Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH:19]=[O:20])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(C=O)cc(Cl)c1Cl)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1cc(CO)cc(Cl)c1Cl)C1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a methanol (0.16 M) solution of 1,1-dimethylethyl cyclopropyl[(2,3-dichloro-5-formylphenyl)methyl]carbamate from the previous step was added at 0° C. sodium borohydride (1.3 eq.). The resulting solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was then partitioned between ether and 1 N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][CH2:15][C:16]([N:18]([O:20][CH3:21])[CH3:19])=[O:17].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][O:20][N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:13]
Reactant: CON(C)C(=O)CN
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CNC(=O)c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
To a mixture of 2-naphthoic acid (5.8 g, 33.7 mmol), 2-amino-N-methoxy-N-methylacetamide (Gly Weinreb amide; prepared from Boc-Gly Weinreb amide 15 as in Example 43) (3.8 g, 32.1 mmol) and DIPEA (12.0 mL, 68.9 mmol) in DCM (70 mL) was added BOP (14.9 g, 33.7 mmol) in one portion at room temperature. The resulting mixture was stirred for 1 hr then saturated NaHCO3 aqueous solution was added. The organic layer was washed with brine (5×60 mL) and 1 N HCl (2×30 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product, which was used in the next reaction without further purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([C:32]1([CH2:40][NH2:41])[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:25]([O:29][C:30]([C:32]1([CH2:40][NH:41][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:4])[CH2:33][CH2:34][S:35](=[O:38])(=[O:39])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)C1(CN)CCS(=O)(=O)CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCS(=O)(=O)CC1
Yield: 12.1 %

Procedure:
A mixture of 4-cyano-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid tert-butyl ester (208 mg) and Raney Ni (0.5 mL in water) in MeOH (20 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product 4-aminomethyl-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid tert-butyl ester (212 mg), which was used in the next step. A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (24 mg) and 4-aminomethyl-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid tert-butyl ester (45 mg) in EtOH (1 mL) was microwaved at 140° C. for 2 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (5 mg). LC MS ESI+: 552 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH2:16]([N:18](CC)CC)[CH3:17].C(N)C>C1COCC1>[CH2:16]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1)[CH3:17]
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: CCN(CC)CC
Agent: CCN
Solvent: C1CCOC1
Product: CCNc1nc(SC)nc(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g) in THF (1000 mL) and triethylamine (110 mL, 0.81 mole) was added ethylamine (2.0 M in THF, 0.81 mole) at 0° C. This reaction mixture was stirred at room temperature overnight and then solvents were removed on a rotary evaporator. H2O was added and the mixture extracted with ethyl acetate several times. Solvents from the combined organic layers were removed on a rotary evaporator affording 58 g (86% yield) of ethyl 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate. This material was used as such without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10]O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.CS(Cl)(=O)=O.Cl.Cl.[C:19]([O:23][C:24]([N:26]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)[C:27]1[N:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CCN(CC)CC.C1COCC1>[C:19]([O:23][C:24]([N:26]([C@@H:40]1[CH2:44][CH2:43][N:42]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH2:41]1)[C:27]1[N:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: OCc1ccc2c(c1)CCO2
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc4c(c3)CCO4)C2)nc1
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a mixture of 2,3-dihydro-1-benzofuran-5-ylmethanol (95.1 mg), Et3N (0.120 mL), and THF (3 mL) was added methanesulfonyl chloride (0.053 mL) at 4° C. The reaction mixture was stirred for 3 hours, and added ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (250 mg) and Et3N (0.281 mL). After stirring for 2 hours at 60° C., the resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (134 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)=[CH:16][C:15]([C:32](OCC)=[O:33])=[N:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1>[CH:7]1([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:20][CH:19]=3)=[CH:16][C:15]([CH2:32][OH:33])=[N:14]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a suspension of LAH (52 mg, 1.36 mmol) in THF (6 ml) at 0° C., was added dropwise a solution of pyrazole ester 1.3 (500 mg, 1.24 mmol) in THF (3 ml). The mixture was stirred at 0° C. for 30 min, quenched with H2O, diluted with 1N HCl, and extracted with EtOAc (3×). The combined organic phase was washed with H2O, brine, and dried (Na2SO4). Filtration through a 1″ pad of SiO2, elution with ethyl acetate, and concentration of the filtrate afforded 448 mg (100%) alcohol 2.1. HRMS (ESI) calc'd for C23H27N2O2 363.1994; found 363.2083 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:31](O)[C@@H:12]2[O:13][Si:14]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:15][Si:16]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:17][CH2:18][C@H:11]2[C:10]1=[CH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:40])CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:31]([F:40])[C@@H:12]2[O:13][Si:14]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:15][Si:16]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:17][CH2:18][C@H:11]2[C:10]1=[CH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](O)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](F)[C@H]1OCc1ccccc1

