Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(-c3c4ccccc4c(-c4ccccc4)c4ccccc34)cc2)cc1
Yield: 40.1 %

Procedure:
Into a 100 mL three-neck flask were put 2.8 g (7.2 mmol) of 9-iodo-10-phenylanthracene and 1.5 g (7.2 mmol) of 4′-bromobiphenyl-4-boronic acid. The air in the flask was replaced with nitrogen. To the mixture were added 40 mL of toluene and 10 mL (2.0 mol/L) of an aqueous solution of sodium carbonate. This mixture was stirred to be degassed while the pressure was being reduced. After the degassing, 120 mg (0.10 mmol) of tetrakis(triphenylphosphine)palladium(0) was added to the mixture. This mixture was stirred at 90° C. for 4 hours. After the stirring, about 50 mL of toluene was added to this mixture. The mixture was subjected to suction filtration through alumina, celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The solid obtained by condensation of the obtained filtrate was purified by high-performance liquid chromatography (a mobile phase: chloroform) to give a light yellow solid. The obtained solid was recrystallized with a mixed solution of chloroform and hexane to give 1.4 g of a light yellow powdered solid, which was the object of the synthesis, in a yield of 40%. A synthesis scheme of Step 1 is shown in (b-1) given below.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(F)cc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 85.9 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) is alkylated using 1-bromomethyl-4-fluoro-benzene (0.88 g; 4.66 mmol) and K2CO3 (1.8 g; 13 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated using hydrochloric acid (60 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(4-fluoro-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.29 g) is obtained and used without further purification.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([F:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:18])=[C:13]([F:22])[CH:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CN1CCNCC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1F
Product: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2F)CC1
Yield: 91.3 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-fluorophenoxy)acetic acid (0.15 g, 0.49 mmol), prepared from the step 4, and 1-methylpiperazine (0.049 g, 0.49 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-fluorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.173 g, 91.3% yield).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[N-:42]=[C:43]=[O:44].[K+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][N:26]([C:43](=[O:44])[NH2:42])[CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCNCC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(C(N)=O)CC3)CN2C(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.5 %

Procedure:
To a solution of the compound prepared in Example 50 (150 mg) in acetic acid (2 mL) and water (2 mL) was added potassium isocyanate (105 mg) and the mixture stirred at room temperature for 4 days. The reaction mixture was then treated with saturated aqueous sodium bicarbonate (10 mL) and extracted into dichloromethane (3×10 mL). The combined organic phases were washed with brine, dried and concentrated. Purification by flash chromatography (silica gel, 5-10% methanol/dichloromethane) gave methyl 4-[(2S,4S)-1-{[4-({[(tert-butoxy)carbonyl]amino}methyl)cyclohexyl]carbonyl}-4-(4-carbamoylpiperazin-1-yl)pyrrolidine-2-amido]benzoate (54 mg) as a colourless oil.
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15]CC(C)(C)N=3)=[C:10]([CH3:21])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC1C[O:26]C(C)=N1.Cl>C(O)(=O)C>[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:15])=[O:26])=[C:10]([CH3:21])[CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=1
Reactant: Cc1cc(C2(O)CCCCC2)ccc1C1=NC(C)(C)CO1
Reactant: CC1=NC(C)CO1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C2=CCCCC2)ccc1C(=O)O
Yield: 80.8 %

Procedure:
To a solution of 2-[4-(1-hydroxy-1-cyclohexyl)-2-methylphenyl]-4,4-dimethyl-2-oxazoline (4.29 g) in acetic acid (40 ml) is added a 10% dimethyl-2-oxazoline (4.29 g) in acetic acid (40 ml) is added a 10% hydrochloric acid (20 ml), and the mixture is refluxed for two days. The precipitated crystals are collected by filtration, washed with water, and dried to give 4-cyclohexenyl-2-methylbenzoic acid (2.61 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].CI.[C:15](O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:15])[C:7]=12
Reactant: Clc1nccc2cc[nH]c12
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2ccnc(Cl)c21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 259 (250 mg, 1.64 mmol) in DMF (16 mL) at 0° C. was added NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture was stirred for 30 min, followed by addition of MeI (112 □L, 1.80 mmol). The reaction mixture was stirred at room temperature for 2 h before acetic acid (1 mL) was added. Solvents were removed under reduced pressure, the residue was partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 263 (200 mg, 92% yield) as an off-white solid. MS (m/z): 167.1 (M+H) (found).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3ccccc3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.1 %

