Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.[CH2:10]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:29]=1)[CH2:25]O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>ClCCl>[CH2:10]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:29]=1)[CH2:25][Cl:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCC)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Dry dichloromethane (5 mL), DMF (3.04 mL, 39.2 mmol) and a magnetic stir bar were placed into a 250 mL RBF, and the RBF was sealed with a rubber septum. N2 inlet and outlet needles were inserted into the septum. The flask was then cooled to 0° C. in an ice bath. Thionyl chloride (2.86 mL, 39.2 mmol) was added to the RBF via a syringe. The RBF was placed into an ice bath and cooled to 0° C. 3,5-diundecoxybenzyl alcohol (15.0 g, 35.7 mmol) was dissolved in a solution of dichloromethane (60 mL) and pyridine (2.88 mL, 35.7 mmol). This solution was added to the RBF via a syringe cautiously over 20 minutes. The reaction mixture gradually changed from a transparent yellow color to an opaque yellow color. The beaker used to dissolve the 3,5-diundecoxybenzyl alcohol was rinsed with dichloromethane and the rinses were added to the RBF. The RBF was removed from the ice bath and the reaction mixture was stirred overnight. The solution was then concentrated using rotary evaporation. A solution of 50/50 ether/hexanes (100 mL) was added to the RBF, changing the solution color from deep yellow to opaque white. The liquid was decanted leaving behind any solid. The RBF was rinsed in this manner 2 more times, saving the decanted liquid. The decanted liquid was run through a silica gel baseline filtration apparatus. The filtrate was then concentrated using rotary evaporation. The compound solidified after approximately 2 hours under high vacuum. This produced a 14.8 g yield or a 94.5% yield of the derivative. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.9, 6H, CH2CH3), 1.27-1.45 (m, 32H, CH2(CH2)8), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.92 (t, J=6.6, 4H, OCH2), 4.50 (s, 2H, ArCH2Cl), 6.39 (t, J=2.2, 1H, ArH), 6.50 (d, J=2.2, 2H, ArH). 13C NMR (75 MHz, CDCl3): 14.23, 22.79, 26.13, 29.31, 29.45, 29.48, 29.68, 29.71, 32.01, 46.56, 68.19, 101.32, 106.97, 139.38, 160.53.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:19][CH2:18][CH:17]2[CH2:20][CH:13]1[CH2:14][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH2:19][CH2:18][CH:17]2[CH2:20][CH:13]1[CH2:14][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2
Reactant: CCOC(=O)N1CC2CCC(O)C(C2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC2CCC(=O)C(C2)C1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
A solution of oxalyl chloride (1.31 mL, 15 mmol) in 50 mL of dichloromethane was cooled in a dry ice-acetone bath, and DMSO (1.4 mL, 20 mmol) was added drop-wise over 5 min. After 10 min, ethyl 6-hydroxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (2.2 g, 10 mmol) in 10 mL dichloromethane was added over 5 min. The mixture was stirred for 20 min, and then triethylamine (6.3 mL, 45 mmol) was added slowly. The mixture was stirred for 1.5 h, gradually warming to −10° C. The reaction was quenched by addition of water (25 mL). The organic layer was separated, washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. This was chromatographed on a silica gel column, with 2% methanol in dichloromethane, to give the desired ketone (1.0 g, 45%). The chromatography also provided a sample of the isomeric ketone, ethyl 7-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate, and some un-reacted alcohol starting material.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:21][NH2:22]>C(O)C>[NH2:2][C:1]1[NH:22][N:21]=[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C(N)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 75 °C

Procedure:
2-cyano-3-(methylthio)-3-((4-nitrophenyl)amino)acrylamide was then suspended in 100 mL of ethanol and hydrazine hydrate (5.153 mL, 2.00 eq.) was added drop wise to the reaction. The reaction was then heated at 75° C. until the starting material was no longer present as confirmed via HPLC. Once starting material was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as an off white to yellow powder as product. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)[N:17]=[C:16]([CH3:21])[N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: Cc1nc(Cl)cc(OC2CCN(C(=O)OC(C)C)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(OC2CCN(C(=O)OC(C)C)CC2)cc(N2CCc3cc(S(C)(=O)=O)ccc32)n1
Temperature: 90 °C

