Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:27])[CH:15]=[C:16]([C:25]#[N:26])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)=[O:12])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:27])[CH:15]=[C:16]([C:25]#[N:26])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:20][CH:19]=1)=[O:12])[CH3:9]
Reactant: [Zn+]C1CCCC1
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)cn1C
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(C3CCCC3)cc2)c(C#N)cn1C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Add cyclopentylzinc bromide (0.5M, 7.2 mL, 3.6 mmol) to 3-(4-bromo-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.50 g, 1.80 mmol, prepared in example E-3a or E-3b), tris(dibenzylideneacetone)palladium(0) (0.06 g, 0.07 mmol), and triphenylphosphine (0.07 g, 0.27 mmol) in dioxane and heat to 80° C. with stirring. After 18 hours, cool the reaction mixture, and pour into water. Extract the quenched reaction mixture with ethyl acetate. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexane to provide the title compound. Mass spectrum (m/e): 323.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[C:47]3([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:46](=[O:53])[NH:45][C:44]2=[O:54])=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:50]3[CH2:49][CH2:48][C:47]4([N:43]([C:40]5[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=5)[C:44](=[O:54])[NH:45][C:46]4=[O:53])[CH2:52][CH2:51]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)C2(CCNCC2)N1c1ccc(F)cc1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)NC(=O)N4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 85 °C

Procedure:
Combine the 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5.0 mmol), 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride (7.5 mmol, 1.5 eq.), N,N-diisopropylethylamine (15 mmol), and DMF (8 mL). Heat the mixture at 85° C. for 48 h. Cool to ambient temperature and add ethyl acetate (100 mL). Extract with water (25 mL), 1N HCl (2×25 mL), saturated NaHCO3 (25 mL), and saturated NaCl (25 mL). Dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]2[CH:8]=[C:9]3[C:14](=[C:15]([OH:16])[C:5]=2[C:4](=[O:38])[CH:3]=1)[C:13]([OH:17])=[CH:12][C:11]([OH:18])=[C:10]3[C:19]1[C:34]2[C:23](=[C:24]([OH:35])[C:25]3[C:30](=[O:31])[CH:29]=[C:28]([CH3:32])[O:27][C:26]=3[CH:33]=2)[C:22]([OH:36])=[CH:21][C:20]=1[OH:37].[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1>[OH:16][C:15]1[C:5]2[C:4](=[O:38])[CH:3]=[C:2]([CH3:1])[O:7][C:6]=2[CH:8]=[C:9]2[C:14]=1[C:13]([OH:17])=[CH:12][C:11]([O:18][C:41]([N:40]([CH3:44])[CH3:39])=[O:42])=[C:10]2[C:19]1[C:34]2[C:23](=[C:24]([OH:35])[C:25]3[C:30](=[O:31])[CH:29]=[C:28]([CH3:32])[O:27][C:26]=3[CH:33]=2)[C:22]([OH:36])=[CH:21][C:20]=1[O:37][C:41]([N:40]([CH3:44])[CH3:39])=[O:42]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(=O)c2c(O)c3c(O)cc(O)c(-c4c(O)cc(O)c5c(O)c6c(=O)cc(C)oc6cc45)c3cc2o1
Solvent: c1ccncc1
Product: Cc1cc(=O)c2c(O)c3c(O)cc(OC(=O)N(C)C)c(-c4c(OC(=O)N(C)C)cc(O)c5c(O)c6c(=O)cc(C)oc6cc45)c3cc2o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 50 mg of 2-methyl-5,6,8-trihydroxy-9-(5,6,8-trihydroxy-2-methyl-4H-naphtho[2,3,b]pyran-4-one-9yl)-4H-naphtho[2,3,b]pyran-4-one in 2 ml of pyridine at 0° C. was added with 0.02 ml of dimethylcarbamoyl chloride. The mixture was then stirred at 0° C. for 2 hours and warmed to room temperature overnight. The mixture was quenched with 1 ml of 0.1N sodium hydroxide solution, stirred for 20 minutes and partitioned between chloroform and water. The chloroform layer was then washed with diluted hydrochloric acid solution, saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated. The resulting solid was purified on HPLC on a C-18 silical gel column to provide the title compound.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[I:13]N1C(=O)CCC1=O>CN(C)C=O>[I:13][C:11]1[CH:12]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
To a solution of Example 110B (1.117 g, 6.03 mmol) in dimethylformamide (60.3 mL) was added N-iodosuccinimide (1.492 g, 6.63 mmol). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was quenched with 10% sodium thiosulfate and saturated aqueous sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated. Water was added to the residue, and the mixture was stirred at room temperature for 10 minutes and filtered to give the title compound (1.55 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.S(Cl)([Cl:15])(=O)=O>CO>[Cl:15][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])=[O:10]
Reactant: CC(=O)c1ccc(Cl)cc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: CO
Product: O=C(CCl)c1ccc(Cl)cc1F

