Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Li+].[Li].N.[CH3:5][O:6][CH:7]([O:15][CH3:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:14].C[O:18][CH:19](OC)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I>CS(C)=O>[CH3:16][O:15][CH:7]([O:6][CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=[O:18]
Reactant: C#CCCCCCC(OC)OC
Reactant: COC(CCCCCI)OC
Agent: N
Agent: [Li+]
Agent: [Li]
Solvent: CS(C)=O
Product: COC(CCCCCC#CCCCCCC=O)OC
Yield: 84.5 %

Procedure:
To a stirred suspension of lithium amide, prepared from 1.45 g (0.21 atom) of lithium in ca. 200 ml of liquid ammonia was added 30.6 g (0.18 Mole) of 1,1-dimethoxy-oct-7-yne over a period of 10 min. Dimethyl-sulfoxide (100 ml) was then added, followed by 62.5 g (0.23 Mole) of 1,1-dimethoxy-6-iodohexane within 10 min. Work-up as above gave an oil, from which low-boiling impurities were removed by heating at 100°/0.05 Torr. Crude tetradec-7-yn-1,14-dial dimethylacetal (40.8 g, 72% yield) was used without further purification. A sample was submitted to a rapid distillation: b.p. 140°/0.05 Torr.--IR: 1125, 1070, 1050 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Br:9])[C:7]=1[F:8].Br[C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].C([O-])([O-])=O.[K+].[K+].N#N>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:9][C:6]1[CH:5]=[C:4]([C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21])[CH:3]=[C:2]([Br:1])[C:7]=1[F:8]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Br)c(F)c(Br)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Br)c(F)c(Br)c1)C(F)(F)F
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 2-(3,5-dibromo-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 0.79 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (207 mg, 1.18 mmol), Pd(dppf)Cl2 (112 mg, 0.16 mmol), K2CO3 (218 mg, 1.58 mmol) in THF (2 mL) and water (1 mL) was heated at 80° C. in a sealed vial under N2 atmosphere for 12 h, cooled to rt, quenched with water, extracted with EA (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluted with PE to give 1,3-dibromo-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (100 mg, yield 30%) as solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:29]1[CH2:30][CH:27]([C:20]2[C:21]([CH3:26])=[C:22]([CH:25]=[C:18]([CH:16]([N:10]3[C:6]4=[N:7][CH:8]=[N:9][C:4]([NH2:3])=[C:5]4[C:12]([CH:13]([F:14])[F:15])=[N:11]3)[CH3:17])[C:19]=2[O:31][CH3:32])[C:23]#[N:24])[CH2:28]1)(=[O:35])[CH3:34]
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (21 mg, 0.043 mmol, racemic intermediate from Example 129, Step 2), acetyl chloride (3.4 μL, 0.048 mmol), and triethylamine (18 μL, 0.13 mmol) in methylene chloride (0.3 mL) was stirred overnight at room temperature. The solvents were evaporated and the crude material was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H24F2N7O2 (M+H)+: m/z=456.2; Found: 456.2.
Reaction SMILES: [NH:1]([C:3]1[C:4]2[C:11](I)=[CH:10][N:9]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@:14]3([CH3:22])[OH:15])[C:5]=2[N:6]=[CH:7][N:8]=1)[NH2:2].[C]=O.C([SnH](CCCC)CCCC)CCC.C1C[O:41][CH2:40]C1>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>[CH:40]([C:11]1[C:4]2[C:3]([NH:1][NH2:2])=[N:8][CH:7]=[N:6][C:5]=2[N:9]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@:14]2([CH3:22])[OH:15])[CH:10]=1)=[O:41]
Reactant: C1CCOC1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(NN)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: [C]=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(C=O)c2c(NN)ncnc21

Procedure:
The compound from Step 1 is dissolved as a 0.1M solution in THF and 0.2 eq. of tetrakis(triphenylphosphine)palladium (0) are added. While bubbling carbon monoxide gas into the solution, 1 eq. of tributyltin hydride is added over the period of 6 hours. The reaction is then evaporated and subjected to silica gel chromatography, to give the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([P:7]([CH3:11])(=[O:10])[O:8]C)([O:5][CH3:6])[CH3:4].Cl.[OH-].[Na+:14]>>[CH3:1][O:2][C:3]([P:7]([CH3:11])(=[O:8])[O-:10])([O:5][CH3:6])[CH3:4].[Na+:14]
Reactant: COC(C)(OC)P(C)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(C)(OC)P(C)(=O)[O-]

