Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.II.[I:16](O)(O)(O)(O)(O)=O.S(=O)(=O)(O)O>O.C(O)(=O)C>[I:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: [O-][I+](O)(O)(O)(O)O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc2oc3ccccc3c2c1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 77 %

Procedure:
In a 500-mL three-neck flask, a suspension of 8.4 g (50 mmol) of dibenzofuran, 6.2 g (25 mmol) of iodine, 5.7 g (25 mmol) of orthoperiodic acid, 150 mL of glacial acetic acid, 30 mL of water, and 500 μL of sulfuric acid was heated and stirred at 60° C. for 4.5 hours. After that, the mixture was stirred at room temperature for 16 hours. The generated precipitate was collected by filtration, and the resulting matter was dissolved in 150 mL of toluene and a toluene solution was made. This toluene solution was washed with water three times. After the washing, magnesium sulfate was added to the toluene solution to adsorb moisture. This mixture was filtered and the given filtrate was concentrated. After that, hexane was added, and the mixture was irradiated with ultrasonic waves to perform recrystallization, so that 11.3 g of white powder, which was the objective substance, was obtained in 77% yield. A synthetic scheme of Step 1 is shown in (a-1) below.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:16]#[N:17])=[C:4]3[S:3][CH2:1][CH3:2])/[C:34](=[O:35])[N:36]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCSc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 4-ethylsulfanyl-6-formyl-quinoline-3-carbonitrile (example 54b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 341 (MH+).
Reaction SMILES: [C:1]([CH:3]=[C:4]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:5]1([C:4]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:3][C:1]#[N:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=CC#N)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC=C(c1ccccc1)N1CCNCC1
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-cyano-1-phenylvinyl)piperazine-1-carboxylate (600 mg) was dissolved in a 10% solution of TFA in methylene chloride (11 ml). After 1 hour at room temperature, the reaction mixture was partitioned between saturated NaHCO3 (20 ml) and EtOAc (20 ml), and the aqueous phase was extracted with EtOAc (3×20 ml). Then the combined organic layer was dried over MgSO4 and concentrated to offer a residue which was purified using silica gel chromatography to give 3-phenyl-3-(piperazin-1-yl)acrylonitrile. MS m/z: (M+H)+ calcd for C13H16N3 214.13, found 214.15. Retention time 0.91 min (column E).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[CH2:22]([Sn](CCCC)(CCCC)C#C)[CH2:23]CC>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.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[CH:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)OCC)C(C(F)(F)F)O2
Yield: 75.6 %

Procedure:
To 0.86 g (2.0 mmole) of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 46 mg (0.040 mmole) tetrakis(triphenylphosphine)palladium(0), 6 mLs degassed toluene and 0.64 mL (0.69 g, 2.2 mmole) tributyl(ethynyl)tin. The stirred mixture was heated to reflux for 3 h. After allowing the reaction to cool, the mixture was washed with 20% aq. ammonium fluoride and the aqueous layer extracted three times with diethyl ether. The combined extracts were filtered through silica, the silica washed with diethyl ether and the organic fractions concd in vacuo. Chromatographic purification (70 g silica, 5% ethyl acetate/hexanes) afforded a solid which was triturated with hexanes to give 0.50 g (75.6%) of a crystalline solid: 1H NMR (d6-acetone/400 MHz) 1.32 (t, 3H, J=7.1 Hz), 3.73 (s,1H), 4.32 (m, 2H), 6.04 (q, 1H, J=6.9 Hz), 7.60 (m, 2H), 7.90 (s, 1H); 19F NMR (d6-acetone/400 MHz) −79.6 (d, 3F, J=6.8 Hz); MS(ESI+) 331 (M+1, 100, one Cl pattern).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccccc1N1CCOCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccccc3N3CCOCC3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-(4-morpholinyl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 422.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].N1([C:25](N2C=CN=C2)=[O:26])C=CN=C1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:25](=[O:26])[NH:15][N:14]=1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (152 mg, 0.41 mmol) in THF (6 mL) contained TEA (60 μl, 0.43 mmol) were added Di-imidazol-1-yl-methanone (95 mg, 0.57 mmol) at 0° C. The reaction mixture was warmed to RT and stirred for 5 h, additional TEA (40 μl) and CDI (50 mg) were added, and the reaction mixture was stirred overnight at RT. The precipitate was filtered, the solid washed with MeOH. Yield: yellow solid 123 mg. LC-MS (Method A) [5.50 min; 399(M+1)].
Reaction SMILES: C(OP([CH2:9][C:10]1[S:11][C:12]([Br:15])=[CH:13][CH:14]=1)(=O)OCC)C.[H-].[Na+].[CH3:18][C:19]([CH3:21])=O.O>O1CCCC1>[Br:15][C:12]1[S:11][C:10]([CH:9]=[C:19]([CH3:21])[CH3:18])=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: CCOP(=O)(Cc1ccc(Br)s1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1ccc(Br)s1
Temperature: 25 °C
Yield: 2.7 %

