Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1NC(=O)C2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)NC=2N=1.[ClH:20].CC[O:23]CC>>[Cl:20][CH2:10][C:9](=[O:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl
Reactant: CCOCC
Reactant: Nc1nc2[nH]c(CCc3ccccc3)cc2c(=O)[nH]1
Product: O=C(CCl)CCc1ccccc1

Procedure:
FIG. 19 presents the method used to synthesize 2-amino-6-phenethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 9. Phenylpropanoyl chloride7 was reacted with CH2N2 in the presence of gaseous hydrogen chloride and ether to produce 1-chloro-4-phenyl-2-butanone 8. 1-chloro-4-phenyl-2-butanone 8 was reacted with 2,6-diamino-3H-pyrimidin-4-one 1 to produce 2-amino-6-phenethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 9 at a 39% yield.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:40][CH2:41][C:42]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:37]=[CH:36][C:23]([C:24](NS(C4C=CC=CC=4)(=O)=O)=[O:25])=[CH:22][C:21]=3[O:38][CH3:39])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.BrCC1C=CC(C(OC(C)(C)C)=[O:57])=CC=1OC.Cl>CN(C)C1C=CN=CC=1.N1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:40][CH2:41][C:42]([N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[O:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:37]=[CH:36][C:23]([C:24]([OH:25])=[O:57])=[CH:22][C:21]=3[O:38][CH3:39])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCN1
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Yield: 41 %

Procedure:
The starting indole was obtained as follows: A solution of 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl)]-3-methoxybenzoic acid (0.68g)(prepared as described in Example 1, parts (a) through (i)) and 4-(dimethylamino)pyridine (0.17 g) in morpholine (4 ml) was heated at 80° for 48 hours under a nitrogen atmosphere. The reaction was diluted with water and acidified with 10% (v/v) hydrochloric acid. The resultant precipitate was collected by filtration and washed with water. The product was purified by recrystallization from ethyl acetate to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(morpholinocarbonyl)ethyl]indol-1-ylmethyl]-3-methoxybenzoic acid as a white powder (0.31 g, 41%); partial NMR (80 MHz, CDCl3) 1.2-1.8(m, 9H, cyclopentyl), 2.70(dd, 2H, CH2NH), 3.15(t, 2H, COCH2), 3.2-3.7(m, 8H, morpholino), 3.92(s, 3H, OCH3), 5.35(s, 2H, ArCH2), 6.58(t, 1H, NH), 7.17(d, 1H), 7.9(s, 1H, H7 -indole).
Reaction SMILES: [Cl:1][Si:2](Cl)([CH3:4])[CH3:3].[CH:6]1([NH-:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Li+].CCCCCC>C1COCC1>[Cl:1][Si:2]([CH3:4])([CH3:3])[NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[Si](C)(Cl)Cl
Reactant: [NH-]C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(Cl)NC1CCCCC1
Reaction time: 8 h
Yield: 84 %

