Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].CN(C)C=[O:40]>O=O>[C:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2](=[O:1])[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5](=[O:40])[C:4]=1[CH3:12])([OH:36])=[O:35]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Agent: O=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCCC(=O)O)=C(C)C1=O

Procedure:
To a solution of 300 mg of 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid (IV:n=21, R=H) in 20 ml of N,N-dimethylformamide is added 50 mg of bis(salicylidene)ethylenediiminocobalt(II) and the mixture is stirred in oxygen gas stream at room temperature for 24 hours. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and dried. The solvent is distilled off and the residue is dissolved in chloroform and column-chromatographed on silica gel, elution being carried out with chloroform. The eluate is recrystallized from ethanol to obtain 6-(21-carboxyheneicosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I:n=21, R=H) as orange-yellow needles melting at 86° C.-87° C.
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C.C(OCC)(=O)C.[OH-].[Na+]>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[O:21][N:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC(=O)Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: Nc1cc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 84 h
Yield: 92.9 %

Procedure:
To a solution of 3-oxo-4-phenylbutanenitrile (690 mg, 4.34 mmol) in ethanol (25 mL) is added pyridine (4.91 mL, 60.7 mmol) and hydroxylamine hydrochloride (301 mg, 4.34 mmol). The reaction mixture is allowed to stir at room temperature 84 h. The mixture is diluted with ethyl acetate and 1M aqueous NaOH solution. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine, dried (Na2SO4), and the solvent is removed in vacuo to afford the title compound as a yellow solid (702 mg, 93%). LCMS: 175.20 (M+H+).
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].C(N(CC)CC)C.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1
Reactant: C#CCOC
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(C(=O)OC)nc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Bis(triphenylphosphine)palladium (II) chloride (82.4 mg), copper iodide (22.3 mg), methyl propargyl ether (828 μL) and triethylamine (1.9 mL) were added to a solution of methyl 5-bromo-pyridine-2-carboxylate (423 mg) in tetrahydrofuran (10.6 mL), and the mixture was stirred at room temperature for 19 hours and 50 minutes. The reaction solution was concentrated under reduced pressure and water was added to the residue. After extraction with ethyl acetate, the organic layer was washed with brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (88.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].[I:12]N1C(=O)CCC1=O>CN(C)C=O>[I:12][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5](=[O:9])[NH:6][CH:7]=1
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COc1c(I)c[nH]c(=O)c1C#N
Temperature: 70 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (3.00 g) and N,N-dimethylformamide (70 mL) was added N-iodosuccinimide (5.84 g) at room temperature, and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. To the residue was added methanol, and the precipitate was collected by filtration to give the title compound (4.60 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH:15]1[CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[CH:14]3[CH2:16][CH:15]3[CH3:17])=[CH:3][C:2]=2[F:1])[CH2:27]1)[CH3:23]
Reactant: CCNCC1CCNC1
Reactant: CC1CC1n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4C)c3c2F)C1
Yield: 80.6 %

Procedure:
To 0.75 g (2.57 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(2-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.38 g (2.57 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.32 g (2.57 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for two hours, cooled, filtered, and the solids washed with ether to give 0.84 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-(2-methylcyclopropyl)4-oxo-3-quinolinecarboxylic acid, mp 225°-228° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[NH:13][C@H:12]([C:14]([NH2:16])=[O:15])[CH2:11][CH2:10]1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]1[C@@H:9]([CH3:8])[CH2:10][CH2:11][C@H:12]1[C:14]([NH2:16])=[O:15])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: C[C@H]1CC[C@@H](C(N)=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(2S,5S)-5-Methyl-pyrrolidine-2-carboxylic acid amide trifluoroacetate (2.0 g, 8.2 mmol, Example 84D) and triethyl amine (1.9 mL, 24.6 mmol) were dissolved in CH2Cl2 (6 mL), and the mixture was cooled to 0° C. Chloroacetyl chloride (0.39 mL, 9.0 mmol) was added slowly via syringe. After 2 h, saturated NaHCO3 was added, and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), concentrated and purified by flash chromatography (10% MeOH/EtOAc) to give the title compound. MS (DCI) m/z 205 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:3]=1.[F-:14].[Cs+].CS(C)=O>CCOC(C)=O>[F:14][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:3]=1
Reactant: Cc1cc(Cl)cc(-c2cncs2)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(F)cc(-c2cncs2)n1
Reaction time: 16 h