Procedure:
(5-Bromothiophen-2-ylmethyl)phosphonic acid diethyl ester described in Preparation Example 142 (3.13 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL), sodium hydride (0.40 g, 10 mmol, 60% in oil) was added to this solution under stirring at room temperature. The solution was stirred for 30 minutes at 60° C., then, acetone (1 g, 17.2 mmol) was added, and the solution was further stirred for 30 minutes. Water (100 mL) was added to the reaction solution, which was then extracted with hexane (50 mL), the organic layer was washed with water, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane), and the title compound (60 mg, 0.27 mmol, 2.7%) was obtained as a colorless oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][O:6][NH2:7].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:24]4=[N:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:10]=1>>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][O:6][N:7]=[CH:30][C:28]1[CH:27]=[CH:26][N:25]2[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:11]4[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=4)[CH:16]=3)=[CH:22][N:23]=[C:24]2[CH:29]=1
Reactant: CN(C)CCON
Reactant: O=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1
Agent: Cl
Product: CN(C)CCON=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using O-(2-dimethylaminoethyl)hydroxylamine hydrochloride and 3-[3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyridine-7-carboxaldehyde to afford a brown oil, essentially as a single geometric isomer. 1H NMR (400 MHz, CDCl3) δH 2.97 (6H, s), 3.43-3.47 (2H, m), 4.65-4.69 (2H, m), 7.28-7.33 (2H, m), 7.42-7.47 (1H, m), 7.62-7.82 (4H, m), 7.94-7.98 (1H, m), 8.20 (1H, s), 8.32-8.35 (1H, m), 8.25 (1H, s), 8.61-8.65(1H, m), 8.90 (1H, s); m/z (ES+) 386 (M++H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:2]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:1]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Temperature: 4 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1h)-one (5.28 g, 21.5 mmol, 1 eq) in 100 ml chloroform was added 27 ml of dimethyl sulfoxide and 18.5 ml of triethylamine and the reaction mixture was cooled with an ice-bath to an internal temperature of 3-5° C. Then sulfur trioxide pyridine complex (17.1 g 107 mmol, 5 eq) was added and the mixture was allowed to thaw to room temperature. After stirring for overnight at room temperature, the reaction mixture was washed with water (2×50 ml) and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo to yield an organe oil. Further purification by column chromatography on silica gel (eluant: Et2O) furnished the pure product (4.6 g, 87.7%) as a white crystalline solid. m.p. 78-81 ° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[C:20](=[O:21])[CH2:19][CH2:18][C:17]3=[O:22])[CH:11]=2)[C:6]2[N:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1.C([N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)(=O)C>C(#N)C>[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[C:20](=[O:21])[CH2:19][CH2:18][C:17]3=[O:22])[CH:11]=2)[C:6]2[N:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1
Reactant: CC(=O)n1ccnc1
Reactant: O=C1CCC(=O)N1c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Solvent: CC#N
Product: O=C1CCC(=O)N1c1cccc(-n2c(=O)c(Cc3ncc[nH]3)nc3cccnc32)c1
Yield: 25.8 %