Procedure:
14a (100 mg) was dissolved in DMF with 5-methanesulfonyl-2,3-dihydro-1H-indole (0.3 mmol) and NaH (0.3 mmol). The mixture was heated at 90° C. for 4 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The organic layer was washed with a saturated NaHCO3 solution, isolated, evaporated and purified by preparative HPLC to give 14-1, LCMS 475.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:12]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:3]=2)[NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A suspension of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (5.0 g), tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (13 g) and potassium carbonate (5.1 g) in N,N-dimethylformamide (30 mL) was stirred at 100° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform/hexane=4/1) to give the titled compound (6.9 g, 65%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N+:6]([O-:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[Cl:9][C:4]1[N:3]=[C:2]([NH:18][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[N+:6]([O-:8])[CH:5]=1
Reactant: [O-][n+]1cc(Cl)nc(Cl)c1
Reactant: NCCc1ccccc1
Solvent: O
Product: [O-][n+]1cc(Cl)nc(NCCc2ccccc2)c1

Procedure:
A suspension of 0.330 g (2.0 mmol) of 2,6-dichloro-pyrazine 4-oxide in 0.485 g (4.0 mmol) of phenethylamine was allowed to stir under reflux for 10 min. pCooled water was added and the mixture extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. pThe residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 97/3/0.3 to give after trituration with diethyl ether 0.370 g (74%) of pure product as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)=[O:4].ClCCl.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(N(CC)CC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH:7]([C:23](=[O:24])[CH2:22][Cl:21])[NH:6]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2C(C(=O)CCl)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
To a mixture of 7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (Example 33 (a), 4.466 g, 18.9 mmol), dichloromethane (130 ml) and triethylamine (3.0 ml), cooled in an ice bath, was added dropwise chloroacetyl chloride (1.74 ml, 21.8 mmol). The resulting reaction mixture was stirred for 2 h at room temperature. The reaction mixture was then washed with dilute hydrochloric acid and then with water. The organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to yield 2-chloroacetyl-7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (6.22 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[NH:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C.CO.C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.52 g, 0.98 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.49 g, 1.5 mmol), and N,N-diisopropylethylamine (0.4 mL, 2.3 mmol) in acetonitrile (12 mL). Heat to reflux. After 18 hours, cool and partition the reaction mixture between ethyl acetate and water. Separate the layers and extract the organic layer with water, saturated aqueous sodium bicarbonate, and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting sequentially with 5% methanol/ethyl acetate and then 50% methanol/ethyl acetate to give a residue. Partition the residue between chloroform and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.39 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][OH:16])=[C:6]([CH3:17])[CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][OH:16])=[C:6]([CH3:17])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCNCCO
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)ccc1NCCNCCO

Procedure:
The 2-[2-(4-nitro-2-methylphenylamino)ethylamino]ethanol (5) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K].[I-].[Na+].O>CN(C)C=O>[CH3:8][N:7]1[C:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])=[N:4][N:5]=[N:6]1
Reactant: Cn1nnnc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1CN1C(=O)c2ccccc2C1=O
Yield: 4 %

Procedure:
5-(Chloromethyl)-1-methyl-1H-tetrazole (a crude product 6.9 g prepared in accordance with Chemical & Pharmaceutical Bulletin, 37(2), 322-6:1989), was dissolved in 50 mL of dimethylformamide and stirred with potassium phthalimide (5.00 g, 27.0 mmol) and sodium iodide (391 mg, 2.60 mmol) at room temperature for 17 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the desired product (550 mg, 4% yield, two steps).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:29](O)(=[O:32])[CH:30]=[O:31].O>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]2[O:11][C:30](=[O:31])[CH:29]([OH:32])[C:9]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)cc2c1OC(=O)C2O
Yield: 99.6 %

Procedure:
18.7 g of 4-tert-butyl-2(1-methyl-pentadecyl)-phenol (J.Amer.Chem.Soc., 74, 1952, 3599), 5.06 g of glyoxylic acid monohydrate and 0.05 g of p-toluenesulfonic acid are heated in 40 ml of 1,2-dichloroethane for 7 hours using a water separator. The reaction solution is then cooled, washed three times with 80 ml of water each time and freed of solvent using a rotary evaporator. 21.4 g of 5-tert-butyl-3-hydroxy-7-(1-methyl-pentadecyl)-3H-benzo-furan-2-one are obtained in the form of a yellowish oil. That yellowish oil is placed in 25 ml of toluene with 8 ml of thionyl chloride and 3 drops of DMF and the reaction mixture is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at that temperature for a further hour. Approximately 25 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 80 ml of toluene and, at room temperature, 7 ml of triethylamine are added dropwise thereto. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off and the filtrate is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is isolated from the residue, in the form of a waxy red mass, by chromatography on silica gel (hexane/ethyl acetate 99:1). 4.1 g (20% of the theoretical yield, based on 4-tert-butyl-2-(1-methyl-pentadecyl)-phenol) of 5,5′-di-tert-butyl-7,7′-bis(1-methyl-pentadecyl)-[3,3′]bibenzofuranylidene-2,2′-dione of formula (LIIIa) are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1cccs1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])c1cccs1
Yield: 42.2 %

