Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([F:32])=[CH:25][C:26]=3F)[N:21]=2)[CH:17]=[C:16]([CH3:33])[N:15]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([F:32])=[CH:25][C:26]=3[O:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:21]=2)[CH:17]=[C:16]([CH3:33])[N:15]=1
Reactant: OCCOc1ccccc1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(-c2nc3cc(F)cc(OCCOc4ccccc4)c3c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-phenoxyethanol (4.81 g, 34.8 mmol) in DMF (20 mL) was added sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol) in portions and the reaction mixture was stirred at room temperature for 1 hour. To this mixture was added 2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.50 g, 1.74 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (1 mL) was added, neutralized to pH approximately 6-7 with acetic acid, concentrated, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (eluted with 50% ethyl acetate in hexanes, then 5% methanol in DCM) to give 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-phenoxyethoxy)-3H-quinazolin-4-one as a light yellow solid. Yield: 0.59 g (83%).
Reaction SMILES: [Mg].C1COCC1.Br[CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCOCC>[CH2:8]([CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: BrCC1CC2C=CC1C2
Reactant: CCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCC1CC2C=CC1C2
Temperature: 50 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
An oven-dried 3-neck round bottom flask was charged with magnesium turnings (0.809 g, 0.033 mol) and 40 mL of dry THF. 5-Bromomethyl norbornene (6.001 g, 0.032 mol) was added dropwise at room temperature. The mixture was then heated to 50° C. for 18 hours. In a separate flask, 10 mL of dry THF, Li2CuCl4 (5 mL, 0.0005 mol), and 1-bromooctane (6 mL, 0.035 mol) were combined and placed in a −10° C. ice bath. The Grignard reagent, which was transferred via cannula into an addition funnel, was added dropwise to the cooled solution. After the addition was complete, the solution was warmed to room temperature and stirred for 18 hours. The solution was diluted with ether, washed with NH4Cl, brine, and dried over Na2SO4. The solvent was removed and the product was distilled at 76° C. at 0.4 mbar to yield a clear, colorless liquid (4.88 g, 69%). 1H NMR (300 MHz, CDCl3) δ6.12 (1H endo, dd, J=2.74, 5.49); 6.09–5.99 (2H exo, m); 5.93 (1H endo, dd, J=2.74, 5.49); 2.75 (1H, s); 1.98–1.78 (2H, m); 1.40–1.07 (18H, m); 0.89 (3H, t, J=6.05); 0.52–0.45 (1H, m). 13C NMR (75 MHz, CDCl3) δ137.0; 132.6; 49.7; 45.6; 42.7; 38.9; 35.0; 32.6; 32.1; 30.1; 29.9; 29.8; 29.5; 28.9; 22.9; 14.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].C(Cl)Cl.Cl.[CH3:11][NH:12][O:13][CH3:14]>O>[CH3:14][O:13][N:12]([CH3:11])[C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: CNOC
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 2-methoxyacetyl chloride (10 g, 92.1 mmol) and DCM (100 mL) cooled to 0° C. was added N,O-dimethylhydroxylamine hydrochloride (9.89 g, 101 mmol) and TEA (38.5 mL, 276 mmol) and the reaction warmed to RT and stirred for 18 h. The reaction mixture was poured into H2O and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 12 g (97.8%) of N,2-dimethoxy-N-methylacetamide.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[C:31]([CH3:32])=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[CH3:33].O>ClCCl>[CH3:21][O:22][C:23]1[C:24]([CH3:33])=[CH:25][C:26]([C:27]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:28])=[CH:30][C:31]=1[CH3:32]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1cc(C)c(OC)c(C)c1)C(=O)OCC
Reaction time: 2 h
Yield: 96 %

Procedure:
116.8 g of diethyl aminomalonate hydrochloride were dissolved in 700 ml of dichloromethane, and 231 ml of triethylamine were added with cooling in an ice bath. A solution of 109.6 g of 4-methoxy-3,5-dimethylbenzoyl chloride in 400 ml of dichloromethane was then slowly added dropwise. After 2 h at 0° C., 200 ml of water were added slowly. After phase separation, the aqueous phase was extracted twice with 200 ml of dichloromethane. The combined organic phases were washed with 2M hydrochloric acid and then with water, dried with sodium sulfate, filtered and evaporated. The residue was treated with methyl tert-butyl ether, after which the precipitate obtained was filtered off, which gave 178.7 g of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([Cl:13])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[OH:14])[CH:2]=[CH2:3].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([C:4]1[C:5]([O:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[CH2:9][CH2:8][CH2:7]2)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(Cl)cc2c(c1O)CCC2
Agent: [H-]
Agent: [Na+]
Product: C=CCc1c(Cl)cc2c(c1OCc1ccccc1)CCC2
Yield: 89.2 %

