Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1[NH+:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[C:9]([CH3:23])[C:8]2[CH:7]=[CH:6][C:5]([O:24][CH3:25])=C(OC)C1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3.[Cl-].C[Mg]Cl.O1C[CH2:35][CH2:34][CH2:33]1.[CH2:37]([O:39][CH2:40][CH3:41])C>>[CH3:37][O:39][C:40]1[C:41]2[C:34]([CH3:35])([CH3:33])[N:11]3[CH2:12][CH2:13][C:14]4[C:19]([C:10]3=[C:9]([CH3:23])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:24][CH3:25])=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=4
Reactant: CCOCC
Reactant: COc1ccc2c(c1OC)C(Cl)[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Product: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2C)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
To a suspension of 8-chloro-9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; chloride (970 mg, 2.3 mmol) in anhydrous diethyl ether (150 mL) at 0° C. was added a solution of methylmagnesium chloride in tetrahydrofuran (3 M, 15 mL, 45 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-8,8,13-trimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (80 mg, 9%). LC/MS m/e calcd for C23H25NO4 (M+H)+: 380.46, observed: 380.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (s, 6 H) 2.12 (s, 3 H) 2.63 (t, J=5.18 Hz, 2 H) 3.16 (t, J=5.31 Hz, 2 H) 3.73 (s, 3 H) 3.79 (s, 3 H) 6.01 (s, 2 H) 6.81 (s, 1 H) 6.86-6.93 (m, 2 H) 6.98 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]CC)=O)[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH3:17].CO>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:17])=[O:14])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Solvent: CO
Product: N#Cc1ccc2cc(C(N)=O)[nH]c2c1
Yield: 88.6 %

Procedure:
Treat 6-cyano-1H-indole-2-carboxylic acid ethyl ester 5a (m=0, 1.0 g, 4.67 mmol) with 7 N NH3/MeOH as described in General Procedure IV to afford the title compound as an ivory colored solid (766 mg, 88.6%), mp 241-242° C.; 1H NMR (DMSO-d6) δ 11.5 (brs, 1H), 8.16 (brs, 1H), 7.83 (s, 1H), 7.80 (d, 1H, J=8.0 Hz), 7.58 (brs, 1H), 7.35 (d, 1H, J=8.0 Hz), 7.23 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:36])=[O:35])=[CH:32][CH:33]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-methoxybenzenesulfonamide. MS (ESI) m/z 505 [M+H]+, 503 [M−H]−, 1H-NMR (CDCl3) δ 1.25 (3H, t, J=7.5 Hz), 2.72 (2H, q, J=7.5 Hz), 2.91 (2H, t, J=6.8 Hz), 3.40-3.55 (2H, m), 6.64 (1H, br), 6.96 (2H, d, J=9.0 Hz), 7.20-7.30 (5H, m), 7.38 (2H, t, J=7.3 Hz), 7.74 (2H, d, J=9.0 Hz), 7.79 (2H, d, J=8.4 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:14]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[C:11]([CH3:19])[N:10]=1.[F:20]F.C(OCC)(=O)C>C(#N)C>[F:20][N+:10]1[C:11]([CH3:19])=[CH:12][CH:13]=[C:14]([S:15]([O-:18])(=[O:17])=[O:16])[C:9]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)O)c(C)n1
Reactant: FF
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])c(C)[n+]1F