Procedure:
Stir a mixture of heptanes (1.5 L), methanol (0.4 L), and 1-(4-chloro-2-fluorophenyl)ethanone (1 kg, 5.81 mol) with cooling to <5° C. Add sulfuryl chloride (0.608 L, 1.02 kg, 7.55 mol) as a heptanes (1.5 L) solution drop-wise to the mixture keeping the reaction temperature <15° C. during the addition. After 2 h quench the reaction at ambient temperature to a pH of 6 with sodium hydroxide (5N, 2.0 L). Extract the reaction mixture with methylene chloride (2 L) and concentrate the extract to form a white solid. Filter and dry the solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[C:22]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)(=[O:24])[CH3:23]
Reactant: O=[N+]([O-])c1cccc(C#CCCOCCCCCCBr)c1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCCCCOCCC#Cc1cccc([N+](=O)[O-])c1
Temperature: 75 °C
Yield: 75.6 %

Procedure:
A mixture of 1-{4-[(6-bromohexyl)oxy]but-1-ynyl}-3-nitrobenzene (4.18 g), sodium acetate (9.68 g), tetrabutylammonium bromide (384 mg) in DMF (15 ml) and water (10 ml) was heated to 75° C. for 6 h. The mixture was then allowed to cool to 20° C. and then extracted with Et2O. The organic solution was concentrated and purified by chromatography on a Biotage (40 g) eluting with Et2O-petroleum ether(1:19 increasing to 1:1) to give the title compound (2.973 g). LCMS RT=3.84 min.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C(#N)C>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)ONCCC1CCNCC1
Reactant: Brc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)ONCCC1CCN(c2ncccn2)CC1

Procedure:
N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared per Method K′ above), DIEA (0.75 mL) and 2-bromopyrimidine (204 mg) (Aldrich) in acetonitrile (5 mL) were heated under reflux overnight. The solvent was removed under reduced pressure and the black liquid was subjected to a column chromatography, eluted with 1:1 EtOAc/hexanes, to give pure N-t-butoxycarbonyloxy 2-[1-(pyrimidin-2-yl)piperidin-4-yl]-ethylamine as a pale yellow oil. 1H NMR (CDCl3) δ=8.21 (d, J=5.1 Hz, 2H), 6.36 (t, J=5.1 Hz, 1H), 4.64 (d, J=13.8 Hz, 2H), 3.14–3.07 (m, 2H), 2.76 (dt, J=2.7, 13.2 Hz, 1H), 1.69 (d, J=13.8 Hz, 1H), 1.57–1.30 (m, 11H), 1.20–1.03 (m, 3H);
Reaction SMILES: CN(C)C=O.[OH:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:23][O:22][C:20]([CH2:19][O:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])=[O:21]
Reactant: COC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 50 ml of dry N,N-dimethylformamide are added 10 g of N-hydroxyphthalimide and 9.38 g of methyl bromoacetate, followed by addition of 8.5 g of potassium carbonate. The mixture is stirred at room temperature for 2 days and, then, poured into 400 ml of water. The resulting crystalline precipitate is recovered by filtration, washed with water, hexane and ether in this order to give colorless needles of N-methoxycarbonylmethyloxyphthalimide, m.p. 137°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][C:15]3=O)[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO.C(O)(=O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][CH:15]3[NH:24][CH3:23])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc2c1CCC2=O
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCc2c(Oc3cc(Cl)ccc3C#N)cccc21
Yield: 78.7 %

Procedure:
4-Chloro-2-(1-oxoindan-4-yloxy)benzonitrile (0.12 g, 0.42 mmol), methylamine (33% in ethanol, 1.0 mL, 8.0 mmol) and sodium cyanoborohydride (100 mg, 0.86 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (1.0 mL) in methanol (30 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (40 mg, 0.34 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(1-methylaminoindan-4-yloxy)benzonitrile fumarate (111 mg, 63%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[NH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[NH:5]3)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1Nc2cc(Br)ccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC1Nc2cc(-c3ccc(Cl)cc3)ccc2NC1=O
Temperature: 25 °C