Procedure:
Treatment of 5-allyl-6-chloroindan-4-ol (4.5 g, 0.0216 mol) with sodium hydride (60 wt. %, 1.32 g, 0.033 mol) followed by benzyl bromide (6.0 g, 0.035 mol) generally according to the procedure described for Intermediate 38 gave 5.76 g (89%) of 5-allyl-4-(benzyloxy)-6-chloroindane as a colorless oil. 1H NMR (CDCl3) 8H 7.40 (m, 5H); 7.05 (s, 1H); 6.00 (m, 1H); 5.00(m, 2H); 4.90 (s, 2H); 3.53 (dd, 2H); 2.90 (m, 4H); 2.05 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61]>C(Cl)Cl.O.C(OCC)(=O)C>[C:60]([O:59][C:58](=[O:64])[NH:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[NH:50][C:14](=[O:16])[CH2:13]/[CH:12]=[CH:11]/[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)[Si](C)(C)OCCC/C=C/C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
A mixture of (E)-6-(tert-butyldimethylsilyloxy)hex-2-enoic acid (12.0 g, 49.2 mmol), HATU (18.69 g, 49.2 mmol), DIEA (30 mL), tert-butyl 2-aminophenylcarbamate (2) (10.23 g, 49.2 mmol) in DCM was stirred at RT for 5 hours, The reaction mixture was poured onto 500 mL of ethyl acetate and 200 mL of water, the organic layer was washed with water (250 mL×3) and brine (3×200 mL), dried over Na2SO4 and concentrated to give the desired compound of (E)-tert-butyl2-(6-(tert-butyldimethylsilyloxy)hex-3-enamido)phenylcarbamate (13.1 g, 44%) as a yellow oil after purification by column chromatography on silica gel (eluent: PE:EA=8:1). LC-MC (M+1) 435 (M+H)+
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:20][C:21]([NH2:23])=[NH:22]>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([C:9]2[N:20]=[C:21]([NH2:23])[N:22]=[C:11]([NH2:12])[C:10]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)N
Reactant: N#CC(=Cc1cccc(F)c1)c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(N)c(-c2ccncc2)c(-c2cccc(F)c2)n1

Procedure:
After sodium (6.2 g, 268 mmol) was dissolved in ethanol (700 mL), 3-(3-fluorophenyl)-2-(4-pyridyl)-2-propene nitrile (50 g, 223 mmol) and guanidine hydrochloride (25.6 g, 268 mmol) were added thereto in this order and heated under reflux for 4 hours. After cooling as it was, the solvent was removed. Tetrahydrofuran (500 mL) was added to the residue, the insoluble matters were filtered off, and the filtrate was concentrated. A suspension of the residues and activated manganese dioxide (200 g) in chloroform (1000 mL) was heated under reflux for 2 hours. After cooling as it was, the manganese dioxide was filtered off through Celite, and washed with tetrahydrofuran (500 mL33 3) and methanol-chloroform (1:1) (1000 mL×2). The collected filtrate was concentrated, and then methanol was added to the residue. The resulting precipitates were collected by filtration, to give the title compound as a crude solid (14.6 g). The crude crystals were recrystallized from methanol-chloroform, to give the title compound (12.4 g, 20%) as a colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[C:25]([C:26](OC)=[O:27])=[CH:24][N:23]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)[N:22]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[C:25]([CH2:26][OH:27])=[CH:24][N:23]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:35][CH:36]=2)[N:22]=1
Reactant: COC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1CO
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Lithium aluminum hydride (320 mg) was added gradually to a solution of methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (4.00 g) in tetrahydrofuran (30 ml) at 0° C., which was stirred for 2 hours. Sodium sulfate decahydrate (2.95 g) was added to the reaction mixture, and the precipitate was separated by filtration. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography to obtain [3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]methanol (3.56 g, yield 97%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 103–104° C.
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:14][CH3:15])[CH:3]=1.C([Li])CCC.[CH3:21][S:22]SC.Cl>C1(C)C=CC=CC=1.O>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([S:22][CH3:21])[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: CSSC
Reactant: COc1cc(Br)c2c(c1)CCN(C)CC2
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(c(SC)c1)CCN(C)CC2

Procedure:
A solution of 6-bromo-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.7 g, 0.01 m) in toluene (30 ml) is added to a solution of n-butyl lithium (0.044 m) in toluene (15 ml) stirred at -78°. The mixture is stirred for thirty minutes, treated with a solution of methyl disulfide (8.2 g, 0.087 m) in toluene (10 ml), stirred for fifteen minutes and poured into water (125 ml). The mixture is acidified with 10% hydrochloric acid and the aqueous phase is washed with ether, made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract is washed, dried with sodium sulfate and concentrated in vacuo to give 8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([NH2:8])[C:5](=O)[CH3:6].[O:10]([C:12]#[N:13])[K].Cl>C(O)C>[CH3:1][O:2][C:3]([C:4]1[NH:8][C:12](=[O:10])[NH:13][C:5]=1[CH3:6])=[O:9]
Reactant: N#CO[K]
Reactant: COC(=O)C(N)C(C)=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 80 °C
Yield: 96.1 %

