Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]12[CH2:14][CH:10]([CH2:11][NH:12][CH2:13]1)[C:9]1[CH:8]=[CH:7][C:6]([NH:15][C:16]3[N:21]=[C:20](NC4CC4)[C:19]([C:26]([F:29])([F:28])[F:27])=[CH:18][N:17]=3)=[CH:5][C:4]2=1.CCN([CH:36]([CH3:38])[CH3:37])C(C)C.Cl.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1>O1CCOCC1>[CH:36]1([C:20]2[C:19]([C:26]([F:28])([F:29])[F:27])=[CH:18][N:17]=[C:16]([NH:15][C:6]3[CH:7]=[CH:8][C:9]4[CH:10]5[CH2:14][CH:3]([CH2:13][N:12]([C:40]([C:41]6[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=6)=[O:47])[CH2:11]5)[C:4]=4[CH:5]=3)[N:21]=2)[CH2:38][CH2:37]1
Reactant: FC(F)(F)c1cnc(Nc2ccc3c(c2)C2CNCC3C2)nc1NC1CC1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cccnc1)N1CC2CC(C1)c1cc(Nc3ncc(C(F)(F)F)c(C4CC4)n3)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
A solution of 13 (200 mg, 446 μmol) and DIEA (124 μL, 880 μmol) in 1,4-dioxane (2 mL) was treated with in one portion with nicotinoyl chloride hydrochloride (80 mg, 446 μmol). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The resultant residue was purified on silica (3% CH3OH/CH2Cl2) to provide 15 as an off-white solid (52 mg, 20% yield). HPLC Rt 5.7 minutes; LC/MS (Method F) m/z 427 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH:20]([CH3:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29](C)[CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH:20]([CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH3:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: COc1cccc2c(N3CC(C)c4ccccc4C3C)nc(Cl)nc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CC(C)c4ccccc4C3C)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 30 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 3.00 g of the compound (8.40 mM) prepared in Example 16 and 10 ml of dimethyl-formamide, 1.90 ml of 4-fluoro-2-methylaniline(20 mM) was added, 1.10 g of the title compound was prepared.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1.[CH2:25](N(CC)CC)C.[H-].[Na+].CI>C(Cl)Cl.CCOCC>[C:20]([O:19][C:18]([N:17]([CH3:25])[C@@H:14]1[CH2:15][CH2:16][N:12]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:13]1)=[O:24])([CH3:21])([CH3:23])[CH3:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CCN(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (0.749 mL, 5.25 mmol) was added to a solution of tert-butyl(3R)-pyrrolidin-3-ylcarbamate (0.93 g, 5.0 mmol, TCI, Cat. No. A1171) and triethylamine (1.39 mL, 10.0 mmol) in methylene chloride (15.0 mL) at 0° C. The mixture was stirred at r.t. for 1 h. The mixture was diluted with CH2Cl2, washed with 0.5 N aqueous HCl, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10.0 mL), and cooled with ice-water. To the solution was added sodium hydride (0.300 g, 7.50 mmol) in small portions. The mixture was stirred for 15 min at r.t., and then methyl iodide (1.42 g, 10.0 mmol) was added. The mixture was stirred for additional 30 min., then diluted with ether, washed with water and brine, over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was directly used in the next step reaction without further purification. LCMS (M+Na)+: m/z=357.3.
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([OH:10])=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:10]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Reactant: Nc1ccccc1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)Nc3ccccc3)cc2OCC(O)CO)c1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid with aniline there was obtained 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-N-phenyl-benzamide as a foam.
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][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[OH:29])=[O:18].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1ccc2ccccc2c1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3c(C(C)=O)ccc4ccccc34)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 1-hydroxy-2-acetonaphthone (250 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (5 mg, yield 30%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])(=[O:10])[CH3:9]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:8]([O:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:13][C:14]([OH:16])=[O:15])(=[O:10])[CH3:9]
Reactant: CCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(C)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(CC(=O)O)OC(C)=O
Reaction time: 2 h
Yield: 85.4 %