Procedure:
To a solution of alcohol 6 (6.5 g, 13.2 mmol) in anhydrous CH2Cl2, (diethylamino)sulfur trifluoride (DAST, 1.84 mL, 13.9 mmol) was added slowly at room temperature. The reaction mixture was quenched with iced H2O after 20 min. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer was then combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was used immediately for the next deprotection step. The analytic sample of 8 was obtained by the purification using column chromatography on a silica gel (EtOAc:Hexanes=1:100 to 1:20).[α]24D −104.08° (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 5.36 (t, J=2.5 Hz, 1H), 5.20 (dd, J=2.5 and 5.0 Hz, 1H), 4.92 (ddd, J=6.0, 7.5 and 55.0 Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.31-4.26 (m, 1H), 4.23-4.16 (m, 1H), 4.01-3.92 (m, 1H), 1.08-0.94 (m, 27H); 13C NMR (100 MHz, CDCl3) δ 142.6 (d, J=9.2 Hz), 137.9, 128.4, 127.8, 127.7, 112.7, 103.4 (d, J=189.0 Hz), 80.4 (d, J=21.3 Hz), 73.8 (d, J=19.8 Hz), 71.3, 61.6, 48.8 (d, J=5.3 Hz), 17.5, 17.4, 17.1, 17.0, 16.9, 16.8, 13.4, 13.3, 12.7, 12.5. HR-MS Calcd. for (C26H43FO4Si2+H)+ 495.2762, found 495.2769.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[CH3:13]>C(#N)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[CH3:13])=[O:1]
Reactant: CC(=O)Nc1ccc(CO)c(C)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CC(=O)Nc1ccc(C=O)c(C)c1
Temperature: 120 °C
Yield: 92 %

Procedure:
N-[4-(Hydroxymethyl)-3-methylphenyl]acetamide (D51) (0.36 g, 2 mmol) and manganese dioxide (0.875 g, 10 mmol) were combined in acetonitrile (16 ml) and heated to 120° C. in the microwave for 7 minutes. The MnO2 was filtered off and the reaction mixture was concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% EtOAc/petroleum ether yielded the title compound as a cream solid (0.326 g). δH (CDCl3, 400 MHz) 10.27 (1H, s), 7.79 (1H, d), 7.50 (1H, d), 7.45 (1H, s), 7.35 (1H, br.s), 2.66 (3H, s), 2.20 (3H, s). MH+ 178.2.
Reaction SMILES: C([O:8][C:9]1[C:10]([N+:26]([O-])=O)=[C:11]([CH:16]=[CH:17][C:18]=1[C:19]1[C:20]([CH3:25])=[N:21][O:22][C:23]=1[CH3:24])[C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1>CO>[NH2:26][C:10]1[C:9]([OH:8])=[C:18]([C:19]2[C:20]([CH3:25])=[N:21][O:22][C:23]=2[CH3:24])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(-c2c(C)noc2C)c(OCc2ccccc2)c1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1ccc(-c2c(C)noc2C)c(O)c1N
Yield: 99.7 %

