Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[N:8]=[N:7][C:6]=1[NH2:38])=[O:4].CN(C)C=O.[OH-].[K+]>CO>[CH3:39][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[N:8]=[N:7][C:6]=1[NH2:38])=[O:4]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)N(C)C)c(N)nn3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(C(=O)N(C)C)c(N)nn3)cc12
Reaction time: 5 h
Yield: 14.1 %

Procedure:
Crude 3-amino-6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridazine-4-carboxylic acid dimethylamide (56.6 mg, 0.104 mmol) was dissolved in methanol (0.5 mL) and dimethylformamide (0.5 mL) and 50% w/v aqueous potassium hydroxide (0.2 mL) was added. After 5 hours, the reaction was quenched by addition of acetic acid (0.5 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 3-amino-6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridazine-4-carboxylic acid dimethylamide (5.7 mg, 14.1%, 3 steps). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.90 (s, 3H), 3.0 (s, 3H), 3.82 (s, 3H), 6.44 (s, 2H), 7.07 (dt, J=7.5 Hz, J=1.0 Hz, 1H), 7.13 (br d, J=7.5 Hz, 1H), 7.30 (dt, J=7.5 Hz, J=1.5 Hz, 1H), 7.61 (dd, J=7.5 Hz, J=2.0 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.92 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.87 (d, J=2.5 Hz, 1H), 11.89 (s, 1H). MS: m/z 389 (M+H+).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])=[CH:4][CH:3]=1.CO.C([O-])(O)=[O:24].[Na+]>Cl.C(Cl)(Cl)Cl>[OH:24][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(F)nc2)C1=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc(O)nc2)C1=O
Temperature: 100 °C
Yield: 98.96 %

Procedure:
1-(6-Fluoro-pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (30A: 0.1 g, 0.00036 mmol) in 5% HCl (10 mL) was added into the reaction flask and the flask was heated to reflux at 100° C. overnight. The reaction was monitored by TLC (10% MeOH in chloroform. The reaction mixture was basified with NaHCO3 solution and extracted with chloroform. The organic layer was washed with water, brine solution, dried and concentrated to afford 72 mg of the product (98.96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:29](=[O:36])[C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1ccncc1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with isonicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 502. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.9 (d, 2H)) 8.5 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 2H) 7.9 (m, 1H) 7.5 (d, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.5 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1nc(N2CCC2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 6-chloro-2-methyl-3-nitropyridine and azetidine following the method used to prepare Intermediate 46. LCMS (ES+) 194 (M+H)+, RT 2.55 minutes (method 1).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[CH2:8][CH2:9][N:10]([CH2:15][CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:11][CH2:12][C:13]=2[N:14]=1)(=O)C.Cl>>[NH2:4][C:5]1[S:6][C:7]2[CH2:8][CH2:9][N:10]([CH2:15][CH:16]=[CH:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:11][CH2:12][C:13]=2[N:14]=1
Reactant: CC(=O)Nc1nc2c(s1)CCN(CC=Cc1ccc(Cl)cc1)CC2
Agent: Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(Cl)cc1)CC2
Yield: 71 %

