Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH3:5][O:6][C:7](=[O:18])[C:8](=[C:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH3:12][O:11][C:9](=[O:10])[CH:8]([C:13]([CH2:1][CH3:2])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:7]([O:6][CH3:5])=[O:18]
Reactant: CC[Mg]Cl
Reactant: CCC(CC)=C(C(=O)OC)C(=O)OC
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(CC)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Step B To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at −50° C. was added ethylmagnesium chloride (2 M, 40 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to −50° C., a tetrahydrofuran solution (50 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3.5 g, 17.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:30) to give 2-(1,1-diethyl-propyl)-malonic acid dimethyl ester as a colorless oil (2.6 g, 57%).
Reaction SMILES: [CH:1]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)N([O])C(C)(C)CCC1.[Br-].[Na+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH:1]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCCCCCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=CC1CCCCCCCCCCC1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of 9.92 g (50 mmol) of cyclododecane methanol in 100 ml of methylene chloride under a nitrogen atmosphere is added 50 mg of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO) and 510 mg (5 mmol) of sodium bromide in 5 ml of water. The solution is cooled to 10°-15° C. and a solution of 100 ml of 5.25% aqueous sodium hypochlorite and 2.0 g of sodium bicarbonate is added over 1 hour. The reaction mixture is allowed to warm to room temperature and after 1 hour is diluted with methylene chloride. The organic phase is washed with aqueous sodium thiosulfate, aqueous bicarbonate and water. The methylene chloride layer is dried over magnesium sulfate, filtered and evaporated in vacuo to give 9.43 g of crude title compound as an oil: IR (film) 1723 cm-1 ; NMR (CDCl3)) δ 1.34 (bs, 18 H), 1.41 (m, 4 H), 1.54 (m, 2 H), 1.65 (m, 2 H), 2.40 (m, 1 H), 9.64 (d, 1 H, J=1.6 Hz) M+ (EI) 196
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][N:13]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[C:14]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:18]([CH3:19])=[N:17][CH2:16][CH2:15][N:13]4[C:14]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NCCn1ccc2c1-c1cccc(Cl)c1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1=NCCn2c1cc1c2-c2cccc(Cl)c2CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
N-[2-(6-Chloro-4,5-dihydro-1H-benz[g]indol-1-yl)ethyl]acetamide (6.0 g) was treated with 30 ml of phosphorus oxychloride and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was added to 2500 g of ice-water and treated with 100 ml of 2N sodium hydroxide solution and 200 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. 5.7 g of residue were dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 6.6 g (82%) of 4-chloro-5,6,10,11-tetrahydro-8-methylbenz[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 191°-192° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:40]=[CH:41][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:50][CH:51]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Reaction time: 0.13 h

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/water mixture (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na2CO3 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd(PPh3)4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100° C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71%). Analytical Data: LCMS: 573.35 (M+1)+; HPLC: 99.5% (@ 254 nm) (Rt; 3.999; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: C(OCCC)=O.[C-:7]#[N:8].[Na+].[CH:10]1[C:15]([CH2:16]O)=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=1.O>CN(C)C=O.C(O)=O>[OH:18][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][C:7]#[N:8])=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: OCc1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCOC=O
Solvent: O
Product: N#CCc1ccc(O)cc1
Temperature: 40 °C
Yield: 78.3 %

Procedure:
n-Propyl formate (264 g.) and granular sodium cyanide (150 g.) were added successively to a stirred suspension of p-hydroxybenzyl alcohol (8310 g.) in N,N-dimethylformamide (148 g.) and the mixture was heated at 67°-68° C. for 1 hour, cooled to 40° C. and poured into water (588 ml.). The mixture was cooled to 20°-25° C., the pH of the mixture was adjusted from 9.5 to 4.0 with 98% formic acid (270 ml.), and the mixture was extracted three times with isobutyl methyl ketone (677 ml, 196 ml. and 196 ml. successively). Each extract was washed twice with water (196 ml. each time) and the combined extracts were dried by azeotropic distillation under reduced pressure at 60°-70° C. There was thus obtained p-hydroxybenzyl cyanide (319 g., 96% yield).
