Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([N:2]1[CH2:3][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:12]=2)=[O:10])[CH3:7])[CH2:5]1)(=[O:49])=[O:48]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a suspension of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-azetidin-3-yl-ethyl)-amide hydrochloride (65 mg, 0.11 mmol) in CH2Cl2 (2 mL) at 0° C. was added triethylamine (47 μL, 0.33 mmol) followed by methanesulfonyl chloride (10 μL, 0.12 mmol). The reaction mixture was stirred at 0° C. for 30 min then at room temperature for 1 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) to afford 35 mg (50%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide as a pale yellow solid.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:45])[C@@H:24]([NH:25][C:26](=[O:44])/[C:27](/[C:31]4[N:32]=[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[S:34][CH:35]=4)=[CH:28]\[CH2:29][CH3:30])[C@H:21]3[S:20](=[O:46])[CH2:19][CH:18]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.ClCCl>[C:40]([O:39][C:37]([NH:36][C:33]1[S:34][CH:35]=[C:31](/[C:27](=[CH:28]/[CH2:29][CH3:30])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:45])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[CH:18][CH2:19][S:20](=[O:46])[C@H:21]23)=[O:44])[N:32]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS(=O)[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS(=O)[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 90.7 %

Procedure:
To a solution of 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylic acid 1-oxide diphenylmethyl ester (265 mg) in a mixture of anisole (0.8 ml) and dichloromethane (1.5 ml) is added trifluoroacetic acid (1 ml) at 0° C. with stirring. After 45 minutes' stirring, the mixture is concentrated in vacuum. The residue is washed with petroleum ether and ether to give 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylic acid 1-oxide (180 mg).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]([CH3:18])=[O:17]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:7]([O:17][C:16]1[CH:18]=[CH:9][C:8]([CH2:13][CH2:1][OH:4])=[CH:7][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: OCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was added 13.8 grams of 2-(4-hydroxphenyl)ethanol, 14.5 grams of anhydrous potassium carbonate, 33.0 grams of tetrabutylammonium bromide, 12 mL of benzyl chloride and 200 mL of acetone. The reaction mixture was heated at reflux for 3 days, and then cooled to room temperature and filtered. The filtrate was concentrated in vacuo, diluted with 500 mL of dichloromethane, and washed with 2% aqueous sodium hydroxide and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was purified by chromatography on silica gel, eluting with dichloromethane, to yield 20.0 grams of the desired product as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:12][C:13](=[O:19])[NH:14][CH2:15][CH2:16][NH:17][CH3:18])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C1COCC1>[C:8]([O:12][C:13]([NH:14][CH2:15][CH2:16][N:17]([CH3:18])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:19])([CH3:11])([CH3:10])[CH3:9]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl bromoacetate (1.27 ml, 11.48 mmol) was added to a mixture of tert-butyl(2-(methylamino)ethyl)carbamate (2.0 g, 11.48 mmol), triethylamine (4.81 ml) and THF (24 ml) at 0° C. After stirring 24 h at room temperature the reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM, extracted 2× with DCM, the organic layers dried over Na2SO4 and evaporated to give the title compound as a clear pale-yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.20 (s, br, 1H), 4.18 (q, 2H), 3.24 (s, 2H), 3.22-3.16 (m, 2H), 2.65-2.61 (m, 2H), 2.38 (s, 3H), 1.42 (s, 9H), 1.24 (t, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32]C(C(O)=O)=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>>[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 4 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol) was added dropwise to a solution of 3-(tertbutyloxycarbonyl)-1,2-dihydro-3H-pyrrolo (3,2-e]indole7-carboxylic acid (1.0 gi 3.7 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J. Org. Chem., 1987, Vol. 52, 1521-1530) and triethylamine (1.5 ml, 10 mmol) in 10 ml of anhydrous CH2cl2. After 4 hrs, CH2cl2 was removed by evaporation at reduced pressure. Flash chromatography (4×20 cm, hexane-ethyl acetate, 1:2) afforded 1b as a yellow crystalline solid (1.25 gr 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.39 (d, 1H, J=1.4 Hz; NH), 8.02 (m, 1H. C6F4H), 7.9 (br s, 1H, C4H)i, 7.45 (d, 1Hj, J=1.4 Hz, C8-H), 7.33 (d, 1H, J=9 Hz, C5-H), 4.02 (t, 2H, J=9 Hz, NCH2CH2), 3.26 (t, 2H, J=9 Hz, NCH2CH2 2)” 1.51 (s, 9H, C(CH3)3).
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][NH:8][C:9]=1[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.O>CN(C)C=O>[C:1]([C:5]1[N:6]=[CH:7][N:8]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:16][N:15]=2)[C:9]=1[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(C)(C)C)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a solution of 0.5 g (3.6 m mol) of 4-tert-butyl-5-methylimidazole in 5 ml of N,N-dimethyl formamide is added slowly 150 mg (3.7 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 20 minutes. After the reaction is completed, to the reaction mixture is added dropwise 0.71 g (3.6 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction is completed, the reacton mixture is poured into water, and extracted with ethyl acetate. Further, then the residue is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product is subjected to silica gel chromatography to give 4-tert-butyl-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methylimidazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:27]1[O:35][C:34]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:28]1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:27]1[O:35][C:34]2[CH:33]=[CH:32][C:31]([C:17]3[C:16]([CH3:19])=[N:15][N:14]4[C:9]([C:4]5[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=5)=[CH:10][C:11]([N:20]5[CH2:24][CH2:23][CH2:22][C@H:21]5[CH2:25][OH:26])=[N:12][C:13]=34)=[CH:30][C:29]=2[O:28]1
Reactant: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1-c1ccc2c(c1)OCO2
Temperature: 85 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
(S)-(1-(7-(3,5-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (40 mg), 3,4-methylenedioxyphenylboronic acid (23 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (5 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred at 85° C. for 4 hours under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (36 mg).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[N-]=C=O.C1(CC2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].[C:22]1(=[O:29])[O:28]CCC[CH2:24][CH2:23]1.C(O)CCC[CH2:34][CH2:35][OH:36].C(OCCO)(=O)C=C>>[C:22]([OH:29])(=[O:28])[CH:23]=[CH2:24].[NH2:1][C:2]([O:36][CH2:35][CH3:34])=[O:3]
Reactant: [N-]=C=O
Reactant: OCCCCCCO
Reactant: O=C1CCCCCO1
Agent: C=CC(=O)OCCO
Agent: [K+]
Agent: [OH-]
Solvent: c1ccc(Cc2ccccc2)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 60 °C

