Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:23]1([C:29]2[N:30]=[C:31]([CH2:34][C:35](O)=[O:36])[S:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:35](=[O:36])[CH2:34][C:31]2[S:32][CH:33]=[C:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:30]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(O)Cc1nc(-c2ccccc2)cs1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC(=O)Cc1nc(-c2ccccc2)cs1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (4-phenyl-thiazol-2-yl)-acetic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 24.2, 25.6, 26.6, 26.7, 35.2, 40.3, 53.6, 55.9, 59.1, 67.2, 105.3, 113.2, 126.5, 128.4, 129.0, 131.4, 134.2, 137.4, 155.5, 163.4, 167.3, 168.6; MS m/z 509.4 (M+1).
Reaction SMILES: Cl[C:2]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)=[O:3].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.CO.[Cu]I>[CH:15]1([C:13]#[C:14][C:2]([C:4]2[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=2)=[O:3])[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: COC(=O)c1ccc(C(=O)Cl)s1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(=O)C#CC2CC2)s1
Reaction time: 8 h

Procedure:
Methyl 5-(chlorocarbonyl)thiophene-2-carboxylate (500 mg, 2.443 mmol) was dissolved in triethylamine (5 mL) and the suspension was degassed with nitrogen. Copper(I) iodide (40 mg, 0.210 mmol) and bistriphenylphosphine palladium (II) chloride (40 mg, 0.057 mmol) were added followed by ethynylcyclopropane (162 mg, 2.443 mmol). The mixture was stirred overnight, diluted with methanol and concentrated to dryness. The crude material was partitioned between dichloromethane and water. The organic extracts were dried with sodium sulfate, filtered, concentrated and purified by normal phase chromatography to afford the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[C:7]2[CH:13]=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)n1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C
Yield: 58.5 %

Procedure:
NaH (0.36 gm, 12.6 mmol) was added to a solution of 2.26 gm (12.6 mmol) 5-chloro-1H-indole-3-carbaldehyde in THF cooled in an ice water bath After 20 m stirring, 1.4 g (12.6 mmol) methanesulfonyl chloride was added, and the solution was warmed to room temperature with stirring overnight. The mixture was diluted with EtOAc and washed with water and brine, dried (MgSO4) and concentrated. Normal phase chromatography (CH2Cl2 followed by gradient elution to 10% EtOAc in CH2Cl2) afforded 1.9 gm of the title compound as a white solid, 1H NMR (DMSO) δ 9.75 (s, 1H), 8.0 (s, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.1 (d, 1H), 2.3 (s, 3H).
Reaction SMILES: C[O:2]C(=O)C=C.C(P)C(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:24]([P:28]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])[CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[CH:25]([CH3:27])[CH3:26].OO>C1(C)C=CC=CC=1>[CH2:24]([P:28](=[O:2])([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:25]([CH3:27])[CH3:26]
Reactant: COC(=O)CCP(CCC(=O)OC)CC(C)C
Reactant: C=CC(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)CP
Agent: OO
Solvent: Cc1ccccc1
Product: CC(C)CP(=O)(CCC(=O)O)CCC(=O)O
Reaction time: 2.5 h