Procedure:
The phosphinate ester product of Example 16 (220 g) was refluxed 2 hr with aqueous sodium hydroxide (2 N: 660 ml). The cooled solution was taken to pH 7.0 with conc. hydrochloric acid, evaporated in vacuo and the solid residue was triturated with methanol and insoluble material filtered off. The filtrate was again evaporated to dryness, the residue triturated with methanol and further insoluble material filtered off. The filtrate was finally evaporated to dryness, triturated with acetone and filtered to give the title compound (2.9 g) mp 258°-262° C., identical (ir nmr) with the product from Example 17.
Reaction SMILES: [CH:1](OCC)=[O:2].[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:9][N:8]=1>CO>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH:1]=[O:2])[CH2:17][CH2:18]2)[C:10]([O:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:9][N:8]=1
Reactant: Nc1ncc(Oc2ccc(Cl)cc2)c(N2CCNCC2)n1
Reactant: CCOC=O
Solvent: CO
Product: Nc1ncc(Oc2ccc(Cl)cc2)c(N2CCN(C=O)CC2)n1
Reaction time: 16 h
Yield: 53 %

Procedure:
Ethyl formate (Acros) (11 mL) was added to a solution of 2-amino-5-(4-chlorophenoxy)-4-(piperazino)pyrimidine (0.433 g, 1.41 mmoles) in methanol, and after 16 hours the solution was spin evaporated in vacuo to give a colorless syrup. The syrup was triturated under hexanes containing 1% ethyl acetate to give a solid that was collected and recrystallized from ethyl acetate to give 0.250 g (53% yield) of 2-amino-5-(4-chlorophenoxy)-4-(4-formylpiperazino)pyrimidine as white crystals, mp 159-161° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cccc(Cl)n1

Procedure:
6-Chloro-2-pyridylmethanol, 0.982 g (6.84 mmole) in 10 ml methylene chloride was treated with 0.814 g thionyl chloride at room temperature for one hour. The mixture was neutralized with saturated sodium bicarbonate solution, extracted with methylene chloride, the extracts dried and solvent evaporated to give 815 mg of product as colorless crystals. 1H-NMR(CDCl3)ppm (delta): 4.7 (s, 2H), 7.1-8.0 (m, 3H).
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1cccc(C(F)(F)F)c1

Procedure:
2-(3-(trifluoromethyl)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (3-(trifluoromethyl)phenyl)boronic acid (100 mg, 135.1 mg theoretical, 74%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:23][NH:24][C:25](=[O:31])[CH:26]([F:30])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:23][NH:24][C:25](=[O:31])[CH:26]([F:30])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: O=C(O)C(F)C(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)C(F)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=468.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-fluoro-malonamic acid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:27]C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH2:23][CH3:27])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CCI
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2cn(C)nc2C)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 0.698 mmol) in DMF (5 ml) cooled with an ice-bath was added 55% NaH in oil (1.398 mmol). The RM was stirred for 30 min at rt then was added iodoethane (0.085 ml) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc and washed with saturated aqueous NaHCO3, with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (CH2Cl2/MeOH 0% to 3.5%). The fractions containing product were evaporated together to give the title compound as a brown solid. (HPLC: tR 2.41 min (Method A); M+H=386, 388 MS-ES)
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:27])[C:7]([N:9]([CH:14]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=O)C>N>[SH:4][CH2:5][CH:6]([CH3:27])[C:7]([N:9]([CH:14]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)O)C(=O)C(C)CSC(C)=O)CC2
Agent: N
Product: COc1cc2c(cc1OC)C(N(CC(=O)O)C(=O)C(C)CS)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 738.5 %