Procedure:
A suspension of methyl 3-(benzyloxy)-4-(3,5-dimethylisoxazol-4-yl)-2-nitrobenzoate (0.959 g, 2.51 mmol) in methanol (49.9 mL) was degassed with nitrogen, treated with 10% Pd/C, Degussa type, (0.144 g), and hydrogenated with a balloon of hydrogen for 1 h. A solution formed during the first 30 min. The reaction mixture was filtered through a cartridge and the solids were washed with methanol. The filtrate was concentrated to give the desired product (0.656 g, quantitative) as an orange solid that was used without further purification. LCMS calculated for C13H15N2O4 (M+H)+: m/z=263.1. found: 263.1.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:10]=[CH:9]2)#[N:2].N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+]>CCO>[NH2:2][CH2:1][C:3]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:10]=[CH:9]2
Reactant: CN(C)C(=O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCO
Product: CN(C)C(=O)Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
To a solution of 2-[5-(2-cyano-4-fluorophenoxy)-indazol-1-yl]-N,N-dimethylacetamide (0.090 g, 0.266 mmol) in EtOH (0.5 mL) was added CoBr2 (27 μL, 0.005 mmol) followed by [2,2′]bipyridinyl (81 μL, 0.015 mmol). NaBH4 (0.030 g, 0.798 mmol) was added to the mixture and it was stirred at room temperature for 18 hours. The mixture was treated with another portion each of CoBr2, [2,2′]bipyridinyl, and NaBH4 and stirred for another 18 hours. The mixture was quenched with MeOH, followed by acetic acid and then concentrated under reduced pressure. The white residue was partitioned between saturated NaHCO3 and ethyl acetate. The organic layer was filtered and concentrated under reduced pressure to afford 10 mg of white solid (11% yield).
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:28][CH2:27][N:26]([CH3:31])[CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCNC1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCN(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a suspension of 400 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-pyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride, 0.26 ml of triethylamine, and 0.23 ml of a 37% aqueous formaldehyde solution in 11 ml of dichloroethane was added 592 mg of sodium triacetoxyborohydride under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 249 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-1-methylpyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC1CCC(=C(C)C)CC=1.C(C1C=CC=CC=1)C.[C:27]([OH:31])(=[O:30])[CH:28]=[CH2:29].C(OOC(C)(C)C)(=O)C.C([O-])(=O)CCCCCC(C)(C)C>C(C(C)=O)C>[CH:1]([CH:29]=[CH:28][C:27]([OH:31])=[O:30])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC(=O)O
Agent: CC(=O)OOC(C)(C)C
Agent: CC(C)(C)CCCCCC(=O)[O-]
Agent: CC1=CCC(=C(C)C)CC1
Solvent: CCc1ccccc1
Solvent: CCC(C)=O
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Blend C Copolymer--Into a polymerization reactor equipped with an agitator and a reflux condenser were charged 770 ml of styrene, 4 grams of terpinolene, 200 ml of ethylbenzene and 200 ml of methyl ethyl ketone. Then 100 grams of medium cis-polybutadiene from Firestone Tire & Rubber Company (Diene 35) was dissolved in the mixture. After the rubber had dissolved, 50 ml of acrylic acid was added to the mixture. The temperature of the reaction mixture was raised to 80° C. and maintained between 80° and 120° C. during the course of the polymerization. Polymerization was initiated by introducing into the system a mixture of 0.3 ml of tert-butyl peracetate and 0.3 ml of tert-butyl per-neo-decanoate. About 1.5 hours later, continuous addition of 50 ml of acrylic acid was initiated and this addition was continued for about 5 hours. Additional 0.3 ml portions of tert-butyl peracetate were introduced into the polymerization mixture at 135 minutes and 270 minutes after the initiation of polymerization. To control the viscosity of the reaction mixture, 350 ml of methyl ethyl ketone was added from 315 minutes to 390 minutes after initiation of polymerization. Polymerization was terminated about 6.75 hours after initiation and a solution of two grams of 1,3,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-benzene and 0.5 gram of tris(nonylphenyl)phosphite dissolved in 100 ml of methyl ethyl ketone was added. The resultant polymer was recovered and dried, first in air and then in a vacuum oven, to yield 660 grams of rubber-modified styrene-acrylic acid graft copolymer. The resultant polymer contained about 85.6% styrene and about 14.4% acrylic acid. Its rubber content was approximately 15.1% based on the weight of the resin phase.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Clc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Clc1cccc(CCCCc2ccccc2OCc2ccccc2)c1
Yield: 86.4 %

