Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl[C:20](=[O:40])[CH2:21][NH:22][C:23](=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:40])[CH2:21][NH:22][C:23](=[O:39])[O:24][CH2:25][CH:26]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:3][C:4]=1[NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1)#[N:9]
Reactant: Cc1cc(C)nc(Nc2cc(N)cnc2C#N)c1
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(Nc2cc(NC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.8) (100 mg, 0.418 mmol), 9H-fluoren-9-ylmethyl (2-chloro-2-oxoethyl)carbamate (264 mg, 0.835 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (3.2 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 0.29 mL, 0.50 mmol). The reaction mixture was stirred for 2 hours while warming to room temperature. The reaction mixture was diluted with ethyl acetate and washed with sodium hydroxide (1.0 M in water). The organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane (3 mL) was slowly added, and the precipitated solids were filtered and collected to afford 9H-fluoren-9-ylmethyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-2-oxoethyl]carbamate. MS ESI calc'd for C30H27N6O3 [M+H]+ 519. found 519. 1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.09 (s, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 7.88 (d, J=7.5 Hz, 2), 7.75-7.65 (m, 3H), 7.40 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 6.65 (s, 1H), 6.61 (s, 1H), 4.29 (d, J=7.0 Hz, 2), 4.24-4.20 (m, 1H), 3.84 (d, J=6.1 Hz, 2H), 2.28 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([Cl:11])[N:3]=1.S(=O)(=O)(O)[OH:13]>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([F:10])=[CH:6][C:7]=1[C:8]([NH2:9])=[O:13]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
A suspension of 25 g (130.90 mmol) of 2,6-dichloro-5-fluoro-3-cyanopyridine in conc. sulfuric acid (125 ml) was stirred at 60-65° C. for 1 h. After cooling to RT, the contents of the flask were poured onto ice-water and extracted three times with ethyl acetate (100 ml each time). The combined organic phases were washed with water (100 ml) and then with saturated aqueous sodium bicarbonate solution (100 ml), dried and concentrated on a rotary evaporator. The material obtained was dried under high vacuum.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:14]([N:21]1[CH2:26][C:25]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)([CH2:27][CH2:28]OS(C)(=O)=O)[CH2:24][O:23][C:22]1=[O:42])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[ClH:40].[CH2:14]([N:21]1[CH2:26][C:25]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)([CH2:27][CH2:28][N:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)[CH2:24][O:23][C:22]1=[O:42])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2ccccc2)C1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1OCC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Yield: 73.9 %

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 1 from 1.32 g of 4-hydroxy-4-phenylpiperidine, 1.55 g of the compound obtained in step C of EXAMPLE 1 and 0.56 g of potassium iodide in 10 ml of DMF. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is dissolved in DCM and acidified to pH 1 by the addition of a saturated solution of gaseous HCl in ether and the solvents are evaporated off under vacuum to give 0.72 g of the expected compound after crystallization from ether. M.p.=172° C.
Reaction SMILES: [NH2:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15])=O>C(O)C>[OH:15][C:14]1[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=2)=[N:2][N:1]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccn1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: Oc1nnc(-c2ccccn2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3M-solution of hydrazine (20 ml, 60 mmol) in ethanol is added to the solution of crude 2-(2-pyridylcarbonyl)benzoic acid hydrochloride(4.54 g, 20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation yields 1-hydroxy-4-(2-pyridyl)phthalazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].FC(F)(F)C(O)=[O:35].OO.[OH2:41]>C(Cl)(Cl)Cl>[CH3:25][C:9]1[CH:10]=[C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:19])[F:17])[CH:12]=[C:13]([CH3:14])[C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:26]=[C:27]([F:30])[C:28]([F:29])=[C:2]([N+:1]([O-:35])=[O:41])[C:3]=1[F:31]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(F)c(N)c1F
Reactant: O
Agent: OO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(F)c([N+](=O)[O-])c1F
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of 3-amino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2,4,5-trifluoro-benzamide (32.8 g, 71 mmol) (Example I14) and trifluoro-acetic acid (237 ml) in chloroform (118 ml) was added drop-wise aqueous hydrogen peroxide (67 ml) (35% w/v). The reaction mixture was kept at approximately 50° C. with external cooling. The reaction mixture was stirred at 55° C. for 30 minutes, then poured onto a mixture of ice and water. The mixture was extracted twice with dichloromethane. The combined organic phases were washed with aqueous sodium hydrogen carbonate (1M), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-2,4,5-trifluoro-benzamide (23.94 g, 68.5% yield). 1H-NMR (400 MHz, CDCl3): 2.35 (6H, s), 7.38 (2H, s), 7.68 (1H, d), 8.25 (1H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:36])[CH3:35])[CH:20]=3)=[O:17])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:35])[CH3:36])[CH:20]=3)=[O:17])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:46])[CH3:45]
Reactant: CC(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(N)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)C)nn3-c3ccc4ncccc4c3)c(F)c2)ccn1
Reaction time: 60 h
Yield: 76 %

