Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[O:7])[CH:24]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[O:47])[CH2:37][CH2:36]1)=[O:34]
Reactant: C1COCCN1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of roughly purified [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (150 mg) in N,N-dimethylformamide (1.5 ml) was added morpholine (0.100 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white powder (12.2 mg).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N: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.O.[CH:26](/B(O)O)=[CH:27]/[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([N: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)=[C:2](/[CH:26]=[CH:27]\[CH3:28])[CH:7]=1)=[O:9]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Reactant: C/C=C\B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-(2-iodo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (127 mg, 0.285 mmol) was dissolved in N,N-dimethylformamide:water=3:1 (2.8 mL). At room temperature, (Z)-propenylboronic acid (59 mg, 0.684 mmol), tetrakistriphenylphosphine palladium (16 mg, 0.0143 mmol) and sodium carbonate (121 mg, 1.14 mmol) were added sequentially, and the mixture was stirred at 80° C. for 1 hour, under microwave irradiation. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (96 mg (yield 94%)) was obtained as a yellow crystal.
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[NH:40][C:39]2=[O:49])[CH2:34][CH2:33]1>C(#N)C>[CH2:27]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[CH2:25][CH3:26])[CH2:18][C@@H:2]([NH:1]/[C:35](=[N:38]/[C:39]#[N:40])/[N:32]1[CH2:33][CH2:34][CH:35]([N:38]2[CH2:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[NH:40][C:39]2=[O:49])[CH2:36][CH2:37]1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4])[CH3:28]
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(C[C@@H](N/C(=N/C#N)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 390 mg (1.01 mmol) (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(1-methylpiperidin-4-yl)-piperazin-1-yl]-propan-1-one, 270 mg (1.01 mmol) diphenylcyano-carbonimidate and 50 mL DCM was stirred for 4 h at RT and then evaporated down under reduced pressure. The residue was combined with 30 mL acetonitrile and 270 mg (1.10 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and refluxed for 14 h. The reaction mixture was evaporated down under reduced pressure and the residue was purified by chromatography. The product fractions were evaporated down, the residue was triturated with PE and suction filtered.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19]C(=O)C)(=O)[CH3:17]>C(#N)C>[C:16]([N:2]([CH3:1])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5])(=[O:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(C)=O
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a mixture of 1,2-dimethyl-3-nitroisothiourea (2.93 g), potassium carbonate (4.07 g), and acetonitrile (60 ml) was added acetic anhydride (2.53 g) at room temperature and the mixture was stirred for 3 hour at this temperature. Insoluble materials were removed by filtration and the filtrate was concentrated. Chloroform (100 ml) was added to the residue and the mixture was washed with water twice. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated to give 3.48 g of 1-acetyl-1,2-dimethyl-3-nitroisothiourea.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24]#[C:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([C:24]#[C:25][CH2:26][CH2:27][CH3:28])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29]
Reactant: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
The mixture of 2-(3-methyl-2-pent-1-ynyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (122) (180 mg, 0.46 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. After filtration, the solid is purified by HPLC to give a pure product (123) as white solid (114 mg, 69%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]2=[N:17][CH:18]=1)=[O:11].[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]2=[N:17][CH:18]=1)=[O:11])(=[O:35])=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCN3)cnc21
Reactant: CC(C)CS(=O)(=O)Cl
Agent: Cl
Product: CC(C)CS(=O)(=O)N1CCCC1CNC(=O)Nc1cnc2c(ccn2COCC[Si](C)(C)C)n1

Procedure:
Racemic 1-[1-(2-methyl-propane-1-sulfonyl)-pyrrolidin-2-ylmethyl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-pyrrolidin-2-ylmethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and 2-methyl-propane-1-sulfonyl chloride.
Reaction SMILES: C(O)(=O)C.[C:5]([N:9]1[C:14](=[O:15])[C:13]([S:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[NH2:18][C:12]1[CH:11]=[N:10][N:9]([C:5]([CH3:6])([CH3:7])[CH3:8])[C:14](=[O:15])[C:13]=1[S:16][CH3:17]
Reactant: CSc1c([N+](=O)[O-])cnn(C(C)(C)C)c1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1c(N)cnn(C(C)(C)C)c1=O
Temperature: 65 °C
Yield: 78.7 %

