Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.N1C=CC=CC=1.[C:39](Cl)(=[O:43])[CH2:40][CH2:41][CH3:42]>ClCCl>[C:39]([O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])(=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCC(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Yield: 94.7 %

Procedure:
To a stirred suspension of Compound 2A (3 g, 6.27 mmol) in dichloromethane (30 mL) was added pyridine (2.54 mL, 31.35 mmol) followed by butyryl chloride (0.98 mL, 9.41 mmol) over 1-2 mins. The resultant solution was stirred at room temperature for 1 h 30 mins. The reaction was quenched with methanol (2 mL) and the mixture diluted with 1:1 NaHCO3 (aq)/brine (50 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (10 mL) and the combined organics dried over MgSO4. After filtration, the volatiles were removed and the residue azeotroped with toluene (3×10 mL). The crude material was purified by silica chromatography eluting 8% Methanol/(1:1 ethyl acetate/dichloromethane) to provide the desired product, Compound 2B (3.26 g, 5.94 mmol, 95% yield).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32]([O:34]CC)=O.N.C(#[N:40])C.O>C(#N)C.CO.C(O)(C(F)(F)F)=O.C1COCC1>[O:19]=[C:7]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[C:3]2[CH2:2][NH:40][C:32](=[O:34])[C:4]=2[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[NH:6]1
Reactant: CC#N
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (4 ml), a 7 N solution of ammonia in methanol (5 ml) was added and the mixture was stirred at RT for 60 min. The reaction mixture was then concentrated under reduced pressure, and the residue was triturated with acetonitrile (3 ml). The crystals formed were filtered off with suction, washed with acetonitrile and water and, for further purification, separated by preparative HPLC [column: Sunfire C-18, 5 μm, 19 mm×150 mm; sample preparation: the sample was dissolved in 3 ml of acetonitrile+3 ml of 1% strength aqueous TFA solution+2 ml of THF; injection volume: 1000 μl; mobile phase: acetonitrile/water/1% aq. TFA 25:60:15 (0-12 min); flow rate: 25 ml/min; temperature: 40° C.; detection: 210 nm]. This gave 59 mg (36% of theory) of the target compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[SH:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[CH3:17][C:18]([CH3:24])([CH2:22][CH3:23])[C:19](Cl)=[O:20].II>C(OC(C)C)(=O)C.CCCCCCC.CCOC(C)=O>[CH3:17][C:18]([CH3:24])([CH2:22][CH3:23])[C:19]([S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:20]
Reactant: COC(=O)CCS
Reactant: CCC(C)(C)C(=O)Cl
Agent: II
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)C
Product: CCC(C)(C)C(=O)SCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of N,N-diisopropylethylamine (19.9 mL, 120 mmol) and methyl 3-mercaptopropanoate (7.21 60 mmol) in isopropyl acetate (i-PrOAc, 100 mL) was cooled to an internal temperature of 2° C. (brine ice bath). To this vigorously stirred solution was added 2,2-dimethylbutanoyl chloride (8.1 g, 60 mmol) dropwise over 10 min. The resulting suspension was then stirred at 25° C. for 2 h. The reaction was monitored by checking the disappearance of methyl 3-mercaptopropanoate using thin-layer chromatography (TLC) on silica plates. Spots were stained with iodine (eluent: 5% EtOAc/heptane; Rf of methyl 3-mercaptopropanoate: 0.20). The reaction was then quenched by addition of saturated ammonium chloride (100 mL) followed by i-PrOAc (100 mL) and the resultant mixture was stirred until all solid dissolved. The phases were separated and the organic phase was washed successively with 1% aqueous hydrochloric acid (100 mL) and then water (2×50 mL). The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure (45° C. bath, 50 mm Hg) to obtain a crude mixture as a pale yellow liquid. The crude mixture was subjected to column chromatography over silica gel using a heptane to 2% EtOAc:heptane gradient. Fractions comprising the pure product were combined and concentrated to afford 10.5 g (80%) of methyl 3-(2,2-dimethylbutanoylthio)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([O:30][CH2:31][CH3:32])[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)[C:4]=2[CH:3]=1.[OH:33]O>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([O:30][CH2:31][CH3:32])[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Sc3ccc(Cl)cc32)cc1)C(=O)O
Reactant: OO
Solvent: CCO
Product: CCOC(Cc1ccc(OCCN2c3ccccc3S(=O)c3ccc(Cl)cc32)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 3-(4-(2-(2-chloro-phenothiazin-10-yl)-ethoxy)-phenyl)-2-ethoxy-propionic acid (122 mg; 0.26 mmol) in ethanol (1 ml) was stirred at 60° C. and hydrogen peroxide (30%; 0.15 ml) was added. The reaction mixture was stirred for 30 min. and allowed to go to room temperature. The reaction mixture was evaporated and residue dissolved in water (5 ml). The aqueous phase was acidified with 1N HCl to pH 2 and extracted with methylene chloride (2×25 ml). The combined extracts were dried and evaporated. After column chromatography using ethyl acetate:methanol (4:1) as eluent the title compound was isolated in 116 mg (92%) yield. 1H NMR (CDCl3) δ1.10 (t, 3H), 2.80-3.04 (m, 2H), 3.24-3.38 (m, 1H), 3.45-3.60 (m, 1H), 3.93 (m, 1H), 4.38 (t, 2H), 4.58 (t, 2H), 6.82 (d, 2H), 7.10-8.0 (m, 9H), 8.0-8.7 (br. s, 1H). Compound 7.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a mixture of tetrahydro-2H-pyran-4-carboxylic acid (4.8 g) and potassium carbonate (7.6 g) and DMF (73 mL) was added dropwise benzyl bromide (4.6 mL) at 0° C. The reaction mixture was stirred at room temperature for one day, diluted with ice water, and extracted with ethyl acetate. The extract was washed with water, 0.5N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (solvent gradient; 0→20% ethyl acetate/hexane) to give benzyl tetrahydro-2H-pyran-4-carboxylate (7.6 g, 94%) as a colorless oil.
Reaction SMILES: [N:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][N:12]=3)[CH:7]=[C:6](N)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc2cccnc2c2ncccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1cnc2c(c1)ccc1cccnc12
Temperature: 25 °C
Yield: 85 %

