Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].C([O-])(O)=O.[Na+].[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O.N1C=CC=CC=1.S(Cl)(Cl)=O>ClCCCl>[Cl:22][CH2:23][C:24]1[N:1]=[C:2]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[S:3][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115.1 %

Procedure:
1,1-Dimethylethyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.50 g, 6.14 mmol), NaHCO3 (0.570 g, 6.78 mmol) and 1,3-dichloroacetone (0.860 g, 6.77 mmol) were combined in 1,2-dichloroethane (4 mL) and the reaction mixture was stirred at room temperature for 12 h. The crude reaction mixture was filtered using CH2Cl2 and the filtrate was concentrated in vacuo until approximately 30 mL of solvent remained. To this solution was added pyridine (0.75 mL, 9.2 mmol), and the solution was cooled with an ice bath. Thionyl chloride (0.49 mL, 6.8 mmol) was added and the solution was allowed to warm slowly to room temperature. The solvent was removed in vacuo and the residue was taken up in 10% MeOH/ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo to yield 2.24 g (>100%) of crude 1,1-dimethylethyl 4-[4-(chloromethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, d6-DMSO): 7.62 (s, 1H), 4.60 (s, 2H), 3.98 (m, 1H), 3.63 (dd, 2H), 3.16 (m, 1H), 2.90 (broad s, 2H), 2.01 (dd, 1H), 1.51 (m, 2H), 1.40 (s, 9H). MS (EI) for C14H21N2O2SCl: 261 (M-tBu).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])=[O:6])[CH3:2].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:3][C:4](=[O:23])[C@H:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1I
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2nc(C)c([C@H](O)C(=O)OCC)c(I)n2n1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a stirred yellow solution of ethyl 6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (6.4 g, 14.8 mmol) in anhydrous toluene (300 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (5.40 mL, 5.94 mmol). The mixture was cooled to −35° C. and a solution of 50% catechoborane/toluene (5.09 mL, 20.78 mmol) was added over the course of 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h, then diluted with EtOAc (600 mL) and sat. aq. Na2CO3 (100 mL). The mixture was stirred vigorously for 30 min, and the organic phase was washed with sat. aq. Na2CO3 (2×100 mL), dried (Na2SO4), filtered, concentrated. The residue was purified by silica gel chromatography (5-100% EtOAc/hexane) to afford the desired (S)-ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.3 g, 12.2 mmol, 82% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.33 (s, 1H), 5.75 (d, J=2.4 Hz, 1H), 4.52 (qd, J=7.1, 1.1 Hz, 2H), 4.38-4.29 (m, 2H), 3.59 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H). LCMS (M+H)=434.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([O:19]C)=O)=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.CO.O.[NH2:24][NH2:25]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([NH:24][NH2:25])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCCc2ccncc2)s1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1ccc(C(=O)NCCc2ccncc2)s1
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl 5-[2-(pyridin-4-yl)ethylcarbamoyl]thiophene-2-carboxylate (0.40 g, 1.4 mmol) was suspended in a liquid mixture of methanol (4.0 mL) and tetrahydrofuran (2.0 mL) and left at 55° C. until conversion to a homogeneous amber solution was confirmed. After addition of 80% hydrazine monohydrate (0.17 mL, 2.8 mmol), it was left at 55° C. for 24 hours. After addition of 80% hydrazine monohydrate (0.17 mL, 2.8 mmol), it was left at 55° C. for 4.5 hours and then at room temperature for 14 hours. The precipitated solid was recovered by filtration and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid (2-pyridin-4-yl)ethylamide (yield 82%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)CCC.[OH-:10].[K+].CS(C)=O.[Br:16][CH2:17][CH2:18]Br>O>[Br:16][CH2:17][CH2:18][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[CH:1]=[O:10]
Reactant: CCCCc1ccc[nH]1
Reactant: [OH-]
Reactant: BrCCBr
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccn1CCBr