Procedure:
In a flask equipped with a thermometer, a stirrer and a condenser was charged 524 parts of diphenylmethane diisocyanate and heated to 60° C. with stirring. To the flask was added dropwise 520 parts of a ring opening reaction product (OH value: 215 KOH-mg/kg) between ε-caprolactone and 1,6-hexanediol over a period of 1 hour while giving care to heat generation. The reaction was carried on over 10 hours, and 232 parts of hydroxyethyl acrylate was added thereto, followed by further continuing the reaction for 10 hours. After confirming disappearance of the absorption of an isocyanate group in the infrared absorption spectrum, an urethane acrylate containing a hard segment and a soft segment was obtained as a comparative composition (designated RSH-1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37]C)[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([O:32]C)[CH:25]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([OH:37])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(O)c(O)c2)cc1O
Temperature: 25 °C

Procedure:
To a solution of (R,R)-1,6-bis-[2-(3,4-dimethoxy-benzyl)pyrrolidin-1-yl]hexane (0.001 mol) in dry CH2Cl2 at -70° C. under an inert atmosphere was added BBr3 (4 mL of a 1M solution, 0.004 mol). The reaction mixture was warmed to room temperature, recooled to -70° C., and CH3OH (4 mL) was added. After warming to room temperature, the solvent was removed in vacuo. The residue was subjected to column chromatography, eluting with CH3OH. The fractions containing the desired product were concentrated in vacuo to provide (R,R)-1,6-bis[2-(3,4-dihydroxybenzyl)pyrrolidin-1-yl]-hexane, [α]D25 =12.86°.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[C:8](=[O:21])[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[NH2:20])[CH:12]=1)(=[O:5])[CH3:4].O1CCCC1.Cl>O>[C:3]([NH:6]/[C:7](=[CH:12]/[C:11]1[C:13]2[C:14](=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[NH:20][CH:10]=1)/[C:8]([OH:9])=[O:21])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1cc(-c2ccc(C)cc2N)coc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N/C(=C/c1c[nH]c2cc(C)ccc12)C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
110 ml. of 1 N sodium hydroxide were added dropwise over 30 minutes to a mixture of 26.95 g. (10.2 mmol) of crude 3-acetamido-5-(2-amino-4-methylphenyl)-2H-pyran-2-one in 200 ml. of tetrahydrofuran and 200 ml. of water under a nitrogen atmosphere. The resulting dark suspension was stirred for 30 minutes. 110 ml. of 1 N hydrochloric acid were added dropwise to the dark suspension. After removal of the tetrahydrofuran in vacuo and adjustment to pH 3, the dark suspension was cooled to 5° C., and filtered. The filter cake (21.1 g.) was dissolved in 1100 ml. of boiling methanol, treated with 2.0 g. of charcoal for 10 minutes and filtered through a bed of diatomaceous earth (which as washed with 200 ml. of hot methanol). The filtrate was concentrated to about 750 ml.; 150 ml. of water were added portionwise thereto; and the resulting solution was allowed to crystallize. A total of 16.1 g. (61%) of (E)-α-acetamido-6-methylindole-3-acrylic acid (mp 204.5°-206° C.) was obtained in two crops.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Cl:5][CH2:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>C(O)C>[ClH:5].[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=1[CH2:6][S:3][C:2](=[NH:4])[NH2:1]
Reactant: NC(N)=S
Reactant: Fc1ccccc1C1=C(CCl)CCCC1
Solvent: CCO
Product: Cl
Product: N=C(N)SCC1=C(c2ccccc2F)CCCC1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
Thiourea (2.09 g) was added to a solution of 1-(2-chloromethylcyclohex-1-enyl)-2-fluorobenzene obtained in Preparation Example 1-(4) (5.88 g) in ethanol (200 mL). The reaction solution was heated to 80° C. and stirred for 270 minutes. Thiourea (399 mg) was added to the reaction solution, followed by stirring at the same temperature for one hour. After cooling to room temperature, the solvent was evaporated under reduced pressure. Diethyl ether and ethyl acetate were added to the residual syrup. A white solid was precipitated by ultrasonic treatment. After standing at room temperature for 30 minutes, the supernatant was removed. Further, the solid was washed with diethyl ether and the supernatant was removed again. The resulting solid was dried under reduced pressure to obtain the title compound (6.38 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C
Reaction time: 0.05 h
Yield: 82.1 %