Procedure:
In the drybox in a 250 mL flask 60.0 mL (490.89 mmol) of dichlorodimethylsilane was stirred in about 80 mL of THF. To this stirring solution 6.00 g (57.08 mmol) of lithium cyclohexylamide was added as a solid slowly and stirred overnight. The THF was removed under vacuum leaving a cloudy solution. Hexane was added to this mixture and the solids were filtered off and washed with hexane. The hexane was then removed from the filtrate under vacuum leaving a clear light yellow product weighing 9.18 g. Yield 84 percent.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH3:28][N:29]=[C:30]=[S:31]>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:30]([NH:29][CH3:28])=[S:31])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: CN=C=S
Solvent: O
Solvent: C1CCOC1
Product: CNC(=S)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 150 mg (0.391 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5), 31.4 mg (0.429 mmol) of methyl isothiocyanate and 5 ml of THF is stirred at 20° C. for 15 hours. Concentration to a volume of about 1 ml, addition of 5 ml of diethyl ether to the concentrate and filtration yield 4-(3-chloro-phenylamino)-3-[4-(methylamino-thiocarbonylamino-methyl)phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 1.22%; m.p. 216-218° C. (decomp.), ESI-MS: (M−H)−=437.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([NH:31]C(OC(C)(C)C)=O)[C:28](=[O:39])[N:27]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(Cl)[Cl:46].CO>>[ClH:46].[NH2:31][C:29]1[C:28](=[O:39])[N:27]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[CH:30]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Solvent: CO
Product: Cl
Product: Nc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
4-[6-(6-tert-Butoxycarbonylamino-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 0.511 mmol) prepared as in Example 10, was added to 1:1 chloroform/methanol (20 ml) and the mixture was purged with anhydrous hydrogen chloride gas then stirred at room temperature for 18 hours. The resulting solid was collected by filtration, washed with diethyl ether, and dried in vacuo to provide 6-amino-8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride as a yellow solid (0.202 g, 100%). MS (APCI); M++1: Calc'd, 407.48. Found, 407.4. Analyses for C21H26N8O.1.25 H2O.2HCl: Calc'd: C, 50.46; H, 6.02; N, 22.14; Cl (ionic), 15.98; H2O, 4.58. Found: C, 50.25; H, 6.13; N, 22.32; Cl (ionic), 14.13; H2O, 4.49.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]=1[CH:24]=O>C(OC(=O)C)(=O)C.C(O)(=O)C.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2](/[CH:1]=[CH:24]/[C:14]2[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][O:17][C:13]=2[CH3:12])=[N:3][CH:4]=1
Reactant: Cc1onc(-c2ccccc2)c1C=O
Reactant: COC(=O)c1ccc(C)nc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Temperature: 120 °C
Reaction time: 192 h
Yield: 54.3 %

Procedure:
To a solution of methyl 6-methylnicotinate (800 mg, 5.29 mmol) in acetic anhydride (2.5 mL) and acetic acid (0.5 mL) was added 5-methyl-3-phenyl-4-isoxazolecarbaldehyde (1.0 g, 5.34 mmol) and the reaction mixture warmed to 120° C. After 8 days at this temperature, the reaction mixture was cooled to room temperature then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, then dried, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 1:1) to give the title compound (920 mg, 54%) as an off white solid. MS: m/e=321.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([B:32]([OH:34])[OH:33])=[CH:28][CH:27]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][S:25][C:26]2[CH:31]=[CH:30][C:29]([B:32]([OH:34])[OH:33])=[CH:28][CH:27]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: OB(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(B(O)O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 131.2 %

Procedure:
A mixture of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (152 mg, 0.5 mmol), cesium carbonate (489 mg, 1.5 mmol) and 4-mercaptophenyl boronic acid (75 mg, 0.5 mmol) in dimethylformamide (5 mL) was allowed to stir for 24 hours in a 60° C. oil bath. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield 277 mg of crude [4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]boronic acid and dimethylformamide. 1H NMR (400 MHz, d6-DMSO): δ 7.63-7.59 (m, 4H), 7.55-7.51 (m, 1H), 7.17 (d, J=8 Hz, 2H), 3.86 (s, 2H), 3.12 (septet, J=7 Hz, 1H), 1.13 (d, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][CH:11]1[S:15][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][C:12]1=[O:23]>CC(O)=O>[NH:16]([C:14]1[S:15][CH:11]([CH2:10][C:9]2[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[C:12](=[O:23])[N:13]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1NC(=O)CC1SC(Nc2ccccc2)=NC1=O
Solvent: CC(=O)O
Product: O=C1N=C(Nc2ccccc2)SC1Cc1nc2ccccc2[nH]1
Reaction time: 0.17 h