Procedure:
3.50 g of this 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butadiene were dissolved in 125 ml of a 4:1 by volume mixture of tetrahydrofuran and ethanol. The resulting solution was stirred for 4 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 100 mg of 5% w/w palladium-on-charcoal, whilst ice-cooling. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.06 g (yield 86%) of 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butane as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.CO[CH:13](OC)[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:13]=[CH:14][N:15]=[CH:5]2)=[CH:8][C:9]=1[CH3:10]
Reactant: COC(CN)OC
Reactant: Cc1ccc(C=O)cc1Br
Product: Cc1cc2ccncc2cc1Br

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 75, Step 1 starting from 3-bromo-4-methylbenzaldehyde (Aldrich, Cat. #4017458) and. aminoacetaldehyde dimethyl acetal. Analytic LCMS (M+H)+: m/z=221.95/223.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH:16]=[N:17][CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-c2ccc3c(c2)C2C=NCCC2O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.221 g, 0.53 mmol) was dissolved in CH2Cl2 (7 mL). Trifluoracetic acid (0.81 mL, 20 equiv.) was added, and the reaction mixture was stirred at rt under N2 for 2 h. The reaction mixture was cooled to −5° C. and 2N aqueous NaOH (8 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The water layer was extracted with CH2Cl2 (2×) and with 25:1 CH2Cl2:CH3OH (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.16 g, 98%). MS (ESI+) for C17H15Cl2NO m/z 320.1 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][CH2:15][CH:14]2[CH:10]([CH2:11][C:12]3[CH:19]=[CH:18][S:17][C:13]=32)[CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(Cl)OC(Cl)=O>ClC(Cl)C>[CH:19]1[C:12]2[CH2:11][CH:10]3[CH:14]([C:13]=2[S:17][CH:18]=1)[CH2:15][CH2:16][NH:8][CH2:9]3
Reactant: c1ccc(CN2CCC3c4sccc4CC3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: c1cc2c(s1)C1CCNCC1C2
Temperature: 22 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
The product of step f) (1.16 g, 4.3 mmol) in dichloroethane (21 ml) was treated with K2CO3 (2.38 g, 17.2 mmol) and Ace-Cl (1.86 ml, 17.2 mmol) at 800C for 16 hours. Next, the reaction mixture was filtered, concentrated and the residue was dissolved in anhydrous MeOH (25 ml) and stirred for 1 hour at 22° C. The MeOH was concentrated and triturated with ether to give 874 mg (94%) of the subtitle compound. MS calculated for C10H13NS+H 180, observed 180.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][CH3:19].C(O[C:24](=[O:26])[CH3:25])(=O)C>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[N:18]([CH3:19])[C:24](=[O:26])[CH3:25]
Reactant: CNc1nc(-c2cccnc2)nc2ccc(Br)cc12
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1nc(-c2cccnc2)nc2ccc(Br)cc12
Temperature: 195 °C
Yield: 52.2 %

Procedure:
To a solution of 6-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (1.20 g, 3.81 mmol) in acetic acid (10 mL) was added acetic anhydride (1.94 g, 19.0 mmol) and stirred at 195° C. using microwave for 6 h. The reaction mixture was checked by LC-MS, no starting material was observed, ice was added into the reaction. The precipitate was collected by filtration and washed with water. The product was dried at 60° C. to give N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)-N-methylacetamide (711 mg, 52%) as a light brown powder. 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.2, 0.8 Hz, 1H), 8.85-8.79 (m, 1H), 8.76 (dd, J=4.8, 1.7 Hz, 1H), 8.09 (dd, J=1.8, 0.8 Hz, 1H), 8.05-8.01 (m, 2H), 7.46 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 3.52 (s, 3H), 2.11 (s, 3H).