Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CO.Cl[CH2:15]Cl.C[Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 2-(4-aminophenyl)acetic acid (170 mg, 1.1 mmol) in a mixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mL vial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N in hexane) at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hr. The volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using hexane/dichloromethane (2:1) followed by dichloromethane as eluent to give methyl 2-(4-aminophenyl)acetate as an yellowish oil (97 mg, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:21]=[CH:20][C:11]([C:12]([NH:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[O:13])=[C:10]([F:22])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:24]([C:27]1([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]=[CH:35][CH:34]=[CH:33]3)[CH2:29][CH2:28]1)[CH:25]=O>C(O)C>[F:22][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:24]([C:27]4([C:30]5[CH:31]=[C:32]6[C:37](=[CH:38][CH:39]=5)[N:36]=[CH:35][CH:34]=[CH:33]6)[CH2:29][CH2:28]4)=[CH:25][N:1]=3)[CH:4]=2)[CH:21]=[CH:20][C:11]=1[C:12]([NH:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[O:13]
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: CC(NC(=O)c1ccc(-c2cnc(N)nc2)cc1F)C(=O)O
Solvent: CCO
Product: CC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[4-(2-aminopyrimidin-5-yl)-2-fluorobenzoyl]aminopropanoic acid (0.20 g, 0.66 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.19 g, 0.79 mmol) in ethanol (4.0 mL) was stirred overnight at 90° C. The mixture was concentrated to afford the crude product. LCMS: (M+H)=496.1.
Reaction SMILES: C([O:5][C:6](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[CH2:7][C@H:8]([NH:11][C:12](=[O:33])[C@H:13]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:14][C:15](=[O:28])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH:9]=[O:10])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]1([NH:17][CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[OH:5])=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)C[C@H](NC(=O)CNc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)C[C@H](NC(=O)CNc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(O)=NNC(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.4 %

Procedure:
To a solution of (3S)-3-[N-((1-naphthylamino)acetyl)leucinyl]amino-4-oxobutanoic acid tert-butyl ester semicarbazone (0.201 g, 0.38 mmol) in CH2Cl2(2.0 mL)-anisole(0.5 mL) at room temperature under nitrogen was added trifluoroacetic acid (2.0 mL). The resulting solution was stirred at room temperature for 5 hrs, evaporated to dryness and chased with CH2Cl2 and toluene-CH2Cl2 (1:1). The resulting solid was triturated with CHCl2-Et2O to give the title compound (0.176 g, 98%) as a pale gray solid. TLC(EtOAc-pyridine-AcOH-H2O; 60:20:5:10) Rf=0.45.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:13][CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In DMF (120 ml) was dissolved 4-bromobenzyl alcohol (10.1 g). To the mixture was added under ice-cooling 65% sodium hydride (3.6 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise at room temperature iodoethane (12.6 g),and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(ethoxymethyl)benzene (10.1 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])[CH3:4].Cl[C:13]1[C:14]([N+:27]([O-:29])=[O:28])=[C:15]2[C:20](=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.O>O1CCCC1>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:13]1[C:14]([N+:27]([O-:29])=[O:28])=[C:15]2[C:20](=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[CH3:4]
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])c2cccnc12
Reactant: CCc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccccc1Sc1cc(NC(C)=O)c2ncccc2c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.09 g of 60% in oil) is added to 2-ethylthiophenol (0.26 g) in tetrahydrofuran (10 mL) and stirred for 15 minutes. N-(6-chloro-5-nitro-quinolin-8-yl)-acetamide (Gilman H., et al., Journal of American Chemical Society, 1946;66:1577) (0.5 g) is added and the mixture stirred at room temperature for 12 hours. The mixture is added to water (150 mL) and extracted with ethyl acetate (3×100 mL). The extracts are washed with saturated brine (150 mL), dried over magnesium sulfate, filtered, and evaporated to leave an oil. The oil is purified by chromatography on silica gel eluting with 50% ethyl acetate/hexane to give the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17]([O:25][CH3:26])=[N:18][C:19]([NH:22][CH2:23][CH3:24])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:23]([NH:22][C:19]1[N:18]=[C:17]([O:25][CH3:26])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=1)[CH3:24]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(OC)n1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Temperature: 90 °C
Yield: 70.9 %