Procedure:
A solution of the above 1-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (44 mg, 0.061 mmol theory) and pyridine (0.30 mL, 3.7 mmol) in CH2Cl2 (1 mL) was treated with acetic anhydride (0.040 mL, 0.39 mmol). The reaction was stirred for 60 h and then partitioned between EtOAc and 2 M aq Na2CO3. The organic layer was washed with water and brine. The aqueous phases were back extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated in vacuo and purified by reverse-phase chromatography to provide 1-(4-(2-acetamidopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (25 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.01 (s, 1H), 8.96-8.94 (m, 2H), 8.49 (m, 1H), 8.18-8.11 (m, 4H), 7.95 (dd, J=8.8, 2.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.21 (dd, J=11.8, 2.7 Hz, 1H), 6.98 (m, 1H), 6.65 (dd, J=5.8, 2.4 Hz, 1H), 6.43 (s, 1H), 2.93 (m, 1H), 2.03 (s, 3H), 1.26 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 540.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:15]1[C:2]([OH:1])=[C:3]([CH:12]=[CH:13][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccccc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 43.6 %

Procedure:
2-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.42 g, 16.7 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.60 g, 44%). 1H NMR (CD3COCD3): δ 8.30 (d,1H), 7.86 (m,3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd 2H), 7.24 (t, 1H).
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[N:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[C:41]([OH:43])=O.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)[C:41]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][N:35]=2)=[O:43])=[CH:14][CH:15]=1
Reactant: O=C(O)c1cnccn1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnccn1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (183 mg, 0.40 mmol) in dry CH2Cl2 (5 mL) was added 2-pyrazinecarboxylic acid (68 mg, 0.55 mmol), N,N -diisopropylethylamine (0.21 mL, 1.21 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.60 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (115 mg, 0.60 mmol) and the mixture was stirred at room temperature for 20 hours. Following standard work-up procedures, the crude material was purified by column chromatography on silica gel (CH2Cl2/MeOH, 98:2 followed by 95:5) to give the desired amide (131 mg, 58%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][CH:8]=[O:9])=[N:4][C:3]=1[C:10](=[N:37][O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:11]([NH:13][CH:14]1[C:35](=[O:36])[N:16]2[C:17]([C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]12)=[O:12]>CO.O1CCCC1.C(O)(=O)C.[C].[Pd]>[Cl:1][C:2]1[S:6][C:5]([NH:7][CH:8]=[O:9])=[N:4][C:3]=1[C:10](=[N:37][O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:11]([NH:13][CH:14]1[C:35](=[O:36])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]12)=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1nc(NC=O)sc1Cl
Yield: 80.1 %

Procedure:
p-Nitrobenzyl 7-[2-(5-chloro-2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (6.2 g) was dissolved in a mixed solution of methanol (60 ml), tetrahydrofuran (40 ml) and glacial acetic acid (0.5 ml). After adding 10% palladium carbon (3.1 g) to the solution, the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filterate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue and the mixture was adjusted to pH 7.5 with saturated aqueous sodium bicarbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated to give 7-[2-(5-chloro-2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (4.03 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[OH:9])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccnc2ccccc12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1c(Br)cnc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
N-Bromosuccinimide(1.3 g) was added to a DMF solution (15 ml) of 4-hydroxy quinoline(1.0 g) and the mixture was stirred at room temperature for 15 hours. A sodium hydrogencarbonate aqueous solution of 25% sodium sulfite was added to the mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was dissolved in a mixture of ethyl acetate and methanol, and an insoluble matter was removed by filtration. The filtrate was condensed under reduced pressure, and the residue was washed with ethyl acetate and dried to give the title compound(1.1 g) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]2[CH3:34])=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([N:30]1[CH2:29][C@H:28]([CH3:34])[N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:32][C@H:31]1[CH3:33])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)/C=C/c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Yield: 82.7 %