Procedure:
3.05 mM of the 4-di(2-thienyl)-1,4-butanedione obtained from Step 1 described above, 3.03 mM of 1,10-phenanthroline-5-amine, and 5.4 mM of p-toluene sulfonic acid were dissolved in toluene, and then refluxed under a nitrogen current for 4 days. The refluxed mixture was cooled to room temperature, and then toluene was removed from the mixture. The remaining material was dissolved in 5 ml of 99.8% dichloromethane solution, and eluted by using a silica column to obtain 5-di(thiophen-2-yl)-1H-pyrrol-1-yl)-1,10-phenanthroline. The yield was 85%, and the structure was confirmed by using 1H NMR. The spectroscopic data thereof is as follows:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[K+:23]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20].[K+:23]
Reactant: O=C(O)CCCCCCCCCC#CC#Cc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCCCCCC#CC#Cc1ccco1
Temperature: 40 °C

Procedure:
To a solution of 1 mmol 14-(furan-2-yl)tetradeca-11,13-diynoic acid in water, 1 m molar aqueous potassium hydroxide was added at room temperature with stirring. After 2-3 hours the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in acetone and heated to 40° C. for 10 min, then the solid product filtered off and washed several times with acetone. The resultant solid product was evaporated under reduced pressure yielding potassium 14-(furan-2-yl)tetradeca-11,13-diynoate. The sodium salt 14-(furan-2-yl)tetradeca-11,13-diynoate (XI″) was achieved in like manner from 14-(furan-2-yl)tetradeca-11,13-diynoic acid.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[NH:19]1.[CH:26]([CH2:28][C:29](O)=[O:30])=[CH2:27].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[N:19]1[C:29](=[O:30])[CH2:28][CH:26]=[CH2:27]
Reactant: C=CCC(=O)O
Reactant: C=C[C@@H]1CCC[C@H](c2ccccc2F)N1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccccc1F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Diethyl cyanophosphonate (1.23 mL) was added to a solution of (2R*,6S*)-2-(2-fluorophenyl)-6-vinylpiperidine (518 mg), vinylacetic acid (0.66 mL), and triethylamine (2.1 mL) in DMF (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 21 hours. Ethyl acetate and 1 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 442 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[S:20]>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[N:4]([CH2:5][CH2:6][CH3:7])[C:19]([Cl:21])=[S:20]
Reactant: CCCNc1ccccc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCN(C(=S)Cl)c1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of 25.4 g. 2-chloro-N-propylaniline and 15.15 g. dry triethylamine in 200 ml. dry ether was added to a solution of 13 ml. thiophosgene in 200 ml. of the same solvent at -20° C. The reaction mixture was allowed to warm to room temperature and then filtered, the filtered solid being washed with ether. The ethereal extract was added to the ethereal liquor and after drying over sodium sulphate, was evaporated to give a dark oil. On standing further solid precipitated, which was then separated from the oil. The oily filtrate was distilled to give the product N-2-chlorophenyl-N-propyl(thiocarbamoyl) chloride, b.p. 119°-120° C./0.4 mm. Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:31](N)([NH2:34])(=[O:33])=[O:32]>O1CCOCC1>[C:17]1([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:31](=[O:33])(=[O:32])[NH2:34])=[CH:30][CH:29]=3)[CH2:13][CH2:12]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NS(N)(=O)=O
Reactant: Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 41.7 %

Procedure:
A solution of 1-(4-aminophenethyl)-4-(diphenylmethoxymethyl)piperidine (200 mg, 0.50 mmol) (see Example 21) and sulphamide (480 mg, 5.0 mmol) in dioxane (5 ml) was heated under reflux for 3 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-4% methanol as eluant. Appropriate fractions were combined and evaporated and the residue triturated with diisopropyl ether. The resulting solid was collected, washed with diisopropyl ether and dried to give the title compound (100 mg) as a pale yellow solid, m.p. 172°-174° C., which was characterised by its 1H-NMR spectrum.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][CH2:26][CH2:27][CH:28]=[O:29]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH2:26][S:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COc1ccccc1SCCC=O
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1SCCC(O)CC(C)=O
Reaction time: 3 h
Yield: 75.7 %

