Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH:7]([OH:15])[CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])#[N:2].OO.[ClH:22]>CCOCC>[C:1]([C:3]1[CH:19]=[C:18]([Cl:22])[CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH:7]([OH:15])[CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])#[N:2]
Reactant: CC(C)(CO)NCC(O)COc1ccccc1C#N
Reactant: Cl
Agent: OO
Solvent: CCOCC
Product: CC(C)(CO)NCC(O)COc1ccc(Cl)cc1C#N
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
9.7 gm (about 0.037 mol) of 1-(2'-cyano-phenoxy)-2-hydroxy-3-[(1",1"-dimethyl-2"-hydroxy-ethyl)-amino]-propane, prepared as in Example 1, were dissolved in 75 ml of concentrated hydrochloric acid, the solution was heated to 45° C., and then 4.7 gm of an aqueous 30% hydrogen peroxide solution (about 0.038 H2O2) were added dropwise. A strong exothermic reaction ensued, and the temperature of the reaction mixture was kept at 65° C. by exterior cooling. After all of the peroxide had been added, the reaction solution was stirred for 30 minutes at 60°-65° C. and subsequently evaporated to dryness in vacuo. The residue was dissolved in water, the resulting solution was extracted twice with ether, and the aqueous phase was made alkaline with 2N sodium hydroxide. The oily precipitate formed thereby was taken up in ether, and the resulting solution was washed with water, dried and evaporated, leaving 9.3 gm of a solid residue which was recrystallized twice from ethyl acetate by addition of petroleum ether (40°-60° C.). 6.6 gm of the compound of the formula ##STR13## having a melting point of 102°-103° C. were obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=O)[C:13]=2[C:20]=1[CH3:21].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[CH2:1])[C:13]=2[C:20]=1[CH3:21]
Reactant: COc1c(C)c(C)c2c(c1C)C(=O)C(C)(C)O2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1c2c(C)c(OC)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Potassium tert-butoxide (4 g, 35.5 mmol) is added portionwise at 0° C. and under nitrogen to a suspension of methyltriphenylphosphonium bromide (12.7 g, 35.5 mmol) in dry tetrahydrofuran (120 mL) and the reaction mixture is stirred for 1 hr at room temperature. The 5-methoxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (5.55 g, 23.7 mmol) in dry tetrahydrofuran (40 mL) is added dropwise at 0° C. to the yellow suspension and the reaction is stirred overnight at room temperature. Water (50 mL) is carefully added and most of the solvent is evaporated under reduced pressure. The residue is taken in ethyl acetate (200 mL), washed with brine, dried (magnesium sulfate) and evaporated to dryness. Purification through a small pad of silica gel using dichloromethane as a solvent gave 5.47 g 5-methoxy-3-methylene-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (99%) as a yellow oil. Rf=0.48 (heptane/ethyl acetate 90:10).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:11]([F:13])([F:12])[F:14])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)nc1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(F)(F)F)nc1Cl
Yield: 100 %

Procedure:
2-Chloro-3-nitro-6-trifluoromethylpyridine (22.7 g, 0.10 mol) and platinum(IV) oxide (500 mg) in ethyl acetate (500 ml) were hydrogenated at 20 psi hydrogen for 2 hrs, then the catalyst was removed by filtration. The filtrate was concentrated to give the product as a tan solid (19.5 g, 0.1 mol, 99% yield).
Reaction SMILES: BrBr.[CH2:3]([O:5][C:6]([CH:8]1[CH2:19][N:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]1=[O:26])=[O:7])[CH3:4].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:3]([O:5][C:6]([C:8]1[C:9](=[O:26])[C:10]2[CH:15]=[N:14][C:13]([S:16][CH3:17])=[N:12][C:11]=2[N:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH:19]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CN(C2CCCCC2)c2nc(SC)ncc2C1=O
Agent: BrBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(SC)ncc2c1=O
Reaction time: 0.08 h
Yield: 102 %