Procedure:
A mixture of 2-butylpyrrole (1 g), potassium hydroxide (23 g) and dry DMSO (20 mL) was stirred under nitrogen atmosphere. 1,2-dibromoethane (7.9 g) was added dropwise at 20-25° C. and stirred till the reaction is complete. Water (50 mL) was added and the reaction mixture was extracted with diethyl ether (3×50 mL). The combined organic layer was washed with water (30 mL), followed by brine (30 mL) and was dried over Na2SO4. The solvent was evaporated and the compound obtained was purified by column chromatography (silica gel 100-200) using ethyl acetate:hexane (2:8) as an eluent to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]>[Fe].CC(O)=O.CCOC(C)=O>[NH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(N)ccc1C#N
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additional 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1.C([OH:28])C.[OH-].[Na+]>O>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:28])=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc(C(F)(F)F)ccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(C(F)(F)F)ccc1S2
Temperature: 75 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a mixture of 40 mg of 2-(10,11-dihydro-8-trifluoromethyl-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 1 ml of ethanol was added 200 mg of sodium hydroxide in 1 ml of water, and the mixture was stirred at 75° C. for 5 hours. After cooling, the solvent or ethanol was removed by distillation to obtain a residue, to which was added water, and the resulting mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a yellow oil, which was thin-layer chromatographed and developed with chloroform-methanol (10:1), thereby obtaining 15 mg (yield: 38%) of 2-(10,11-dihydro-8-trifluoromethyl-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH3:16])[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.CCCCCC>CCOCC>[CH2:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:5]([CH2:3][OH:2])[CH2:6]1)[CH3:16]
Reactant: CCN1CC(C(=O)OC)Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCN1CC(CO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-Ethyl-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid methyl ester (123 mg, 0.56 mmol) in 1.5 mL of Et2O at 0° C. under nitrogen. LAH (1M in Et2O) was added dropwise with vigorous gas evolution and a white precipitate formation. After 30 min., TLC in 3/7 EtOAc/hexane showed complete loss of s.m. and appearance of a clean lower rf spot. The reaction was carefully quenched with 15% NaOH (3 mL) and 3 mL of Et2O was added and the mixture stirred rapidly at RT for 15 nin. The layers were separated and the aqueous layer extracted 1×10 mL with Et2O. The organics were combined, dried (MgSO4), filtered and concentrated to a clear oil corresponding to the desired alcohol (105 mg, 95%).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[F:13][C:14]1[N:19]=CC=CN=1.[CH3:20][S:21]SC>O.C1COCC1>[F:13][C:14]1[C:11]([S:21][CH3:20])=[CH:10][CH:9]=[CH:8][N:19]=1
Reactant: [Li]CCCC
Reactant: CSSC
Reactant: Fc1ncccn1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1cccnc1F
Reaction time: 0.5 h

Procedure:
To 140 ml of an anhydrous THF solution of 7.7 g of diisopropylamine was added 50 ml (1.6 M solution in hexane) of n-butyllithium at −78° C., and the mixture was stirred at that temperature for 30 minutes. To the reaction mixture was added 10 ml of a THF solution of 7.4 g of 2-fluoropyrimidine, followed by stirring at the same temperature for 30 minutes. To the reaction mixture was further added a THF solution of 8.61 g of dimethyl disulfide, followed by stirring at the same temperature for 20 minutes. The reaction mixture was poured into about 200 ml of water, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using a mixture of ethyl acetate and hexane (1:19 by volume) as a developing solution. The fraction containing the desired compound was concentrated to yield 6.11 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:35])([F:34])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]([F:35])([F:34])[F:21])=[CH:30][N:29]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(2,2,2-trifluoroethoxy)picolinic acid [D. Banner et al. WO2010128058 (2010)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=495.4 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(F)cc1)N1CCN(C2CCCC2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (34%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17]CC=C)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C[N+]1([O-])CC[O:37]CC1.[CH3:41][C:42]([OH:45])(C)[CH3:43]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:41][CH:42]([OH:45])[CH2:43][OH:37])[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C=CCCCn1cnc2c(F)c(Nc3ccc(Br)cc3C)c(C(=O)NOCC3CC3)cc21
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC(O)CO)c1F
Reaction time: 5 h
Yield: 74 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11f (0.307 g, 0.612 mmol) is dissolved in 4:1 THF/water (8 mL) and 1.134 mL (0.061 mmol) of an 0.054 M OsO4 solution in t-BuOH was added followed by NMO (0.093 g, 0.796 mmol). After 5 hours, the reaction mixture is quenched by the addition of 10% NaHS2O3 solution. After 10 minutes, the reaction mixture is filtered through Celite rinsing with ethyl acetate and methylene chloride. The filtrate is diluted with ethyl acetate and washed with 0.01 N HCl, and brine. The organic layer is dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by FCC eluted with 9:1 ethyl acetate/MeOH to give 0.244 g (74%) pure desired product.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1.[P:16]([O-:23])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[C:5]1([CH3:6])[CH:11]=[CH:10][CH:9]=[C:14]([PH:16](=[O:23])[C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH:13]=1
Reactant: CCOP([O-])OCC
Reactant: BrCCBr
Reactant: Cc1cccc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc([PH](=O)c2cccc(C)c2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Under a nitrogen stream, a solution of magnesium (3.60 g, 3.50 equivalents) and a small amount of iodine and 1,2-dibromoethane in THF (25 mL) solution was stirred at room temperature for 30 min. A solution of m-bromotoluene (25.36 g, 3.51 equivalents) in THF (130 mL) was added at 24° C., and the mixture was stirred at 40° C. for 30 min. Then, a solution of diethyl phosphite (5.84 g, 42.3 mmol) in THF (10 mL) was added at 25° C., and the mixture was stirred at 24° C. for 1.5 hrs. 6M—HCl (20 mL) was added at 4° C., and then water (20 mL) and toluene (60 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with 10% aqueous NaHCO3 solution (20 mL), water (20 mL) and 10% aqueous NaCl solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and further passed through a membrane filter (0.2 μm) under reduced pressure. The filtrate was concentrated under reduced pressure to give the title compound (9.09 g, colorless oil). yield 93.3%
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(Cl)c2)ccc1OCCN1CCCC1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (0.029 g, 0.10 mmol) in CH2Cl2 (1.5 mL) was added 3-chlorobenzoyl chloride (0.015 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.037 g, 87%). LCMS m/z (%)=425 (M+H35Cl, 100), 427 (M+H37Cl, 42). 1H NMR (400 MHz, DMSO-d6) δ: 10.40 (s, 1H), 8.01-8.00 (m, 1H), 7.94-7.87 (m, 2H), 7.72 (d, J=2.6 Hz, 1H), 7.70-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.32-4.28 (m, 2H), 3.69 (s, 3H), 3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.95-2.82 (m, 2H), 1.95-1.85 (m, 2H), 1.78-1.68 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([CH:33]1[O:35][CH2:34]1)Br>CN(C=O)C>[O:35]1[CH2:34][CH:33]1[CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.89 g, 5.90 mmol), (prepared as described in Example 49), potassium carbonate (2.43 g, 17.6 mmol) and epibromohydrin (1.61 g, 11.7 mmol) in DMF (40 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The insoluble inorganic material was removed by filtration and the solvent was removed by evaporation. The residue was triturated with diethyl ether, filtered, washed with further diethyl ether and dried to give 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.97 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:30]([CH3:33])(=[O:31])=[O:32])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)Cc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CS(C)(=O)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.075 g, 0.24 mmol) and 2-bromo-6-[(methylsulfonyl)methyl]pyridine (0.060 g, 0.24 mmol) as starting materials.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ncc2c(n1)N(C1CCCC1)C(=O)NC2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C3CCCC3)C(=O)NC4)cc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 2.0 g (7.1 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 2.7 g (14.3 mmol) of 1-(4-aminophenyl)-4-methylpiperazine in 32 mL of acetonitrile is added 2.75 mL (35.7 mmol) of trifluoroacetic acid. The mixture is heated at 85° C. overnight. The cooled reaction mixture is diluted with ethyl acetate and washed two times with saturated aqueous sodium bicarbonate solution and once with brine. The combined aqueous phase is back extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and concentrated. The dark solid residue is stirred for 2 hours in 30 mL of 1:1 dichloromethane/ethyl acetate, filtered, washed with ethyl acetate, and dried to give 2.3 g (80%) of the title compound: mp 236-239° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C(O)C.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]N.C(N)([NH2:31])CC>C(O)C.O>[CH3:21][N:22]([CH3:27])[CH:23]([NH2:31])[CH2:24][CH3:25].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CCC(N)N
Reactant: CN(C)CCCN
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCO
Solvent: O
Product: CCC(N)N(C)C