Procedure:
A solution of Example C1 (0.12 g, 0.26 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.070 g, 0.35 mmol) in dioxane (4 mL) was sparged with Ar, treated with a solution of K2CO3 (0.07 g, 0.51 mmol) in water (1 mL), Pd(PPh3)4 (0.03 g, 0.026 mmol) and heated at 90° C. for 2 h. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by column chromatography (MeOH/DCM) to afford N-ethyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine as a white solid (77 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.36 (br s, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.40-3.30 (m, 2H), 2.37 (s, 3H), 1.14 (br m, 3H); MS (ESI) m/z: 418.2 (M+H+).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=O)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:9](=[O:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N:4]2[CH:5]=[N:1][N:2]=[CH:3]2)[CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2cnnc2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
Prepared from methyl 3-[1,2,4]triazol-4-yl-benzoate [prepared by reaction of 3-aminobenzoic acid with hydrazine hydrate and triethyl orthoformate in acetic acid at 120° C., followed by esterification with conc. H2SO4 in refluxing MeOH] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light yellow gum (870 mg).
Reaction SMILES: CO[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5])=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(C)cc1
Product: COC(=O)C(=O)CC(=O)c1ccc(C)cc1
Yield: 74 %

Procedure:
The title compound was prepared from dimethyloxalate (47.24 g, 400 mmol) and 4′-methylacetophenone (26.84 g, 200 mmol) using the procedure for Example 1d. Work-up and recrystallization provided the title compound as white needles (32.6 g, 74% yield). Mp 82–84° C. 1H NMR (300 MHz, CDCl3) δ 15.36 (br.s, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 7.08 (s, 1H), 3.96 (s, 3H), 2.46 (s, 3H). Mass spectrum (API-TIS) m/z 221 (MH+). Anal calcd. for C12H12O4: C, 65.45; H, 5.49. Found: C, 65.46; H, 5.53.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[CH3:26][S:23]([O:22][CH2:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:27])=[C:11]2[C:9]([OH:10])=[O:8])(=[O:24])=[O:25]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.22 g, 3.15 mmol, Example 56, Step D) in dry THF (10 mL) was added 20% palladium on carbon (1 g). The mixture was stirred under hydrogen atmosphere at room temperature overnight. The TLC showed the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by chromatography (50%-100% ethyl acetate in hexanes) to give 450 mg (48%) of the desired product as a white solid: mp 157-158° C.; MS(APCI−): m/z 296.0 (M−H).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:9])[CH3:2].[OH-:36].C([N+](C)(C)C)C1C=CC=CC=1.O=O>N1C=CC=CC=1>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:17][CH:18]=3)[C:13](=[O:36])[C:12]=2[CH:11]=1)=[O:9])[CH3:35]
Reactant: [OH-]
Reactant: CCN(CC)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(CC)CC)ccc1-2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: c1ccncc1
Product: CCN(CC)CCCCC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)CCCCN(CC)CC)ccc1-2

Procedure:
A solution of 12.0g (0.025 mole) 2,7-bis[5-(diethylamino)valeryl]-fluorene, prepared in Example 16, 2.0 ml 40% benzyltrimethylammonium hydroxide in pyridine and 200 ml pyridine was stirred at room temperature while oxygen was bubbled through the solution at a rate of 500 ml/min. for a total of four hours. The reaction mixture was evaporated to dryness leaving a residue which was chromatographed on alumina using chloroform as the eluant. The solvent was removed from the fraction collected leaving a solid which was recrystallized once from chloroform-petroleum ether to yield the desired product. M.P. 108°-109.5° C, λmaxEtOH 280, E1cm1% 1530.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:26][O:27][CH3:28])[C:21]2[S:22][CH:23]=[CH:24][N:25]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[NH2:35][NH2:36]>C(O)C>[Cl:1][C:2]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:26][O:27][CH3:28])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[NH:35][N:36]=1
Reactant: NN
Reactant: COCN(c1nccs1)S(=O)(=O)c1ccc(C=CC(=O)CCCOc2ccc(Cl)cc2Cl)cc1
Solvent: CCO
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C2CC(CCCOc3ccc(Cl)cc3Cl)=NN2)cc1