Procedure:
Bromine (0.15 g, 0.94 mmol) was added to a solution of 8-cyclohexyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.28 g, 0.79 mmol) in dichloromethane (10 mL). After 5 min, the solution was concentrated and the crude residue was redissolved in dichloromethane (10 mL) and diisopropylethylamine (0.42 mL, 2.4 mmol) was added. After 15 h, the reaction mixture was partitioned between water and dichloromethane, the organic layer was separated, dried (MgSO4) and concentrated to provide 0.28 g (87%) of the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C17H21N3O3S: 347.13. found: (M+H) 348.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][CH2:9][C:4]=2[Se:5][C:6]=1[C:7]#[N:8].[OH-:13].[Na+].O>C(O)C>[NH2:1][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][CH2:9][C:4]=2[Se:5][C:6]=1[C:7]([NH2:8])=[O:13]
Reactant: N#Cc1[se]c2c(c1N)CCCC2
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1[se]c2c(c1N)CCCC2
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a suspension of 3-amino-4,5,6,7-tetrahydrobenzo[1,2-b]selenophene-2-carbonitrile (2.4 g) in ethanol (50 mL) was added aqueous sodium hydroxide solution (50 mL, 10%) at rt and the mixture was refluxed for 1 h. The cooled reaction mixture was poured into ice cooled water and stirred for 15 min. The precipitated solid filtered, washed with cold water and dried to give the product as a pale brown color solid (1.4 g, 54%), mp 152-154° C. 1H NMR (400 MHz, DMSO-d6): δ 6.58 (1H, s, —CONH2), 6.45 (1H, s, —CONH2), 2.66 (2H, s, H-7), 2.24 (2H, s, H-4), 1.73 (4H, s, H-5,6); LC-MS (positive ion mode): m/z 265, 267 (M+Na)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([C:14]2[CH:22]=[CH:21][C:17]3[NH:18][N:19]=[N:20][C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C)C=O>[Cl:3][C:4]1[C:5]([C:14]2[CH:22]=[CH:21][C:17]3[N:18]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:19]=[N:20][C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: FC(F)(F)c1cnc(-c2ccc3[nH]nnc3c2)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1nnc2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reaction time: 0.25 h

Procedure:
0.5 g of sodium hydride (80% strength by weight suspension in mineral oil) in 25 ml of anhydrous dimethylformamide was treated dropwise with a solution of 4.4 g of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)benzotriazole in 25 ml of dimethylformamide. After stirring for 15 min, 2.6 g of ethyl bromoacetate were added dropwise, after which the mixture was stirred at 23° C. for 20 hours. The batch was then poured into 200 ml of water. After extracting three times with 100 ml of tert-butyl methyl ether each time, the combined organic phases were washed with 100 ml of water, dried over sodium sulfate and concentrated. The oil residue was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate=6:1). The following were eluted in succession (without taking into account mixed fractions): 1.0 g of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-2-ethoxycarbonylmethylbenzotriazole; m.p.: 127-129° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:29])[C:8]([C:30]([O:32]CC)=[O:31])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CO.Cl>O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9](=[O:29])[C:8]([C:30]([OH:32])=[O:31])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1ncc(C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The title compound is prepared by treating 2-n-butyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl-5-ethoxycarbonylpyrimidin-4(3H)-one (from Example 8) with an ester hydrolyzing agent such as sodium hydroxide in an appropriate solvent such as methanol, possibly with heating. Addition of water, acidification with concentrated HCl, saturation with NaCl, extraction with ether, washing of the combined organic extracts with brine, drying of the organic material over an appropriate drying agent such as MgSO4, and stripping of solvent in vacuo should give the crude organic acid which may then be purified by appropriate means such as silica gel chromatography. Alternatively, the ester from Example 8 is hydrolyzed using an appropriate esterase such as pig liver esterase followed by standard purification procedures.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]([F:38])([F:37])[CH2:35]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:35][C:34]([F:38])([F:37])[F:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC(F)(F)F)C1
Yield: 39 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2,2,2-trifluoroethylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (70 mg, 39%). LCMS (method B): RT=4.00 min, M+H+=528.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH2:1]([O:8][C:9](=[O:12])[CH2:10][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(=O)OCc1ccccc1)OCC
Yield: 80.3 %