Procedure:
A 0.05 mole sample of bis-phenol A was dissolved in an ethanol-water solution containing 95% ethanol. This solution then was added dropwise to a 0.05 mole fraction of N,N-dimethyl-1,3-propanediamine sample dispersed in 50 milliliters of an ethanol-water solution containing 95% ethanol. The addition of the bis-phenol A fraction to the propanediamine sample was at room temperature (70° F.) over a 15 minute period. There was a slight exotherm during the addition. After all the bis-phenol A was added, the solution was stirred for an hour and then the solvent flashed using a rotary vacuum distillation apparatus. The residual solids were transferred to a vacuum oven to dry, and a N,N-dimethylpropanediamine salt of bis-phenol A was obtained.
Reaction SMILES: [Na].[S:2]1(=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.[F:14][C:15]1[N:20]=[C:19]([F:21])[C:18]([F:22])=[C:17](F)[C:16]=1[F:24].C1OCCOCCOCCOCCOC1>C(#N)C.O>[F:21][C:19]1[C:18]([F:22])=[C:17]([N:3]2[C:4](=[O:11])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:2]2(=[O:12])=[O:13])[C:16]([F:24])=[C:15]([F:14])[N:20]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2S(=O)(=O)N1c1c(F)c(F)nc(F)c1F
Reaction time: 3.5 h
Yield: 77 %

Procedure:
A mixture of the sodium salt of 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (0.81 g, 3.95 mmol), pentafluoropyridine (0.68 g, 4.0 mmol) and 15-Crown-5 (0.88 g, 4.0 mmol) in acetonitrile (15 ml) was heated to reflux for 6 hours, cooled, and the solvent evaporated in vacuo. The oily residue thus obtained was suspended in water and stirred for 3-4 hours. The solid which percipitated was collected by filtration and dried to afford 1.01 g (77%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 164°-165° C. after recrystallization from carbon tetrachloride.