Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1([CH3:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][CH2:12][CH2:11]1.Cl>C(=S)=S>[C:5]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][CH2:11][C:10]2([CH3:20])[CH3:9])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCOc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 319.8 %

Procedure:
To a mixture of 16.3 g (122 mmol) of aluminum chloride, 11.77 g (10.7 mmol) of acetyl chloride and 110 ml of carbon disulfide was added, slowly, with stirring, 18.0 g (111 mmol) of 4,4-dimethylchroman, at 0 to 5° C. After the addition was complete, stirring was continued for 4 hours at 0° C. The mixture was then poured onto 200 ml of 6N hydrochloric acid and 200 g of ice. The resulting mixture was extracted with 500 ml of diethyl ether. The ether extract was dried (MgSO4) and evaporated in vacuo to give an oil, which was fractionally distilled, under reduced pressure, to give 6.99 g (31% yield) of the title compound, bp 110°-113° C. (0.03 mm Hg).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:19]
Reactant: O=Nc1ccccc1
Reactant: O=CC1CCCCC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(C1CCCCC1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of cyclohexanal (112 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Sodium hydride (60%, 0.12 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro 4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.00 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C., which is stirred for 15 minutes. To the reaction solution is added dropwise a solution of 2-chloro-5-trifluoromethyl pyridine (0.60 g) in 1,2-dimethoxyethane (20 ml) at -5° C., which is stirred for 15 minutes. The reaction mixture is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.80 g of desired compound (refractive index: 1.5879).
Reaction SMILES: C(OC(C1C(C)=C(CC)C2C(=CC=CC=2)C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:30]([O:34][CH:35]([C:39]1[C:48]([CH3:49])=[C:47]([C:50]#[C:51][CH2:52][N:53]([CH3:55])[CH3:54])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]=1[C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=1)[C:36]([OH:38])=[O:37])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][CH:35]([C:39]1[C:48]([CH3:49])=[C:47]([CH2:50][CH2:51][CH2:52][N:53]([CH3:54])[CH3:55])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]=1[C:56]1[CH:57]=[CH:58][C:59]([Cl:62])=[CH:60][CH:61]=1)[C:36]([OH:38])=[O:37])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1C#CCN(C)C
Agent: CCc1c(C)c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc12
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CCCN(C)C

Procedure:
2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)propyl)-3-methylnaphthalen-2-yl)acetic acid (132) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-4-ethyl-3-methylnaphthalen-2-yl)acetic acid of Example 127, except using 2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H35ClNO3: 468.2; Found: 468.2.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][CH2:31][CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: CCCBr
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 22 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and propyl bromide (92.2 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 22%).
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12]CC)=[O:11])[CH2:9][C:4]=2[NH:3][CH:2]=1.[ClH:15]>>[ClH:15].[N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=[O:11])[CH2:9][C:4]=2[NH:3][CH:2]=1
Reactant: CCOC(=O)C1CCc2nc[nH]c2C1
Agent: Cl
Product: O=C(O)C1CCc2nc[nH]c2C1