Procedure:
To a solution of 2-(bromomethyl)-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (420 mg) in acetonitrile (4 ml) was added 1-acetylimidazole (179 mg). The solution was refluxed for an hour. The mixture was evaporated. The residue was dissolved in water, and to the solution was added sodium carbonate. The mixture was extracted by ethyl acetate. The organic layer was evaporated. The residue was purified by column chromatography to obtain 2-(1-imidazolylmethyl)-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (105 mg) as yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:22][CH:23]([CH3:29])[CH2:24][CH2:25][C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][CH:23]([CH3:29])[CH2:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCN
Reactant: CC(C)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)NCC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To (3S,4S)-1-amino-3-hydroxy-4-t-butyloxycarbonylamino-5-cyclohexylpentane (30.8 mg, 0.102 mmol) in dry methylene chloride (3 mL) at 0° C. was added 4-methylpentanoyl chloride (17.0 microliters, 0.123 mmol) and triethylamine (20.0 microliters, 0.143 mmol). The mixture was stirred at 0° C. for 1 hour, evaporated, taken up in methanol (3 mL) and treated with 1M NaOH (1 mL). After stirring for 1 hour, the mixture was diluted with ether, washed sequentially with 0.5M H3PO4, saturated NaHCO3 solution, and brine, and then dried over Na2SO4 and evaporated to afford 41.0 mg (100%) of the desired product as an oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:27])[C:16]=3[CH:15]=2)[CH2:9]1)(OC(C)(C)C)=O.O.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>CCOC(C)=O>[C:29]1([CH3:39])[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:27])[C:16]=3[CH:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)C(=O)c2ccccc2-3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2-c2ccc(O[C@H]3CCNC3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A solution of 2-[(S)-N-Boc-pyrrolidin-3-yloxy]-fluoren-9-one (315 mg, 0.863 mmol; Example 4A) and p-toluenesulfonic acid monohydrate (165 mg, 0.868 mmol; Aldrich) in EtOAc (15 mL) was heated to reflux. A precipitate began to form after about 30 min of heating. After 18 h, the mixture was cooled to room temperature and the yellow crystals were collected by filtration to afford the title compound (334 mg, 0.763 mmol; 88% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.67-7.73 (m, J=8 Hz, 2H), 7.55-7.63 (m, 3H), 7.52 (dt, J=7, 1 Hz, 1H), 7.27 (dt, J=7, 1 Hz, 1H), 7.20-7.24 (m, J=5, 3 Hz, 3H), 7.14 (dd, J=8, 3 Hz, 1H), 5.24-5.30 (m, 1H), 3.44-3.63 (m, 4H), 2.29-2.39 (m, 5H); MS (DCl/NH3) m/z 266 (M+H)+; Anal. C17H15NO2.C7H8O3S: C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.[Cl:18][C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:22]=[CH:21][N:20]=1
Reactant: Clc1cc(I)ccn1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Product: Clc1cc(Nc2ncc(-c3cccnc3)c3cccnc23)ccn1

Procedure:
The title compound, MS: m/e=334.2 (M+H+), was prepared in accordance with the general method of example 6 step 3 from 5-pyridin-3-yl-[1,7]naphthyridin-8-ylamine and 2-chloro-4-iodopyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:25]2=[S:26])=[C:4]([CH3:17])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Cl)ccc1NCCCNCC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)ccc1N1CCCN(CC(C)C)C1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To an ice-cold solution of the diamine of Step A (4.8 g) and triethylamine (5.0 mL) in dry chloroform (75 mL) was added thiophosgene (2.2 mL). After 10 minutes at ambient temperature, the reaction was quenched with water and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title product (2.4 g, 43.0%) as a white solid, m.p. 88-90° C.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:30])[C:14]=2[NH:18][C:19](=[O:29])[CH2:20][C:21]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]1=[O:31])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[OH:28][C:21]1([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:30])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:31])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)CC3(O)CCCCCC3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)CC1(O)CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(5-(2-(1-hydroxycycloheptyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (100.00 mg, 0.14 mmol), potassium carbonate (58.0 mg, 0.000420 mol) and methanol (4 mL, 0.1 mol) and the reaction mixture stirred at room temperature 1 hour. The solvent was removed under reduced pressure and the residue was purified by reverse phase preparative HPLC to afford the product.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].I[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[CH2:12][CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: Cc1ccncc1I
Reactant: CCn1c2c(c3ccccc31)CCNC2=O
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1c2c(c3ccccc31)CCN(c1cnccc1C)C2=O
Yield: 13.3 %

