Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH3:11])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.ClC(Cl)(O[C:23](=[O:29])OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:9][N:10]([CH3:11])[C:23](=[O:29])[NH:8]2
Reactant: CNCc1c(N)cccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1Cc2c(Br)cccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-methylaminomethyl-phenylamine (1.153 g, 5.36 mmol) in CH2Cl2 (50 ml) was added NEt3 (1.5 ml, 10.76 mmol), triphosgen (555 mg, 1.87 mmol) at 0° C. The reaction was allowed to warm up to room temperature and stirred overnight. After the solvent was removed by using a rotary evaporator, the residue was partitioned between water and ethyl acetate. The organic layer was washed by H2O and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 5-bromo-3-methyl-3,4-dihydro-1H-quinazolin-2-one as white solid. (650 mg, 50%) MS: (M+H)+ 241.1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:14][C:15]([N:17]1[C:21]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[C:22]2=[O:39])[C:20](=[O:40])[NH:19][C:18]1=[O:41])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOCC>[CH2:7]([O:14][C:15]([N:17]1[C:21]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[C:22]2=[O:39])[C:20](=[O:40])[N:19]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:18]1=[O:41])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: O=C1NC(=O)C2(C(=O)N(Cc3ccc(Cl)c(Cl)c3)c3ccccc32)N1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)N1C(=O)N(C(=O)OCc2ccccc2)C2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 16 h
Yield: 61.9 %

Procedure:
Ethyl chloroformate (0.6 g.) was added slowly to a stirred mixture of 3-benzyloxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (2.55 g.) and sodium carbonate (2.0 g.) in 1,2-dimethoxyethane (60 ml.). The mixture was stirred for 16 hours and the solid then removed by filtration. The filtrate was evaporated to give an oil which solidified on treatment with a few drops of ether. This solid was recrystallised from ethyl acetate/petrol 60-80 to give 3-benzyloxycarbonyl-1-ethoxycarbonyl-1'(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.), m.p. 128°-131° C.
Reaction SMILES: C1(C[CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCCC1.C1C=C2C(COC(NCC=O)=O)C3C(C2=CC=1)=CC=CC=3>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH2:8][C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Agent: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Product: O=C(O)CNC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 55 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Gly Wang resin (125 mg, 0.8 mmol/g), producing 30 mg of the title compound (55% yield). MS: 504.21 (M−H+) HPLC Procedure A, retention time=12.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:17]([F:28])[C:16]=3[F:29])=[C:11]([C:30]([F:33])([F:32])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[Li+].[OH-].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[C:17]([F:28])[C:16]=3[F:29])=[C:11]([C:30]([F:33])([F:32])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl)propanoate (101 mg, 0.20 mmol, 1.00 equiv), tetrahydrofuran (2.0 mL), a solution of LiOH (100 mg, 4.18 mmol, 20.91 equiv) in water (2.0 mL). The resulting solution was stirred overnight at 30° C. The reaction progress was monitored by LCMS. The pH value of the solution was adjusted to 1 with aqueous HCl (2 N). The resulting mixture was concentrated under vacuum. The solids were collected by filtration and washed by hexane and EtOAc. Then the solid was dried under vacuum. This resulted in 85 mg (89%) of 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl)propanoic acid as a white solid. 1H-NMR (300 MHz, CD3OD) δ 7.69 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.01 (t, J=7.5 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H), 5.19 (s, 2H), 2.94 (t, J=7.8 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H13ClF5NO3S, 478.0 (M+H). found 478.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)(=[O:3])[CH3:2].Cl.Cl.C(NC1C=CC(O)=C(N)C=1)(=O)C.[C:29]([C:32]1[C:33](=[O:43])[O:34][C:35]([OH:42])=[C:36]([C:39](=O)[CH3:40])[C:37]=1[OH:38])(=[O:31])[CH3:30].C(=O)(O)[O-].[Na+]>O.[Pd].CO.C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH:12][C:39](=[C:36]2[C:37]([OH:38])=[C:32]([C:29](=[O:31])[CH3:30])[C:33](=[O:43])[O:34][C:35]2=[O:42])[CH3:40])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CC(=O)Nc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC(=O)Nc1ccc(O)c(N)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1ccc(O)c(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
Following the procedures of Example 1, 4.0 g. (0.0204 mol) of 4-acetamido-2-nitrophenol (prepared by acetylation of the corresponding amine) is hydrogenated in a mixture of 150 ml. of ethanol, 3.3 ml. of concentrated hydrochloric acid and 0.5 g. of 10% palladium-on-carbon in a Parr apparatus at room temperature. Filtration of the reaction mixture gives a powder which is dissolved in a minimum amount of water and filtered. This aqueous solution of 4-acetamido-2-aminophenol hydrochloride is added to a mixture of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one (3.42 g., 0.0162 mol) and 1.36 g. (0.0162 mol) of sodium bicarbonate in 130 ml. of methanol. After 18 hours at reflux, the reaction mixture is filtered and the solid is recrystallized from dioxane-acetonitrile to give 3-[1-(5-acetamido-2-hydroxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 253°-254° C. (dec.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.O>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (2.22 g, 10.0 mmol), 4-hydroxybenzotrifluoride (1.21 g, 7.45 mmol), tri-n-butylphosphine (2.26 g, 11.2 mmol) and 1,1′-(azodicarbonyl)dipiperidine (2.82 g, 11.2 mmol) were dissolved in benzene (20 ml), and the mixture was stirred at room temperature for 2 days. To which water was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and thereafter filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) ro afford tert-butyl 4-(4-trifluoromethylphenoxy)piperidine-1-carboxylate (1.13 g, yield 44%) as a colorless oil.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O.C(#N)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC(CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NN=Cc1ccc(NC(=O)CCC(=O)NC(CCC(=O)O)CC(=O)O)cc1
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Diethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]hexanedioate (700 mg) prepared in Example 19, Step 2 was added to water/acetonitrile (20 ml) followed by lithium hydroxide (150 mg) at 25° C. The mixture was stirred for 30 min. The course of the reaction was monitored by RPHPLC. After satisfactory product was formed the reaction was neutralized with TFA and purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 350 mg of a white solid: H NMR (d6 -DMSO) δ1.55 (m, 1H), 1.7 (m, 1H), 2.3 (m, 2H), 2.57 (m, 2H), 2.67 (m, 2H), 4.03 (m, 1H), 7.79 (s, 4H), 7.99 (d, 1H, J=8 Hz), 8.86 (bs, 2H), 9.17 (bs, 2H), 10.2 (s, 1H); MS (FAB) m/z 379.2 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.[N:26]1([C:32](=[O:34])[CH3:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[CH3:14][C:12]1[CH:13]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:32](=[O:34])[CH3:33])[CH2:27][CH2:28]3)[CH:7]=2)[CH:9]=[C:10]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:11]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccnc(F)c2)c1
Reactant: CC(=O)N1CCNCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2cc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)ccn2)CC1
Temperature: 130 °C