Procedure:
Prepared from 2-acetylamino-6-(3-(4-chloro-phenyl)allyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine with semi-concentrated hydrochloric acid. Yield: 71% of theory, Melting point: 145°-150° C.
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.C([O:35]B(OC(C)C)OC(C)C)(C)C.C([Li])CCC.C(=O)=O.C(O)(=O)C.OO>O1CCCC1>[CH:25]1([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:13]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([OH:35])=[CH:3][C:4]=3[Cl:31])=[O:14])[CH2:16][CH2:17]2)[CH2:27][CH2:26]1
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a solution of 1.0 g (1.93 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 20 mL dry tetrahydrofuran was added 0.85 mL (3.72 mmol) triisopropylborate (commercially available, CAS RN 5419-55-6). The solution was cooled to −75° C. using a dry ice bath and 1.50 mL (2.4 mmol) n-butyllithium solution (1.6M in n-hexane) was added over 3 min. to the reaction mixture. Stirring was continued for another 1.5 hours. The dry-ice bath was replaced by an ice bath and 0.98 g (8.17 mmol) acetic acid (50% solution in water) and 0.28 g (2.89 mmol) hydrogen peroxide (35% solution in water) were added. The reaction mixture was stirred at 0° C. for 1 hour, the cooling batch was removed and stirring was continued at room temperature for 20 hours. The solution was poured on 10% aqueous sodium thiosulfate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 0.575 g (65%) of the title compound as a light brown solid. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1)=[O:11].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:21]([O:25][C:26](=[O:27])[NH:28][C@@H:29]([CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C:30]([N:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:12]1[C:10](=[O:11])[NH:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:31])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(Nc1c(F)cccc1F)[C@H]1NCc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of (S)-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide (160 mg, 412 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetic acid (106 mg, 412 μmol, Eq: 1.00) and HATU (172 mg, 453 μmol, Eq: 1.1) in DMF (500 μL) at 0° C. was added DIEA (160 mg, 216 μL, 1.24 mmol, Eq: 3). The reaction was stirred at RT for 1 h, diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give {(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenyl-carbamoyl)-1,3-dihydro-isoindol-2-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (174 mg) as a white foam.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>>[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:34]
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: Cn1cccc1C(=O)Cl
Agent: Cl
Product: Cn1cccc1C(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1-methyl-2-pyrrolyl)carbonyl]amino]-1-oxopropyl]hydrazide (29) was prepared from 8-chlorodibenz[b,f][1,4] oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl) hydrazide, monohydrochloride (9), prepared as described above in Example 9, and 1-methylpyrrole-2-carbonyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.58 g (66%) of product. Analysis calculated for C23H22N5O4Cl (M.W. 467.92): C, 59.04; H, 4.74; N, 14.95; Cl, 7.58. Found: C, 59.22; H, 4.73; N, 14.95; Cl, 7.75.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:10]2[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:34]([NH:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=4)=[O:35])[CH:7]=[CH:6][CH:5]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: Nc1cccc(-c2cn3ccnc3c(NCc3ccncc3)n2)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2cn3ccnc3c(NCc3ccncc3)n2)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.00 eq. of [6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-pyridin-4-ylmethyl-amine (5) and 1.00 eq. of 3-trifluoromethylphenyl isocyanate in toluene is stirred at room temperature for 24 hrs. The mixture is partitioned between EtOAc and saturated NaHCO3. The aqueous phase is extracted with EtOAc and the combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield 1-(3-{8-[(Pyridin-4-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea 6. MF═C26H20F3N7O, MW=503.48; Mass Spec m/z (M++1) 504.17.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:11]([C:9]2[S:8][C:5]3[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=3[N:10]=2)=[O:13])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)sc2CN1
Reaction time: 38 h

Procedure:
To a solution of lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (293 mg) in N,N-dimethylformamide (10 ml) were added 1-(tert-butoxycarbonyl)piperazine (294 mg), 1-hydroxybenzotriazole monohydrate (214 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (303 mg) at room temperature. After stirring for 38 hours, methylene chloride (20 ml) and water (200 ml) were added to the reaction mixture to separate it into layers. The water layer thus obtained was extracted with methylene chloride (3×10 ml). The organic layers were combined, washed with a saturated aqueous solution (100 ml.) of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=2:1), whereby the title compound (300 mg) was obtained as a pale yellow viscous substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH2:34][OH:35])[CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)[CH2:34][O:35][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)cc2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)cc3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (30 mg, 0.162 mmol), sodium hydride (12.93 mg, 0.323 mmol) and (3,5-difluoro-4-(4-(trifluoromethyl)phenoxy)phenyl)methanol (49.2 mg, 0.162 mmol) in DMF (1.5 mL).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: CCO
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OC