Procedure:
9-Ethyl-2,3,4,9-tetrahydro-b-carbolin-1-one (I-38f: 0.1 g, 0.4672 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.102 g, 0.4672 mmol), 1,4-dioxane (15 mL), copper iodide (0.0089 g, 0.0467 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.019 g, 0.01401 mmol) and potassium phosphate (0.247 g, 1.168 mmol) to afford the crude product. Purification by column chromatography on silica gel (70% ethylacetate in hexane), followed by preparative HPLC afforded 0.019 g of the product (13.3% yield).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].[CH2:15]([Mg]Br)[CH2:16]C>>[CH2:11]([C:6]1[NH:7][C:8]([C:9]#[N:10])=[C:4]([C:1](=[O:3])[CH2:2][CH2:15][CH3:16])[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCC[Mg]Br
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Product: CCCCc1nc(C(=O)CCC)c(C#N)[nH]1
Yield: 57.2 %

Procedure:
Following a procedure similar to that described in Preparation 24(i), but using propylmagnesium bromide instead of methylmagnesium bromide, the title compound, melting at 91°-92° C., was obtained in a 57.2% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#CCCCCCC
Product: CCCCCCC#Cc1ccc(C=O)cc1
Yield: 84 %

Procedure:
The same procedure as employed in the preparation of Example 275 (step a) but using 4-bromobenzaldehyde and 1-octyne gave the title compound as a yellow oil (84%). 1H NMR (CDCl3, 300 MHz) δ 9.97 (s, 1H), 7.78 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.3 Hz), 2.42 (t, 2H, J=7.0 Hz), 1.67-1.54 (m, 2H), 1.50-1.24 (m, 6H), 0.89 (m, 3H). M−(LC/MS(ESI)): 215.4. HPLC (Condition A), Rt: 5.17 min (HPLC purity: 78.6%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[C:9]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[OH:5][C:4]1[CH:3]=[C:1]([CH:8]=[CH:7][CH:6]=1)[NH:19][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc2ccccc12
Reactant: Oc1cccc(O)c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: Oc1cccc(Nc2cccc3ccccc23)c1
Yield: 86 %

Procedure:
Using the method described in Example 1, 220 parts of resorcinol, 286 parts of α-naphthylamine and 8 parts of triphenyl phosphite give 411 parts (86% of theory) of 3-hydroxy-N-naphthyl-aniline, of boiling point 225° - 227° C/2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: NCCc1cccnc1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2ccccc21
Solvent: CCOCCO
Product: Clc1ccc2c(c1)N=C(NCCc1cccnc1)c1ccccc1N2
Yield: 73.9 %

Procedure:
A solution of 0.5 g (1.9 mmol) of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 10 mL of 2-ethoxyethanol was treated with 0.46 g (3.8 mmol) of 3-(2-aminoethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed five times with H2O, then saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Recrystallization from acetone/water gave 0.49 g (74% yield) of the product as a yellow solid, mp 195-196° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =349.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.Br>[Br:23][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:22][CH:21]=2)=[CH:11][CH:12]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Agent: Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
To a suspension of 1.6 g of methyl α-[p-(p-methylsulfonylphenoxy)phenyl]acetate in 25 ml of carbon tetrachloride is added 0.98 g of N-bromosuccinimide and 1 drop of 48% HBr. The mixture is stirred and refluxed for 19.5 hours and 10 mg of benzoyl peroxide is added. The mixture is refluxed for 3 hours and 1/2 inch of 22 gauge nichrome wire is added. After refluxing an additional 18 hours the solvent is removed under vacuum to give the product as a gum.