Procedure:
To a 2 dram vial equipped with a stir bar and charged with the entirety of 5-(4-chloro-6-methylpyridin-2-yl)thiazole from step 1 was added CsF (200 mg, 1.32 mmol) and DMSO (0.7 mL). The vial was capped and then placed in a 140° C. heating block with stirring for 16 h. The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with EtOAc (50 mL). The solution was twice washed with brine:water (25 mL:25 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford an amber solid residue. This material was subjected to silica gel chromatography (hexanes:EtOAc) to afford 5-(4-fluoro-6-methylpyridin-2-yl)thiazole as a colorless solid (7.1 mg, 21% over two steps). 1H-NMR (500 MHz, CDCl3) 8.84 (d, J=0.3 Hz, 1H), 8.32 (d, J=0.3 Hz, 1H), 7.22 (dd, J=9.3, 1.7 Hz, 1H), 6.82 (dd, J=9.2, 2.0 Hz, 1H), 2.59 (s, 3H); MS: MS m/z 195.2 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[NH:23][N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:13]=2)=[O:11])[CH3:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl.Br[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH2:43][CH2:44][N:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)[N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:13]=2)=[O:11])[CH3:8])=[CH:5][CH:6]=1
Reactant: BrCCN1CCOCC1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12)c1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(F)ccc34)nc12)c1ccncc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide (100 mg, 0.19 mmol) was combined with DMF (2 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 23 mg, 0.56 mmol) was added and the reaction was stirred at 0° C. for 10 min. 4-(2-Bromoethyl)morpholine hydrochloride (55 mg, 0.28 mmol) was added and the reaction was stirred at 0° C. for 30 min then warmed to room temperature. The reaction mixture was stirred for 2 h at room temperature then quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give 70 mg (58%) of 2-[6-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=645.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH2:17]O)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:28][CH2:17][C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:4]=3)=[CH:9][N:10]=[C:11]2[N:16]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(CO)ccn23)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(CBr)ccn23)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2′-fluoro-5′-(7-hydroxymethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (100 mg, 0.291 mmol) in dichloromethane (5 ml) was added carbon tetrabromide (289 mg, 0.872 mmol) and polymer-supported triphenylphosphine (291 mg, 0.872 mmol). This mixture was stirred at ambient temperature for 1 h followed by removal of the polymer by filtration. N,N-Dimethylformamide (5 ml) was added to the reaction mixture and dichloromethane removed by evaporation under vacuum without heating to give 5′-(7-bromomethylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile as a solution in N,N-dimethylformamide.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH3:8])[N:3]=1.[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=1[C:12](Cl)=[O:13].C([O-])(O)=O.[Na+].C(OC(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:8][N:4]1[C:5]([CH3:7])=[CH:6][C:2]([NH:1][C:12](=[O:13])[C:11]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:10]=2[CH3:9])=[N:3]1
Reactant: Cc1cc(N)nn1C
Reactant: Cc1cccc(C)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1C(=O)Nc1cc(C)n(C)n1
Reaction time: 18 h
Yield: 38.2 %

Procedure:
To a cooled (0°-5° C.) solution of 3-amino-1,5-dimethyl pyrazole (95%, 32.7 g, 0.28M) in anhydrous CH2Cl2 (200 ml) was added a CH2Cl2 (100 ml) solution of the 2,6 dimethyl benzoyl chloride (23.6 g, 0.14M). The reaction mixture was allowed to room temperature for 18 hours and then CH2Cl2 was concentrated to give an oily mixture which was diluted in AcOEt. This suspension was then treated with saturated NaHCO3. After usual work-up, the crude material was cristallized with diisopropyloxide to give 13 g of the desired amide (38% : yield based on the 2,6-dimethyl benzoyl chloride).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6](=[N:9]O)[CH2:5][CH2:4]1>CO.[OH-].[Na+].O>[CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=NO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(N)CC1

Procedure:
4-Dimethylamino-4-phenyl-cyclohexanone oxime (11 g) was dissolved in methanol (200 ml) and diluted with 5M NaOH (200 ml). Devarda alloy (30 g) was added in portions to this mixture. The reaction temperature here was between 50-60° C. 15 minutes after completion of the addition, the mixture was diluted with water (150 ml), methanol was removed in vacuo, and the aqueous solution was extracted with ether (5×50 ml). The combined extracts were dried over Na2SO4 and concentrated. N,N-Dimethyl-1-phenylcyclohexane-1,4-diamine was obtained as a yellow oil (10.0 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2.O[C:21]1[N:22]=CC2C(C=1)=CC=CC=2C#N>>[C:21]([C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2)#[N:22]
Reactant: N#Cc1cccc2cc(O)ncc12
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Product: N#Cc1cccc2cc(OS(=O)(=O)C(F)(F)F)ncc12

Procedure:
Following the procedure for trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, using 3-hydroxyisoquinoline-8-carbonitrile in place of 6-fluoroisoquinolin-3-ol, the title compound was obtained as a yellow solid. MS (ES+): m/z=303.04 [MH+]. HPLC: tR=3.55 min (ZQ2, polar—5 min).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.CN(C)C=O.[Na+].[CH3:31][S:32]([O-:34])=[O:33]>O>[CH3:31][S:32]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2)(=[O:34])=[O:33]
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(S(C)(=O)=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 120 h
Yield: 68.6 %

