoylpropyl)- 4-(4-methyl-2-thiazolyl)pyridinium chloride, prepared as described in Example 4, in 20 ml. of methanol is added portionwise with stirring 0.4 g. of sodium borohydride. The mixture is stirred for 2 hours and then poured into water causing the formation of white solid which is separated and recrystallized from acetone and water, m.p. 89°-90.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(OC(Cl)=O)C.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[CH2:26][CH2:27][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCCCOC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(C=Cc1cccnc1)NCCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.4 g (16.2 mmol) 3-(3-pyridyl)-acrylic acid and 2.3 ml (16.2 mmol) TEA are suspended in 50 ml abs. toluene and a solution of 1.5 ml (15.5 mmol) chloroformic acid ethyl ester in 20 ml abs. toluene are added dropwise under moisture exclusion and light cooling. This yellow suspension is stirred at RT for two hours and then a solution of 3.5 g (14.1 mmol) 3-(1-benzylpiperidin-4-yloxy)-propylamine in 20 ml abs. toluene is added dropwise. The mixture is stirred for two hours at RT and extracted by shaking three times in the heat, each with 10 ml water, 2 M sodium hydroxide and water again. The organic phase is concentrated under vacuum and the orange colored oily residue is chromatographically purified twice over silica gel with CHCl3/CH3OH/NH4OH (90/9/1 and 95/5/0 to 90/10/0) and crystallized from 10 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 100–102° C.; yield: 1.9 g (35%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].O.[Se](=O)=[O:12]>O1CCOCC1>[C:1]([C:3]1[C:4]([CH:9]=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ncccc1C#N
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccnc1C=O
Yield: 9.7 %

Procedure:
To a solution of 3-cyano-2-picoline (166 mg, 1.41 mmol) in dioxane (3 mL) was added water (0.2 mL) and selenium(IV) oxide (228 mg, 2.05 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1 then 1:1) to afford the title compound (18 mg, 10%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.69 (dd, 1H, J=9, 6 Hz), 8.20 (d, 1H, J=9 Hz), 9.00 (d, 1H, J=3 Hz), 10.13 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17](O)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([CH3:32])[C:22]=4[OH:21])[CH2:27]3)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2
Yield: 14 %

Procedure:
Reaction of 2-phenylquinazolin-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 21 (14% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.13 and 2.17 (2s, 3H), 2.66 and 2.92 (2t, 2H), 3.50 and 4.05 (2t, 2H), 4.41 and 4.93 (2s, 2H), 6.29-7.00 (4d, 2H), 7.56-7.80 (m, 4H), 7.86-7.98 (2d, 1H), 8.10-8.19 (m, 2H), 8.37 and 8.44 (2s, 1H), 8.49-8.57 (m, 2H); MS (ESI) m/z 396 ([M+H]+).
Reaction SMILES: CO.Cl.[CH3:4][O:5][NH2:6].[CH3:7][CH:8]1[O:12][CH:11](O)[CH:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1>C(N(CC)CC)C>[CH3:4][O:5][N:6]=[CH:11][CH:10]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:9][CH:8]([OH:12])[CH3:7]
Reactant: CC1CC(Sc2ccccn2)C(O)O1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=CC(CC(C)O)Sc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
8.0 mL of methanol and 712 mg of O-methylhydroxylamine hydrochloride were added to 1.5 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolan-2-ol, and thereafter, 1.1 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 2 hours. Thereafter, the solvent was distilled away under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were then added to the residue, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone=4/1), so as to obtain 1.74 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14](O)=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>CN(C=O)C.ClCCCl>[CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14]([Cl:24])=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Yield: 102.4 %