Procedure:
N-(3-Acetylthio-2-methylpropionyl)-N-(5,6-dimethoxy-1-indanyl)glycine (1.0 g) is dissolved in 50 ml of 5.5N methanolic ammonia, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated at 40° C. under reduced pressure, and the residue is dissolved in 10 ml of water, made acidic with 10% hydrochloric acid, and extracted with 200 ml of ethyl acetate. The extract is washed with water, dried, and then treated with activated carbon. After ethyl acetate is distilled off under reduced pressure, a mixture of ethyl ether and petroleum ether is added to the residue to give 6.6 g of N-(3-mercapto-2-methylpropionyl)-N-(5,6-dimethoxy-1-indanyl)glycine as colorless powder.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[N+:32](=[CH2:34])=[N-:33]>C(OCC)(=O)C.C(OCC)C>[CH2:10]([C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14](=[O:16])[CH:34]=[N+:32]=[N-:33])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
A solution of Boc-Norleucine (6.9 g, 30 mmol) in ethyl acetate (EtOAc) (80 mL) was cooled to -25° C. and N-methylmorpholine (3.3 mL, 30 mmol) was added followed by isobutyl chloroformate (4.2 mL, 32 mmol). The mixture was stirred for 15 minutes at -25° C. and diethylether (Et2O) (50 mL) was then added. After cooling the mixture to -50° C., the white precipitate was filtered under N2 and the cold filtrate was treated with a solution of diazomethane in Et2O (130 mL, 0.4 M, 52 mmol). The mixture was allowed to proceed overnight, gradually warming up to room temperature. Excess of diazomethane was removed by bubbling a N2 stream through the solution and the solvent was then evaporated. The residual oil was dissolved in EtOAc (100 mL) and was washed with saturated NaHCO3 (1×100 mL) and brine (1×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield 7.5 g (98)% of crude product.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[C:14]([CH3:29])([CH3:28])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][C:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH3:28]
Reactant: CC(C)(Br)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
In 75 ml of dry N,N-dimethylformamide are dissolved 14.7 g of N-hydroxyphthalimide and 27.2 g of p-nitrobenzyl α-bromoisobutyrate, followed by addition of 12.4 g of potassium carbonate. The mixture is stirred at room temperature for one hour. The stirring becomes difficult due to precipitation of an orange-colored solid and, therefore, 75 ml of dry N,N-dimethylformamide is added. After 24 hours of stirring at room temperature, the reaction mixture is concentrated under reduced pressure to about half its original volume and the concentrate is put in 700 ml of water with ice-cooling and stirring. The mixture is further stirred for 30 minutes and the resultant crystalline precipitate is recovered by filtration and washed with water. The crystals are dissolved in 500 ml of methylene chloride, washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The solid residue is washed with ether-petroleum ether (1:1) and a small amount of ether in this order to give 27.0 g of N-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxy]phthalimide as colorless crystals, m.p. 145°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])=[CH:8][C:9]=1[N+:10]([O-])=O)=[O:4].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])=[CH:8][C:9]=1[N:10]=[CH:21][N:24]([CH3:26])[CH3:25])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(CCC(C)(C)O)cc1[N+](=O)[O-]
Product: COC(=O)c1sc(CCC(C)(C)O)cc1N=CN(C)C

Procedure:
5-(3-Hydroxy-3-methylbutyl)-3-nitrothiophene-2-carboxylic acid methyl ester was reacted with dimethoxymethyldimethylamine by method B. The product with the molecular weight of 298.41 (C14H22N2O3S) was obtained in this way; MS (ESI): 299.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@H:10]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[NH2:11][C@H:10]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1.[F:38][C:37]([C:35]([OH:41])=[O:36])([F:40])[F:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Boc-L-tryptophan benzyl ester (0.5 g, 1.27 mmol) was dissolved in a solution of 20% TFA in CH2Cl2. The reaction mixture was stirred under nitrogen at room temperature for 30 min and evaporated to dryness. Trituration of the resulting oil with Et2O provided 7 as a white solid (quantitative yield). mp=143-145° C.; 1H NMR (CD3CN) 9.42 (br s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.35 (m, 3H), 7.26 (m, 2H), 7.16 (m, 2H), 7.04 (t, J=7.9 Hz, 1H), 5.15 (d, J=12.3 Hz, 1H), 5.09 (d, J=12.3 Hz, 1H), 4.36 (t, J=6.2 Hz, 1H), 3.44 (d, J=6.2 Hz, 2H) ppm; 13C NMR (CDCl3) 170.1, 137.6, 136.0, 129.5, 129.4, 129.3, 128.1, 126.2, 122.9, 120.3, 119.1, 112.6, 107.5, 68.8, 54.4, 26.9 ppm; IR (KBr) 3412, 2840, 1742, 1673, 1498, 1205, 1137, 735 cm−1; HRMS calcd for C18H19N2O2 294.1368 found 294.1362.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:16]([N:23]1[CH2:24][CH2:25][N:26]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:27][CH2:28]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCN1CCNCC1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CCO
Product: CCCCCCCN1CCN(CC(O)COc2cccc3ccccc23)CC1
Yield: 92.2 %