Procedure:
Into 10 ml of an acetic acid solution of 1.45 g of 2-tert-butyl-4-methylthio-5-nitropyridazin-3-(2H)-one, 1.33 g of reduced iron was gradually added in a few times over a period of 10 minutes with stirring at 65° C. During the addition, the temperature of the system was maintained from 65° to 75° C. After completion of the addition, the mixture was stirred at a temperature of from 65° to 70° C. for one hour and then left to cool. 100 ml of ethyl acetate was added thereto, and the mixture was filtered through celite. The filtrate was washed twice with water and then with a dilute potassium carbonate aqueous solution, and then it was dried over anhydrous sodium sulfate and concentrated to obtain 1.0 g of 5-amino-2-tert-butyl-4-methylthiopyridazin-3-(2H)-one as a residual powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[NH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: c1ccc2c(c1)CCCN2
Product: O=C(O)c1ccnc(-c2cn(CCN3CCCc4ccccc43)cn2)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 1,2,3,4-tetrahydroquinoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.76 (2H, t, J=5.5 Hz), 2.64 (2H, t, J=6.2 Hz), 3.08 (2H, t, J=5.5 Hz), 3.62 (2H, t, J=6.2 Hz), 4.20 (2H, t, J=6.2 Hz), 6.48 (1H, t, J=7.1 Hz), 6.61 (1H, d, J=8.1 Hz), 6.86 (1H, d, J=6.6 Hz), 6.95 (1H, t, J=7.7 Hz), 7.53 (1H, d, J=3.6 Hz), 7.71 (1H, s), 7.84 (1H, s), 8.25 (1H, s), 8.53 (1H, d, J=5.0 Hz). [M+H] Calc'd for C20H20N4O2, 349. Found, 349.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:9][CH2:10][CH2:11][CH2:12][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCBr
Reactant: CNc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCBr)c1ccccc1
Yield: 37.7 %

Procedure:
N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 9a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=1)[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:31]=[CH:30][CH:29]=[C:22]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:21]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1cccc(N)c1
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.1 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (2.54 g, 9.3 mM), allyl 3-aminobenzoate (1.5 g, 8.5 mM), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.72 g, 11 mM) were dissolved in toluene (50 ml) and stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with 2M HCl (3 by 30 ml), water, saturated NaHCO3, and brine. Drying over MgSO4 and evaporation gave (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidine as a gum (3.7 g, 100%) in a state sufficiently pure for further work. Nmr (CDCl3): δ2.32 (s, 3H); 2.60 (br, 2H); 3.40 (dd, 1H); 4.03 (quintet, 1H); 4.13 (dd, 1H); 4.57 (t, 1H); 4.66 (dm, 2H); 4.82 (dt, 2H); 5.23-5.46 (m, 4H); 5.86-6.12 (m, 2H); 7.41 (t, 1H); 7.82 (d, 1H); 7.91 (d, 1H); 8.07 (t, 1H); 9.18 (br, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]Br.CC([O-])=O.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:22])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2snc(C)c2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 31 (430 mg, 1.44 mmol), bromine (345 mg, 2.16 mmol) and NaOAc (236 mg, 2.88 mmol) in acetic acid (10 mL) was heated at 40–45° C. for 14 h. The reaction mixture was poured into ice water, a yellow solid was collected by filtration. The crude product 32 was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.06–7.31 (m, 5H), 6.13 (d, J=16.41 Hz, 1H), 4.80 (d, J=16.41 Hz, 1H), 4.56 (t, J=7.26 Hz, 1H), 2.77 (s, 3H), 2.33 (m, 1H), 2.13 (m, 1H), 0.67 (t, J=7.27 Hz, 3H).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)([O-:3])=[O:2]
Reactant: NCCSCc1nccs1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene wth an excess of 2-[(2-aminoethyl)thiomethyl]thiazole according to the procedure of Example 3, results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 119°-120° (from acetonitrile).
Reaction SMILES: Br[C:2]1[C:11]([S:12]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C@@H:16]2[CH3:29])(=[O:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:30]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][N:15]([S:12]([C:11]2[C:2]([CH3:30])=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[N:6][CH:5]=[CH:4]3)(=[O:14])=[O:13])[C@@H:16]([CH3:29])[CH2:17]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2cnccc2c1Br
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)N2CCCN(C(=O)OC(C)(C)C)C[C@@H]2C)ccc2cnccc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 80.8 %

Procedure:
100 mg of (S)-5-bromo-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline, 15 mg of methylboronic acid, 12 mg of tetrakis(triphenylphosphine)palladium, and 131 mg of potassium phosphate were suspended in 10 mL of 1,4-dioxane and stirred at 100° C. for 10 hours in an argon gas atmosphere. After the completion of reaction, water was added to the reaction solution, followed by extraction with ethyl acetate (30 mL×2). Then, the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 70 mg of the compound of interest as a colorless oil (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6](=[O:16])[CH:7]=[C:8]1[C:12](=[O:13])OC(C)(C)[O:9]1.C=O.[CH3:26][NH2:27].[CH3:28]O>>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6]([C:7]1[CH2:26][N:27]([CH3:28])[C:12](=[O:13])[C:8]=1[OH:9])=[O:16]
Reactant: CN
Reactant: CON(Cc1ccc(F)cc1Cl)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CO
Agent: C=O
Product: CON(Cc1ccc(F)cc1Cl)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 55 %