Procedure:
A solution of 688 parts of methylacrylate in 285 parts of toluene is reacted with 450 parts of 80% isobutylphosphine in the presence of 3.9 parts of (azobisisobutyronitrile) initiator at 74°-93° C. for 7 hours. The resulting isobutylbis(carbomethoxyethyl)phosphine is oxidized with 600 parts of (10% excess) of 25% aqueous hydrogen peroxide. The reaction is complete within 2-3 hours at 65° C. and the resultant phosphine oxide is isolated as an oil following distillation of toluene and water from the mixture. The recovered phosphine oxide is hydrolyzed in 4 liters of 5% aqueous sulfuric acid solution by refluxing over a 7 hour period. On cooling, the product, isobutyl bis(β-carboxyethyl)phosphine oxide is isolated as a white crystalline solid in 70% yield and purified by recrystallization from water, m.p. 186°-187° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH2:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C1(C)C=CC=CC=1.CCCCCCC>[CH2:1]([O:3][C:4]([C:5]1[CH2:15][CH2:14][C:13](=[O:16])[NH:11][C:6]=1[C:7]([F:10])([F:8])[F:9])=[O:12])[CH3:2]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C1=C(C(F)(F)F)NC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester (529 mL, 3.47 mol) was added acryloylchloride (600 mL, 6.95 mol) dropwise over a period of 15 min. The suspension was stirred at RT for 1 h. The temperature was slowly raised with stirring to 80° C. (HCl gas evolution) and maintained at 80° C. for 5 h. Stirring continued overnight at 40° C. The mixture was cooled, diluted with toluene (2 L) and n-heptane (2 L) to precipitate the product and stirred for another 15 min at room temperature. The product was isoloated by filtration, the filter cake was washed with toluene/n-heptane (1:2; 4×100 mL) and dried in vacuo at 40° C. for 5 h. This procedure yielded the title compound (286 g, 35%) as a white solid, MS (ISP) 236.1 (M−H)−. Concentration of the mother liquor and addition of toluene/n-heptane (1:10) yielded a second crop of 29.8 g.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6].O>CN(C=O)C>[CH:1]([NH:4][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CC(C)N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 18 h

Procedure:
0.22 ml (2.52 mmol) of isopropylamine is added to a solution of 150 mg (0.50 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF. After 18 h at room temperature, 2.5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and dried under high vacuum. 126 mg (64.4% of theory) of the title compound are obtained and reacted further without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([OH:12])[C:5]=2[C@@H:4]2[CH:18]=[C:19]([CH3:22])[CH2:20][CH2:21][C@@H:3]12.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:23][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:5]=2[C@@H:4]2[CH:18]=[C:19]([CH3:22])[CH2:20][CH2:21][C@@H:3]12
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Yield: 77 %

Procedure:
A mixture of 1.73 g (5.50 mmol) of (6aR-trans)-6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, 10 ml of dimethylsulfoxide, 3 ml of ethyl 4-bromobutyrate and 1.73 g of potassium carbonate was degassed and then heated under reflux under argon over night. The reaction was cooled, diluted with 250 ml of water and extracted with ether. The extracts were passed over a column of silica gel, and the fractions containing the intermediate ester were combined and concentrated under vacuum. The residue was dissolved in 100 ml of methanol, the solution was heated to boiling and 20 ml of water, followed by 2.2 g of sodium carbonate, was added. The mixture was heated under reflux for 3 hrs. The methanol was evaporated under vacuum, and the aqueous residue was acidified with hydrochloric acid and extracted with dichloromethane. The extracts were concentrated, and the residue was dissolved in hexane and adsorbed onto silica gel. Elution with 15% ethyl acetate in benzene, followed by evaporation, gave 1.70 g (77%) of (6aR-trans)-4-[(6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid as a colorless oil: ir (CHCl3) 1710 cm-1 ; uv max (C2H5OH) 225 nm (infl) (ε17,830), 274 (1090), and 282 (1120); nmr (CDCl3) δ11.3 (br, CO2H), 6.29 and 6.20 (two sharp d, H-2 and H-4), 5.41 (m, H-8), 4.01 (t, OCH2C), 3.18 (m, H-10a), 2.59 (t, ArCH2C), 2.48 (t, CCH2CO), 1.69 (s, 9-CH3), 1.34 and 1.06 (two s, 6,6-diCH3), and 0.87 (t, ω-CH3); mass mol wt 400; [α]D25° -195.3° (c 1.104, CHCl3).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C:10](=[O:11])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[F:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:2]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:11])[CH2:12][C@H:13]1[C:14]([N:21]1[CH2:22][CH2:23][C@H:19]([F:18])[CH2:20]1)=[O:16])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
N-tert-Boc-4-oxo-L-proline (2.29 g, 10 mmol), (S)-3-fluoropyrrolidine hydrochloride (1.38 g, 11 mmol) and TEA (2.09 mL, 15 mmol) were mixed in anhydrous methylene chloride (30 mL) under nitrogen. HOBT (2.03 g, 15 mmol) was added and the mixture cooled to 0° C. in an ice bath before addition of EDC (2.10, 11 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. The mixture was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. The crude material (3.15 g) was recrystallized from hexane:EtOAc (2:1) to give the title compound as light yellow needles (2.18 g, 73%). MS m/z 301.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([Cl:29])[CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][C:22]3[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([Cl:29])[CH:23]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cc(CBr)cc(Cl)n1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(C2(Cc3cc(Cl)nc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-3-(3-methoxy-phenyl)-6-chloro-1,3-dihydro-indol-2-one (82 mg, 0.3 mmol) (from Example 6b supra), 4-bromomethyl-2,6-dichloro-pyridine (85.3 mg, 0.35 mmol) (Maybridge), potassium iodide (59.2 mg, 0.35 mmol) and potassium carbonate (89.2 mg, 0.645 mmol) in acetone (3 mL) was heated at 60° C. for 3 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a light brown solid. (Yield 60 mg, 45%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([Cl:18])=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 μl, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[H][H]>C(O)(C)C.[Pd]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: COc1ccc([N+](=O)[O-])cc1OCCCN1CCN(C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: COc1ccc(N)cc1OCCCN1CCN(C)CC1