Procedure:
A solution of 6-bromo-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (2.4 g, 10 mmol), 4-chlorophenyl boronic acid (1.6 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakis-(triphenylphosphine)palladium (0) in dimethoxyethane (150 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to obtain crude product (0.83 g, 30%). A sample was recrystallized from ethanol to afford the title compound: m.p. 228-230° C. 1H-NMR (DMSO-d6) δ1.28 (d, J=6.63 Hz, 3H), 3.83 (q, J=6.63 Hz, 1H), 6.16 (bs, 1H), 6.81 (d, J=8.00 Hz, 1H), 6.91 (dd, J=8.05, 1.9 Hz, 1H), 6.95 (d, J=1.7 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 10.32 (s, 1H); MS (EI) m/z 272/274.
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][C:10]([F:15])([F:14])[CH:11]([Cl:13])[F:12])=[CH:7][N:6]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:5]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.O>ClCCl>[Cl:13][CH:11]([F:12])[C:10]([F:15])([F:14])[O:9][C:8]1[C:4]([C:1]#[N:2])=[N:5][N:6]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:24])[F:25])=[CH:18][C:17]=2[Cl:27])[CH:7]=1
Reactant: NC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A mixture of (RS)-3-carbamoyl-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.75g) and phosphorus oxychloride (15ml) was heated at 80° C. for 6 hours. Water (100ml) and dichloromethane (50ml) were added to the cooled mixture and the layers were separated. The aqueous layer was extracted with dichloromethane (2x50ml) and the combined organic layers were washed with aqueous sodium hydrogen carbonate solution (1M; 30ml), dried over magnesium sulfate, and evaporated to give (RS)-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyanopyrazole (0.4g) as an off-white crystalline solid, m.p. 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[Br:12]Br.[K+].[Br-]>O>[Br:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C1Cc2cc(Br)cc(F)c2N1
Reaction time: 0.33 h
Yield: 75 %

Procedure:
7-Fluoroindolin-2-one (800 mg, 5293 μmol) was taken up in 30 mL of boiling water. Br2 (273 μL, 5293 μmol) and KBr (1260 mg, 10586 μmol) were added dropwise in 5 mL of water over 10 minutes. A white precipitate began to form as the solution was added. The mixture was stirred for 20 minutes. The mixture was then chilled in an ice bath for 30 minutes, washed with 30 mL of a saturated NaHCO3 solution and extracted twice with 50 mL of EtOAc. The organic layers were concentrated and purified with silica gel column chromatography, eluting with 0-35% EtOAc/hexane to give 5-bromo-7-fluoroindolin-2-one (913 mg, 75% yield). MS m/z: 230 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 3.58 (s, 2H), 7.20 (dd, J=10.07, 0.88 Hz, 2H), 7.63 (s, 1H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.C([O:8]/C=C\[Sn](CCCC)(CCCC)CCCC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[C:33]([CH:43]([CH3:45])[CH3:44])[C:32]=2C=O)=[CH:27][CH:26]=1>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[C:33]([CH:43]([CH3:45])[CH3:44])[C:32]=2/[CH:2]=[CH:3]/[CH:4]=[O:8])=[CH:27][CH:26]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/C=O
Reaction time: 1 h
Yield: 86.7 %

Procedure:
n-BuLi (1.6M in hexanes, 1.52 ml, 2.43 mmol) was added to a solution of cis-1-ethoxy-2-(tri-n-butylstannyl)ethylene (961 mg, 2.66 mmol) in dry THF (7.5 ml) at -78° C. The mixture was stirred for 1 hour, then treated with a solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (708 mg, 2.22 mmol) in THF (3.5 ml). One hour after the addition, the reaction was immersed in an ice bath, stirred for 5 minutes, then the mixture was quenched with H2O (8 ml) and 10% HCl (8 ml). The solution was stirred at room temperature for 2 hours, then basicified with 10% NaOH (10 ml) and extracted twice with Et2O. The combined Et2O layers were washed with H2O and brine, dried (Na2 SO4), then filtered and stripped to give a yellow oil. Chromatographic purification of the oil (Flash, Merck SiO2, 10% EtOAc in hexane) gave (E)-3-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal (665 mg, 87%) as a white solid. Recrystallization from hot hexane gave analytically pure material (580 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17]CC3C=CC=CC=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].[Hg].CO>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Agent: [Pd]
Agent: [Hg]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reaction time: 6 h
Yield: 48.1 %

