Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7]2=[N:9][C:10]([CH2:12][CH3:13])=[CH:11][C:6]2=[C:5]([Cl:14])[N:4]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.[H-].[Na+]>O1CCCC1>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:14])[C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=3)[C:7]=2[N:8]=1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
A solution of 300 mg (1.31 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 10 mL of tetrahydrofuran (THF) was added to a 0° C. slurry of 377 mg (1.97 mmol) of 3-fluorobenzyl bromide and 55 mg (2.30 mmol) of sodium hydride in 10 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by the addition of 15 mL of brine. The organic phase was dried with sodium sulfate and concentrated to an oil. The product precipitated upon addition of hexanes to provide 384 mg (87%) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine as a light tan solid. nmr (300 MHz, CDCl3) δ1.11 (t, 3H), 2.58 (s, 3H), 2.59 (q, 2H), 5.39 (s, 2H), 6.29 (s, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 6.96 (dt, 1H), 7.26 (dt, 1H)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CC([O-])=[O:27].[K+]>CC(O)=O.O>[F:22][C:21]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[N:3][C:2]([OH:27])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reaction time: 3 h

Procedure:
A solution of 3-chloro-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (100 mg, 0.28 mmol) and KOAc (55 mg, 0.56 mmol) in AcOH/H2O (1:1, 2 mL) was heated at 150° C. After 3 h, the solvent was evaporated and the mixture diluted with water (2 mL), extracted with (3×2 mL) EtOAc and dried over Na2SO4. Evaporation of the solvent followed by purification Combiflash chromatography (SiO2, eluant 5% MeOH/EtOAc) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.86-1.93 (m, 2H), 2.10-2.14 (m, 2H), 3.33-3.39 (m, 2H), 3.54-3.60 (m, 2H), 4.88-4.90 (m, 1H), 6.77 (d, 1H), 7.10 (t, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 7.59-7.65 (m, 2H). MS (+ESI) m/z 340 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:17])[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:18])=[C:6]([OH:17])[C:7]=1[S:8]([N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Yield: 80.1 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-2-hydroxy-3-nitro-1-(4-thiomorpholinylsufonyl)benzene (330 mg, 0.97 mmol) was reduced with hydrogen and 10% Pd/C (150 mg) to form the desired product (240 mg, 80%). 1H NMR (MeOD-d4): δ 7.08 (d, 1H), 6.98(d, 1H), 3.59 (t, 4H), 2.68 (t, 4H).
Reaction SMILES: Cl[Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3]1.[CH2:9]([OH:11])[CH3:10]>C(N(CC)CC)C>[CH2:9]([O:11][Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3]1)[CH3:10]
Reactant: C[Si]1(Cl)CCC(S)C1
Reactant: CCO
Solvent: CCN(CC)CC
Product: CCO[Si]1(C)CCC(S)C1
Reaction time: 18 h

Procedure:
To a 0.5 liter 3-neck round-bottom glass flask was charged 16.7 grams (0.10 moles) of 1-chloro-1-methyl-3-mercaptosilacyclopentane and 0.225 liters of ethanol and 10 grams of triethylamine. The mixture was stirred and refluxed for 16-20 hours. The solvent was removed at 50-75 C./10-50 mm and nitrogen bubbled through the liquid residue at 25 C. for an additional 16-20 hours. After standing for two more days at about 25° C., the mixture was filtered to give 12.4 grams of a liquid product analyzed by GLC to be about 93% pure. Based on these analysis, a 65.5 mole % yield was obtained.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[ClH:1].[C:16]([O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13]2)=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: Oc1ccc(CN2CC=CCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(CN2CC=CCC2)cc1
Reaction time: 17 h

Procedure:
A mixture of 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (1.0 g.), pyridine (7 ml.) and acetic anhydride (7 ml.) was kept at 20°-25° C. for 17 hours. The solid which formed was collected and washed with ether (50 ml.) to yield 1-(4-acetoxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (1.1 g.), m.p. 220°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][C:15]([OH:23])=[C:16](C(OCC)=O)[N:17]=[C:12]2[CH:11]=[N:10]1.[OH-].[Li+].C1C(=O)N([Br:33])C(=O)C1>O.CC#N>[Br:33][C:16]1[C:15](=[O:23])[NH:14][C:13]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=[CH:11][C:12]=2[N:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc2cnn(-c3c(F)cccc3F)c2nc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)nc1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of ethyl 1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate (1.27 g, 3.70 mmol) in 2.5 mL of water and 2.5 mL of CH3CN at RT was added lithium hydroxide (209 mg, 8.72 mmol), and the resulting mixture was warmed to 60° C. for 0.5 h. The reaction mixture was cooled with an ice bath, and NBS (1059 mg, 5.95 mmol) was added in small portions. The reaction mixture was stirred at RT for 0.5 h, then partitioned between a saturated solution of NaHCO3 and EtOAc. The EtOAc layer was washed with brine, dried over MgSO4, filtered and concentrated to afford 5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (1210 mg, 93.3% yield) a a brown amorphous solid. This crude material was used without further purification. MS (ES+): 327.0/329.0 (M+H)+.