Procedure:
An 84 g portion of ethyl 4,5,6,7-tetrahydrobenzimidazole-5-carboxylate was dissolved in 350 ml of 6N hydrochloric acid and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and 200 ml of acetone was added to the residue and the precipitated crystals were collected by filtration and dried to obtain 69 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydro-chloride. A 54 g portion of this 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride was mixed in 75 ml of thionyl chloride and heated under reflux for one hour. The reaction solution was concentrated, and the resultant mixture was added with stirring under ice cooling to 500 ml of a chloroform solution which contained 50 g indoline and 38 ml triethylamine. After stirring the mixture at room temperature overnight, it was washed with 300 ml of a 2N aqueous sodium hydroxide solution and then dried and concentrated. Ethyl acetate was added to the residue to precipitate crystals which were collected by filtration to obtain 71 g of 5-(2,3-dihydroindol-1-yl) carbonyl-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:41][CH2:40][N:18]4[CH2:19][C@H:20]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]#[N:38])[C:31]=5[CH3:39])[N:21](C(OC(C)(C)C)=O)[CH2:22][C@@H:17]4[CH2:16]3)=[O:14])=[CH:8][N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:41][CH2:40][N:18]4[CH2:19][C@H:20]([C:30]5[C:31]([CH3:39])=[C:32]([C:33]([F:36])=[CH:34][CH:35]=5)[C:37]#[N:38])[NH:21][CH2:22][C@@H:17]4[CH2:16]3)=[O:14])=[CH:8][N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CN2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of (3S,9aS)-tert-butyl 8-(2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetyl)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (60 mg, 0.107 mmol) in methylene chloride (2 mL) was added thioanisole (50.5 μl, 0.427 mmol) and trifluoroacetic acid (3287 μl, 42.7 mmol), the resulting solution was stirred at rt for 1 h. After removing the volatile, the residue was participated between methylene chloride (100 mL) and 1N sodium hydroxide (50 mL), the alkaline phase was extracted with methylene chloride, the combined methylene chloride phase was dried over sodium sulphate, concentrated and the residue was purified on TLC using 10% methanol/methylene chloride to give title compound. 1H NMR (500 MHz, CDCl3) δ 9.60 (s, 1H), 8.81-8.80 (two singlets, 2H), 8.43-8.40 (m, 1H), 7.06-7.02 (m, 1H), 5.33 (s, 2H), 4.574-4.40 (m, 1H), 4.23-4.22 (m, 1H), 3.89-3.80 (m, 2H), 3.70-3.54 (m, 1H), 3.26-3.14 (m, 2H), 3.03-2.90 (m, 2H), 2.80-2.67 (m, 2H), 2.64-2.63 (two singlets, 3H), 2.59-2.38 (m, 2H); LC/MS: [(M+23)]+=485.13; [(M+1-28)]+=435.20.
Reaction SMILES: CN(C)C=O.[CH:6]1([N:12]([CH2:30][CH2:31][OH:32])[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:33]=[C:34]1[O:38][C:36](=[O:37])[CH2:35]1>C(N(CC)CC)C>[C:36]([O:32][CH2:31][CH2:30][N:12]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]2)(=[O:37])[CH2:35][C:34]([CH3:33])=[O:38]
Reactant: C=C1CC(=O)O1
Reactant: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To 100 ml of dimethylformamide, there were added 7.45 g of N-cyclohexyl-N-(2-hydroxyethyl)-4-(6-carbostyriloxy)butyramide and 0.5 ml of triethylamine, then the whole mixture was heated at 80° to 90° C. on an oil bath. Next, 1.8 g of diketene were added dropwise to the reaction mixture, then the mixture was stirred for 1 hour at the same temperature. The reaction mixture was concentrated then was purified by a silica gel column chromatography (eluant: chloroform/methanol=50/1), and the solvent was removed by distillation under reduced pressure to yield 6.33 g of N-(2-acetoacetoxyethyl)N-cyclohexyl-4-(6-carbostyriloxy)butyramide in the form of a brownish oily substance.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][NH2:13]>CN(C)C=O.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CN
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nc(Cl)ccc1C(N)=O
Temperature: 60 °C

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (6.23 g, 32.6 mmol) and methylamine (98 mL of 2M in THF, 196 mmol) in anhydrous dimethylformamide (60 mL) was heated to 60° C. for 4 h. The reaction was then cooled to room temperature and diluted with water (800 mL) and extracted with ethyl acetate (4×600 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give a light orange oil (7.10 g). The oil was diluted with CH2Cl2 (300 mL) followed by the addition of silica gel (50 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (200 g, 230-400 mesh) and eluted with gradient 30-50% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (4.73 g, 78% isolated yield). TLC eluted with 50% EtOAc/hexanes and rendered with UV lamp gave Rf=0.5; 1H NMR 400 MHz (CDCl3) δ 7.47 (d, J=8.5 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 1.48 (s, 3H).
Reaction SMILES: [Na].C1C2C(=CC=CC=2)C=CC=1.[OH:12][CH:13]([CH2:32][OH:33])[CH2:14][N:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)S(C1C=CC(C)=CC=1)(=O)=O.Cl>COCCOC.O>[C:26]1([NH:15][CH2:14][CH:13]([OH:12])[CH2:32][OH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(O)CO)c2ccccc2)cc1
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: O
Solvent: c1ccc2ccccc2c1
Product: OCC(O)CNc1ccccc1
Yield: 83.4 %

