Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one (537 mg, 1.33 mmol) in DMF (10 mL) was added a pyrrolidine (758 mg, 10.66 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the solid separated was filtered and dried under vacuum. The solid was triturated with ether and dried to give the title compound as a white solid. Yield: 232 mg (44%). MP 231-232° C. 1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 7.90 (dd, J=8.0 Hz, 1H), 7.806 (br s, 2H), 7.42 (t, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 4.04 (s, 3H), 3.95 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.65 (m, 4H), 2.40 (s, 6H), 1.84 (m, 4H). MS (ES) m/z: 394.15 (M+1).
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([C:23](=O)[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=1>O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=1)[C:24]([CH3:25])=[C:7]2[C:8]([OH:13])=[O:1]
Reactant: [OH-]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc2c1C(=O)O
Temperature: 85 °C
Reaction time: 8 h
Yield: 116.4 %

Procedure:
Potassium hydroxide (29.8 g, 531 mmol) in water (49.2 mL) was added to an orange suspension of 5-bromoisatin (20 g, 88 mmol) in ethanol (172 mL). 1-[3-(Trifluoromethyl)phenyl]-1-propanone (19.68 g, 97 mmol) was added and the mixture was heated to 85° C. for 3 h. The solvent was removed under reduced pressure. The residue was diluted with water (400 mL) and stirred overnight. The aqueous mixture was cooled to 0° C. and adjusted to pH˜3 with concentrated HCl. The solid was collected by filtration and dried in a vacuum oven at 70° C. for 3 days to afford 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (42 g, >99% yield). This material was used without further purification. MS (m/z) 411.8 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:8].O[CH2:10][P+:11]([CH2:16]O)([CH2:14]O)[CH2:12]O>CC(C)=O>[Cl-:8].[NH:1]([CH2:10][P+:11]([CH2:16][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: CC(C)=O
Product: c1ccc(NC[P+](CNc2ccccc2)(CNc2ccccc2)CNc2ccccc2)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Aniline (9.30g) was added all at once to a slurry of 4.76 g of tetrakis(hydroxymethyl)phosphonium chloride (THPC) in 50 ml of acetone. The THPC dissolved within one minute, with slight warming, giving a clear solution that deposited solids on standing. After 2 hr, the mixture was filtered, giving 8.15 g (66.0% yield) of tetrakis(anilinomethyl)phosphonium chloride, m.p. 120°-121°. The filtrate, concentrated on a rotary evaporator, left 16.45 g of a neutral, dark yellow liquid. Beilstein tests on these products were strongly positive on the solid fraction and faintly positive on the liquid fraction, showing that most of the chlorine went into the solid fraction.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:15]1[C:10]2[CH:9]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4]3)[S:18][C:11]=2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2sc(C3CCC(C)(C)CC3)cc2c(=O)[nH]1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 130 °C

Procedure:
To a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (30.0 g) and toluene (240 mL) were added phosphorous oxychloride (40 mL) and DMF (1.0 mL), followed by heating to reflux at 130° C. for 2 hours. The reaction mixture was left to be cooled to room temperature and concentrated under reduced pressure. To the residue were added chloroform and saturated aqueous sodium bicarbonate, followed by stirring. The organic layer was washed sequentially with water and brine. To the organic layer were added MgSO4, activated carbon (10 g), and silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (31.3 g).
Reaction SMILES: C(C1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2C=1)#N.[H-].[Na+].C[N:19]1[C:23](=O)[CH2:22][CH2:21][CH2:20]1.[CH3:25]I>O>[C:23]([C:22]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH3:5])([CH3:25])[C:20]=2[CH:21]=1)#[N:19]
Reactant: CN1CCCC1=O
Reactant: CI
Reactant: N#Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
14.29 g of 2-cyanofluorene, 8.9 g of sodium hydride (60% in oil) and 150 ml of NMP were stirred at room temperature for 2.5 hours. Then, 31.2 g of methyl iodide was added into the reaction mixture drop-wisely and stirred for an additional 2 hours at room temperature. The reaction mixture was poured into 200 ml of water and filtered. The crude product was purified by column chromatography, giving 8.5 g (60%) of 2-cyano-9,9-dimethylfluorene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].CO[C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1>C(O)C>[CH3:12][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Reactant: CN(CCCCN)CCCCN
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)C=C(NCCCCN(C)CCCCNC1=CC(=O)c3sc(C)nc3C1=O)C2=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6 mg (34 μmol) of N-(4-aminobutyl)-N-methylbutane-1,4-diamine is added to a solution of 15 mg (71 mmol; 2.1 equivalents) of 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione in 1.5 ml of ethanol, then the reaction mixture is stirred at 60° C. for 1 hour. The solvent is then evaporated off under reduced pressure and the expected product is obtained by purification by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5) in the form of a red oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)C>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:28])=[O:15])=[CH:20][C:21]=2[O:26][CH3:27])[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Product: COc1cc(CCC(=O)O)ccc1OCc1cccc(SC(C)C)n1
Yield: 55.3 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (32 mg, 0.15 mmol) obtained in Step C of Preparation Example 16 and 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester (39 mg, 0.17 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 61%).
Reaction SMILES: [S:1]([C:5]1[CH:23]=[CH:22][C:8]([N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C[Si]([C:28]#[N:29])(C)C.O>C1COCC1.[Cl-].[Zn+2].[Cl-]>[S:1]([C:5]1[CH:23]=[CH:22][C:8]([NH:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)[C:28]#[N:29])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(-c3ccco3)cc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(-c2ccco2)cc1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of 4-sulfamoyl-N-[4-(2-furyl)benzylidene]aniline (0.37 g, 1.13 mmol) in anhydrous THF (5 mL) at 0° C. was added trimethylsilyl cyanide (0.135 g, 1.36 mmol),zinc chloride (1.36 mL, 1.0 M solution in ether, 1.36 mmol). The temperature of the reaction mixture was then allowed to return to room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water and the whole was extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the subtitle compound (0.288 g).
Reaction SMILES: Cl.[CH2:2]([C@@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH2:26])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1)[CH2:3][CH3:4].[CH3:27][C:28]1[NH:32][C:31]2[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:30]=2[N:29]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>CN(C=O)C.O>[CH3:27][C:28]1[NH:32][C:31]2[CH:33]=[CH:34][C:35]([C:37]([NH:26][C@@H:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]3[C:18]([N:17]3[C@@H:13]4[C@@H:14]([C@H:5]([CH2:2][CH2:3][CH3:4])[NH:6][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=54)[CH2:15][CH2:16]3)=[O:19])=[O:38])=[CH:36][C:30]=2[N:29]=1
Reactant: CCC[C@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc2[nH]c(C)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47 %