Reaction SMILES: [N+](C1C=CC(C2C3C=C4OCOC4=CC=3CC(C)NN=2)=CC=1)([O-])=[O:2].ClCCl.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCCCC(O)=O>>[CH:37]1([NH:36][C:35]([NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:2])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCC(=O)O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of a 2.5 g (7.68 mmol) portion of the product of Example 26 in 40 ml of anhydrous dichloromethane 4.75 g (23 mmol) of dicyclohexylcarbodiimide and 2.88 g (23 mmol) of n-valeric acid were added and the reaction mixture was maintained at 25° C. under intermittent stirring for 24 hours. Then the N,N'-dicyclohexylurea formed as by-product was filtered, the filtrate was evaporated under reduced pressure, the residue was mixed with 2×40 ml of distilled water, decanted and the wet product was left to solidify under 50 ml of 50% ethanol. The solid compound was filtered, washed with 2×10 ml of 50% ethanol and dried at 80° C. The raw product obtained was recrystallized from 24 ml of ethanol and the crystals were dried at 100° C. to yield 2.20 g (70%) of the aimed product as a yellow powder, m.p.: 145°-147° C.
Reaction SMILES: C(N)CN.[Na].[H][H].[CH3:8][C:9]1[CH2:14][CH2:13][CH:12]([C:15]([CH3:17])=[CH2:16])[CH2:11][CH:10]=1>O>[C:12]1([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: C=C(C)C1CC=C(C)CC1
Agent: [Na]
Solvent: NCCN
Solvent: O
Product: Cc1ccc(C(C)C)cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
To mixture of ethylenediamine (525 mmol, 31.6 g, 35.2 ml), anhydrous FeCl3 (0,964 mmol, 0.16 g) and sodium (145 mmol, 3.34 g) was heated to about 50° C. under N2. After sodium dissolution had started, as evidenced by hydrogen evolution and formation of a dark solution, α-limonene (742 mmol, 101 g, 120 ml), certified as derived from biomass (obtained from Sigma-Aldrich (St. Louis, Mo.), was added dropwise into the mixture and the mixture heated to 100° C. The mixture was heated at 100° C. for 8 h. The mixture was then cooled down and diluted with water (300 ml) and extracted two times with dichloro methane (DCM) (300 ml). The organic layers were dried over magnesium sulfate and concentrated using a rotary evaporator obtaining the crude para-cymene product. Yield: 99% (purity 99%)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH:28]([CH2:31][CH2:32][CH3:33])[C:29]#[N:30].O>CN(C=O)C>[C:29]([CH2:28][CH2:31][CH2:32][CH2:33][C:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=1)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])#[N:30]
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Reactant: CCCC(Br)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCCCC#N)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
1.88 g (78.23 mmol) of sodium hydride are added in portions to a solution of 20 g (60.18 mmol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate from Example 12A in 140 ml of DMF at 0° C. The reaction solution is then warmed to 40° C. and is stirred at this temperature for 30 min. The reaction solution is then cooled to 0° C. again and, after addition of 10.73 g (66.20 mmol) of bromovaleronitrile in 140 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1→4:1). 15.5 g (37.49 mmol, 62% yield) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 100%).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:23]=[CH:22][C:15]([CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:25]>O1CCOCC1>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]2[O:25][C:17]2([C:20]#[N:21])[C:18]#[N:19])=[CH:22][CH:23]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC(C#N)=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: N#CC1(C#N)OC1c1ccc(OCc2ccccc2)cc1

Procedure:
5.3 ml of 1.2M aqueous sodium hypochloride solution were added dropwise to a suspension of 1.04 g (4 mmol) of 2-(4-benzyloxybenzylidene)-malononitrile in 12 ml of dioxan while stirring at pH 9-10, the mixture was stirred at room temperature for 1 hour and 2N sulphuric acid was added until a pH of 4.8 was reached. Extraction with ethyl acetate, drying with sodium sulphate and distillation of the solvent gave 1.22 g of 3-(4-benzyloxy-phenyl)-oxirane-2,2-dicarbonitrile as a yellow-brown oil, which was used without further purification for the next step.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH3:11]>>[NH2:11][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: C1CN(CC2CO2)CCO1
Reactant: N
Product: NCC(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
4-Oxiranylmethyl-morpholine 53b (6.3 g, 44 mmol) was added slowly with ammonia (450 ml, 25%, 6.6 mol) while maintaining the temperature below 0° C. in an ice-water bath. Upon completion of the addition, the reaction mixture was allowed to warm up to room temperature and stirred for 18 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound 1-amino-3-morpholin-4-yl-propan-2-ol 53c (7 g, yield 99%) as a white solid.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:9]=1)([CH3:3])[CH3:2].[Br:15]Br.S([O-])(O)=O.[Na+]>CCOCC>[CH:1]([S:4][C:5]1[S:6][C:7]([Br:15])=[C:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[N:9]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)Sc1nc(OS(C)(=O)=O)c(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
3.5 g of 2-isopropylthio-4-methylsulfonyloxy-1,3-thiazole was dissolved in 50 ml of ether, and 0.8 ml of bromine was added dropwise to the solution keeping the temperature below 0° C. After the addition, the solution was stirred at room temperature for 2 hours, then 5% solution of sodium hydrogen sulfite was added thereto to separate ether layer, which was washed with water and dried over anhydrous sodium sulfate, followed by concentration to an oil. The oil was purified by silica-gel column chromatography to obtain 3.7 g of the objective compound as a yellow oil (yield: 80.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 4-(2-chloroethyl)morpholine hydrochloride (252 mg, 0.28 mmole, Aldrich, Cat. No. C42203), cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) in a sealed reaction vial was stirred at 90° C. overnight. LC/MS showed it worked well. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 50 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH2:1]([S:3](C1C=CC(F)=C(F)C=1)(=[O:5])=[O:4])C.N[C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH:22]=1)[C:20]#[N:21].CSSC>>[Cl:23][C:18]1[CH:17]=[CH:16][C:15]([S:3]([CH3:1])(=[O:5])=[O:4])=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Reactant: N#Cc1cc(N)ccc1Cl
Solvent: CSSC
Product: CS(=O)(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The subtitle compound was prepared by the methods of example 2 steps (i) and (ii) using 5-amino-2-chlorobenzonitrile and dimethyldisulfide.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:13])[NH:9][CH:10]([CH3:12])[CH3:11])=[O:5].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29](=N)OCC>C(O)C.C(OCC)(=O)C>[OH:22][CH2:21][C@H:20]([CH3:23])[CH2:19][O:18][C:15]1[CH:14]=[C:3]2[C:2](=[CH:17][CH:16]=1)[N:1]=[C:29]([C:28]1[CH:34]=[CH:35][CH:36]=[C:26]([O:25][CH3:24])[CH:27]=1)[N:6]([CH2:7][C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:13])[C:4]2=[O:5]
Reactant: CCOC(=N)c1cccc(OC)c1
Reactant: CC(C)NC(=O)CNC(=O)c1cc(OC[C@@H](C)CO)ccc1N