Procedure:
The mixture of bromo-acetic acid benzyl ester (229 g, 1.0 mol) and phosphorous acid triethyl ester (166 g, 1.0 mol) was stirred at reflux for 10 hrs and the solvent was evaporated in vacuo to give crude (diethoxy-phosphoryl)-acetic acid benzyl ester (230 g) which was directly used for next step.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:37])=[C:33](Cl)[N:34]=2)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]1)[CH3:25]>C(#N)C>[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:37])=[C:33]([N:10]3[CH2:11][CH2:12][C:6]4([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]4)[CH2:9]3)[N:34]=2)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]1)[CH3:25]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CN1CCC2(CCNC2)C1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCN(C)C4)C3)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 53.3 %

Procedure:
A stirred suspension of 4.40 g (20.7 mmol) of 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 200 ml acetonitrile was treated with 9.42 g (62 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 5.42 g (20 mmol) 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was added. After stirring 23 hours at room temperature the precipitated product was filtered, washed with acetonitrile and ether, and recrystallized from ethanol to afford 3.99 g of the title compound, mp 252°-254° C. (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[C:9]([OH:12])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][O:3]1.CN(C=O)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)[CH2:4][O:3]1
Reactant: CC1(C)Cc2c(O)cccc2CO1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(cccc2Oc2ccc([N+](=O)[O-])cn2)CO1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of 3,3-dimethylisochroman-5-ol (Intermediate 170, 65 mg, 0.36 mmol) in dry DMF (3 ml) potassium carbonate (207 mg, 1.5 mmol) and then 2-chloro-5-nitropyridine (50.8 mg, 0.32 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated affording the title compound (80 mg) as an orange solid that was used in the next step as crude without further purification.
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH:3]=[CH:2]1.[H][H]>CO.[Pd]>[C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=c1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: O=c1ccn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]1
Yield: 97.2 %

Procedure:
A solution of 2′,3′-dideoxy-2′,3′-didehydrouridine (1.0 g, 4.8 mmol) in methanol (10 ml) containing a catalyst (wet 5% palladium on carbon) (400 mg) was stirred in an atmosphere of hydrogen for 1 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel (CHCl3/MeOH=5/1) to give 2′,3′-dideoxyuridine (0.99 g, 97% yield): Mp 121.2-121.7° C.; λmax(MeOH) 262 nm (ε 10560), λmin(MeOH) 232 nm (ε 3810); 1H-NMR (Me2SO-d6) δ 1.74-2.00 (m, 3H), 2.20-2.35 (m, 1H), 3.49-3.55 (m, 1H), 3.64-3.69 (m, 1H), 4.00-4.03 (brs, 1H), 5.03 (s, 1H), 5.58 (d, 1H, J=8.06 Hz), 5.95 (m, 1H), 7.94 (d, 1H, J=8.06 Hz), 11.25 (brs, 1H); Fast atom bombardment mass spectrum m/z 213 (MH+). Anal. Calcd for C9H12N2O4: C, 50.94;H, 5.70; N, 13.20. Found: C, 50.95;H, 5.71; N, 13.20.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C1CCCCC1>[Br:20][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of {4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (intermediate 1, 0.9 g) in dry dichloromethane (30 ml) stirring at 0° C. was added carbon tetrabromide (1.1 g) and triphenylphosphine (0.995 g). The reaction was stirred at 0° C. for 1 hour, diluted with cyclohexane (30 ml) and purified by SPE cartridge (Si cartridge using chloroform:cyclohexane (1:1) to give the title compound as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:13]=2[CH2:12][NH:11]1.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:26][S:23]([N:11]1[CH2:12][C:13]2[C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:10]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc2c1CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc2c1CN(S(C)(=O)=O)C2
Yield: 51.4 %

Procedure:
DIEA (0.438 g, 3.39 mmol) was added to a solution of methyl isoindoline-4-carboxylate (0.5 g, 2.82 mmol) and mesyl chloride (0.36 g, 3.1 mmol) in DCM (10 mL). After 12 h the mixture was concentrated and the residue purified by silica gel chromatography to afford methyl 2-(methylsulfonyl)isoindoline-4-carboxylate (0.37 g 52%) as an off white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1.[C:16]([CH2:18][C:19]([NH:21][CH:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:20])#[N:17].O>CS(C)=O>[Br:7][C:8]1[N:13]=[C:12](/[CH:14]=[C:18](\[C:16]#[N:17])/[C:19]([NH:21][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:29][CH:30]=2)[CH2:23][CH3:24])=[O:20])[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCC(NC(=O)CC#N)c1ccc(OCCOC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOC)cc1
Yield: 90 %