Procedure:
Prepared analogously to example 655a from 4-amino-2-methoxy-5-nitro-benzoic acid with conc. sulphuric acid in ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH3:26])[CH3:27]
Reactant: CCCCCCCCc1ccc(NCc2ccc(OC)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc(OC)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 48.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-methoxyphenyl)methyl](4-octylphenyl)amine (2.2 g) and 2,6-diisopropylphenyl isocyanate (1.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-methoxyphenyl)methyl]-N-(4-octylphenyl)urea (1.5 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[C:21](C(C)C)[CH:22]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[N:6][CH:7]=1.[Cu]([C:29]#[N:30])C#N>>[C:29]([C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[C:21]([O:8][CH:9]([CH3:10])[CH3:22])[CH:22]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[N:6][CH:7]=1)#[N:30]
Reactant: CC(C)c1cc(Oc2ccc(Br)cn2)cc(C(=O)Nc2nccs2)c1
Reactant: N#C[Cu]C#N
Product: CC(C)Oc1cc(Oc2ccc(C#N)cn2)cc(C(=O)Nc2nccs2)c1

Procedure:
The reaction between 3-(5-bromo-pyridin-2-yl-oxy)-5-isopropyl-N-thiazol-2-yl-benzamide and copper cyanide may be carried out by a method described in the relevant literature (for example, Comprehensive Organic Transformations, Richard L. et al., VCH Publishers, 1988), a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([O-])=O.[H][H]>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
N-(2-Nitrophenethyl)-1-benzylpiperidin-4-amine (1.98 g, 5.83 mmol) was dissolved in methanol (60 mL). Platinum(IV) oxide (55 mg, 0.242 mmol) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 75 minutes. Mixture was removed from the apparatus and then filtered over celite. Filtrate was concentrated to dryness. Title compound was obtained as brown oil in quantitative yield. MS (M+H)+=310.4.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[CH:52]=[CH:51][N:50]=[C:49]1[CH2:53][NH2:54]>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:54][CH2:53][C:49]4[S:48][CH:52]=[CH:51][N:50]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: NCc1nccs1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nccs1
Yield: 48 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with thiazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=3.3 Hz, 1H), 7.31-7.23 (m, 3H), 7.07-6.99 (m, 2H), 6.50 (t, J=5.4 Hz, 1H), 6.12 (s, 1 H), 4.90 (d, J=5.4 Hz, 2H), 4.43 (s, 2H), 3.84-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 453.1 (M+23).
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[CH3:17])[CH3:5])[CH2:3][CH2:2]1.C(O)(=O)C>[Fe].O>[CH:1]1([CH:4]([O:6][C:7]2[C:8]([CH3:17])=[CH:9][C:10]([NH2:14])=[C:11]([CH3:13])[CH:12]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OC(C)C1CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OC(C)C2CC2)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 0.97 g of 1-(1-cyclopropylethoxy)-2,5-dimethyl-4-nitrobenzene, 1.15 g of iron powder, 15 mL of acetic acid and 15 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.56 g of 4-(1-cyclopropylethoxy)-2,5-dimethylphenylamine.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][CH:24]([F:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][CH:24]([F:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][C@@H:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[C@@H:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:36])=[CH:27][CH:26]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(C(F)F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H](Cc1ccc(C(F)(F)F)cc1)[C@H](O)c1ccc(F)cc1)c1ccc(C(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-(difluoromethyl)-1-naphthalenecarboxylic acid (213 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the-title compound (410 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[F:13].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[F:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[NH:1][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)cc1F
Temperature: 150 °C
Reaction time: 20 h

Procedure:
A mixture of 4.0 g of ethyl 4-amino-3-fluorobenzoate, 6.66 g of hexadecyl bromide and 3.0 g of potassium carbonate in 25 ml of hexamethyl phosphoramide is stirred at 150° C. for 20 hr. The mixture is cooled, diluted with water and extracted with ether. The ether extract is washed with water, dried, and the ether evaporated. The residue is recrystallized from hexane to yield ethyl 3-fluoro-4-(hexadecylamino)benzoate as a white solid.