Procedure:
Trifluoroacetic acid (32 ml) was added to t-butyl (3RS)-3-acetoxytetradecanoate (14 g) under ice-cooling. The mixture was stirred at the same temperature for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in a mixture of benzene and toluene, and concentrated under reduced pressure to give (3RS)-3-acetoxytetradecanoic acid (10.0 g).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17])(=[O:9])=[O:8])[CH3:6].N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>ClCCCl>[CH2:5]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N:19]=[C:26]=[O:27])(=[O:17])=[O:18])(=[O:9])=[O:8])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCS(=O)(=O)c1ccccc1S(N)(=O)=O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Temperature: 50 °C

Procedure:
102.8 g (0.865 mol) of thionyl chloride were added to 71.8 g (0.288 mol) of 2-(ethylsulfonyl)benzenesulfonamide in 500 ml of 1,2-dichloroethane in the course of 30 minutes while stirring at from 70° to 80° C., and the refluxed mixture was stirred for 2.5 hours. After the mixture had been cooled to 50° C., 2 ml of pyridine were added and gaseous phosgene was passed into the refluxed mixture in the course of 5 hours while stirring. Evaporating down gave 84.1 g of the title compound, which was taken up directly in 1,2-dichloroethane for storage.
Reaction SMILES: C(C1C=CC(C2[CH:20]=[CH:19][C:18]([OH:21])=C(C#N)C=2)=CC=1)CCCCCCC.[CH3:24][C:25](C)([O-:27])[CH3:26].[K+].C1[O:32][C@H]1CCl>C(O)(C)(C)C.CN(C1C=CN=CC=1)C>[CH2:24]([O:32][CH2:20][CH:19]1[O:21][CH2:18]1)[CH:25]1[O:27][CH2:26]1
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCCc1ccc(-c2ccc(O)c(C#N)c2)cc1
Reactant: ClC[C@H]1CO1
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: C(OCC1CO1)C1CO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-n-octylphenyl)-2-cyanophenol (1.9 g) prepared in Preparation 2 in t-butyl alcohol (40 ml) is added potassium t-butoxide (832 mg). After a short period of time, R-(-)-epichlorohydrin (2.5 ml) and 4-(N,N-dimethylamino)pyridine (100 mg) are added to the mixture, and the mixture is stirred at room temperature for 2 days. The reaction mixture is concentrated under reduced pressure, and to the residue is added water. The mixture is extracted with ether and the extract is dried and distilled to remove ether. The crude product thus obtained is purified by silica gel column chromatography to give S isomer of a glycidyl ether (750 mg) of the following formula: ##STR49##
Reaction SMILES: [Br:1][C:2]1[C:45]([N+:46]([O-])=O)=[CH:44][CH:43]=[CH:42][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:7]1.[CH:49]([Mg]Br)=[CH:50][CH3:51].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:4][O:5][CH:6]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:14][CH:13]=3)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:7]2)=[CH:42][CH:43]=[C:44]2[C:45]=1[NH:46][CH:49]=[C:50]2[CH3:51]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1
Reactant: CC=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)c[nH]c3c2Br)cc1
Reaction time: 0.25 h

Procedure:
The solution of 0.500 g of benzyl 3-(2-bromo-3-nitrobenzyloxy)-4-{4-[3-(2-methoxy-benzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 6.5 ml of tetrahydrofuran is cooled to −45° C. under argon and admixed slowly with 4.0 ml of 1-propenylmagnesium bromide (0.5M in tetrahydrofuran). The reaction mixture is stirred over 15 minutes, subsequently poured onto saturated aqueous ammonium chloride solution (10 ml) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with water (25 ml) and brine (25 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:2 EtOAc-heptane); Rt=6.17.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15](C(=O)C(F)(F)F)=[CH:14][CH:13]=2)[N:7]=1)=[O:4].[C:26](OC(=O)CC)(=O)CC>O>[CH3:11][CH:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:26])[CH2:10]1
Reactant: CC1CC(NC(=O)C(F)(F)F)=NN1c1ccc(C(=O)C(F)(F)F)cc1
Reactant: CCC(=O)OC(=O)CC
Solvent: O
Product: CCC(=O)NC1=NN(c2ccccc2)C(C)C1
Reaction time: 16 h