Procedure:
3-[(4Cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoic acid (5.05 g) and thionyl chloride (5.48 g) were added to 1,2-dichloroethane (60 ml) and the mixture, after adding several drops of DMF, was refluxed upon heating. After cooling, the solvent was distilled off to obtain crude 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl chloride (5.46 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[SH:15])=[O:6].[H-].[Na+].Cl[C:28]1[N:33]=[N:32][C:31]([CH:34]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:44])[C:35]#[N:36])=[CH:30][CH:29]=1>CN(C=O)C>[C:35]([CH:34]([C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44])[C:31]1[N:32]=[N:33][C:28]([S:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:16]=[C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:18]=[C:2]([F:1])[CH:3]=2)=[CH:29][CH:30]=1)#[N:36]
Reactant: N#CC(c1ccc(Cl)nn1)c1c(Cl)cccc1Cl
Reactant: O=C(NCc1ccccc1S)c1cc(F)cc(N2CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A solution of 3-fluoro-5-(morpholin-4-yl)-N-(2-sulfanylbenzyl)benzamide (80 mg, 0.23 mmol) in DMF (3 mL) was treated with sodium hydride (60% in mineral oil, 8.8 mg, 0.22 mmol). The mixture was stirred for 5 min and treated with a solution of (6-chloro-pyridazin-3-yl)-(2,6-dichloro-phenyl)-acetonitrile (63 mg, 0.21 mmol) in DMF (1 mL). The reaction mixture was heated at 100° C. for 45 min, cooled to RT and partitioned between aqueous saturated NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (water/acetonitrile+0.1% HCO2H 50% isocratic), afforded the title compound (32 mg, 25%) as a yellow oil. LCMS (Method 3): Rt 11.77 min, m/z 608 [MH+]. 1H NMR (400 MHz, CDCl3): 7.67-7.58 (2H, m), 7.53-7.47 (1H, m), 7.45-7.32 (4H, m), 7.31-7.20 (2H, m), 7.09 (1H, t, J 1.7), 6.75 (1H, br t, J 5.6), 6.71-6.61 (2H, m), 6.33 (1H, s), 4.76 (2H, m), 3.86 (4H, t, J 4.8), 3.21 (4H, t, J 4.8).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([N+]([O-])=O)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]([O:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=2)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ccc(O)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cc(Br)cnc2C#N)c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.2 %

Procedure:
To a 0° C. solution of 2,6-dimethylpyridin-3-ol (10 g, 81.2 mmol) in DMF (50 ml) was added sodium hydride (60% dispersion in oil, 3.4 g, 85 mmol). After 15 minutes, 5-bromo-3-nitropicolinonitrile (18.5 g, 81 mmol) was added and the mixture was allowed to warm slowly to ambient temperature. The reaction mixture was slowly added to 500 mL of rapidly stirring water. A light red solid formed and then the material formed a gum. The gum was extracted into ethyl acetate, and the organics washed with brine, dried over MgSO4 and concentrated in vacuo to afford 5-bromo-3-(2,6-dimethylpyridin-3-yloxy)picolinonitrile (25 g, 82 mmol, 101% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:29][CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1>CN(C=O)C.O>[NH:34]1[CH:35]=[C:31]([CH2:30][CH2:29][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[C:7](=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6][CH2:5]3)[N:32]=[CH:33]1
Reactant: BrCCc1c[nH]cn1
Reactant: CC(=C1CCc2cc(O)ccc2C1=O)c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=C1CCc2cc(OCCc3c[nH]cn3)ccc2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
The product obtained from Step 2 (0.180 g, 0.68 mmol) was dissolved in 5 mL of dry DMF and treated with K2CO3 (0.376 g, 2.72 mmol) and 4-(2-bromoethyl)imidazole hydrobromide (0.192 g, 0.75 mmol). After stirring overnight at room temperature, the reaction was diluted with water and extracted with EtOAc. The pooled extracts were washed well with aqueous 0.5N KOH, water and brine, and then dried, filtered, and concentrated. Purification of the residue (SiO2, 5% MeOH in DCM) afforded 0.120 g (49%) of the title compound as a light yellow foam. Conversion of this product to its HCl salt according to the method of Example 34 afforded 0.063 g of a light yellow powder, mp 170-172° C.: CI-MS m/e 359 (M+ +1).