Procedure:
To a solution of Example 66 (0.100 g, 0.202 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 1.0 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.035 g, 36% yield). MP: 260-262° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.16(s,1H), 8.22(s, 1H), 8.06(dd, J=7.9, 1.5 Hz, 1H), 7.78(m,1H), 7.50(dt, J=8.0,1.0 Hz, 1H), 7.44(d, J=8.5 Hz, 1H), 7.37-7.31(m,5H), 6.86(t, J=1.5 Hz, 1H), 6.82(dt, J=7.6,2.3 Hz, 1H), 6.65(td, J=10.9,2.3 Hz, 1H), 5.50(s,2H). Mass: 480.02(M++1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][CH2:24]I>CN(C=O)C>[Cl:21][CH2:22][CH2:23][CH2:24][S:11]([C:8]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: ClCCCI
Reactant: O=C(O)c1cc(S(=O)O)ccc1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(S(=O)(=O)CCCCl)ccc1O
Temperature: 40 °C

Procedure:
To 16.7 mmol 2-hydroxy-5-sulfino-benzoic acid and 41.7 mmol triethylamine in 40 ml DMF was added 18.3 mmol 1-chloro-3-iodopropane, and the mixture heated at 40° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/methanol/acetic acid gradient) to afford the title compound. MS (m/e): 279.1 ([{37Cl}M−H]−, 33%), 277.0 ([{35Cl}M−H]−, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]([CH:23]=O)=[CH:19]N(C)C)[O:11][N:10]=1.Cl.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:34][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[CH:23]=2)[O:11][N:10]=1
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C(C=O)=CN(C)C
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1
Temperature: 57.5 °C
Yield: 60.1 %

Procedure:
To a solution of raw methyl 3-(2-chloro-6-fluorophenyl)-5-[2-(dimethylamino)-1-formylvinyl]isoxazole-4-carboxylate (36 mg, 0.102 mmol) in ethanol (460 mg), 2-fluorophenyl hydrazine hydrochloride (16 mg, 0.100 mmol) was added. The mixture was warmed to 55-60° C. until a TLC sample showed no starting enamine. The solution was evaporated to dryness in vacuum, the reside was extracted with 3×10 ml of boiling hexane, and the hexane extracts were combined and concentrated and cooled to room temperature. Crystallization gave 25 mg of desired product (example I-89) (yield 60%). Result of LC/MS MH+: 416.05; 1H NMR (CDCl3): 3.67 (s, 3H), 7.30 (t, 1H), 7.45 (m, 4H), 7.57 (m, 1H), 7.93 (t, 1H), 8.50 (s, 1H), 9.13 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NN1C[C@H](CO)OC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1C[C@@H](COS(C)(=O)=O)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a turbid solution of (R)-tert-butyl 5-(hydroxymethyl)-2-oxooxazolidin-3-ylcarbamate (840 mg, 3.62 mmol) in DCM (10 mL), triethylamine (458 mg, 4.52 mmol) and methanesulfonyl chloride (518 mg, 4.52 mmol) were added and the reaction was stirred, at r.t., under nitrogen, for 2 h 30 min. The solution was washed with: cold water (resulting pH=7-8), cold citric acid (resulting pH=4-5) and cold brine. The organic layer was dried over Na2SO4 and evaporated and the residue (beige foam) was triturated with diisopropyl ether, affording (S)-(3-(tert-butoxycarbonylamino)-2-oxooxazolidin-5-yl)methyl methanesulfonate (1.055 g, 3.40 mmol) as a white solid, that was dissolved in 7 mL of DMF. Sodium methanethiolate (317 mg, 4.52 mmol) was added to the solution and the mixture was stirred at 60° C. for 3 h. AcOEt was added and the solution was washed with cold water, cold citric acid (until pH=6) and cold brine. The organic layer was dried over Na2SO4 and evaporated to leave a yellow oil. The title compound was precipitated by crystallization from diisopropyl ether as a white solid, recovered by filtration on Buchner (429 mg, 1.635 mmol). Yield=45%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Cl>O.C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:8]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH3:7])=[O:27])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CNc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)N(C)c2ccc(C(=O)O)cc2)cc1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
Aqueous solution (50 ml) of sodium carbonate (23 g) was added to THF solution (50 ml) of 4-(methylamino)benzoic acid (5.0 g), and p-anisoyl chloride (5.6 g) was added dropwise to the solution under ice-cooling, which was stirred for 15 minutes, and then stirred at room temperature for 30 minutes. Concentrated hydrochloric acid was added to the reaction mixture under ice-cooling to make the water layer acidic, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using silica gel column chromatography (development solvent; hexane˜hexane:ethyl acetate=1:2), and recrystallized (ethyl acetate-hexane) to give the titled compound (4.8 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1[CH-:13][C:12]([CH3:14])=[C:11]([CH3:15])[C:10]=1[CH3:16].[Na+]>C1COCC1>[CH3:8][C:9]1[CH:13]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]([CH3:14])=[C:11]([CH3:15])[C:10]=1[CH3:16]
Reactant: Cc1[cH-]c(C)c(C)c1C
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(C)=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.822 g (22.89 mmol) ethyl bromoacetate in 25 mL THF was cooled to −78° C. and 3.000 g (20.80 g) sodium tetramethylcyclopentadienide in 50 mL THF was slowly added to it. The resulting slurry was allowed to warm to room temperature and was stirred overnight. The solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed to give a mixture of isomers. Yield was 3.733 g (86.3%). Mass spectra m/e 208 (41 percent).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:20])[C:14]=1[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:20])[C:14]=1[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)Oc1cc(C(=O)O)cc(Cl)c1OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC(C)(C)C)c(OC(C)(C)C)c2)cc1
Yield: 50 %

