Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CSCS(C)=O.[F:12][C:13]1[CH:20]=[C:19](F)[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16].S(=O)(=O)(O)O.C1C[O:31][CH2:30]C1>O>[F:12][C:13]1[CH:20]=[C:19]([CH:30]=[O:31])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: C1CCOC1
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: CSCS(C)=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: O
Product: N#Cc1cc(F)c(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
n-Butyllithium solution (1.6 M in hexanes, 8.75 mL, 14 mmol) was added dropwise to a solution of methyl methylthiomethyl sulfoxide (1.58 g, 12.7 mmol) in THF (25 mL) at −78° C. After 30 minutes at −78° C., 2,4,5-trifluorobenzonitrile (commercial, 1 g, 6.35 mmol) was added dropwise. The solution was then allowed to warm to room temperature, and stirred for 18 hours under a nitrogen atmosphere. The deep red reaction mixture was poured into water (75 mL), and extracted with EtOAc (2×75 mL). The combined organics were dried over magnesium sulphate and evaporated to yield a brown oil. The oil was redissolved in THF (15 mL) and concentrated sulphuric acid (4.1 mL, 77.2 mmol) and water (4 mL) were added. After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over magnesium sulphate, and evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM to afford the title compound as a yellow oil (280 mg, 26%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(COS(C)(=O)=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (1.25 g, 9.46 mmol) and triethylamine (9.2 ml, 66.2 mmol) in dichloromethane (60 ml) at 0° C. was slowly added methanesulfonyl chloride (2.2 ml, 28.4 mmol). The reaction mixture was stirred at 0° C. for 2 h then quenched with water and the aqueous layer was extracted with dichloromethane. The combined organics were washed with 10% citric acid, sat NaHCO3, and brine then dried over MgSO4 and concentrated to afford methanesulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as a light brown oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH2:37][NH:43][CH2:44][CH2:45][CH2:46][N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCCN1CCCC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 82 %

Procedure:
The title compound was prepared in 82% yield following steps 5 and 6 described above, using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 1-(3-aminopropyl)pyrrolidin-2-one as the reactant amine MS: m/e 687.5 (MH+), 1.71 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.96 (s, 3H) 0.98 (s, 3H) 1.02 (s, 3H) 1.08 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 0.90-1.91 (m, 20H) 1.96-2.20 (m, 6H) 2.44 (t, J=8.03 Hz, 2H) 2.47-2.55 (m, 1H) 2.83 (d, J=13.05 Hz, 1H) 3.06 (t, J=7.03 Hz, 2H) 3.20 (d, J=13.55 Hz, 1H) 3.43 (t, J=6.53 Hz, 2H) 3.51 (t, J=7.15 Hz, 2H) 4.62-4.66 (m, 1H) 4.75 (d, J=1.76 Hz, 1H) 5.35 (dd, J=6.15, 1.88 Hz, 1H) 6.94 (dd, J=11.80, 1.25 Hz, 1H) 7.02 (dd, J=8.03, 1.51 Hz, 1H) 7.83 (t, J=7.91 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −112.76 (s, 1 F).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:14][C:15]1[CH:16]=[C:17]([CH2:24][C@@H:25]2[CH2:30][O:29][C:27](=[O:28])/[C:26]/2=[CH:31]/[C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)[CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[OH:21].C(O[CH2:48][CH3:49])(=O)C>CN(C=O)C>[CH2:8]([O:14][C:15]1[CH:16]=[C:17]([CH2:24][C@@H:25]2[CH2:30][O:29][C:27](=[O:28])/[C:26]/2=[CH:31]/[C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)[CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[O:21][CH2:8][CH2:9][CH2:10][CH2:11][CH2:48][CH3:49])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(C)=O
Reactant: CCCCCCI
Reactant: COc1cc(C[C@@H]2COC(=O)/C2=C/c2cc(OC)c(OC)c(OC)c2)cc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(C[C@@H]2COC(=O)/C2=C/c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OCCCCCC
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
Potassium carbonate (500 mg, 3.6 mmol) and 1-iodohexane (1.0 ml, 6.79 mmol) were added to a solution of (S)-(E)-3-[1-(3,4-dihydroxy-5-methoxyphenyl)methyl]-2-(3,4,5-trimethoxybenzylidene)butanolide (324 mg, 0.78 mmol) in 10 ml of DMF, followed by stirring at 60° C. for 4.5 hours. The reaction mixture was poured into 50 ml of ethyl acetate and then the resulting solution was washed successively with water, 2N-HCl, water and saturated NaHCO3. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Brown oil thus obtained was purified by column chromatography (silica gel: "FUJI-DAVIDSON BW-300", eluent: 1:3 mixed solvent of ethyl acetate and hexane), whereby 310 mg of the title compound were obtained as colorless oil (yield: 68%).
Reaction SMILES: N[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:24]>O>[F:24][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: CN1Cc2c(N)ncn2-c2ccccc2C1=O
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CN1Cc2c(F)ncn2-c2ccccc2C1=O
Reaction time: 0.33 h