Procedure:
A mixture of N-[3-(2-fluoropyridin-4-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (50.0 mg, 0.144 mmol), 1-(piperazin-1-yl)ethanone (36.8 mg, 0.287 mmol), and tribasic potassium phosphate (60.9 mg, 0.287 mmol) in DMSO (250 μL) was heated at 130° C. for 48 hours. The reaction mixture was diluted with DMSO (600 μL) and filtered through a plug of CELITE. The residue was purified by mass triggered reverse phase HPLC (21-55% acetonitrile in water+0.1% formic acid) to afford 1-{4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]piperazin-1-yl}ethanone as a tan solid. MS APCI calc'd for C23H24F3N6O [M+H]+ 457. found 457. 1H NMR (600 MHz, DMSO-d6) δ10.20 (s, 1H), 8.80 (d, J=4.8 Hz, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.24 (d, J=4.9 Hz, 1H), 7.22 (s, 1H), 6.98 (s, 1H), 6.88 (d, J=5.3 Hz, 1H), 3.62-3.56 (m, 2H), 3.52 (d, J=7.5 Hz, 6H), 2.34 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][C:6]1=[O:17])=[O:4].[C:18]1([CH2:24]CO)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:1]([O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][C:6]1=[O:17])=[O:4])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCc1ccccc1
Reactant: CCCCCCCC1CC(C(=O)OC)C(=O)O1
Solvent: CO
Product: CCCCCCCC1CC(C(=O)OCCc2ccccc2)C(=O)O1
Temperature: 25 °C