Procedure:
To a solution of 2-((1-naphthyloxy)methyl)oxirane (106 mg, 0.53 mmol) in ethanol (1 mL) was added 4-heptylpiperazine (118 mg, 0.64 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1018 (188 mg, 93%).
Reaction SMILES: [S:1]1[C:5]2[C:6]3[S:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:10]1[S:11][C:6]2[C:5]3[S:1][CH:2]=[CH:3][C:4]=3[S:8][C:7]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2sc3ccsc3c2s1
Product: Brc1cc2sc3ccsc3c2s1

Procedure:
Compound 2 was synthesized as shown in Scheme 2. Under acid condition, dithieno[3,2-b:2′,3′-d]thiophene (Organic Syntheses, Vol. 83, p. 209 (2006)) was reacted with NBS affording 2-bromodithieno[3,2-b:2′,3′-d]thiophene 7, which underwent Suzuki cross-coupling reaction with boronic acid R1—B(OH)2 (J. Mater. Chem., 2010, 20, 2182-2189) to afford intermediate 8 in 71% yields. Finally 8 was converted to PhN-OFFT-TCN by reacting with n-BuLi and tetracyanoethylene at low temperature in 85% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCC1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.9 %

Procedure:
To a solution of 3 mL (34.4 mmol) of oxalyl chloride in 80 mL of CH2Cl2 at −78° C. was added a solution of 4.9 mL (68.8 mmol) of DMSO in 5 mL of CH2Cl2. After stirring for 10 min, a solution of 4 g (18.24 mmol) of 1-benzyl-4-(2-hydroxy-1-ethyl)piperidine (Acros Chemical) in 20 mL of CH2Cl2 was added dropwise. After 30 min, 12 mL (86.1 mmol) of Et3N was added and the reaction mixture was allowed to warm to rt over a period of 30 min. To the reaction mixture was added 100 mL of H2O and it was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, and dried over MgSO4 and filtered. The filtrate was concentrated to give 4 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)([OH:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][C:9]1([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2ccccc2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3ccccc3O2)CC1
Temperature: 110 °C
Yield: 105.6 %

Procedure:
A mixture of tert-butyl 4-(1-(2-bromophenyl)-2-hydroxypropan-2-yl)piperidine-1-carboxylate (1.14 g, 2.86 mmol), BINAP (0.266 g, 0.427 mmol), Pd(OAc)2 (93 mg, 0.412 mmol), and K2CO3 (1.188 g, 8.59 mmol) in toluene (14.3 mL) was degassed for 10 min. After this time, the reaction mixture was heated in 110° C. oil bath overnight. At the conclusion of this period, the resulting solid was collected by filtration and rinsed with CH2Cl2. The filtrate was concentrated to afford the crude product, which was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 25% EtOAc) to afford Compound 11B as a colorless oil (0.959 g, 97% yield). LC/MS (m/z)=657 (2M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]=[C:6]([S:9][CH3:10])[S:7][CH3:8].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH3:10][S:9][C:6](=[N:5][C:4](=[CH:14][N:15]([CH3:17])[CH3:16])[C:3]([O:2][CH3:1])=[O:11])[S:7][CH3:8]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CN=C(SC)SC
Solvent: CN(C)C=O
Product: COC(=O)C(=CN(C)C)N=C(SC)SC

Procedure:
Commercially available N-[Bis(methylthio)methylene]glycine methyl ester (5.06 g, 26.18 mmol) and N,N-Dimethylformamide dimethyl acetal (4.03 g, 31.41 mmol) were dissolved in N,N-dimethylformamide (10 mL) and heated to reflux under nitrogen for 4.5 h. The solvent was removed under reduced pressure and the product solidified (6.44 g, 99%) after storage at room temperature under high vacuum over night. 1H NMR (CDCl3, 400 MHz): δ 6.96 (s, 1H); 3.68 (s, 3H); 2.95 (s, 6H); 2.53 (s, 3H); 2.49 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:7]([CH3:49])=[N:6]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:7]([CH3:49])=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cc(F)ccc4F)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(Cc2cc(F)ccc2F)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 25.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (230 mg, 0.305 mmol) was hydrolyzed by lithium hydroxide (129 mg, 3.05 mmol), THF/Methanol/water (12/4/4 ml) to afford 46 mg (25.2% yield) of the titled compound. MS: m/z=599.3 (M+1).