Procedure:
N-(2-Chloro-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 44, Method 44B, to give the title compound as white crystals (55% yield); mp 152–155° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.17 (2H, s, NCH2), 5.01 (2H, s, NCH2), 6.99 (1H, m, aromatic), 7.15 (1H, dd, J=2.5 Hz, J=8.0 Hz, aromatic), 7.36 (1H, dd, J=5.7 Hz, J=8.8 Hz, aromatic). Anal. calcd for C14H14ClFN2O4: C, 51.15; H, 4.29; N, 8.52. Found: C, 50.62; H, 4.18; N, 8.40.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].[Br:5][C:6]1[CH:7]=[C:8]([C:17]#[N:18])[C:9]([NH:12]C(=O)OC)=[N:10][CH:11]=1.[CH3:19]N1CCCC1=O>>[Br:5][C:6]1[CH:11]=[N:10][C:9]2[NH:12][C:1](=[O:2])[N:3]3[N:4]=[CH:19][N:18]=[C:17]3[C:8]=2[CH:7]=1
Reactant: NNC=O
Reactant: COC(=O)Nc1ncc(Br)cc1C#N
Reactant: CN1CCCC1=O
Product: O=c1[nH]c2ncc(Br)cc2c2ncnn12
Temperature: 120 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Formyl hydrazine (60 mg, 1.0 mmol) was added to a solution of methyl 5-bromo-3-cyanopyridin-2-ylcarbamate (255 mg, 1.0 mmol) in 1-methylpyrrolidinone (5 mL). The resulting mixture was stirred at 120° C. for 3 h. The mixture was cooled to room temperature and poured into ice-water (20 mL). The resulting solid was separated by filtration, washed with water and hexanes and dried under vacuum to afford the title compound (160 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.70 (s, 1H), 8.80 (s, 1H), 13.00 (br s, 1H). [M+H]=266.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2I)=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2[CH:20]=[CH2:21])=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ccccc2c1-c1ccc(Cl)cc1
Yield: 89.2 %

Procedure:
A solution of 1-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E) (1.50 g, 3.98 mmol), tributyl(vinyl)tin (1.28 mL, 4.37 mmol) and PdCl2(PPh3)2 (0.279 g, 0.398 mmol) in DMF (20 mL) was stirred at 90° C. under argon overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with 5% LiCl solution (2×), brine and dried (MgSO4). The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 3F as a white solid (0.9894 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.74 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.40-7.13 (m, 5H), 7.15 (d, J=8.1 Hz, 2H), 6.50 (dd, J=18, 11.7 Hz, 1H), 5.27 (d, J=11.7 Hz, 1H), 5.03 (d, J=18 Hz, 1H), 2.50 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][C:8]=1[CH3:9])#[N:2].[Se](=O)=[O:27]>CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[N:7][C:8]=1[CH:9]=[O:27])#[N:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Nc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Product: CCOC(=O)c1cc(C#N)c(C=O)nc1Nc1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
69.8 g of 5-cyano-6-methyl-2-[[3-(trifluormethyl)phenyl]amino]-3-pyridine-carboxylic acid, ethyl ester (0.2 mol) are dissolved in 400 ml of diethyleneglycoldimethyl ether. After addition of 24.2 g of selenium dioxide, the mixture is heated at 160° with stirring for 2 hrs. The selenium is filtered off and the filtrate evaporated. The resulting yellow title compound is recrystallized from butanol. Yield 56 g (77%); m.p. 183°-185° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:12]1[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccnc1Oc1cccc(CCl)c1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(Oc2ncccc2C)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-3-methylpyridine (3.6 g, 15 mmol) from Step 2 was treated neat with triethylphosphite (3.3 mL, 19.3 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-60%, EtOAc:CH2Cl2) to afford the title compound (4.3 g, 83% yield) as a thick oil.
Reaction SMILES: [CH2:1]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9](Br)[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Na]>CO>[CH3:15][O:16][C:17](=[O:23])[CH:18]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:8])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1CCCCCCCCCCC1Br
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C1CCCCCCCCCCC1=O

Procedure:
reacting α-bromocyclododecanone with sodium malonic acid dimethyl ester in methanol at from about 10° to 40° C. to form 2-(2-oxocyclododec-1-yl)-malonic acid dimethyl ester;