Procedure:
To a solution of 2-amino-3-oxo-butyric acid methyl ester (100 mmol) (Lida, H. et al. Synthetic Communication, 1973, 3, 225–230) in 150 mL of ethanol was added KOCN (16.2 g, 200 mmol). The mixture was heated at 80° C. for 2 h. The solution was acidified with 2 N HCl and concentrated to half of the volume in vacuo. The product precipitated out upon cooling. Filtration, followed by washing with water, provided 5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4a (15 g, >95%). MS (ESI+) (M+1)=157.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.C(N(CC)CC)C.[CH3:49][N:50]([CH3:55])[S:51](Cl)(=[O:53])=[O:52].O.NN>CN(C=O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([S:51](=[O:53])(=[O:52])[N:50]([CH3:55])[CH3:49])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)S(=O)(=O)N1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.3 mmol; see Example 88) in DMF (1 mL) was added with triethylamine (1.5 mmol) and N,N-dimethylsulfamoyl chloride (0.4 mmol). The resulting mixture was stirred at RT for 4 h and added with hydrazine hydrate (2 mmol). The contents were warmed to 50° C. and stirred vigorously for 60 min. The reaction mixture was then poured into ice cold water, and the solid was filtered, washed with water, and dried under vacuum. The crude product was then purified on a silica gel column chromatography using MeOH/DCM as eluent to afford 6-(4-dimethylsulfamoyl-piperazin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a white solid. MS: m/z 628 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc(-c2ccccc2Cl)c(NC(=O)OC(C)(C)C)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: CSc1ncc(-c2ccccc2Cl)c(N(C)C(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 2.0 g (5.68 mmol) [5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-carbamic acid tert.-butyl ester in 30 ml N,N-dimethylformamide 0.34 g (8.53 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.56 ml (9.09 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was distributed between 75 ml H2O, 75 ml brine and 75 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 75 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 2.0 g (96%) [5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-methyl-carbamic acid tert.-butyl ester as a pale yellow oil, MS (EI): 365 (M+).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[NH:11][CH:10]1[CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:57](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=3)[CH:32]=2)[N:11]([CH3:57])[CH:10]1[CH2:48][O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccc(Cc2cc(C3NC(COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOc1ccc(Cc2cc(C3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)C(COCc4ccccc4)N3C)ccc2Cl)cc1
Reaction time: 8 h
Yield: 57 %

Procedure:
Compound from step D (50 mg, 0.065 mmol) was dissolved in acetonitrile (1 mL) and treated with potassium carbonate (18 mg, 0.13 mmol) for 30 minutes To this mixture iodomethane (20 uL, 0.32 mmol) was added and stirred overnight. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water, brine, dried (sodium sulfate), and concentrated under vacuum. Chromatography on silica gel (50 to 100% acetonitrile containing 0.1% ammonium acetate/water gradient) provided (3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methylpiperidine (29 mg, 56%). MH+782.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:32]=[CH:31][C:29]([OH:30])=[CH:28][C:27]=1[OH:33]>C(OCCO)C>[OH:33][C:27]1[CH:28]=[C:29]([OH:30])[CH:31]=[CH:32][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(O)cc1O
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3O)c2cc1OC
Yield: 97.9 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 210.0 mg (1.3 mmol) of 4-aminoresorcinol to give 330.4 mg (98.0%) of the product as a deep purple solid, m.p.>250° C., mass (electrospray, m/e): M+H 337.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: C[C@H](C(=O)N(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 45 °C
Yield: 47.8 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.25 hours with a stream of nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (22 ml of a 2.29M solution, 0.050 mole) was added and the reaction mixture was heated at 45° C. for two days under nitrogen. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. It was then dried over magnesium sulfate, charcoaled, filtered, and evaporated to a residue which was dissolved in hot isopropyl ether, filtered, and cooled to room temperature. The resulting solid was collected by filtration and dried under high vacuum at 50° C. to give 2.61 g (48%) of title compound, mp 124°-127° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:24]2[CH:28]=[N:27][C:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([CH2:39][NH2:40])[CH:36]=[CH:35][N:34]=3)=[N:25]2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:40][CH2:39][C:37]2[CH:36]=[CH:35][N:34]=[C:33]([O:32][CH2:31][CH2:30][CH2:29][C:26]3[N:27]=[CH:28][NH:24][N:25]=3)[CH:38]=2)=[O:14])[NH:3]1
Reactant: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccnc(OCCCc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (25.0 mg, 0.11 mmol), 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methanamine obtained in Reference Example 28 (28.0 mg, 0.069 mmol) and diisopropylethylamine (159 mg, 1.20 mmol) in ethanol (3 mL) was stirred at 80° C. for 15 hr. After cooling the mixture to room temperature, the resulting solid was collected by filtration, and washed with ethanol. 4N Hydrochloric acid and ethyl acetate were added to the crude crystals, and the mixture was stirred at room temperature for 2 hr. Water was added to the mixture, and the aqueous layer was weakly acidified with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (28.0 mg, 60%).