Procedure:
Methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5) (185 mg, 50%) was prepared from 3,4-di-tert-butoxy-5-chlorobenzoic acid (3) (250 mg, 0.831 mmol) using a procedure essentially the same as in Step (i) for AAA-019 except that methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylenzoate and TEA (579 μL, 4.16 mmol) was used as base instead of DIPEA: m/z 432 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.54 (1H, s), 7.96 (2H, d), 7.91 (2H, d), 7.86 (1H, d), 7.60 (1H, d), 3.84 (3H, s), 1.41 (9H, s), 1.32 (9H, s).
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[C:7]=1[S:26]([CH3:28])=[O:27].I[CH:30]([CH3:32])[CH3:31]>C(O)C>[CH:30]([O:25][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)([CH3:32])[CH3:31]
Reactant: CC(C)I
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A suspension of sodium ethoxide (0.34 g) in ethanol was added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in ethanol. 2-Iodopropane (1 ml) was then added and the mixture stirred overnight at 20° C. and evaporated. The residue (in dichloromethane) was water-washed, dried (magnesium sulfate), concentrated and purified by chromatography on silica gel to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(isopropyl)oxime (0.35 g), m.p. 128-130° C. Compound 24. By proceeding in a similar manner the following compounds were also prepared: 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(ethoxycarbonylmethyl)oxime, Compound 25, m.p.127-128° C.; and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(carbamoylmethyl)oxime, Compound 26, m.p.165-167° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[C:16]=2[S:23](Cl)(=[O:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH3:27]>CO>[Cl:22][C:17]1[C:18]([Cl:21])=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16]=1[S:23]([NH2:27])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2S(=O)(=O)Cl)CC1
Reactant: N
Solvent: CO
Product: NS(=O)(=O)c1c(OC2CCNCC2)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl-4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-1-carboxylate (0.80 g, 1.8 mmol) was dissolved in 7N ammonia in methanol and stirred at room temperature for 20 min. The solution was concentrated in vacuo and then azeotroped once with toluene. The residue was redissolved in dichloromethane:trifluoroacetic acid/1:1 (20 ml) and stirred at room temperature for 15 minutes. The solution was concentrated in vacuo, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous was reextacted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in vacuo afforded the title compound as a white powder (0.54 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH:31]=[CH2:30])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: C=CCCCBr
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (22 mg, 63%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 5-bromo-1-pentene (23 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.68-1.79 (m, 2H), 2.01-2.26 (m, 7H), 2.43-2.62 (m, 4H), 2.71 (t, J=6.3 Hz, 2H), 2.83-2.92 (br, 1H), 2.95-3.07 (br, 1H), 3.27-3.44 (m, 3H), 3.86 (s, 3H), 4.93-5.05 (m, 2H), 5.70-5.85 (m, 1H), 6.80 (s, 1H), 6.84 (s, 1H), 7.02 (dd, J=8.1, 2.6 Hz, 1H), 7.18-7.24 (m, 2H) ppm. MS (CI, NH3): 457.2 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.F[C:21](F)(F)C(OC(=O)C(F)(F)F)=O.CI>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH3:21])[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Solvent: CO
Solvent: CI
Product: CNc1cc(Cc2ccc(F)cc2)cnc1C(=O)OC

Procedure:
This compound was prepared from methyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate as described in Example 89, Steps 9-10 by reacting with trifluoroacetic anhydride, followed by alkylation with methyl iodide and subsequent deprotection upon heating in the presence of MeOH.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])C)=[O:4].[CH3:13][O:14][C@H](C)[C@@H](C(O)=O)N>>[CH3:13][O:14][C@H:7]([CH3:9])[C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]([OH:12])=[O:11]
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC

Procedure:
(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using O-Methyl-L-Threonine instead of L-Valine. Dichloromethane extraction was carried out 10 times instead of 3 times.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:52]=[CH:53][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:50][CH:49]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 63.4 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.320, 0.41 mmol) was reacted following Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.141 g, 0.26 mmol).