Procedure:
Potassium t-butoxide (0.014 g, 0.127 mmol) was added to a stirred solution of 6-bromo-2-pyridinecarboxaldehyde (0.094 g, 0.51 mmol) and 2-cyano-N-(1-(4-(2-methoxyethoxy)-phenyl)propyl)acetamide (0.07 g, 0.25 mmol) in dimethylsulfoxide (10 mL) under nitrogen at room temperature. After 26 hours the mixture was shaken with water and then extracted with ethyl acetate several times. The combined extracts were washed with water and then dried over sodium sulfate. The solvent was removed in vacuo leaving 0.10 g of a clear amber syrup, which was flash chromatographed on a column (5×10 cm) of silica gel with gradient elution utilizing dichloromethane/EtOAc (10:0 gradually changing to 12:1) to afford 0.040 g of the product as a clear pale yellow syrup; mass spec ES+m/z=444, 466 (m+1, m+23).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[CH:3]=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 4.8 g, 120 mmol) in DMF (100 ml) was added dropwise at an ice bath temperature a solution of 2-formylpyrrole (9.5 g, 100 mmol) in DMF (10 ml). The mixture was stirred for 15 minutes at room temperature and cooled again. To the mixture was added dropwise a solution of benzylbromide (20.5 g, 120 mmol) in DMF (10 ml). The reaction mixture was stirred for 60 minutes at room temperature and poured to ice-water, and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated to give 1-benzyl-2-formylpyrrole (18.0 g) as an oil quantitatively.
Reaction SMILES: [CH3:1][SH:2].CN(C=O)C.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]=1>O1CCCC1>[CH3:28][C:22]1[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]=[C:18]([C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:2][CH3:1])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1Cl
Reactant: CS
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1SC
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
To a solution of methyl mercaptan-DMF solution (methylmercaptan 66 g/DMF 306 g) (3.8 ml) and methyl 4-(2-chloro-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate (1.5 g) in tetrahydrofuran (25 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give a residue, which was chromatographed on silicagel eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from n-hexane to afford methyl 6-methyl-4-(2-methylthio-5-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.2 g).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.Cl.[NH2:6][C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]=2[C:17]#[N:18])[C@H:8]1[OH:27].[Cl-].[Na+]>CO>[CH2:20]([O:19][C:12]1[C:13]([C:17]#[N:18])=[C:14]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([OH:27])[C@H:7]([NH:6][CH:2]([CH3:4])[CH3:1])[CH2:16][CH2:15]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Reactant: CC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C#N)[C@H]1O
Reaction time: 2 h

Procedure:
In a mixture of 15 m. acetone and 20 ml. methanol is dissolved 450 mg. of trans-2-amino-6-benzyloxy-5-cyano-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride and, while nitrogen gas is introduced, 150 mg. of the adduct of lithium cyanoborohydride-dioxane complex is added in small portions at 5°-10° C. After stirring for 2 hours, a saturated aqueous solution of sodium chloride is added and the mixture is extracted with ethyl acetate. The ethyl acetate layers are washed with a saturated aqueous solution of sodium chloride and dried. The solvent is distilled off under reduced pressure and the residue is recrystallized from ethanol-ethyl acetate. The procedure yields white crystals of trans-6-benzyloxy-5-cyano-1-hydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene. This compound is in agreement with the sample according to the prcedure of Example 3. Yield 297 mg.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:30]=[CH:29][C:12]=1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:10][C:11]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:30]=[CH:29][C:12]=1[CH2:13][N:14]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[CH:17][CH:16]=1)[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
To a solution of cyclohexanecarbonyl chloride (990 mg, 6.75 mmol) in methylene chloride (30 mL) was added a mixture of (2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (1.94 g, 4.5 mmol) and triethylamine (1.3 mL, 9.0 mmol) in methylene chloride (15 mL) dropwise. The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and the aqueous solution was washed with methylene chloride. The organic solution was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by Biotage® chromatography using 5% methanol/methylene chloride to afford the title compound of Step A as an oil (2.12 g). MS 541.3 (M+1)+