Reaction SMILES: [C:1]([CH:3]1[C:12]2[CH2:11][CH2:10][C:9]3=[N:13][N:14]([CH2:16][C:17]4[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=4)[N:15]=[C:7]([C:8]=23)[C:6]([N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:5][S:4]1)#[N:2].Cl.C(N(CC)CC)C.[N-:50]=[N+:51]=[N-:52].[Na+]>CN(C)C=O>[CH3:25][O:24][C:21]1[C:20]([CH3:26])=[CH:19][N:18]=[C:17]([CH2:16][N:14]2[N:13]=[C:9]3[CH2:10][CH2:11][C:12]4[CH:3]([C:1]5[NH:2][N:52]=[N:51][N:50]=5)[S:4][N:5]=[C:6]([NH2:27])[C:7]([C:8]=43)=[N:15]2)[C:22]=1[CH3:23]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(C)cnc(CN2N=C3CCC4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4C#N)c1C
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)cnc(CN2N=C3CCC4=C3C(=N2)C(N)=NSC4c2nnn[nH]2)c1C
Temperature: 105 °C
Reaction time: 15 h
Yield: 19 %

Procedure:
A mixture composed of di-tert-butyl {7-cyano-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Step 4) of Example 23 (53 mg), N,N-dimethylformamide (1 mL), triethylamine hydrochloride (14.5 m) and sodium azide (6.8 mg) was sealed in a tube and heated with stirring at a bath temperature of 105° C. for 15 hours. After cooling to room temperature, the reaction solution was separated with ethyl acetate and a 0.1 N sodium hydroxide solution. The aqueous layer was made acidic with a 0.1 N hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol-lower layer of water) to obtain the title compound (5.6 mg, 19%) as a solid.
Reaction SMILES: C(O[CH:5]=[CH2:6])(=O)C.C(N1[CH2:13][CH2:12][CH2:11][C:10]1=O)=C>>[CH3:10][CH2:11][CH2:12][CH2:13][CH2:13][CH2:12][CH2:11][CH2:10][CH2:5][CH3:6]
Reactant: C=CN1CCCC1=O
Reactant: C=COC(C)=O
Product: CCCCCCCCCC
Yield: 3957.8 %

Procedure:
A mixture of 14 g of the resin P-2 obtained in Production Example 2 of dispersion stabilizing resin, 85 g of vinyl acetate, 15 g of N-vinylpyrrolidone, 1.2 g of the macromonomer M-1 obtained in Production Example 1 of macromonomer, and 380 g of n-decane was heated to 75° C. with stirring under nitrogen gas stream. After adding thereto 1.7 g of A.I.B.N., the reaction was carried out for 4 hours and, after further adding thereto 0.5 g of A.I.B.N., the reaction was carried out for 2 hours. After cooling, the reaction mixture was passed through a 200 mesh nylon cloth to obtain a latex having a mean grain size of 0.23 μm as a white dispersion.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:10]=1[C:11]([O:13]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[OH:13][C:11]1[C:10]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:1]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(OC)cccc1SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2sc(-c3ccccc3)c(O)c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-benzylthio-6-methoxybenzoate (0.50 g, 1.7 mmol) in N,N-dimethylformamide (2 ml) was added dropwise with stirring under a nitrogen atmosphere to a suspension of sodium hydride (50% dispersion in mineral oil) (90 mg, 1.9 mmol) in N,N-dimethylformamide (5 ml) at room temperature. The mixture was stirred at 80° C. for 2 hours and then at 100° C. for 10 hours. The cooled mixture was then poured into ice containing 2N hydrochloric acid and extracted with diethyl ether. The combined organic layers were washed with water (3×), saturated aqueous sodium chloride solution, dried (sodium sulfate), and evaporated. The residue was vacuum filtered through a pad of silica gel (Merck No. 7734), eluting with 2:1 hexane-ether. Fractions containing pure product were evaporated, and the resulting syrup triturated with methanol to afford 3-hydroxy-4-methoxy-2-phenylbenzo[b]thiophene as a white solid; yield 0.12 g (27%); m/z 256 (M30. ).