Procedure:
(E)-3-(2-tert-Butoxycarbonylamino-4-chlorophenyl)-acrylic acid (595 mg, 2.0 mmol) and (2S,5R)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (Mavunkel, Babu J. et al., WO 00/71535) (445 mg, 2.0 mmol) were dissolved in CH2Cl2, combined with EDCl.HCl (384 mg, 2.0 mmol) and stirred for 3 hours at room temperature. The reaction mixture was purified via chromatography (SiO2, EtOAc/hexanes 2/8) to yield the title compound as colorless foam (830 mg, 81%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[O:17]([CH2:24]C(Cl)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[N:28]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH2:39])[CH:32]=[CH:31][CH:30]=[CH:29]1>>[O:16]=[C:14]1[CH2:15][N:8]([C:6](=[O:7])[CH2:24][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:9]([C:10]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:28]2[CH:32]=[CH:31][CH:30]=[CH:29]2)=[O:12])[CH2:13]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1ccccc1-n1cccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: O=C1C[C@@H](C(=O)Nc2ccccc2-n2cccc2)N(C(=O)COc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, phenoxyacetyl chloride, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=404.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[N:21]1[CH:26]=[CH:25]C=C[CH:22]=1.Cl[C:28](OC1C=CC=CC=1)=[O:29].COC(OC)CNC>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N:20]4[CH:25]=[CH:26][N:21]([CH3:22])[C:28]4=[O:29])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Agent: CNCC(OC)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3ccc(-n4ccn(C)c4=O)cc23)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of N4-(3-ethynylphenyl)quinazoline-4,6-diamine (100 mg, 0.38 mmol) in DMF (2 mL) containing pyridine (37 μL, 0.46 mmol) was added phenyl chloroformate (49 μL, 0.38 mmol) dropwise at room temperature. After 10 min, (methylamino)acetaldehyde dimethylacetal (45.2 mg, 0.38 mmol) was added and the reaction mixture was heated to 100° C. for 1 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layers were concentrated and purified with a silica column to give Compound 126 as a yellow solid in 83% yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OC)=O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(Cl)cc1
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(Cl)cc3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.83 g (10.7 mmol) of methyl 4-chlorophenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:14][CH:15]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cc(F)cc(Cl)c1-c1csc(N)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(F)cc(Cl)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a solution of 4-(2-chloro-4-fluoro-6-methoxyphenyl)thiazol-2-ylamine (14-2, 0.10 g, 0.39 mmol) in CH2Cl2 (10 mL) was added DMAP (95 mg, 0.78 mmol) followed by isonicotinoyl chloride hydrochloride (90 mg, 0.51 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-(4-(2-chloro-4-fluoro-6-methoxyphenyl)-thiazol-2-yl)isonicotinamide (14, 55 mg, 0.15 mmol) as white solids in 39% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (s, 2 H), 7.91 (d, J=4.7 Hz, 2 H), 7.12 (s, 1 H), 6.72 (m, 1 H), 6.50 (m, 1 H), 3.75 (s, 3 H); ESI-MS: m/z 364.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27]Br>>[F:22][C:23]([F:36])([F:37])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1)[CH2:27][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 49.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (255 mg, yield: 49.8%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:1][S:2]([C:9]1[CH:10]=[CH:11][C:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:8]=1)(=[O:5])=[O:3]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid (87 ml) was added dropwise to ethyl phenylacetate (48 g), and the mixture was stirred at 40° C. for 30 minutes. The reaction mixture was poured into ice water (1000 ml), and the separated oily substance was extracted with methylene chloride. The methylene chloride layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave ethyl 4-chlorosulfonylphenylacetate (42 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][C:18](=[O:20])[CH3:19].[BH4-].[Na+].CO.O>C(O)C>[CH3:19][CH:18]([OH:20])[CH2:17][C:5]1[N:4]([CH2:3][CH:2]([CH3:21])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(=O)Cc1nc2cnc3ccccc3c2n1CC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(CC(C)O)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-2-one (8 g, 28.4 mmol, Example 73) was suspended in ethanol (400 mL). Sodium borohydride (1.64 g, 43.3 mmol) was added and the reaction mixture was stirred at room temperature for about 2 hours. Methanol (about 20 mL) was added and stirring was continued over night. Water was added then the solvents were removed under vacuum. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated, dried over magnesium sulfate then concentrated under vacuum to give the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.