Procedure:
1-Benzyl-4-benzyloxy-2-methyl-1H-indole 2 (86 g, 0.263 mole) was dissolved with ethyl acetate (1.5 L) and methanol (300 mL). To the mixture 10% Pd/C wet (18 g) was added to the solution. The reaction was then subjected to H2 gas passed through a mercury bubbler at room temperature and 1 atm. The mixture was left to stir for 6 h. The reaction mixture was filtered through Celite and concentrated. The residue was purified by column chromatography (3:1 Hexane:EtOAc) to afford 3 (30 g, 49%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18].CCN=C=NCCCN(C)C.Cl.[C:36]([O:40][C:41](=[O:55])[CH2:42][CH2:43][S:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](O)=[O:50])([CH3:39])([CH3:38])[CH3:37]>ClCCl.CN(C)C1C=CN=CC=1>[C:36]([O:40][C:41](=[O:55])[CH2:42][CH2:43][S:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:50])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinate (800 mg, 2.57 mmol, 1.00 equiv) in dichloromethane (2 mL), EDC.HCl (608 mg, 3.09 mmol, 1.20 equiv), 4-dimethylaminopyridine (380 mg, 3.11 mmol, 1.20 equiv), and 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (837 mg, 2.83 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at room temperature. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1-5:1). This resulted in 600 mg (40%) of methyl 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinate as yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[ClH:27].[ClH:27].[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(c2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C3CCCNC3)cc2)CC1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.56 mmol) in methanol (20 mL) was added 4N hydrochloric acid in ethyl acetate (20 mL) at room temperature. After stirring for 1 h, the resulting suspension was concentrated in vacuo. The residue was washed with ethyl acetate to furnish 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine trihydrochloride (1.84 g, 4.99 mmol, 90%) as white crystals.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5].[H][H]>O.[Ni]>[CH2:2]([OH:1])[CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5]
Reactant: O=CC[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Product: OCC[C@H](O)[C@H](O)CO
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
An 80 g (0.60 mole) portion of 2-deoxy-D-ribose was dissolved in 240 ml of water to form an aqueous solution into which 15 g of Raney nickel were added. The thus prepared reaction mixture in an autoclave was heated under a hydrogen pressure of 40 kg/cm2G up to a temperature of 70° C. taking 30 minutes and kept for additional 1 hour at the same temperature and under the same hydrogen pressure. After cooling, the reaction mixture taken out of the autoclave was filtered to remove the solid catalyst and the filtrate, as combined with the washings of the solid catalyst with water, was subjected to removal of the water to give about 80 g of 2-deoxy-D-erythropentitol. The yield of the product was almost quantitative.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH:23][C:9](=[O:11])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN)OC
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(CNC(=O)OCc1ccccc1)OC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (74.5 Kg) was charged to a 200-gallon reactor, followed by toluene (235.1 Kg). The mixture was stirred for 15 minutes and cooled to 5° C. A solution of aminoacetaldehyde dimethylacetal (30 Kg) and triethylamine (28.9 Kg) in toluene (26.1 Kg) was charged slowly to the reactor over a 1 hour period while maintaining the internal temperature below 30° C. The mixture was stirred at 20° C. until there remained no more than 1.0% CbzOSu, as determined by HPLC. Water (150 Kg) was charged to the reactor and the contents of the reactor were stirred for 15 minutes. The layers were separated and the organic layer was washed with 5% ammonium chloride (2×151 Kg) followed by a water wash (150 Kg). The product was taken onto the next step as a solution, without isolation.
Reaction SMILES: [NH2:1][C:2](=O)[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4])#[N:1]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 1-amino-2-methyl-1-oxopropan-2-ylcarbamate (Example 12 a, 12.5 g) and triethylamine (CAN 121-44-8, 29 g) in methylene chloride (150 mL) was added trifluoroacetic acid anhydride (CAN 407-25-0, 27.2 g) dropwise at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 4 h. After that the mixture was washed with water, 5 N citric acid and brine, the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (11 g, 97%) as a yellow solid; MS: m/e=207.1 [M+Na]+.