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](C(OC(C)(C)C)=O)[N:9]=[CH:10][C:3]=12.[Cl:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[Cl:18][C:19]1[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)n1ncc2c(I)ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To tert-butyl 4-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1.00 g, 2.90 mmol), 2-chloropyridin-3-ylboronic acid (1.14 g, 7.24 mmol), and sodium carbonate (1.23 g, 11.6 mmol) was added dioxane (10 mL) and water (4 mL). The mixture was stirred at RT for 5 minutes, then tri-t-butylphosphonium tetrafluoroborate (0.084 g, 0.290 mmol) and palladium(II) acetate (0.033 g, 0.145 mmol) were added and the mixture was heated to 100° C. in a sealed tube for 23 hours. The reaction was diluted with EtOAc and extracted with 1N sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrated. The crude was purified by ISCO silica gel chromatography (10-90% EtOAc/hexanes; 80 g column) and product fractions were concentrated to yield 4-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. MS m/z=231 [M+1]+. Calc'd for C11H7ClN4: 230.66.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>C1COCC1>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:4][CH2:3][C:2]([NH2:1])([CH3:6])[CH3:5])[C:11]=1[C:12]#[N:13]
Reactant: CC(C)(N)CO
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(N)COc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) in anhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineral oil) in small portions at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for another 30 minutes. The solution was cooled down to 0° C. again, and to this solution was added dropwise a solution of 2-amino-6-fluorobenzonitrile (20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture was then refluxed overnight under nitrogen. The reaction mixture was cooled down to room temperature and carefully quenched with aqueous NH4Cl solution and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel eluting with 10% MeOH in DCM to give the title compound as yellow solid (23.4 g 71%). 1H NR (400 MHz, DMSO-d6) δ 1.08 (s, 6H), 3.15 (s, 2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H). MS 236 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([S:11][CH3:12])[CH:3]=1.[Cl-].[NH4+].O[N:16]1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:16])=[O:7])=[C:4]([S:11][CH3:12])[CH:3]=1
Reactant: On1nnc2cccnc21
Reactant: CSc1cc(F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CSc1cc(F)ccc1C(N)=O
Reaction time: 16 h

Procedure:
To a solution of 4-fluoro-2-(methylthio)benzoic acid (8.1 g, 43.6 mmol) in degassed DMF (100 mL) under nitrogen was added ammonium chloride (4.66 g, 87.2 mmol) followed by 1-hydroxy-7-azabenzotriazole (11.87 g, 87.2 mmol) and N,N,N-diisopropylethylamine (30.38 mL, 174.4 mmol). To this mixture was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and the reaction was stirred for 16 hour. LCMS analysis indicated that the reaction was complete. The DMF was removed in vacuo and the residue was partitioned between methylene chloride (800 mL) and 5% aqueous HCl (400 mL). The organic phase was washed with water (400 mL), saturated sodium bicarbonate solution (400 mL), and brine (400 mL). The organics were dried over Na2SO4, filtered, and reduced to a small volume in vacuo. The product crystallized upon solvent reduction. The crystals were filtered and dried iii vacuo to afford the title compound.