Procedure:
To a suspension of (1R,2S)-2-{[(3aR,4R,9bR)-4-(propyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (203 mg, 0.490 mmol) in DMF (4 ml) were added 2-methyl-1H-benzimidazole-5-carboxylic acid (86.2 mg, 0.490 mmol), triethylamine (0.206 ml, 1.47 mmol) and DEPC (0.0812 ml, 0.490 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and eluted with ethyl acetate-methanol (1:0-9:1) to give the title compound (115 mg, 47%) as an amorphous form.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1)=[O:28]>CC#N>[Cl-:25].[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])[CH:35]=1
Reactant: Cc1ccnc(NC(=O)CCl)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: Cc1ccnc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 51.2 %

Procedure:
To a solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3yl) ester (Example 14e) (100 mg) in 1 mL MeCN was added 2-chloro-N-(4-methyl-pyridin-2-yl)-acetamide (Example 44a) (62 mg) and the mixture was stirred at room temperature for 21 h. The precipitate was filtered off and dried under vacuum at 50° C. to give the title compound (80 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10]O.P(Br)(Br)[Br:13]>ClCCl>[Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10][Br:13]
Reactant: CC(C)n1ncc(CO)c1Br
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)n1ncc(CBr)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a stirred solution of (5-bromo-1-isopropyl-1H-pyrazol-4-yl)methanol (10.0 g, 45.7 mmol) in dichloromethane (200 mL) was added PBr3 (6.5 mL, 68.5 mmol) at 0° C. After the addition was complete the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was poured into ice-cold water (300 mL), shaken, separated, and then washed twice with ice-cold water (2×100 mL) and then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to give 5-bromo-4-(bromomethyl)-1-isopropyl-1H-pyrazole (12.2 g, 95%). 1H NMR (300 MHz, CDCl3, δ): 7.58 (s, 1H), 4.64 (m, 1H), 4.35 (s, 2H), 1.43 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13](C)(C)[O:14][SiH2]C(C)(C)C)[CH:7]=1.Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][OH:14])[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: OC[C@@H]1CCCN1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridine (intermediate A-3 [B], 0.1 g, 0.269 mmol) in MeOH (2 mL) was added 4M HCl in dioxane (0.202 mL, 0.808 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, the residue diluted with DCM, poured into aq. NaHCO3 (10 mL) and extracted with DCM (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (0.060 g, 87%) as a yellow oil. MS: 257.0, 259.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:19][C@H:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:21]([NH2:23])=[O:22])=[N:7][C:8]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[S:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:23][C:21](=[O:22])[C@H:20]([NH:19][C:6]1[N:7]=[C:8]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[S:12][CH:11]=2)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:24][CH:25]1[CH2:26][CH2:27]1
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1csc2ncccc12
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1csc2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(thieno[2,3-b]pyridin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (33 mg, 0.087 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (34 mg). MS 398.2 (M+H); UV 203.6, 224.8, 262.1, 294.1, 357.3 nm; t 0.532 min.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([C:4]2[CH:3]=[C:2]([CH3:1])[S:6][C:5]=2[C:7]([O:9][CH3:10])=[O:8])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(C)cc1OS(=O)(=O)C(F)(F)F
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: C1COCCO1
Product: CCc1ccc(-c2cc(C)sc2C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed methyl 5-methyl-3-(((trifluoro methyl)sulfonyl)oxy)thiophene-2-carboxylate (1.7 g, 5.59 mmol), (4-ethylphenyl)boronic acid (1.0 g, 6.69 mmol), K3PO4 (3.84 g, 18.1 mmol), Pd(PPh3)4 (157 mg, 0.136 mmol), 1,4-dioxane (40 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 1.46 g (100%) of methyl 3-(4-ethylphenyl)-5-methylthiophene-2-carboxylate as light yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[C:8]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[CH:16]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[S:19][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: COC(=O)CS
Product: COC(=O)c1cc2c3ccccc3n(-c3ccccc3)c2s1
Yield: 79.6 %