Procedure:
To a mixture of acetonitrile (4 ml) and 2,6-dimethylpyridine-3-sulfonic acid (410 mg, 2 mmol), triethylamine (404 mg, 4 mmol) was added at room temperature while stirring, followed by evaporation to dryness under reduced pressure to obtain 2,6-dimethylpyridine-3-sulfonic acid triethylamine salt. The triethylamine salt was dissolved in acetonitrile (4 ml). To the resulting solution cooled with a cooling bath kept at -20° C., a mixed gas of 10% fluorine/ 90% nitrogen was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 6 mmol. Thereafter, the nitrogen gas alone was introduced for 30 minutes. Ethyl acetate was added to the reaction mixture. The precipitated crystal was recovered by filtration to obtain N-fluoro-2,6-dimethylpyridinium-3-sulfonate (257 mg). Yield, 63%. Decomposition point, 200°-210° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C(OC)(OC)OC.[CH2:18]([N:21]([CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH3:20].[BH4-].[Na+]>CO.O>[CH2:27]([N:21]([CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCN
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: O
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
3.94 g (0.03 mol, 1.0 equivalent) of 4-cyanobenzaldehyde was charged in a 300 ml four-necked flask, and dissolved in 60 ml of methanol. 9.55 g (0.09 mol, 3.0 equivalents) of trimethyl orthoformate was added dropwise therein at room temperature, and the mixture was then cooled to −20° C. 5.17 g (0.03 mol, 1.0 equivalent) of 4-dipropylaminobutylamine (4) was added dropwise therein, the mixture was stirred for one hour and further stirred at room temperature for three hours. After confirming the disappearance of the raw material, the mixture was again cooled to −20° C. 1.36 g (0.036 mol, 1.2 equivalents) of sodium borohydride was added dropwise therein, and the mixture was stirred for two hours. The reaction solution was added into 250 ml of water and extracted with 120 ml of chloroform. The chloroform layer was washed with 150 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 8.58 g of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) as a colorless oily substance (yield: 99%, GC: 96.7%).
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:22][O:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[N:14][CH:13]=1.O>O1CCOCC1>[CH:5]([NH:8][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:22][O:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[N:14][CH:13]=1)([CH3:7])[CH3:6]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 529 μL, 1.1 mmol) was added dropwise (exothermic) to a solution of isopropylamine (63 mg, 91 μL, 1.1 mmol) in dioxane (7 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 5 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (102 mg, 95%) which was obtained as a white solid. MS: m/e=406.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>O>[Cl:33][CH2:32][CH2:31][O:14][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Nc1cc(OCCCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)phenol (2.10 g, 10.1 mmol) and cesium carbonate (4.00 g, 12.2 mmol) in acetonenitrile (50 ml) was added 2-chloroethyl p-toluenesulfonate (2.9 g, 12 mmol) slowly. The resulting mixture was stirred at RT for 5 hr, poured into water (100 ml) and then extracted with EtOAc (3×80 ml). The combined organic layer was washed with brine (100 ml) and dried over Na2SO4. Solvent was removed under vacuum and the residue was purified by flash column chromatography on the silica gel (hexane/EtOAc=5 to 25%) to afford the desired compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:42][CH2:43][CH2:44][C:45]2C=[CH:49][C:48](OC3C=CC=CC=3)=[CH:47][CH:46]=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Product: CCCCCCCNC(=O)C(C)(C)Oc1ccc(C[C@H](OCC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and hepthylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H33NO5 [M+H]+: 394.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[NH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Li+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[NH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc2c([nH]1)C(c1cccc(C#N)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(C2CCc3cc(C(=O)O)[nH]c32)c1
Yield: 34 %

Procedure:
The title compound was synthesized from methyl 6-(3-cyanophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.027 g, 0.10 mmol) and lithium hydroxide (0.044 g, 1.0 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (5-6 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-80% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 8.6 mg (34% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.21-2.30 (m, 1H) 2.65 (s, 1H) 2.76 (s, 1H) 2.93-3.03 (m, 1H) 4.33 (s, 1H) 6.68 (s, 1H) 7.40-7.44 (m, 1H) 7.44-7.49 (m, 2H) 7.54-7.58 (m, 1H); LC-MS ESI− 251.2 (m−H); HPLC (UV=97.75%), (ELSD=100%).
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([O:30][CH3:31])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21]([O:30][CH3:31])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution mixture of methyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-5-methoxy-4-phenylbenzoate (0.034 g) in methanol (2.5 mL) and ethyl acetate (2.5 mL), 10% palladium-carbon (6.8 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the solid substance was collected by filtration to obtain 0.020 g of methyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-5-methoxy-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Br:12])=[C:8](Br)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH-:14].[Na+].Cl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Br:12])=[C:8]([SH:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Br)c(Br)c1=O
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)n1ncc(S)c(Br)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 30.4 %

Procedure:
To 200 ml of water were added 31.0 g of 2-tert.-butyl-4,5-dibromo-3(2H)-pyridazinone and 15.8 g of 70% sodium hydrosulfide. After stirring at 60° C. for 4 hours, the resulting mixture was allowed to cool to room temperature and incorporated with about 8 ml of concentrated hydrochloric acid to lower the pH of the liquid to not higher than 2. The resulting solid was filtered off, washed with water, dried and then recrystallized from benzene/n-hexane to give 8.0g of the intended product as white crystals of m.p. 107°-110° C. (yield: 30.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1cc(Cl)c(F)cc1C(=O)c1ccc(Cl)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c(F)cc1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone (Example 47) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 457.1106, Calcd for (M+H)+: 457.1107. Ki for cdk4=0.008 μM, cdk1=0.154 μM, cdk2=0.039 μM, and IC50 for HCT116 cell line=3.0 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:33])[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH:22]([F:33])[F:21])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS1174323-34-2, WO2009091016) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=459.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9](OC)[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1.[CH2:17]([CH:19]1[CH:21]([CH2:22][CH3:23])[O:20]1)[CH3:18].[CH3:24][OH:25]>>[CH3:24][O:25][C:9]1[CH:10]=[C:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH:21]([CH2:22][CH3:23])[CH:19]([OH:20])[CH2:17][CH3:18])[CH:6]=[C:7]([O:15][CH3:16])[C:8]=1[O:13][CH3:14]
Reactant: CCC1OC1CC
Reactant: CNCCc1cc(OC)c(OC)c(OC)c1
Reactant: CO
Product: CCC(O)C(CC)N(C)CCc1cc(OC)c(OC)c(OC)c1