Reaction SMILES: C([O-])(O)=O.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][C:8]=1[C:19]([F:22])([F:21])[F:20].I[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])/[C:15](/[CH3:17])=[CH:16]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:9][C:8]=1[C:19]([F:20])([F:21])[F:22]
Reactant: Oc1cccc(I)c1
Reactant: C=C(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC#N
Product: C/C(=C\c1cccc(O)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flame-dried flask, NaHCO3 (5.20 g, 61.88 mmol), 3 Å molecular sieves (10.9 g), N-(4-chloro-3-(trifluoromethyl)phenyl)methacrylamide (6.51 g, 24.75 mmol), and 3-iodophenol (5.99 g, 27.23 mmol) were added under an atmosphere of argon. The solids were then dissolved in ACN (100 mL) and stirred at rt for 10 min. PPh (650 mg, 2.48 mmol) was added and argon bubbled through the reaction mixture. Pd(OAc)2 (278 mg, 1.24 mmol) was added and the reaction mixture was heated at 60° C. for 12 h. Additional palladium acetate was added and the reaction mixture was heated for 24 h. The mixture was cooled to rt and filtered through a pad of Celite. The filtrate was washed with sat. NaHCO3 and the aqueous solution extracted with EtOAc. The combined organic solutions were dried over Na2SO4, filtered, and concentrated to provide a brown oil. Purification by column chromatography (SiO2, 0-10% Et2O in DCM) provided the titled compound. LCMS, FA: Rt=1.94 min, [MH+ 356.0].
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([CH2:25][N:26]([C:36](=[O:48])[C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([CH3:45])=[C:39]([O:46][CH3:47])[CH:38]=3)[CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:23][CH:24]=2)=[O:19])(=[O:16])=[O:15])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH3:44][O:43][C:41]1[CH:42]=[C:37]([CH:38]=[C:39]([O:46][CH3:47])[C:40]=1[CH3:45])[C:36]([N:26]([CH2:25][C:22]1[S:23][CH:24]=[C:20]([C:18]([NH:17][S:14]([N:11]2[CH2:12][CH2:13][CH:9]([OH:8])[CH2:10]2)(=[O:16])=[O:15])=[O:19])[N:21]=1)[CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:48]
Reactant: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)NS(=O)(=O)N3CCC(O[Si](C)(C)C(C)(C)C)C3)cs2)cc(OC)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)NS(=O)(=O)N3CCC(O)C3)cs2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
N-[(3-{[tert-Butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide (580 mg) was added to THF (10 mL), and subsequently, a 1 M TBAF/THF solution (2.02 mL) was added dropwise thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized by the addition of an appropriate amount of 1 M hydrochloric acid, and then extracted with CHCl3 several times. The organic layer was washed with brine and dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3:MeOH=20:1) to obtain 2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-1,3-thiazole-4-carboxamide (383 mg) as a white solid.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([BH3-])#[N:19].[Na+]>CO.C(Cl)Cl>[C:5]1([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:19])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ammonium formate (18 g, 285 mmol) was added to a solution of 4-phenylcyclohexanone (5 g, 28.7 mmol) in methanol (150 ml) under nitrogen at room temperature followed by the portionwise addition of sodium cyanoborohydride (1.85 g, 29.4 mmol). After stirring the reaction mixture at room temperature for 24 hours, the methanol was removed under vacuum to leave an oily residue. The residue was dissolved in methylene chloride (100 ml) which was then washed with 1N sodium hydroxide (2×100 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to leave an off-white solid. Purification by flash chromatography (silica gel, 0-20% methanol/methylene chloride) provided 3.46 g of trans-4-phenyl-cyclohexylamine as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]2[C:13](=[O:31])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=3)[O:16][C:11]=2[C:10]([F:32])=[CH:9][C:8]=1[F:33].[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C)C=O>[N:34]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]2[C:13](=[O:31])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=3)[O:16][C:11]=2[C:10]([F:32])=[CH:9][C:8]=1[F:33])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCl)c(F)cc(F)c3o2)cc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCN=[N+]=[N-])c(F)cc(F)c3o2)cc1F
Temperature: 70 °C
Reaction time: 10 h
Yield: 66.8 %

Procedure:
489 mg (1.02 mmol) of the above 5-(4-chlorobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 20 mL of dimethylformamide under argon atmosphere, 332 mg (5.10 mmol) of sodium azide was added and the mixture was stirred at 70° C. for 10 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 332 mg of 5-(4-azidobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 67%).