Procedure:
A solution of 5 g (22 mmol) of 3-amino-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 100 ml of hydrofluoboric acid (50 percent in water) is diazotized at 0° to 5° with a solution of 1.95 g (28 mmol) of sodium nitrite in 4 ml of water. The yellow solution is stirred in an ice-bath for 20 minutes, diluted with 85 ml of hydrofluoboric acid, poured into a quartz vessel and irradiated overnight with a UV-lamp. Subsequently, the mixture is extracted with chloroform. The chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column there is obtained 3-fluoro-4,5 -dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 171°-172°.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2cccc(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(3-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.29 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.52 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.48 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.88 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:41]/[C:42](/[CH3:48])=[CH:43]\[C:44]([O:46][CH3:47])=[O:45]>C(O)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([CH3:48])[NH:41][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25]1)=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)C1c1cccc(Cl)c1Cl
Yield: 52.9 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde, 2-[4-(4,4'-difluorobenzhydryl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4,4'-difluorobenzhydryl)-1-piperazinyl]ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 90°-93° C. (sintering). Yield 52.9%. IR(KBr)cm-1 : 3340, 1695. NMR(CDCl3) δ: 2.28(6H,s, ##STR24## 3.57(3H,s,COOCH3), 4.12(2H,t,J=6,--COOCH2CH2 --), 4.16(1H,s,>N--CH<), 5.42(1H,s,C(4) --H), 5.70(1H,broad s, NH).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:15]>>[C:1]1([CH:7]=[C:8]([S:10]([NH2:15])(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CC(=Cc1ccccc1)S(=O)(=O)Cl
Agent: [OH-]
Product: CC(=Cc1ccccc1)S(N)(=O)=O

Procedure:
The 1-phenylpropene-2-sulfonyl chloride is added to 200 ml. of concentrated ammonium hydroxide. After one hour the crystalline precipitate which has formed is filtered off, and washed sequentially with water and hexane. The crude product so obtained is partitioned between 150 ml. of 1N sodium hydroxide and 50 ml. of ether, giving two clear phases. The ether phase is removed and washed with 50 ml. of water, and then the water wash is added to the original aqueous phase. This combined solution is acidified using concentrated hydrochloric acid, which causes the product to precipitate. It is filtered off, and after drying this affords 10.9g. of 1-phenylpropene-2-sulfonamide, m.p. 138°-139.5° C.
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[Na+].[F:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]3[N:23]([CH:25]=[CH:26][N:27]=3)[CH:24]=2)[CH:16]=[CH:15][C:10]=1[C:11]([NH:13][CH3:14])=[O:12]>C(O)(=O)C>[Br:1][C:25]1[N:23]2[CH:24]=[C:19]([C:17]3[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[C:9]([F:8])[CH:18]=3)[CH:20]=[N:21][C:22]2=[N:27][CH:26]=1
Reactant: BrBr
Reactant: CNC(=O)c1ccc(-c2cnc3nccn3c2)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(-c2cnc3ncc(Br)n3c2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Bromine (17.4 mL, 0.338 mmol) was added to a mixture of sodium acetate (40.3 mg, 0.491 mmol) and 2-fluoro-4-imidazo[1,2-a]pyrimidin-6-yl-N-methylbenzamide (83.0 mg, 0.307 mmol) in acetic acid (2.6 mL) and the reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel with ethyl acetate in dichloromethane (0-50%) to afford the desired product (95 mg, 88.6%). LCMS: (M+H)=348.8/350.9.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2([O:12][Si](C)(C)C)[C:4]3([CH3:20])[CH:5]=[CH:6][CH:7]([CH2:19][CH:3]13)[C:8]2([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C(O)(=O)C.O1CCCC1.O>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2([OH:12])[C:4]3([CH3:20])[CH:5]=[CH:6][CH:7]([CH2:19][CH:3]13)[C:8]2([CH3:17])[CH3:18]
Reactant: CC1(C)C2C=CC3(C)C(C2)C(=O)CCC13O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C2C=CC3(C)C(C2)C(=O)CCC13O
Yield: 94.8 %

