Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=S)[C:10]([C:19](OCC)=[O:20])=[CH:9]2)=[CH:3][CH:2]=1.[NH2:30][NH2:31]>C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:30][NH:31][C:19](=[O:20])[C:10]3=[CH:9]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2ccccc2c1=S
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-c4ccccc4)cc3)cc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-(biphenyl-4-ylmethyl)-4-thioxo-1,4-dihydroquinoline-3-carboxylate (0.43 g, 1.1 mmol) and hydrazine (38 μL, 1.1 mmol, 1 equiv) were combined in absolute ethanol (10 mL) and placed into a preheated oil bath at 75° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Cl)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:10]
Reactant: CCOC(=O)CCl
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(F)c1
Temperature: 0 °C

Procedure:
3-Fluoro-phenol (100 g, 892 mmol) is dissolved in acetone (250 ml) and after addition of chloro-acetic acid ethyl ester (114 ml, 1.07 mol) and K2CO3 (249 g, 1.78 mol) the mixture is refluxed for 24 h. After cooling down to 0° C., the mixture is filtrated and the filtrate is evaporated under reduced pressure. Yield: 198 g (100%) of a red oil.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[C:6]([O:27][CH2:28][CH3:29])=[C:7]([CH:13]2[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14]2)[C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)[CH3:4].Br[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][NH:35]2.CCN(C(C)C)C(C)C>C(O)C.C([O-])(O)=O.[Na+]>[Cl:11][C:9]1[C:8]([CH3:12])=[C:7]([CH:13]2[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14]2)[C:6]([O:27][CH2:28][CH3:29])=[C:5]([CH:3]([NH:2][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][NH:35]3)[CH3:4])[CH:10]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CCOc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate (65 mg, 0.13 mmol, second peak from chiral separation in previous step) was treated with 4.0 M HCl in dioxane (0.4 mL, 2 mmol) in methylene chloride (0.4 mL, 6 mmol) at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give benzyl 3-[3-[1-aminoethyl]-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylate hydrochloride. LCMS calculated for C22H28ClN2O3 (M+H)+: m/z=4012. found: 403.1. A mixture of the above HCl salt, 6-bromo-9H-purine (31 mg, 0.16 mmol) and DIPEA (0.11 mL, 0.65 mmol) in ethanol (1 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (83 mg). LCMS calculated for C27H30ClN6O3 (M+H)+: m/z=521.2. found: 521.1.
Reaction SMILES: C(OC([C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1)=O)C.[CH3:34][O:35]C1C=CC(B(O)O)=CN=1>>[CH3:34][O:35][C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1
Product: COc1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1

Procedure:
The title compound was prepared according to the method used for the preparation of 2-[6-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]-3-pyridinyl]-6-benzothiazolecarboxylic acid ethyl ester, from 2-methoxy-5-pyridineboronic acid (0.48 g, 3.14 mmol), and obtained as a solid (0.29 g) after purification by flash column chromatography using 15% ethyl acetate in hexane. 1H NMR δ 8.94 (d, 1 H) 8.81 (s, 1 H) 8.40 (dd, 1 H) 8.00-8.19 (m, 2 H) 7.04 (d, 1 H) 4.37 (q, 2 H) 3.97 (s, 3 H) 1.36 (t, 3 H); MS m/z (M+H) 315.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=[C:5]([NH2:17])[N:4]=1.[C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29])([O:20][CH3:21])=[O:19].CCOCC>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:6]=[C:5]([NH:17][C:32]([NH:31][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:30])=[O:29])=[O:33])[N:4]=1
Reactant: COc1cc(COc2ccccc2)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(COc2ccccc2)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a mixture of 0.23 g (1.0 mmol) of 4-methoxy-6-(phenoxymethyl)-2-pyrimidinamine in 15 ml dry acetonitrile was added 0.48 g (2.0 mmol) o-carbomethoxybenzenesulfonyl isocyanate and stirred at ambient temperature overnight. Ether was added to the suspension of white solids which were then collected by filtration to afford 0.37 g of the title compound, m.p. 178°-180°. NMR (90 MHz, CDCl3 +DMSO-d6): δ 3.91 (s, 3H); 4.02 (s, 3H); 5.20 (s, 2H); 6.69 (s, 1H); 7.0-7.9 (m, 8H); 8.5 (m, 1H); 9.20 (s, NH); 12.9 (s, NH) ppm; IR (nujol) 1725, 1700 cm-1.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([OH:23])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[F:40][C:41]([F:56])([S:52](F)(=[O:54])=[O:53])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>ClCCl>[F:56][C:41]([F:40])([S:52]([O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:12]1=[N:13][O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[C:11]1[CH2:22][CH2:21]2)(=[O:54])=[O:53])[C:42]([F:50])([F:51])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(O)ccc2-3)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(-c2onc3c2CCc2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 72.1 %