Procedure:
Following a similar treatment to that in Example 33 and using 0.38 g of 2-thiophenecarboxylic acid and 0.50 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: C(OC1C=CC(C)=CC=1Br)C1C=CC=CC=1.O[C@H:18]([CH3:28])[CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[OH:27]>>[CH3:28][C@H:18]1[CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[O:27]1
Reactant: Cc1ccc(O)c(C[C@@H](C)O)c1
Agent: Cc1ccc(OCc2ccccc2)c(Br)c1
Product: Cc1ccc2c(c1)C[C@H](C)O2

Procedure:
The title compound 5c was prepared according to the method for preparation of compound 3d of Example 3 by replacing 3c with 5b.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:13]([NH2:15])[CH3:14].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[Cl:2][C:3]1[C:8]([C:9]([F:11])([F:12])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:13]([NH:15][C:45]([C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([C:24]3[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:34][CH:33]=1)[C:37]([CH3:49])=[C:38]2[CH3:48])=[O:46])[CH3:14]
Reactant: C[C@@H](N)c1cccc(C(F)(F)F)c1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cccc(C(F)(F)F)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 605 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])[CH3:5].I[C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.CCOCC>CCCCCC.CN(C)C=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[CH:6][N:4]([CH3:3])[CH3:5])[C:8]2=[O:16])[CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C=C1C(=O)Nc2ccccc21
Reactant: COc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1
Temperature: 0 °C

Procedure:
In a flame dried flask under nitrogen, sodium hydride (50% dispersion in oil, 0.96 g, 20 mmoles) was washed free of oil with hexane. Dry dimethylformamide (DMF, 50 ml) and 3-(dimethylaminomethylene)-2(1H,3H)-indolone [Chem. Ber. 85:774 (1952); 3.77 g, 20 mmoles] were added, and the mixture stirred for 30 minutes (until gas evolution ceased), m-Iodoanisole (9.36 g, 40 mmoles) in 20 ml DMF was added, followed by Cu2Br2 (5.74 g, 20 mmoles). The reaction mixture was heated at 120°-130° for 40 hours, poured over 300 g of ice, stirred with 300 ml ether, filtered and the ether layer separated, dried over MgSO4, filtered and concentrated to an oil. The oil was chromatographed on silica gel, using ethyl acetate as eluant and title product initially isolated as an oil, crystallized from ether, 2.46 g (42%), m.p. 106°-108.5° (dec.).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]2([CH3:46])[CH3:45].Cl>CN(C)C=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=4[CH:34]=3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(Cn3c(=O)c(C(=O)NCC(=O)O)c(O)n(C4CCCCC4)c3=O)ccc21
Reaction time: 8 h
Yield: 34.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (250 mg, 0.89 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (156 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (br. s., 1 H), 7.24 (dd, J=4.80, 3.28 Hz, 2 H), 6.98 (dd, J=8.21, 1.39 Hz, 1 H), 4.93 (s, 2 H), 4.66 (t, J=11.87 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.19-2.36 (m, 2 H), 1.79 (d, J=12.63 Hz, 2 H), 1.62 (s, 7 H), 1.01-1.37 (m, 15 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:28]([NH:31][CH:32]([CH3:34])[CH3:33])([CH3:30])[CH3:29]>CN(C=O)C>[OH:26][C@H:25]([CH2:27][N:31]([CH:32]([CH3:34])[CH3:33])[CH:28]([CH3:30])[CH3:29])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CC(C)NC(C)C
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 19 h
Yield: 89 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), and diisopropylamine (1.35 ml, 9.7 mmol) in DMF (5 ml) was stirred at 70° C. for 19 hours under an atmosphere of nitrogen then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified on silica gel using gradient elution with dichloromethane, dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10) to give (2R)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (343 mg, 86%).