Procedure:
A mixture of 5.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 5) and 25.0 ml. of propionic anhydride is allowed to remain at room temperature for 16 hours. The reaction mixture is poured into water to separate an oil which crystallizes. The solid is collected by filtration and dissolved in dichloromethane. The solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated at reflux and hexane is added. The first heavy precipitate (purple color) is discarded. The solution is cooled and the ensuing precipitate is collected by filtration. The solid is again dissolved in dichloromethane, columnized and recrystallized with hexane to give 2.3 g. of the product of the Example as plates, m.p. 96.0°-96.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][C:18]=2[O:25][CH3:26])[CH:15]=[CH:14][CH:13]=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:1]3[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]3)=[CH:19][C:18]=2[O:25][CH3:26])[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: COc1cc(CO)ccc1Cn1cccn1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2ccc(Cn3cccn3)c(OC)c2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of Ethyl 1H-pyrazole-4-carboxylate (117 mg, 0.833 mmol), crude (4-((1H-pyrazol-1-yl)methyl)-3-methoxyphenyl)methanol (256 mg, 71%, 0.833 mmol) and Triphenylphosphine (328 mg, 1.249 mmol) in THF (8 ml) DEAD 40% in Toluene (0.494 ml, 1.249 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 2 h and continued to stir for 12 h at rt. A saturated solution of NaHCO3 was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude Ethyl 1-(4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzyl)-1H-pyrazole-4-carboxylate. MS [M+H]+=341.
Reaction SMILES: [NH2:1][CH:2]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH:26](=[O:28])[CH3:27]>C1COCC1.C(OCC)(=O)C>[C:26]([NH:1][CH:2]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:28])[CH3:27]
Reactant: NC(COC(F)F)C(=O)NCc1ccc(F)cc1
Reactant: CC=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC(COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a solution of 2-amino-3-difluoromethoxy-N-(4-fluorobenzyl)propionamide (200 mg, 0.762 mmol) and triethylamine (293 mg, 2.9 mmol) in THF (5 mL), acetic hydride (93 mg, 0.915 mmol) was added. The reaction mixture was stirred at room temperature for three hours, diluted with ethyl acetate, and washed with water. The organic layer was concentrated with silica gel and purified by column chromatography with 50-100% ethyl acetate in hexanes. The product was triturated with diethyl ether to give 2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (140 mg, 60.3%) as a white solid, MP: 130.8° C. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.24 (dd, 2H), 7.03 (t, 2H), 6.73 (w, 1H), 6.41 (d, 1H), 6.24 (wt, 1H), 4.71 (m, 1H), 4.44 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.[Br:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH2:28][CH2:27][Br:26])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCBr)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
A mixture of 3.2 g. (9.2 mmol.) of 5-chloro-3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 3.5 ml. (0.035mol.) of 1,3-dibromopropane and 4.0 g. (0.029 mol.) of potassium carbonate in 100 ml. of acetone is refluxed for 3 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated to give 5-chloro-3-[4-(3-bromopropoxy)benzoyl]-2-phenylbenzofuran.
Reaction SMILES: Cl.C1(C(C)[CH2:9][N:10]=C=O)C=CC=CC=1.[C:14]1([CH:20](C)[CH2:21][NH2:22])C=CC=[CH:16][CH:15]=1.[O:24]=C(Cl)OC(Cl)(Cl)Cl>C(OCC)(=O)C>[NH:16]1[CH:15]=[C:14]([CH2:20][CH2:21][CH2:22][OH:24])[N:10]=[CH:9]1
Reactant: CC(CN=C=O)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(CN)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: OCCCc1c[nH]cn1

Procedure:
HCl and 5 mmol of 2-phenylpropyl isocyanate (freshly prepared from 2-phenylpropylamine and diphosgene in ethyl acetate (Japan Kokai Tokkyo Koho JP, 60, 162, 262 (05.07.1985): Chem. Abstr. 103, 215012) are treated as described in Example 1.
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]5[O:42][CH:3]=[CH:4][N:5]=5)[CH:10]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(OCc2ncco2)cc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 20-45—90 mins) to afford N-(1H-indazol-5-yl)-2-(3-(oxazol-2-ylmethoxy)phenyl)quinazolin-4-amine. (12 mg, 0.028 mmol).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].S([O-])([O-])(=O)=[O:8].[Mg+2].[C:13]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.[OH2:21]>C(O)C>[OH:21][C:13]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[OH:8]
Reactant: O
Reactant: O=S(=O)([O-])[O-]
Reactant: OCC1=CCCCC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCO
Product: OCC1(O)CCCCC1O