Procedure:
4-[6-(2,4-Dichloro-phenoxy)-3-oxo-hex-1-enyl]-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (0.259 mmol) and hydrazine (2 mL) was heated to 80° C. in ethanol (15 mL) for 2 h. The solution was concentrated in vacuo. The crude 4-{5-[3-(2,4-dichloro-phenoxy)-propyl]-3,4-dihydro-2H-pyrazol-3-yl}-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]([OH:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(=O)c2ccccc2OC1(C)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1C(O)c2ccccc2OC1(C)c1ccc(Cl)c(Cl)c1
Yield: 98.6 %

Procedure:
A solution of methyl 2-(3,4-dichlorophenyl)-2-methyl-4-oxochroman-3-carboxylate (490 mg, 1.34 mmol) in THF (2.0 mL) was diluted with methanol (4.0 mL) and treated at rt with sodium borohydride (51 mg, 1.34 mmol). Additional sodium borohydride was added after 4 h. After 2.5 h more the solution was concentrated under vacuum. The residue was partitioned between water (containing a few drops of 1.0 M aqueous sodium hydroxide) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under vacuum to provide crude methyl 2-(3,4-dichlorophenyl)-4-hydroxy-2-methylchroman-3-carboxylate as a white solid (485 mg, 98%), which was used without further purification. Mass spectrum m/z 389, 391 (M+Na)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[C:24]2[CH2:23][CH2:22][N:21]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][C:15]=1[Cl:31]>C(Cl)Cl>[Cl:31][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][CH2:20][N:21]([C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH2:22][CH2:23][C:24]=2[C:14]=1[O:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Solvent: ClCCl
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)Nc1ccccc1

Procedure:
Combine phenyl isocyanate (16.3 mg, 0.137 mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for 16 h. Concentrate in vacuo. Purify by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5 μm, 12 nm, 100×20 mm) to give 7-chloro-6-[2-(3-phenyl-ureido)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[N:3]=[C:2]1[C:11]1[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].[CH:23]1(C2C(I)=CC(C(O)=O)=C(C)C=2)C[CH2:24]1.IC1C(C)=CC(C)=C(C=1)C(O)=O>>[CH:22]1([C:12]2[C:11]([C:2]3[NH:3][C:4]4[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=4[N:1]=3)=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:21])[CH:13]=2)[CH2:24][CH2:23]1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C)cc1C
Reactant: Cc1cc(C2CC2)c(I)cc1C(=O)O
Agent: Cc1cc(C)c(C(=O)O)cc1I
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C2CC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 83.4, except 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3) was used in place of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[C:6]2=[O:18].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.O(C(C)(C)C)[Na].C(P)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CCCCCC>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:9]2[C:10]3[C:5](=[C:4]([CH3:19])[C:3]([O:2][CH3:1])=[C:12]([CH3:13])[C:11]=3[CH3:14])[C:6](=[O:18])[C:7]3([CH2:15][CH2:16][CH2:17]3)[CH2:8]2)=[CH:23][CH:22]=1
Reactant: COc1c(C)c(C)c2c(c1C)C(=O)C1(CCC1)CN2
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1c(C)c(C)c2c(c1C)C(=O)C1(CCC1)CN2c1ccc(Cl)cc1
Temperature: 120 °C
Yield: 65.8 %

Procedure:
6′-Methoxy-5′,7′,8′-trimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (146.7 mg), palladium (II) acetate, 1-chloro-4-iodobenzene (202.5 mg) and NaO-t-Bu (81.6 mg) were added to an oven dried tube. The flask was capped and the air evacuated with a house vacuum line, then refilled with nitrogen. This nitrogen flushing was repeated 3 times. Toluene (1.5 mL) was then added and the suspension was stirred for 15 min at room temperature before ter-butylphosphine (1.7 mL, 0.056 mmol, 33.7 mM in toluene) was added. The mixture was then heated up in oil bath (120° C.) for 2.5 h. It was then quenched with water and extracted with ethylacetate. The organic phase was washed with brine, dried and evaporated to give an oil, which was passed through a silica column (EtOAc/Hexane: 0-10%) to give 1′-(4-chlorophenyl)-6′-methoxy-5′,7′,8′-trimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (137.6 mg) as a solid. 1H-NMR (300 MHz, CDCl3) δ=7.257-7.026 (d, 2H), 6.904-6.553 (d, 2H), 4.09 (s, 2H), 3.71 (s, 3H), 2.62 (s, 3H), 2.454-2.276 (m, 2H), 2.24 (s, 3H), 2.125-1.836 (m, 2H), 1.81 (s, 3H), 1.746-1.554 (m, 2H) ppm. 13CNMR (75 MHz, CDCl3) δ=201.17, 148.99, 144.28, 137.51, 131.65, 129.92, 129.28, 125.56, 125.37, 121.03, 60.28, 60.04, 50.71, 9.71, 15.57, 15.44, 14.63, 13.92 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)[CH3:2].ClN1C(=[O:25])CCC1=O.P(=O)(O)(O)O>C(Cl)Cl.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:25])[CH2:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cnc2ccn(-c3ccccc3)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOc1cnc2c(c1)N(c1ccccc1)C(=O)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.7 %