Procedure:
A solution of 21 mg of 1,2,3,4,4a,5,6,8a-octahydro-2-oxo-4a-trimethylsilyloxy-5,5,8a-trimethyl-1,6-methanonaphthalene in 4 ml of acetic acid/tetrahydrofuran/water (3:1:1) was stirred under argon at 25° C. over 10 hours, then poured into saturated aqueous NaHCO3 solution and extracted with CH2Cl2. After chromatography (SiO2, ethyl acetate/CH2Cl2) and sublimation, there were obtained 15 mg of 1,2,3,4,4a,5,6,8a-octahydro-2-oxo-4a-hydroxy-5,5,8a-trimethyl-1,6-methanonaphthalene (m.p. 112°-115° C., 95 o/o yield).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=O)[CH2:18]2.O>COCCOC>[CH:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:18]2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CC2CCC(C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C=C1CC2CCC(C1)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (1.55 g, 38.7 mmol, 60% dispersion in oil) in 1,2-dimethoxy ethane (70 mL) at 0° C., triethyl phosphono acetate (8.38 mL, 41.9 mmol) was added. The resulting mixture was stirred 15 minutes at 0° C., 15 minutes at room temperature, and cooled to 0° C. Then, a solution of bicyclo[3.2.1]octan-3-one (Biogene, 4.0 g, 32.2 mmol) in 1,2-dimethoxy ethane (20 mL) was added and the resulting solution was stirred for 5 minutes at 0° C. and then stirred at room temperature overnight. Water was added and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with H2O (50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using an Analogix® Intelliflash280™ (Hex-EtOAc, 0 to 25%) to give the title compound. MS (DCI/NH3) m/z 212 (M+NH4)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.CC1(C)C2[C:34](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:33][C:15]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[OH:55].C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:11][C:8]([C:4]1[CH:3]=[C:2]([C:15]([O:33][CH3:34])=[O:55])[CH:7]=[N:6][CH:5]=1)([CH3:10])[CH3:9]
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CO
Reactant: CC(C)(O)c1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(C(C)(C)O)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of the title compound from Step A (1.99 g, 9.21 mmol), palladium acetate (0.041 g, 0.041 Xantphos (0.213 g, 0.368 mmol), methanol (3.73 mL, 92.1 mmol), and triethylamine (18.33 mL, 132.0 mmol) was stirred under an atmosphere of carbon monoxide at 70° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, filtered through CELITE© and concentrated under reduced pressure. Purification by flash chromatography on silica gel (30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 195.99 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.8 Hz, 1 H), 8.92 (d, J=2.2 Hz, 1 H), 8.41 (t, J=2.0 Hz, 1 H), 3.96 (s, 3 H), 2.27 (br s, 1 H), 1.64 (s, 6 H).
Reaction SMILES: [CH2:1]([Hg:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2][CH:3]=[CH2:4].C([Mg]Br)CC=C.BrCCC=C.[Mg]>O1CCCC1.O>[CH:1]([Hg:5][CH:6]=[CH:7][CH2:8][CH3:9])=[CH:2][CH2:3][CH3:4]
Reactant: C=CCC[Hg]CCC=C
Agent: C=CCCBr
Agent: C=CCC[Mg]Br
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC=C[Hg]C=CCC
Yield: 60 %