Procedure:
To a solution of 1-[3-(2-methoxy-5-nitro-phenoxy)-propyl]-4-methyl-piperazine (2.5 g, 8.1 mmol) in 25 mL of iso-propanol was added 10% Pd-C (0.25 g, 10 wt. %). This mixture was shaken under 35-40 psi of hydrogen in a Parr shaker until hydrogen uptake ceased. The reaction mixture was purged with nitrogen and filtered through celite. The resulting solution was concentrated in vacuo to give the crude 4-methoxy-3-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamine as a yellow oil which was used directly in the coupling step described below. 1H NMR (300 MHz, CDCl3) δ 6.71 (d, J=8 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 6.23 (dd, J=2.4, 8 Hz, 1H), 4.05 (t, J=8 Hz, 2H), 3.80 (s, 3H), 2.53 (m,10H), 2.30 (s, 3H), 2.02 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.C[Si](C)(C)O[Si](C)(C)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>CN(C)P(N(C)C)(N(C)C)=O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:21]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)c1cccnc1N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: NC(=S)c1cccnc1N
Temperature: 110 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
2-Amino-nicotinamide (1.6 g) described in Manufacturing Example 14-1, hexamethyldisiloxane (3.2 g), phosphorus pentasulfide (950 mg), and hexamethylphosphoramide (13 mL) were stirred for 18 hours at 110° C. The reaction solution was passed through a glass filter (eluted with ethyl acetate) lined with NH-silica gel and silica gel in a 1:1 ratio. The eluate was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (290 mg).
Reaction SMILES: FC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.[F:41][C:42]1[CH:43]=[CH:44][C:45]([CH:66]2[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=3)[CH2:67]2)=[C:46]([NH:48][CH2:49][C:50]2C=CC(OCCN3CCCCC3)=C(F)C=2)[CH:47]=1>>[CH2:49]([N:48]([C:46]1[CH:47]=[C:42]([F:41])[CH:43]=[CH:44][C:45]=1[CH:66]1[CH2:75][CH2:74][C:73]2[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=2)[CH2:67]1)[CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[CH3:50]
Reactant: COc1ccc2c(c1)CCC(c1ccc(F)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc2c(c1)CCC(c1ccc(F)cc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(F)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 5-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 282, [5-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (376 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[5-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (317 mg). This compound (315 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (265 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:23]([NH2:25])=[O:24].C(O)=O>O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([NH:25][CH:23]=[O:24])[CH3:2])=[CH:5][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: NC=O
Reactant: CC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Solvent: O
Solvent: O=CO
Product: CC(NC=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 8 h