Procedure:
To a solution of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Example 9, 115 mg, 0.377 mmol), dimethylaminopyridine (4.60 mg, 0.038 mmol), and triethylamine (0.262 mL, 1.883 mmol) in anhydrous dichloromethane (2 mL) was added perfluoro-1-butanesulfonyl fluoride (0.102 mL, 0.565 mmol) dropwise at room temperature under nitrogen. The mixture was stirred at room temperature for 4.5 hr and allowed to stand in the freezer overnight and quenched by the addition of saturated aqueous sodium bicarbonate solution (3 mL). The dichloromethane layer was separated and the aqueous layer was re-extracted with dichloromethane (2 mL). The combined organic solutions were dried over sodium sulfate, filtered through a silica gel pad and concentrated under reduced pressure to give 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (160 mg, 0.272 mmol, 72.3% yield) as a white solid. LC/MS M+1=588
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+:10](C)C3C=CC=CC=3)[S:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].N[N:27]1[C:31](=[O:32])[CH2:30][S:29][C:28]1=[S:33].CN(C)C=O>O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:10][N:27]3[C:31](=[O:32])[CH2:30][S:29][C:28]3=[S:33])[S:9][C:5]=2[CH:4]=1
Reactant: NN1C(=O)CSC1=S
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSC(=S)N1N=c1sc2ccc(Cl)cc2s1
Temperature: 50 °C
Yield: 79 %

Procedure:
A mixture of the methiodide of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (1.9 g), sodium carbonate (121 mg), N-aminorhodanine (338 mg) and dimethylformamide (20 ml) is heated at 50° C for 3 hours. The mixture is poured into water and the precipitate which forms is filtered and washed with water. The product is recrystallized from dimethylformamide to yield 600 mg of the title compound, melting point 312°-314° C.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1csc(C2(O)CCC(=O)CC2)n1
Product: Cc1csc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(4-methyl-thiazol-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH2:12][CH3:13])[NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5]([CH2:12][CH3:13])=[N:4][N:3]2[C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:16]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: CCOC(=O)c1c(N)n[nH]c1CC
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CC)nn2c(-c3cccnc3)ccnc12

Procedure:
As for Example 2, 1.83 g. of 3-amino-4-carboethoxy-5-ethylpyrazole is heated at reflux temperature for 16 hours with 1.76 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 1.20 g. of the product of the example as colorless crystals, m.p. 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]1[C:20]2[C:19](=[O:21])[NH:18][CH:17]=[CH:16][C:15]=2[NH:14][C:13]([CH3:22])=[C:12]1[N+:23]([O-:25])=[O:24])[C:6]#[N:7].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32].ClCCl>CO>[CH2:31]([O:21][C:19]1[N:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:11]([C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([N+:23]([O-:25])=[O:24])=[C:13]([CH3:22])[NH:14]2)[CH3:32]
Reactant: COc1cc(C#N)ccc1C1C([N+](=O)[O-])=C(C)Nc2cc[nH]c(=O)c21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C([N+](=O)[O-])=C(C)N2