Procedure:
The compound of step 3 (2.05 g, 8.60 mmol) was dissolved in DCM (30 ml) and N-chlorosuccinimide (1.26 g, 9.46 mmol) was added. The reaction mixture was stirred at room temperature for 3 days. The solvent was removed, and the obtained solid was dissolved in acetic acid (10 ml) and heated to 70° C. After addition of phosphoric acid (7.31 ml, 107 mmol, 85%), the reaction mixture was heated to 120° C. for 3 days. After cooling, the mixture was diluted with water and extracted with EA. The extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:6). 650 mg of the title compound were obtained.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31]C(=O)C)=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)Oc1ccc(CCc2ccc(OC(C)=O)cc2)cc1
Agent: O=C(O)c1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc(CCc2ccc(O)cc2)cc1
Temperature: 250 °C
Reaction time: 12 h

Procedure:
A charge consisting of 82 parts of isophthalic acid and 148 parts of 1,2-bis(4-acetoxyphenyl)ethane and 0.005 moles sodium carbonate per mole of 1,2-bis(4-acetoxyphenyl)ethane is placed in a reaction vessel equipped with a stirrer, condenser and receiver. The vessel is evacuated and purged with nitrogen three times. A nitrogen blanket is maintained in the reactor while it is heated to 250° C. for about three hours during which period approximately 35 to 40 parts of acetic acid distills. Thereupon the vessel is evacuated to a pressure of about 200 torr for about 5 minutes and the pressure is slowly reduced to about 1 torr while the temperature is increased to about 290° C. When the amperage on the stirrer motor increases by 0.02 to 0.04 amps, the stirrer motor is switched off and the vacuum is released with nitrogen. From 95 to 97 percent of the theoretical amount of acetic acid is collected. The polymer is extruded from the vessel under slight nitrogen pressure and is reduced in a Thomas mill to a powder of particle size in the range of about 0.1 to 0.25 mm. The inherent viscosity is about 0.3. The powder is charged to a reaction vessel which is then purged with nitrogen. The pressure is reduced to 0.1 to 0.2 torr. and the temperature is raised to about 10° to 15° C. below the melting point of the polymer. Heating is continued for 12 hours. The vessel is cooled and the crystalline polymer is discharged. The inherent viscosity of the polymer is 0.90. The polymer melts at 279°-290° C. The rate of crystallization is 2.56 min.-1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl.[C:20](Cl)(Cl)=[O:21]>ClC1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N:14]=[C:20]=[O:21])=[CH:15][CH:16]=2)=[N:7][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
20.3 g (0.08 mol) of 4-(5-trifluoromethylpyrid-2-yloxy)aniline are dissolved in 200 ml of dry chlorobenzene. This solution is cooled to -20° C. and rapidly added a solution of 3.7 g of gaseous HCl in 80 ml of dry chlorobenzene. The resultant crystalline slurry is cooled to -30° C. and a strong flow of about 40 g of phosgene is introduced over 1 hour. The addition of phosgene is then discontinued and the reaction mixture is stirred for 1 hour at 20° C. and subsequently for 1 hour in an oil bath at 110° C. A clear solution forms which is then cooled in a stream of nitrogen and, with stirring, excess phosgene is expelled with nitrogen. First the chlorobenzene is distilled off under normal pressure and then the isocyanate is distilled off under a high vaccum. Boiling point 105°-107° C./0.03 mbar; yield>90%.