Procedure:
A mixture of 24.2 g 5-heptyl-2-oxo-tetrahydro-furan-3-carboxylic acid methyl ester, 24.4 g phenylethyl alcohol and 1.4 g tetraisopropyl-ortho-titanate was heated under nitrogen atmosphere to 130° C. for 5 minutes while methanol was distilled off. Then the reaction mixture was cooled to room temperature, poured into water and extracted with hexane. The organic layer was dried and evaporated to dryness. The residue was chromatographed to yield 23.9 g of a slightly yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccccc1COc1ccc(C(C)C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonylbenzyloxy)-α-methylphenylacetate with potassium hydroxide by the method described in Example 1c provides colorless crystals, m.p. 145°-146° C. of 4-(2-carboxybenzyloxy)-α-methylphenylacetic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[O:3][C:4](=[O:20])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][NH:13][C:14](OCC)=[O:15].C([O-])([O-])=O.[K+].[K+]>CCO>[O:19]=[C:11]1[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4](=[O:20])[O:3][C:2]([CH3:1])([CH3:22])[CH3:21])[C:14](=[O:15])[NH:13][NH:12]1
Reactant: CCOC(=O)NNC(=O)NCCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCn1c(=O)[nH][nH]c1=O
Temperature: 65 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
To ethyl 13,13-dimethyl-4,11-dioxo-12-oxa-2,3,5,10-tetraazatetradecan-1-oate (I-8a: 1.045 g, 3.28 mmol) in EtOH (13.13 mL) was added K2CO3 (1.815 g, 13.13 mmol). The mixture was stirred at 65° C. for 16 hours. Cooled to room temperature, filtered, and then 4N HCl in dioxane was added up to pH or approximately 4. The white solid was filtered, rinsed with some methanol, and then the filtrate was concentrated in vacuo. The residue was purified by silica flash chromatography (0-10% MeOH/CH2Cl2) giving tert-butyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)butylcarbamate (388 mg, 43%) as a oily white solid. LC-MS (M−1) 271.1, t=0.73 minute. 1H NMR (400 MHz, CD3CN) δ ppm 1.39 (s, 9 H) 1.42-1.49 (m, 2 H) 1.52-1.65 (m, 2 H) 3.03 (q, J=6.40 Hz, 2 H) 3.42 (t, J=6.95 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.CO.O1CCCC1.C(N(CC)CC)C>[C].[Pd].C(OCC)(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][CH:11]=[C:10]2[O:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)nc3Cl)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N)nc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
After suspending 6-chloro-5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-ylamine (500 mg, 1.51 mmol) in a mixed solvent of methanol (20 ml), tetrahydrofuran (10 ml) and triethylamine (3 ml), palladium carbon (300 mg) was added and the mixture was stirred for 15 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off by celite filtration, washing was performed with ethanol, and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (138 mg, 0.465 mmol, 31%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=O)[N:6]=[N:5]1)[CH:2]=[CH2:3].[CH3:27][O:28][CH:29]([O:38][CH3:39])[CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CCCC(C)C>[CH2:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH:29]([O:38][CH3:39])[O:28][CH3:27])=[O:19])[N:6]=[N:5]1)[CH:2]=[CH2:3]
Reactant: COC(CNC1CCCCC1)OC
Reactant: C=CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: C=CCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCCC3)c2)nn1

Procedure:
The subtitled compound (584 mg) was prepared from tert-butyl 3-(3-(1-allyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoate [Ex 4, Step iii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii) the elution gradient 20 to 100% ethyl acetate in isohexane. 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.69 and 7.67 (2 s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.322 and 7.318 (2×t, J=7.7 Hz, 1H), 7.20 (d, J=6.9 Hz, 1H), 6.17-6.06 (m, 1H), 5.36-5.27 (m, 2H), 5.06 (d, J=5.9 Hz, 2H), 4.52 and 4.36 (2×t, J=5.5 Hz, 1H), 3.99 and 3.65 (tt, J=5.3 and 11.7 Hz, 1H), 3.76-3.66 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.34 and 3.25 (2×d, J=4.9 Hz, 2H), 2.92-2.85 (m, 2H), 2.68-2.61 (m, 2H), 1.79-1.02 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [BH4-].[Na+].[N:3]([CH2:6][C:7]1[C:14]([F:15])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:16])[CH:8]=1)=[N+]=[N-].Cl>O.C1COCC1.[Pd]>[NH2:12][CH2:11][C:10]1[C:9]([F:16])=[CH:8][C:7]([C:6]#[N:3])=[C:14]([F:15])[CH:13]=1
Reactant: N#Cc1cc(F)c(CN=[N+]=[N-])cc1F
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(CN)cc1F