Procedure:
40 mg (0.11 mmol) of 3-methoxy-4-(2-methyl-3-nitro-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)benzonitrile and 43 mg of triethyloxonium tetrafluoroborate (0.23 mmol) are mixed under a dry argon atmosphere. After addition of dichloromethane (5 ml), the suspension is stirred until a solution is obtained, then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 13 mg (29% of theory) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1cccc(-c2nc(Nc3cc[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [6-methoxy-1-(3-methoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([N:25]3[CH:34]([CH3:35])[CH2:33][C:32]4[C:27](=[CH:28][C:29]([C:36]5[CH:40]=[CH:39][NH:38][N:37]=5)=[CH:30][CH:31]=4)[CH2:26]3)[N:22]=[C:21]([NH2:41])[N:20]=2)[CH2:15][CH2:14]1.Br[CH2:43][C:44]#[N:45]>CN(C=O)C>[NH2:41][C:21]1[N:22]=[C:23]([N:25]2[CH:34]([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][C:29]([C:36]4[CH:40]=[CH:39][N:38]([CH2:43][C:44]#[N:45])[N:37]=4)=[CH:30][CH:31]=3)[CH2:26]2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: N#CCBr
Reactant: CC1Cc2ccc(-c3cc[nH]n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1Cc2ccc(-c3ccn(CC#N)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide in THF (1.0 M, 74.2 uL, 0.0742 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (15.0 mg, 0.0371 mmol) in DMF (0.3 mL) and stirred at r.t. for 10 min, and then bromoacetonitrile (3.71 uL, 0.0556 mmol) was added. The mixture was stirred at r.t. for 1 h. LCMS showed the reaction was complete. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=444.2.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc(Br)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Br)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.74 (1H, s), 7.28 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=7.6 Hz), 7.42 (1H, d, J=4.4 Hz), 7.49 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=1.2 Hz), 7.64 (1H, s), 8.05 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H11BrN4O, 355. Found, 355.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][OH:33].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCCCCl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCCO)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 7.66 g of sodium 4-(n-hexadecylamino)benzoate, 7.55 g of 4-chloro-1-butanol, and 20.0 ml of hexamethylphosphoramide is stirred at 150° C for two hours, allowed to cool, and poured into water. The solid is collected by filtration and then is dissolved in methylene chloride. The solution is washed with water, dried, and evaporated. The residual solid is crystallized from hexane to yield 4-hydroxybutyl 4-(n-hexadecylamino)benzoate as a white solid, mp 61°-63° C.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1.[N+]([O-])([O-])=O.[Na+].OC1C(N2CCOCC2)=NC=C(OC)N=1.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(N2CCOCC2)c(N)n1
Agent: COc1cnc(N2CCOCC2)c(O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrate as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methoxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:24][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc2c(c1)c1c(C(N)=O)ccc(OC)c1n2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of ethane sulphonyl chloride (34 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixture was stirred for 1 hr. THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-ethane sulphonamido-9H-4-carbazolecarboxamide (20 mg), mp>250° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31](I)[CH3:32].O>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][C:18]([C:24]([O:26][CH2:31][CH3:32])=[O:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(O)c1ccc2oc(-c3ccc(OCc4ccccc4)cc3)cc(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc2oc(-c3ccc(OCc4ccccc4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
4'-Benzyloxy-6-carboxyflavone (1 eq.) was dissolved in HMPA (hexamethylphosphoramide), followed by the addition of sodium hydride (1.1 eq.). Thirty minutes later, ethyl iodide (2 eq.) was added, and the resulting mixture was stirred further for 2 hours at room temperature. The mixture was charged into water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby the title compound represented by the following formula was obtained (yield: 25%). ##STR18##
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9](OOC(=O)C1C=CC=CC=1)(=[O:16])C1C=CC=CC=1.FC(F)(F)C(O)=O>CO>[Cl:8][C:5]1[N:6]=[C:7]([CH2:9][OH:16])[C:2]([F:1])=[CH:3][N:4]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OCc1nc(Cl)ncc1F
Temperature: 65 °C
Yield: 24.7 %