Procedure:
Preparation of bis(3-butenyl)mercury: To a solution of 3-butenylmagnesium bromide, prepared from 25 g of 1-bromo-3-butene (187 mmole) and 5 g of magnesium (208 mmole) in 40 mL of tetrahydrofuran, was added dropwise, at 50° C. with stirring, a solution of 25.2 g of mercuric chloride (93 mmole) in tetrahydrofuran. After stirring for 2 hours at 60° C., the reaction mixture was hydrolyzed with water at 0°-5° C. Organic layer was separated from aqueous layer; the product was distilled to give bisbutenyl mercury in 60% yield. The yield of the desired product was confirmed by gas chromatography (GC) and 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])#[N:26].O1CCOCC1.C([O-])(O)=O.[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.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[C:28]([F:36])[CH:29]=2)[N:3]=1
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(Cl)nc(N)n2)C1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To N-[(3R,5R)-1-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-3-piperidinyl]-N,3,3-trimethylbutanamide (80 mg, 0.23 mmol) and (4-cyano-3-fluorophenyl)boronic acid (49 mg, 0.29 mmol) were added 1,4-dioxane (4 mL) and sat. aq. NaHCO3 (2 mL), and the resulting mixture was purged (“degassed”) with N2 into a sealable tube. Pd(Ph3P)4 (26 mg, 0.023 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The reaction was allowed to cool down to room temperature and poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 75% EtOAc/Hexanes) afforded the title compound (84 mg) as a solid. LC-MS (ES) m/z=439 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:16][N:17]([CH:19](OC)OC)[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:1][C:2]1[N:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C
Reactant: COC(OC)N(C)C
Product: CCOC(=O)c1cc([N+](=O)[O-])cnc1C=CN(C)C

Procedure:
A solution containing 20.88 g of ethyl 2-methyl-5-nitronicotinate in 100 mL 1,1-dimethoxytrimethylamine is heated at reflux for three hours and 15 minutes. The mixture is cooled and the solid collected by filtration, washed with methanol and air dried to give 26 g of the desired enamine as a dark red solid mp 176°-179° C.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][NH:17][C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])=[CH:13][N:12]=[CH:11]2)=[CH:7][CH:6]=1)#[N:4].CCN(CC)CC.[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([N:22]2[CH2:23][CH2:24][CH2:25][C@H:20]([C:18](=[O:19])[NH:17][CH2:16][CH2:15][C:14]3[N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:27][CH:26]=4)[CH:11]=[N:12][CH:13]=3)[CH2:21]2)=[O:43])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2CCCNC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2CCCN(C(=O)N(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3(S)-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine dihydrochloride (Example 11, Step E) (0.346 g, 0.843 mmol) was dissolved in CH2Cl2 (10 mL), treated with Et3N (0.587 mL, 4.2 mmol) and diphenylcarbamoyl chloride (0.390 g, 1.686 mmol) and stirred at ambient temperature for 1 hr. The reaction mixture was concentrated to dryness, partitioned between EtOAc and satd NaHCO3 soln, the organic layer separated, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification on a silica gel column eluting with 0-2% MeOH/CH2Cl2. Anal. calculated for C32H32N6O2.0.95 H2O: C, 69.91; H, 6.22; N, 15.29; Found C, 69.97; H, 6.15; N, 14.80.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([NH2:19])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl:29][C:30]1[S:34][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=1>C(Cl)Cl.CCOC(C)=O>[Cl:29][C:30]1[S:34][C:33]([S:35]([NH:19][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])(=[O:37])=[O:36])=[CH:32][CH:31]=1
Reactant: CCC(CC)C(N)c1ccnn1Cc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1Cc1ccc(OC)cc1
Yield: 51 %

Procedure:
To {2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}amine (0.500 g, 1.74 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.29 mL, 2.1 mmol) and 5-chlorothiophene-2-sulfonyl chloride (0.450 g, 2.09 mmol). After 2 days the reaction mixture was diluted with EtOAc (30 mL), washed with 1 N HCl (30 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexane, 3:7, then 1:1) provided 5-chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (0.415 g, 51%) as an oil.