Procedure:
250 Grams of 40% sodium dispersion in mineral oil was added to a solution of 600 g of naphthalene in 1.8 l of 1,2-dimethoxyethane ("Glyme") stirred under nitrogen and maintained at a temperature between 20° to 30° C. After all the sodium was added, the mixture was stirred 20 minutes, and then 305 g of N-(2,3-dihydroxypropyl)-4-methyl-N-phenylbenzenesulfonamide was added through a powder addition funnel while maintaining the temperature of the reaction mixture below 35° C. After all of the solid was added, the mixture was stirred one hour. Water was then added until the color of the mixture faded from dark green or black to yellow; then concentrated hydrochloric acid was added until the solution was strongly acidic. The mixture was extracted twice with toluene and then three times with hexane, was sparged with nitrogen to remove the hexane, saturated with sodium chloride and then made basic with concentrated ammonium hydroxide. The product was extracted with dichloromethane, and the extract was dried over potassium carbonate. The filtered dichloromethane was concentrated to yield 132.3 g of 3-phenylamino-1,2-propanediol, a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11]
Reactant: Cc1cccc(CC(=O)O)c1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(C)c1Br

Procedure:
2-(2-bromo-3-methylphenyl)acetic acid (7.9 g, 0.034 mol) and sulfuric acid (0.1 ml) were added to ethanol (25 ml) and the mixture was refluxed overnight. The solvent was evaporated and to the residue was added saturated sodium carbonate. The aqueous solution was extracted twice with diethyl ether, the organic extracts were combiened, washed twice with water, dried and evaporated under reduced pressure to give the desired product as an oil. (8.5 g,97.7%).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:31])=[CH:25][N:26]=[C:27]2[Cl:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])CCC.[C:33](OC(=O)CNCC1C=CC=CC=1C)([CH3:36])([CH3:35])[CH3:34].CCN(CC)CC>C(Cl)Cl>[C:33]([O:5][C:6](=[O:32])[CH2:7][N:8]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:31])=[CH:25][N:26]=[C:27]2[Cl:30])=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCCOC(=O)CN(Cc1ccccc1C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: Cc1ccccc1CNCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine 1-butyl ester ##STR121## 1,4-Dichloro-7-isoquinolinesulphonyl chloride (400 mg, 1.35 mmol) was added to a stirred solution of N-(2-methylbenzyl)glycine t-butyl ester (380 mg, 1.61 mmol) in CH2Cl2 (20 mL) containing NEt3 (0.28 mL, 2.5 mmol) under N2 and the mixture was stirred at room temperature for 18 h. The mixture was diluted with CH2Cl2 and washed with dilute HCl (2 M), saturated aqueous NaHCO3, brine, dried (MgSO4) then and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (100:0 to 90:10) as eluant to give N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine t-butyl ester (480 mg, 0.97 mmol) as a white solid.
Reaction SMILES: CO[CH:3](O)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:17].CC([N:23]([C@@H:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[OH:33])[C:24](=[O:26])[O-:25])(C)C.OCC[CH2:37][C:38]1[C:43](=O)N(CC2C=CC(OC)=CC=2)NC(=O)[CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[OH:33][C@@H:28]1[C@H:27]([NH:23][C:24](=[O:26])[O:25][C:38]([CH3:43])([CH3:39])[CH3:37])[CH2:32][CH2:31][N:30]([CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:17])[CH2:29]1
Reactant: COc1cnc2ccc(=O)n(CC(O)OC)c2c1
Reactant: COc1ccc(Cn2[nH]c(=O)cc(CCCO)c2=O)cc1
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H]1CCNC[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde methyl hemiacetal (200 mg) and 1,1-dimethylethyl[(3S,4R)-3-hydroxy-4-piperidinyl]carbamate (for a synthesis see WO2004058144, Example 5(c), cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester Enantiomer 2) (182 mg) were stirred in chloroform (10 ml) plus MeOH (0.5 ml) under argon for 2 h. Sodium triacetoxyborohydride (534 mg) was added in one portion and the mixture was stirred at rt overnight, then quenched by addition of saturated aqueous sodium hydrogen cabonate (2 ml). The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×20 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica, eluted with 0-20% (2M ammonia in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound (226 mg) as an off-white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.C1(=O)C=CC(=O)C=C1>CC(O)C.O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=Cc1ccco1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=C1C=CC(=O)C=C1
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccco3)[nH]c2c1