Procedure:
To a solution of 5-fluoro-2-chloropyrimidine (500 μL, 5.24 mmol) in methanol (50 mL) is added benzoyl peroxide (1.5 g, 6.0 mmol) and trifluoroacetic acid (450 μL, 5.95 mmol). The resulting colorless clear solution is degassed by bubbling nitrogen through for 5 minutes and it is then heated at 65° C. for 18.5 hours. The solution is then cooled and concentrated. The resulting residue is diluted with chloroform (50 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and the layers are separated. The aqueous layer is re-extracted with chloroform (50 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to dryness under reduced vacuum. The residue is purified by flash silica gel column chromatography, eluting with gradient of ethyl acetate/dichloromethane (0% to 30%) to give the title compound (210 mg, 25%). 1H-NMR (CDCl3): δ (ppm) 8.42 (s, 1H), 4.85 (s, 2H), 3.57 (br, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH3:10])=[N:4]1)[CH3:2].CCCCCCCCCCCCCCCC(OCC(O)[C@H]1OC[C@H](O)[C@H]1O)=O.[I:39]I>[OH-].[Na+]>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([I:39])[C:5]([CH2:9][CH3:10])=[N:4]1)[CH3:2]
Reactant: II
Reactant: CCc1cc(C)n(CC)n1
Agent: CCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Product: CCc1nn(CC)c(C)c1I

Procedure:
A mixture of 13.2 g (95.7 mmol) of 1,3-diethyl-4-5-methylpyrazole (from Step C) and 1.50 g (3.7 mmol) of sorbitan monopalmitate in 200 mL of 2.5 N NaOH was treated with 44 g (0.17 mol) of iodine. Additional portions of sorbitan monopalmitate and iodine were added after 30 min and 60 min. The mixture was partitioned between 1 L of ether and 500 mL of water and the layers were separated. The organic layer was washed with 500 mL of 5% Na2S2O3, dried over MgSO4 and concentrated. Chromatography on a Biotage 75L using 9:1 heptane/EtOAc as the eluant afforded the title compound. 1H-NMR (400 MHz) δ 1.22 (t, J=7.6, 3H), 1.36 (t, J=7.2, 3H), 2.27 (s, 3H), 2.58 (q, J=7.6, 2H), 4.10 (q, J=7.2, 2H).
Reaction SMILES: NCC[NH:4][C:5](=S)[NH:6][C:7]1[C:15](C)=C2C(C=CN2)=CC=1.[N:18]([C:21]1[C:29]([CH3:30])=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=C=S.C(N)CN>C1(C)C=CC=CC=1>[CH3:30][C:29]1[C:21]([NH:18][N:6]2[CH2:7][CH2:15][N:4]=[CH:5]2)=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][CH:26]=[CH:25]2
Reactant: Cc1c(NC(=S)NCCN)ccc2cc[nH]c12
Reactant: Cc1c(N=C=S)ccc2cc[nH]c12
Solvent: Cc1ccccc1
Solvent: NCCN
Product: Cc1c(NN2C=NCC2)ccc2cc[nH]c12

Procedure:
6-[-N′-(2-Aminoethyl)thioureido]-7-methylindole. A solution of 6-isothiocyanato-7-methylindole (0.85 g, 4.52 mmol) in 25 mL of toluene is added to a solution of ethylenediamine (1.06 mL, 15.8 mmol) in 50 mL of toluene. The milky white mixture is stirred for 30 minutes as the desired product precipitates. The reaction is filtered to yield 1.1 g of 6-[-N′-(2-aminoethyl)thioureido]-7-methylindole as a flaky white solid (99% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:8]=[CH:7][C:6]=1[OH:20])([O:3][CH3:4])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32].[I-].[K+]>C(#N)C>[C:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:8]=[CH:7][C:6]=1[O:20][CH2:28][CH2:29][CH2:30][C:31]#[N:32])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(OCc2cccc(Cl)c2)ccc1O
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(OCc2cccc(Cl)c2)ccc1OCCCC#N
Yield: 79 %

Procedure:
2-Carbomethoxy-4-(m-chlorophenylmethyloxy)-phenol, 1 gram (3.32 mmoles), was treated with 1 gram potassium carbonate, 0.4 ml 4-bromobutyronitrile, and 70 mg potassium iodide in 18 ml acetonitrile under reflux for 64 hours. Then the mixture was filtered and the filtrate was stripped in vacuo. The residue was chromatographed on silica gel using 1.3 ethyl acetate/hexanes to give 0.97 grams of the title product at 79% yield. Mp 97°-98° C. Elemental analysis. Calculated for C19H18ClNO4 : C 63.42, H 5.04, N 3.89, Cl 9.85; found: C 63.38, H 5.01, N 3.81, Cl 9.77.