Procedure:
Combine 22.5 g (0.1 mol) of N-methyl-3,4,5-trimethoxybenzeneethanamine and 10 g (0.1 mol) of 2,3-diethyloxirane in 150 mL of 90% aqueous methanol. Heat the reaction at 50° C. and follow the progress of the reaction by thin-layer chromatography. At the completion of the reaction remove the solvent in vacuo and chromatograph the residue on silica gel to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:5]1[C:6]([OH:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: BrBr
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(C(F)(F)F)cc1Br
Temperature: 80 °C
Yield: 95.8 %

Procedure:
5-Trifluoromethyl-2(1H)-pyridone (10.0 g) and sodium acetate (5.25 g, 64 mmol) in acetic acid (100 ml) was treated with bromine (3.3 ml, 63 mmol) and heated at 80° C. for 2 hrs, before being cooled and concentrated. The residue was basified with sodium hydrogen carbonate solution (250 ml) and extracted with ethyl acetate (2×250 ml). The extracts were dried (MgSO4) and concentrated to give the product as a tan solid (14.22 g, 96% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2.[N:25]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:32](=[O:33])[CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: O=C(O)CN1CCOCC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CN4CCOCC4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine and morpholin-4-yl-acetic acid; MS: m/e=447.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)N1CCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 10.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([Br:19])=[CH:11][N:10]=1.C(N(CC)CC)C.O>ClCCl>[Br:19][C:12]1[C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]([NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:10][CH:11]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In an ice bath, 29.8 g of pivaloyl chloride (226 mmol) was added dropwise to a solution of compound 5 (50.0 g, 207 mmol) and triethylamine (37.9 mL) in dichloromethane (300.0 mL) within one hour and then stirred for 2 hours until the starting materials disappeared. 150 mL of water was added into the reaction solution and stirred at room temperature for 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and separated through a short column with ethyl acetate to give white solid (57.7 g, 85.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51]O)[CH2:46][CH2:45]1>>[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:46][CH2:45]1
Reactant: CN1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCN2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(4-methylpiperazin-1-yl)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(4-methyl-piperazin-1-yl)-ethyl ester. MS (ES+) m/z calcd. for C38H44Cl2F2N5O4: [(M+H)+]: 742. found: 742.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Li])=[C:21]([O:26][CH3:27])[C:20]=1[O:28][CH3:29]>>[OH:13][C:9]1([C:23]2[CH:22]=[C:21]([O:26][CH3:27])[C:20]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:24]=2)[C:10]2[C:5](=[C:4]([N+:14]([O-:16])=[O:15])[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Reactant: [Li]c1ccc(OC)c(OC)c1OC
Product: COc1cc(C2(O)CCCc3c2ccc(OC)c3[N+](=O)[O-])cc(OC)c1OC
Reaction time: 2 h
Yield: 55 %

Procedure:
6-Methoxy-5-nitro-1-tetralone (21) (2.65 g, 12.0 mol) was added at −20° C. to the trimethoxyphenyllithium and stirring was continued for 2 h (−20° C. -RT). The mixture was partitioned between CH2Cl2 and water, the organic layer was dried over anhydrous sodium sulfate, and, after filtration, the organic layer was concentrated in vacuo, to afford 1-Hydroxy-6-methoxy-5-nitro-1-(3′,4′,5′-trimethoxyphenyl)tetralin (30) as a crude yellow oil. (GC-MS shows the yield is about 55%). This compound, without purification, was added to a refluxing mixture of acetic acid (10 mL) and water (80 mL), and iron (0.5 g) was added. After heating at reflux for 1 h, the mixture was partitioned between CH2Cl2 (3×100 mL) and water (100 mL). The organic layer was washed with NaHCO3 (sat.) and water (100 mL each), dried over anhydrous sodium sulfate, and, after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. Purification by column chromatography afforded 5-Amino-6-methoxy-1-(3′,4′,5′-trimethoxyphenyl)-3,4-dihydronaphthalene (31):