Procedure:
4.93 Grams of methyl acetoacetate were dissolved in 7.5 ml of water, and 6.34 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.30 g of sodium acetate and 1.00 g of tetrabutylammonium bromide were added thereto and then an additional hydrochloric acid was added thereto so that the mixture had a pH of 6.9. Further, 17.8 g of a toluene solution containing 27.5% of 3-(2-methoxyphenylthio)propanal were added thereto and the resulting mixture was stirred at 45°-50° C. for 9 hours. The organic layer was separated from the mixture. It was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then it was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 5.78 g of crude 4-hydroxy-6-(2-methoxyphenylthio)-2-hexanone (purity: 79.9%, yield: 75.7%). A purified product was obtained by column chromatography. The purified product had an nD21 of 1.5705.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:17]=[CH:18][C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[N:9]=[CH:10][CH:11]=4)=[CH:14][C:15]=23)=[CH:25][CH:24]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2Cl)cc1
Product: Clc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4Cl)cc23)cc1

Procedure:
The title compound, grey solid (110 mg, 81%), MS (ISP) m/z=406.2 [(M+H)+], mp 172° C., was prepared in accordance with the general method of example 1 from 1-(2-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate L) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-pyridine-2-carbaldehyde (1.0 eq.) in THF:EtOH (1:1; 0.2M) at −78° C. was added NaBH4 (4.0 eq.). The mixture was stirred for 2 h at −78° C., quenched with excess AcOH, poured in aqueous HCl (1M), stirred for 15 min, neutralized to pH=7 with NaOH (1M) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[N:11][CH:10]=[CH:9]3)[CH:3]=[N:2]1.[F:16][C:17]([F:40])([F:39])[C:18]1[CH:38]=[CH:37][C:21]([CH2:22][C@H:23]2[CH2:27]OS(=O)(=O)[N:24]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4]3[CH:5]=[N:1][N:2]([CH2:27][C@@H:23]([NH:24][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:22][C:21]4[CH:37]=[CH:38][C:18]([C:17]([F:40])([F:39])[F:16])=[CH:19][CH:20]=4)[CH:3]=3)=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: c1cc2cc(-c3cn[nH]c3)ccc2cn1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)Cn1cc(-c2ccc3cnccc3c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of 6-(1H-pyrazol-4-yl)isoquinoline (40 mg, 0.21 mmol) (prepared as shown in Scheme 20), tert-butyl (4S)-4-[4-(trifluoromethyl)benzyl]-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (102 mg, 0.27 mmol) (prepared as shown in Scheme 1), and cesium carbonate (134 mg, 0.41 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (acetone/hexanes=0-25%) to give the product as an off-white solid (97 mg, 95%). MS (API-ES) m/z: 497 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:31][CH3:32].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:31][CH3:32])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (150 mg, 0.355 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% dispersion in mineral oil, 17 mg, 0.426 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, iodoethane (0.131 mL, 0.533 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from isopropyl ether/n-hexane to give the title compound (73.1 mg, 0.154 mmol, 69%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br.[CH3:24][C:25]1C=C(NN)C=C[N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:24]=[CH:25][N:26]=[C:18]([CH3:17])[CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: Cc1cc(NN)ccn1
Agent: Br
Product: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
500 mg (1.53 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 342 mg (1.68 mmol) of 2-methylpyridin-4-yl-hydrazine hydrobromide. After hydrolysis, 425 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([CH2:14][CH3:15])[CH:5]=1.[OH-].[Na+].Cl>O>[CH2:10]([C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([CH2:14][CH3:15])[C:7]=1[O:12][CH3:13])[C:3]([OH:16])=[O:2])[CH3:11]
Reactant: CCc1cc(C(=O)OC)cc(CC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(C(=O)O)cc(CC)c1OC

Procedure:
A mixture of 11.6 g. (0.052 mol.) of 3,5-diethyl-4-methoxybenzoic acid methyl ester and 3.5 g. (0.09 mol.) of sodium hydroxide in 150 ml. of water is refluxed for 2 hours. The reaction mixture is cooled and acidified with 10% aqueous hydrochloric acid to give 3,5-diethyl-4-methoxybenzoic acid. The acid is refluxed with thionyl chloride as described in the procedure of Example 27 to give 3,5-diethyl-4-methoxybenzoyl chloride.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([OH:15])[CH:6]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN1CCCC1=O.CO.C(OCC)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([O:15][CH2:29][C@@H:30]2[CH2:32][O:31]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OC(C)=O)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: CO
Product: CC(=O)Nc1ccc(OC(C)=O)cc1OC[C@@H]1CO1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 4-(acetylamino)-3-hydroxyphenyl acetate (669 mg, 3.2 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (748 mg, 2.9 mmol) and Cs2CO3 ((1.05 g, 3.2 mmol) in 1-methyl-pyrrolidinone (10 mL) was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetatwe and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil which was suspended in methanol/diethyl ether. The precipitate was filtered off and dried to give the sub-title compound (296 mg).