Procedure:
A solution of 24.9 g of potassium permanganate and 18.7 g of magnesium sulfate in 498 ml of water was added dropwise during 1.5 hours to a solution of 22.23 g of 1-cyclohexenemethanol in 373 ml of ethanol. During the dropwise addition, the reaction mixture temperature was maintained at 15°-20°. The reaction mixture was filtered to remove the by-product manganese dioxide. The filtrate was evaporated under reduced pressure to a residual oil. The residual oil was taken up in ethanol and dried with magnesium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to a residual oil. The residual oil was distilled using a short-path distilling system to give 6.44 g of 1,2-dihydroxycyclohexanemethanol; bp 124°-125°/0.025 mm.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:27])[N:7]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH3:28][N:29]([CH2:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:27])[N:7]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:34]=[CH:35][CH:36]=1)[CH3:46]
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1cccc(-c2nc3cc(Cl)ccc3c(=O)n2CC(=O)NC(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3cc(-c4cccc(CN(C)C)c4)ccc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 80 °C

Procedure:
An oven dried flask was charged with 2-[7-chloro-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.11) (38.5 mg, 0.10 mmol), dimethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amine (INTERMEDIATE XI.1) (40 mg, 0.15 mmol) and K3PO4(69 mg, 0.33 mmol) followed by mixture of DMF: H2O (4:1, 5 mL) and purged with argon for a minimum of 10 minutes. CombiPhos™-Pd catalyst (CombiPhos Catalysts Inc., Princeton, N.J.) (1 mole %) was added and the mixture was heated at 80° C. for 18 h. The solvent was removed under vacuum and the residue was dissolved in methanol, filtered and purified by preparative HPLC to give 2-[7-(3-dimethylaminomethylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 8a) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1I
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(OS(=O)(=O)c2ccccc2I)cc1
Yield: 70.6 %

Procedure:
A solution of 2-iodobenzenesulphonyl chloride (obtained as described in J. Org. Chem. 1977, 42, 3265) (8.28 g) and 4-nitrophenol (3.81 g) in pyridine (50 ml) was heated at 100° C. for 3 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the combined extracts were washed with 1M hydrochloric acid (2×200 ml) and dried (MgSO4). Solvent was removed by evaporation and the residue was recrystallised from a mixture of ethyl acetate and hexane to give 4-nitrophenyl 2-iodobenzenesulphonate (7.83 g), m.p. 131°-133° C.; mass spectrum (+ve CI): 405 (M+).
Reaction SMILES: [C:1]([NH:8][C:9](=[NH:18])[NH:10]C(OC(C)(C)C)=O)([O:3][C:4](C)(C)[CH3:5])=[O:2].Cl.O1CCOCC1>>[NH2:10][C:9]([NH2:18])=[NH:8].[C:1](=[O:2])([O:3][CH2:4][CH3:5])[NH2:8]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(N)=O
Product: N=C(N)N
Reaction time: 24 h

Procedure:
Ethylcarbazate (208 mg, 2 mmol) was added to a solution of N′N′-di-boc N″-triflylguanidine (800 mg, 2 mmol) in dichloromethane (10 mL). The mixture was stirred for overnight then diluted with EtOAc, washed with sodium bisulfat (2M), saturated sodium bicarbonate, dried over anhydrous NaSO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 30% EtOAc/hexane to afford a white solid (0.55 g). To this bis-boc guanidine was added 4M HCl/Dioxane (5 mL). The mixture was stirred for 24 hours and then concentrated to afford the title compound. 1H NMR (MeOD): δ 3.4.18 (d, 2H), 3.26 (s, 1H), 1.28 (t, 3H). MS (M+1) 134.