Procedure:
A mixture of 1,2-diamino-4-nitrobenzene (31 g, 0.2 mol) and 2-furancarboxaldehyde (25 g, 0.26 mol) in 2-propanol is treated with p-benzoquinone (24 g, 0.22 mol). The reaction mixture is heated under reflux for 2 h. The reaction solution is diluted with water to precipitate the product. After drying, the crude product weighs 46 g (100%). Recrystllization from nitromethane provides an analytical sample which melts at 228°-229° C. Anal. Calcd for C11H7N3O3 ; C, 57.64; H, 3.08; N, 18.34. Found: C, 57.55; H, 3.04; N, 18.53.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[C:10]([O:30][CH3:31])=[CH:9][C:8]=1[N:32]([CH3:44])[CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:31][O:30][C:10]1[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])=[C:8]([N:32]([CH3:44])[CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:39])[CH3:40])[CH:9]=1
Reactant: COc1cc(N(C)CCN(C)C(=O)OC(C)(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Acryloyl chloride (0.069 mL, 0.85 mmol) in CH2Cl2 (2.5 mL) was added dropwise over 5 minutes to a solution of tert-butyl N-[2-[[2-amino-5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-methylamino]ethyl]-N-methylcarbamate (Intermediate 171, 377 mg, 0.71 mmol) and DIPEA (0.234 mL, 1.42 mmol) in CH2Cl2 (8 mL) cooled in an ice/methanol bath. The mixture was stirred for 0.5 h. The mixture was then diluted with 10% CH3OH in CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and then concentrated in vacuo. Purification by FCC, eluting with 0-3% CH3OH in CH2Cl2 gave the title compound (325 mg, 78%) as a yellow foam; 1H NMR: 1.38 (9H, s), 2.71 (3H, s), 2.77 (3H, s), 3.00 (2H, t), 3.34 (2H, t), 3.88 (3H, s), 3.91 (3H, s), 5.73-5.78 (1H, m), 6.27 (1H, dd), 6.67 (1H, dd), 6.99 (1H, s), 7.17 (1H, t), 7.21-7.27 (2H, m), 7.53 (1H, d), 7.87 (1H, s), 8.26 (1H, d), 8.33 (1H, d), 8.62 (1H, s), 8.99 (1H, s), 9.10 (1H, s); m/z: ES+ MH+ 584.73.
Reaction SMILES: C(O)CCC.CC1C2C(=CC=CC=2)CCN1.[Cl:17]C1C(C)=C(C)N=C(NC2C=CC(F)=CC=2)N=1.[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]>C(O)CO>[ClH:17].[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Agent: CC1NCCc2ccccc21
Agent: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Solvent: CCCCO
Solvent: OCCO
Product: Cl

Procedure:
110 ml of n-butanol, 240 ml of triethylanmine and 236 g (1.60 mmole) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 600 ml of ethylene glycol. 400 g (1.59 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140° C. for 48 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl- 1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([C@H:23]2[CH2:27][S:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[S:24]2)[CH:20]=[C:19]([O:40][CH3:41])[C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:10].[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C>ClCCl>[C:42]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9]([O:8][CH2:7][CH2:6][O:5][C:4]1[C:19]([O:40][CH3:41])=[CH:20][C:21]([C@H:23]2[CH2:27][S:26][C@H:25]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[S:24]2)=[CH:22][C:3]=1[O:2][CH3:1])=[O:10])(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1cc([C@H]2SC[C@H](c3cc(OC)c(OCCOC(=O)NCc4ccccn4)c(OC)c3)S2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc([C@H]2SC[C@H](c3cc(OC)c(OCCOC(=O)N(Cc4ccccn4)C(C)=O)c(OC)c3)S2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans-2-[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonylaminomethyl]pyridine (31) (FIG. 26) (0.313 g,0.520 mmole) was dissolved in 20 ml dry dichloromethane. The reaction was cooled to 0° C. under an argon atmosphere and 44 μl of acetyl chloride was added. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was recooled to 0° C. and 87 μl triethyl amine and 44 μl acetyl chloride was added. The reaction was then allowed to warm to room temperature and was stirred for an additional 12 hours. The reaction was then quenched with 10% NaHCO3 and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated to a brown oil which was purified by flash column chromatography using 1:1 hexane/ethyl acetate--1:2 hexane/ethyl acetate as eluent. The column yields 293 mg (88%) as a white foam.