Procedure:
This reaction was carried out according to the procedure described in J. Chem. Res. (M) (1992) 3128. To a suspension of 300 mg of 10% Pd/C (50% moisture) in 20 mL of water was added a solution of sodium borohydride (0.779 g, 0.0206 mol) in 20 mL of water. Some gas evolution resulted. 4-Azidomethyl-2,5-difluorobenzonitrile (1.00 g, 5.15 mmol; from step (v) above) was dissolved in 60 mL of THF and added to the aqueous mixture on an ice bath. The mixture was stirred for 1.5 h whereafter 10 mL of 2M HCl was added and the mixture was filtered through Celite. The Celite was rinsed with more water and the combined aqueous phase was washed with EtOAc and subsequently made alkaline with 2M NaOH. Extraction three times with methylene chloride followed and the combined organic phase was washed with water, dried (Na2SO4) and evaporated.
Reaction SMILES: O=[C:2]1[C:15]2[C:14]3[S:13][C:12]4=[CH:16][CH2:17][CH2:18][CH:19]=[C:11]4[CH:10]=[C:9]([C:20]([OH:22])=[O:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.O=C1C2C3CCC4C=CC(C(O)=O)=CC=4SC=3C=CC=2CC1>>[CH2:2]1[C:15]2[C:14]3[S:13][C:12]4=[CH:16][CH2:17][CH2:18][CH:19]=[C:11]4[CH:10]=[C:9]([C:20]([OH:22])=[O:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Agent: O=C(O)c1ccc2c(c1)Sc1ccc3c(c1CC2)C(=O)CC3
Product: O=C(O)C1=CC2=CCCC=C2Sc2c1ccc1c2CCC1

Procedure:
Substituting an equivalent amount of 1-oxo2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic acid in Example 41 in place of 1-oxo2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]thiepin-8-carboxylic acid and heating under reflux for 9 hours instead of 3 hours yielded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].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>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[O:36])[CH:38]=3)=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=4)[CH:30]=[CH:31][N:32]=3)[CH:4]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of 26 mg of 2-(2-amino-5-cyclobutoxyphenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide, 21 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 27 mg of HATU, and 63 μL of DIEA in 0.2 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 24 mg of a yellow solid. 1H NMR (400 MHz, CD3OD, ppm): δ 9.46 (t, J=5.8 Hz, 1H), 8.85 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.85-7.80 (m, 1H), 7.80-7.47 (m, 6H), 7.31 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.9, 2.6 Hz, 1H), 4.83-4.71 (m, 1H), 4.67 (s, 2H), 4.09 (s, 2H), 3.96 (m, 2H), 3.77 (m, 4H), 3.52 (t, J=4.9 Hz, 2H), 3.24 (s, 2H), 3.07 (s, 3H), 2.59-2.39 (m, 2H), 2.25-2.04 (m, 2H), 1.93-1.60 (m, 2H). MS (ESI, m/z) 716.26 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11]C(C)(C)C)=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:17]O.C(O)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(O)CCC>[Br:1][C:2]1[C:3]2[S:11][N:17]=[CH:5][C:4]=2[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: NO
Reactant: CC(C)(C)Sc1c(Br)ccc(F)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CC(C)O
Solvent: O
Product: Fc1ccc(Br)c2sncc12
Temperature: 70 °C
Yield: 40 %

Procedure:
A mixture of 3-bromo-2-(tert-butylsulfanyl)-6-fluorobenzaldehyde (1.20 g, 4.12 mmol) and hydroxylamine hydrochloride (1.432 g, 20.60 mmol) in isopropanol (60 mL, 800 mmol) and water (10 mL) was heated to 70° C. for 20 min. The organic solvent was removed in vacuo, and saturated aqueous sodium bicarbonate was added to bring the pH to 8.5. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo. The residue was treated with p-toluenesulfonic acid (141.9 mg, 0.8242 mmol) in n-butanol (60 mL) and the solution was heated to 120° C. overnight. The solvent was removed in vacuo. The residue was purified by column chromatography (1 to 2% EtOAc:hexanes) to afford 382 mg (40%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, J=9.1, 8.3 Hz, 1 H), 7.60 (dd, J=8.3, 4.0 Hz, 1 H), 9.10 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccccc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccccc2)n1
Yield: 44 %

Procedure:
This compound was synthesized from 2-methyl-2-(2-phenyloxazol-4-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (15 g, yield 44%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.66 (t, J=1.5 Hz, 1H), 8.29-8.26 (m, 2H), 8.20-8.17 (dt, J=8.0 Hz, 1.2 Hz, 1H), 8.09-8.06 (m, 2H), 7.68-7.64 (t, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.47-7.40 (m, 3H), 3.66 (d, J=5.6 Hz, 2H), 1.43 (s, 6H). MS (ESI) m/z: Calculated for C23H19F3N4O3: 456.14. found: 457.2 (M+H)+.