Procedure:
Reflux 1.4 gm. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carboxylate in 6 cc. of thionyl chloride for 10 minutes. Strip away excess thionyl chloride by evaporation and dissolve the chloro intermediate so produced in 14 cc. of N,N-dimethylformamide. Add 582 mg. of methanesulfinic acid sodium salt (10% excess). Stir at room temperature for 5 days. Dilute with water and separate the solids by filtration. Crystallize from 15 cc. of benzene to obtain the title product (yield 1.18 gm. 68.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12].O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:11]([NH2:12])=[N:16][NH:17][C:13]=1[NH2:14]
Reactant: NN
Reactant: N#CC(C#N)Cc1cccc(Cl)c1Cl
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Yield: 46.8 %

Procedure:
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0° C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.57 mL, 52.4 mmol). The mixture is heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.77 (s, 2H) 7.09 (m, 1H) 7.19 (t, J=7.96 Hz, 1H) 7.38 (m, 1H); LC/MS: MS (ES+) m/e 257.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[Cl:15])[CH2:25][CH2:24]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccccc1OCC1CCNCC1
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3Cl)CC2)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 10.9 %

Procedure:
After adding 1.16 g of 2-tert-butoxy-6-vinylpyrazine, 860 mg of 4-(2-chlorophenoxymethyl)piperidine hydrochloride and 0.43 g of anhydrous potassium carbonate to 10 ml of N,N-dimethylformamide, the mixture was stirred for 2 days at 100° C. Ice water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (145 mg, 11% yield).
Reaction SMILES: [O:1]1[C:3]2([CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:4]2)[CH2:2]1.[NH3:17].[C:18]([O:22][C:23]([O:25]C(OC(C)(C)C)=O)=O)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:19][C:18]([O:22][C:23]([NH:17][CH2:2][C:3]1([OH:1])[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1)=[O:25])([CH3:21])[CH3:20]
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CC2(CO2)C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7 %

Procedure:
Phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (165 mg, 0.75 mmol), prepared using procedures similar to those described in Reference 3, in THF (1 mL) was added to anhydrous ammonia saturated in THF (10 mL) and the mixture was allowed to stir in a sealed vessel at room temperature over 24 hours. The solution was then concentrated and taken back into THF (1 mL) followed by addition of di-tert-butyldicarbonate (164 mg, 0.75 mmol) and stirred for one hour at room temperature. The mixture was then concentrated and the residue purified by silica gel flash chromatography using hexanes:ethyl acetate (1:1) as eluent to give phenylmethyl 3-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-hydroxyazetidine-1-carboxylate (16.5 mg, 7% yield) and unreacted epoxide (120 mg, 73% recovery). 1H-NMR (400 MHz, CDCl3): 7.34 (m, 5H), 5.10 (br, 1H), 5.09 (s, 2H), 4.68 (s, 1H), 3.90 (dd AB, 4H), 3.41 (d, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8][C:7]12[O:20][CH2:19][CH2:18][O:17]1)([OH:3])=[O:2].[CH2:22]([N:24]1[C:28](O)=[CH:27][CH:26]=[N:25]1)[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:14][C:12]1[CH:13]=[C:4]([C:1]([O:3][C:28]2[N:24]([CH2:22][CH3:23])[N:25]=[CH:26][CH:27]=2)=[O:2])[C:5]([CH3:21])=[C:6]2[C:11]=1[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8][C:7]12[O:20][CH2:19][CH2:18][O:17]1
Reactant: Cc1c(C(=O)O)cc(Cl)c2c1C1(CCS2(=O)=O)OCCO1
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCn1nccc1OC(=O)c1cc(Cl)c2c(c1C)C1(CCS2(=O)=O)OCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
0.92 Gram (2.8 mmol) of 6-carboxy-8-chloro-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide was dissolved in 10 ml of methylene chloride, and 0.34 g (1.1 eq., 3.0 mmol) of 1-ethyl-5-hydroxypyrazole and 0.63 g (1.1 eq., 3.1 mmol) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 5 hours. Then, an insoluble substance was removed by filtration, and the filtrate was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 0.96 g (yield 81%) of 8-chloro-6-(1-ethylpyrazol-5-yl)oxycarbonyl-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[O:7][CH:8]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[O:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCc1coc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)co5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(4-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B30) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (168 mg; compound C10) and HBTU (191 mg) in DCM (10 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 2 to afford the title compound after purification by twofold flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 0/1 (v/v) and DCM/MeOH, 1/0 to 1/1 (v/v)] as a solid.