Procedure:
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.24 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 48 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (82%) of the {9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.56 (br s, 1H), 7.5-7.1 (m, 9H), 6.9 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.8 (s, 3H), and 2.5 (s, 3H). IR (KBr, cm−1) 3367, 3153, 1760, 1740, 1672, 1644, 1619, 1591, 1578, 1498, 1456, 1425, 1327, 1200, 1153, 1109, 1100, and 777. MS (FD) m/e 402.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[K+]>O1CCCC1.O>[C:15]1([C:14]2[NH:21][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=3)[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1Cl
Reaction time: 2 h

Procedure:
A solution of 68.0 g (0.254 mol) of the above-mentioned crude 2-bromo-3′,4′-dichloroacetophenone in 110 ml of tetrahydrofuran was added dropwise over 30 minutes, under reflux with heating, into a suspension of 39.8 g (0.254 mol) of benzamidine hydrochloride, 102.1 g (1.02 mol) of potassium bicarbonate in 400 ml of tetrahydrofuran and 100 ml of water. After the addition was complete, further refluxing with heating was carried out for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, to give a residual solid. This solid was successively washed with water and toluene, to give 45.5 g (62.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile, to give a purified white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>C1COCC1.C(O)(=O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1
Yield: 40.4 %

Procedure:
A solution of 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (307.5 mg, 1.107 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (248 mg, 1.107 mmol) in THF (3 mL) and acetic acid (3.00 mL) was heated at 80° C. overnight. The solvent was removed in vacuum and the residue was triturated with methanol, cooled in the freezer and filtered. The precipitate was thoroughly washed with methanol and dried to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (207.9 mg, 0.447 mmol, 40.4% yield) as off-white solid. LC-MS (M+H)+=465.0. 1H NMR (500 MHz, CDCl3) δ ppm 9.18 (1H, s), 8.15 (1H, d, J=1.8 Hz), 7.73 (1H, d, J=1.5 Hz), 7.41 (1H, d, J=1.5 Hz), 7.18-7.26 (2H, m), 7.07-7.18 (2H, m), 6.88-7.00 (1H, m), 4.12-4.20 (1H, m), 4.04-4.12 (1H, br s), 3.60 (3H, s), 3.17 (1H, s), 2.96 (3H, d, J=4.6 Hz), 2.71-2.81 (1H, m), 2.52-2.66 (2H, m), 1.83-1.96 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][S:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)(=[O:28])=[O:27])[CH:17]=1)=[CH:5]2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with thiophene-2-sulfonyl chloride (0.192 g, 1.0 mmol) and pyridine (3 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (7 mL) was added and the mixture allowed to stand 1.75 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL) and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a purple-tinted solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v to give the product (0.322 g), mp 211-213° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13](=[N:15]O)[NH2:14])[C:10]([CH3:17])=[N:9]1)=[O:7])(C)(C)C.[CH3:18]O>[Pd]>[C:6]([OH:5])(=[O:7])[CH3:18].[CH3:17][C:10]1[C:11]([C:13]([NH2:15])=[NH:14])=[CH:12][NH:8][N:9]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1C(N)=NO
Reactant: CO
Agent: [Pd]
Product: CC(=O)O
Product: Cc1n[nH]cc1C(=N)N
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
A mixture of tert-butyl-4-(N′-hydroxycarbamimidoyl)-3-methyl-1H-pyrazole-1-carboxylate (7.91 mmol, 1.90 g), Pd/C (190 mg) and anhydride acetic (7.91 mmol, 0.81 g) in MeOH (50 mL) was stirred at room temperature for 6 hours under hydrogen atmosphere. After filtration and evaporation of the solvent, the crude product was triturated with Et2O and dried to yield 3-methyl-1H-pyrazole-4-carboxamidine acetate (1.21 g, 6.57 mmol, 83%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[OH:54])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:42]1[CH2:47][CH2:46][N:45]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:44][CH2:43]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 57.1 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (451 mg, 1.05 mmol, 57%) was obtained.