Procedure:
Prepared from 1-Phenyl-2-chloroindole-3-carbaldehyde (0.90 g), K2 CO3 (1.38 g) and methyl 2-mercaptoacetate (0.55 ml) yielding (51) 0.86 g (79.6%). M.p. 147°-149° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[SH:16]>>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[S:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: Cc1cccc(C)c1S
Product: Cc1cccc(C)c1Sc1ccccc1

Procedure:
The general procedure was used to convert iodobenzene and 2,6-dimethylthiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (409 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.1–6.98 (m, 5H; Hc, Hc, Hd, Hd′, He), 6.93–6.86 (m, 1H; Hb), 6.77 (d, J=7.16, 2H; Ha, Ha′) 2.34 (s, 6H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 143.86 (C2, C6), 137.98 (C9), 130.43 (C1), 129.22 (C4), 128.86 (C10, C14), 128.40 (C1, C13), 125.59 (C3, C5), 124.57 (C12), 21.82 (C7, C8). Anal. Calcd. for C14H14S: C, 78.45; H, 6.58; S, 14.96; Found C, 78.58; H, 6.71; S, 14.98.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[ClH:13]>CC(C)=O.CCOCC>[ClH:13].[CH3:1][N:2]1[N:6]=[N:5][C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[N:3]1
Reactant: Cn1nnc(-c2cccnc2)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cn1nnc(C2CCCNC2)n1
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of 12 (1.93 g, 0.012 mol) in acetone (50 ml) was added hydrogen chloride in ether until acidic reaction. The precipitate was filtered off, dried, and dissolved in methanol (25 ml). 5% palladium on charcoal (0.6 g) was added, and the mixture was shaked overnight under 3 atm. of hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. Crystallization from ethanol yielded 0.63 g (0.0031 mol, 26%) of title product M.P. 168°-172° C. Anal. (C7H14ClN5) C, H, N.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)NNC(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)NNC(=O)CCc1ccccc1
Yield: 98.2 %

Procedure:
22.0 g. (0.1 mole) of methyl 3-(β-phenylacryloyl)-carbazate are dissolved in 300 ml. of methanol and the solution is hydrogenated in the presence of 0.2 g. of a palladium-charcoal catalyst. The solution is evaporated. Thus 21.8 g. of the white crystalline desired compound are obtained. Yield: 98.2%. M.p.: 118° C.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:15][CH2:16][CH2:17][C:18](OC)=[O:19].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:15][CH2:16][CH2:17][C:18]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:19]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CCCC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.62 g (3.5 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (16 mL). After addition of 1.0 g (3.5 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[S:8](N)([NH2:11])(=[O:10])=[O:9]>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: NS(N)(=O)=O
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(S(N)(=O)=O)CC1

Procedure:
N-Methyl piperazine (5 ml) and sulfamide (11.26 g) in 1,4-dioxane (100 ml) were heated at reflux for 48 h. The solvent was evaporated under reduced pressure and the resulting solid dissolved in a mixture of methanol and water and applied to a plug of SCX-silica followed by further elution with aqueous methanol. This was then followed by elution with 1M ammonia in methanol (×4) and these fractions collected and solvent evaporated to dryness leaving a white solid. This was triturated with Et2O and filtered leaving the subtitle compound as a white solid. Yield: 5.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:20]([CH2:21]I)[CH2:19][C:18]3[C:23]4[C:10]2=[N:11][CH:12]=[N:13][C:14]=4[CH:15]=[C:16]([O:26][CH3:27])[C:17]=3[O:24][CH3:25])[CH:5]=[CH:6][C:7]=1[F:8].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:20]([CH3:21])=[CH:19][C:18]3[C:23]4[C:10]2=[N:11][CH:12]=[N:13][C:14]=4[CH:15]=[C:16]([O:26][CH3:27])[C:17]=3[O:24][CH3:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(F)c(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccc(F)c(Cl)c1
Temperature: 120 °C

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene (0.125 g, 0.25 mmol) (from Example 18, Step F, supra) in toluene (25 mL) was added DBU (0.37 mL, 2.5 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hours. The mixture was then diluted with chloroform (100 mL) and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (3:1:0.05) as eluent to give the desired 4-(3-chloro-4-fluoro-phenyl)-7,8-dimethoxy-5-methyl-4H-1,3,4-triaza-phenalene as a white solid. (Yield 0.093 g, 100%).