Procedure:
A mixture of 7.25 g of N-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinamine, 100 ml of formamide and 31 ml, of 98% formic acid was refluxed with stirring overnight. The solvents were then boiled off for 1/2 hour, the reaction cooled and poured into one liter of water. This was extracted with 725 ml of chloroform. The chloroform extract was back washed with 150 ml of water, then dried, filtered and evaporated to a foam. The foam was partitioned between chloroform and water. An equal volume of saturated potassium bicarbonate was added. The organic phase was separated, dried, filtered and evaporated to a foam. This foam was chromatographed on silica gel topped with a thin layer of hydrous magnesium silicate and eluted with chloroform (first four fractions), then with 2% methanol in chloroform (last two fractions). The sixth (final) fraction was evaporated and then crystallized from chloroform-hexane, giving 1.05 g of the desired product as cream colored crystals, mp 118°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][OH:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:17]([C:34]([F:37])([F:36])[F:35])[CH:16]=1.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][O:13][C:39](=[O:41])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]5)=[C:17]([C:34]([F:37])([F:35])[F:36])[CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(Cl)cc34)cc2C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(Cl)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a solution of tert-butyl 4-(4-(6-chloro-3-(hydroxymethyl)quinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (407 mg, 0.75 mmol) in dichloromethane (10 mL) at 0° C. was added triphosgene (225 mg, 0.75 mmol) and Et3N (125 μL, 0.9 mmol). The resultant solution was allowed to warm up to room temperature and continued to stir for 4 h before being quenched with a satd. aqueous sodium bicarbonate (10 mL), extracted with EtOAc (3×20 mL), and dried over Na2SO4. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to afford the title product (57%) as colorless oil. LC-MS: (M+H)=563.26
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=1B(O)O.Br[C:20]1[CH:21]=[N:22][C:23]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=3)[C:28]([CH2:39][OH:40])=[CH:27]2)=[N:24][CH:25]=1.O>CC(O)(CC)C>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([F:7])=[C:9]([C:20]2[CH:25]=[N:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=4)[C:28]([CH2:39][OH:40])=[CH:27]3)=[N:22][CH:21]=2)[CH:10]=1)[CH3:15]
Reactant: CCc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: O
Product: CCc1ccc(F)c(-c2cnc(-n3cc(CO)c4ccc(C(=O)OC)cc43)nc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (0.915 g, 6.62 mmol) and 2-fluoro-5-ethylphenylboronic acid (0.742 g, 4.14 mmol) were added at room temperature to a solution 331a) (0.8 g, 2.2 mmol) in 2-methyl-2-butanol 1/water (44 mL, 10:1). The reaction apparatus was set under an argon atmosphere and (Ataphos)2PdCl2 (0.156 g, 0.22 mmol) was introduced. The reaction mixture was stirred at 100° C. for 4 h, cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the remnant purified by flash column chromatography [silica; dichloromethane with 1-2% methanol]. White solid. Yield: 0.5 g (56% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:10][C:11]2[O:12][CH2:13][CH2:14][C@:15]([C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[F:27])([CH:17]([F:19])[F:18])[N:16]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:79](=[NH:92])([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:10][C:11]2[O:12][CH2:13][CH2:14][C@@:15]([CH:17]([F:19])[F:18])([C:20]3[CH:25]=[C:24]([N:92]=[C:79]([C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)[C:86]4[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=4)[CH:23]=[CH:22][C:21]=3[F:27])[N:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@@](c3cc(Br)ccc3F)(C(F)F)CCO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(NC2=N[C@@](c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)(C(F)F)CCO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
Under argon in a sealed tube were added to a solution of (S)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(5-bromo-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate E7.1) (725 mg, 1.16 mmol) in toluene (15 ml) sodium tert-butoxide (334 mg, 3.48 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (73.8 mg, 174 μmol) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (60.0 mg, 58.0 μmol) and benzophenone imine (420 mg, 389 μl, 2.32 mmol), the tube was sealed under argon and the mixture was stirred at 105° C. for 4 h. The brown solution was extracted with ethyl acetate/water. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give a brown oil. The residue was chromatographed on 20 g silica gel with ethyl acetate 0-50% to give (S)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(difluoromethyl)-4-(5-(diphenylmethyleneamino)-2-fluorophenyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (525 mg, 723 μmol, 62.4% yield) as a yellow oil. MS (ISP): m/z=726.8 [M+H]+.