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(-c2nc3ccc(OC[C@@H](C)CO)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of crude (S)-(+)-2-amino-5-(3-hydroxy-2-methylpropoxy)-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE VII.1) (223 mg, 0.70 mmol) (prepared in Procedure VIII) and ethyl 3-methoxybenzimidate*HCl (INTERMEDIATE III.2) (449 mg, 2.08 mmol) in anhydrous ethanol (5 mL) was heated to 80° C. in a tightly capped scintillation vial for 16 h. This was then cooled and concentrated in vacuo. The crude residue was partitioned between dichloromethane/2-propanol (3:1, v/v) and water and the aqueous extracted with further dichloromethane/2-propanol (3:1, v/v). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The crude solid thus obtained was suspended in cold ethyl acetate and collected by filtration affording (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (145 mg, 0.33 mmol, 43% from 2-amino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]benzoic acid) as a light brown solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.O.C[NH:13][CH:14]1[CH2:26][C:25]2[C:24]3C(=CC(C)=CC=3)N[C:17]=2[CH2:16][CH2:15]1>C(O)C>[CH3:1][NH:2][CH:3]1[CH2:8][C:7]2[C:26]3[C:14](=[CH:15][CH:16]=[CH:17][C:25]=3[CH3:24])[NH:13][C:6]=2[CH2:5][CH2:4]1
Reactant: CNC1CCC(=O)CC1
Reactant: CNC1CCc2[nH]c3cc(C)ccc3c2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC1CCc2[nH]c3cccc(C)c3c2C1

Procedure:
A solution of 15 g. of 4-methylaminocyclohexanone and 18.4 g. of 3-methylhydrazine hydrochloride in 200 ml. of absolute ethyl alcohol and 50 ml. of 4-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for six hours, cooled, and filtered to give 12.3 g. of solids which were slurried in 50 ml. of water. The slurry was cooled, the solids were collected by filtration, suspended in ether-chloroform, and the suspension was treated with dilute potassium hydroxide. The ether-chloroform extract was evaporated to dryness under reduced pressure to give 7.6 g. of 3-(methylamino)-7-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 163°-166° C. The alcoholic reaction mixture filtrate was evaporated to dryness under reduced pressure, the residue was boiled in isopropyl alcohol, and the insoluble material was collected by filtration, dissolved in water and the resulting solution was made alkaline with dilute potassium hydroxide. The resulting solids were collected by filtration to give, after recrystallization from ethyl acetate, 3.6 g. of 3-(methylamino)-5-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 187°-190° C., which contained about 6% of the 7-methyl isomer as determined by gas chromatographic analysis.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([CH2:25]Br)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:27]([C:21]1[CH:22]=[C:23]([CH2:25][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:24]=[CH:19][CH:20]=1)#[N:28]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C#N)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-m-tolunitrile (1.0 g, 4.9 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL of DMF was stirred at 25° C. for 24 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was dried in vacuo to afford 1.18 g (82%) of the 9-[(3-cyanophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.65-7.2 (m, 6H), 7.15 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 2226, 1729, and 1646. MS (ES) m/e 357, 359.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH3:18][C:19]1[N:24]=[C:23]2[N:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH2:38][CH2:39][CH3:40])[CH:32]=3)[C:26]([CH2:28][CH3:29])=[N:27][C:22]2=[C:21]([CH3:41])[CH:20]=1.Br[CH:43]([C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:44]([O:46][CH3:47])=[O:45]>>[C:44]([CH:43]([C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:25]2[C:23]3=[N:24][C:19]([CH3:18])=[CH:20][C:21]([CH3:41])=[C:22]3[N:27]=[C:26]2[CH2:28][CH3:29])=[CH:32][C:33]=1[CH2:38][CH2:39][CH3:40])([O:46][CH3:47])=[O:45]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccc(Cl)cc1
Yield: 50 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 4; 5,7-dimethyl-2-ethyl-3-[4-hydroxy-3-propylphenyl methyl]-3H-imidazo[4,5-b]pyridine (Step A, Example 8) was alkylated with methyl 2-bromo-2-(4-chlorophenyl)acetate. Standard workup and purification by flash chromatography afforded a 50% yield of the title compound.