Procedure:
N-(2-Aminophenyl)-2-(2-anilino-4-oxo-4,5-dihydro-1,3-thiazol-5-yl)acetamide (40.8 mg, 1 eq) was taken up in HOAc (2 mL), transferred to a micro-tube and run at 100° C. for 600 s. The reaction mixture was evaporated to give 42 mg, as a crude brown oil. Purified by HP-LCMS, to the pooled fractions was added NaOH (1M) to pH=14, the MeCN was evaporated and the aqueous layer extracted with DCM/H2O (9:1), dried and evaporated to give the title compound as an off-white powder: HPLC 99%, RT=2.02 min (System A, 10-97% MeCN over 3 min), 99%, RT=0.96 min (System B, 2-95% MeCN over 2 min); 1H NMR (400 MHz, METHANOL-D4) δ ppm 3.23 (m, 1H) 3.80 (m, 1H) 4.70 (m, 1H) 7.02 (m, 1H) 7.17 (m, 3H) 7.32 (m, 2H) 7.50 (m, 2H) 7.62 (m, 1H); MS [M+H]+ m/z=323.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])=[O:10].Cl[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].C[O-].[Na+]>CO>[CH3:13][CH:12]([CH3:14])[CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:7][C:2]=1[OH:1])=[O:10].[CH3:13][CH:12]([CH3:14])[CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[C:7]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:2]=1[OH:1])=[O:10]
Reactant: CC(C)=CCCl
Reactant: CC(C)CC(=O)c1ccc(O)cc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCOc1ccc(C(=O)CC(C)C)c(O)c1
Product: CC(C)=CCc1c(O)ccc(C(=O)CC(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, 486 mg (2.50 mmol) of (2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52) and 784 mg (7.50 mmol, 3.00 equivalents) of 1-chloro-3-methyl-2-butene were dissolved in 7.0 ml of dry methanol. To the solution which was stirred at room temperature, a methanol (7.5 ml) solution of 405 mg (7.50 mmol, 3.00 equivalents) of sodium methoxide was slowly added dropwise. The resultant mixture was stirred at room temperature for three hours and then at 50° C. for one hour, and distilled at room temperature under a reduced pressure to remove methanol, and combined with ether. The ether layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, distilled off the solvent and obtain 661 mg of a red oily substance. The crude product was subjected to silica gel column chromatography (20 g of Wako Gel C-300, eluted with hexane:ether at varying ratios=50:1-4:1) to produce sequentially by fractionation in the order of elution 139 mg of {2-hydroxy-4-(3-methyl-2-butenyloxy)phenyl} (2-methylpropyl) ketone (53) in the form of a colorless oily substance and 41 mg of {2,4-dihydroxy-3-(3-methyl-2-butenyl)phenyl} (2-methylpropyl) ketone (54) in the form of colorless crystals.
Reaction SMILES: O=C1C2C3C(C(OC)=O)=CC=CC=3NC=2CNC1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].C1(C([N:31]2[CH2:43][C:42]3[NH:41][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=3[C:35]=45)[CH2:32]2)=O)CC1>>[C:19]([N:31]1[CH2:43][C:42]2[NH:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=2[C:35]=34)[CH2:32]1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32
Agent: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Product: CC(C)(C)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 51 was prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and pivaloyl chloride according to the procedures similar to those for Compound 47. 1H NMR (DMSO-d6) δ 9.63 (s, 1H), 7.27-7.47 (m, 2H), 6.96 (s, 1H), 4.89 (s, 2H), 4.33 (s, 2H), and 1.24 (s, 9H). MS (ESI) m/e [M+1]+ 311.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2].C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
A mixture of 2-ethylanthraquinone (25 Kg, 105.9 mol), NBS (19.1 Kg, 107.3 mol) and benzoyl peroxide (70%, 200 g, 0.58 mol) in CCl4 (˜150L) is stirred at reflux for 1.5 hours. On cooling, the precipitate is collected by filtration and washed on the filter with ethanol, hot water and finally ethanol again. After drying, this may be used without further purification (i.e. recrystallisation from benzene/methanol (1:1)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([N:16]=[N+]=[N-])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(O)CC1
Yield: 99.5 %

Procedure:
6.54 g 4-Azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester in 51 ml methanol were hydrogenated in the presence of 0.6 g palladium on charcoal (10%) to yield 5.85 g (quant.) 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester as viscous oil; MS (ISP): m/e=231 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[N:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.28 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (148 mg, 0.56 mmol) and K2CO3 (115 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 2 h, additional Pd (PPh3)4 (16 mg, 0.014 mmol) was added into the reaction mixture and stirring continued at 90° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide as an off-white solid. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.21 (d, 1H), 7.82 (d, 1H), 7.76 (m, 3H), 7.6 (d, 2H), 7.23 (s, 1H), 6.9 (d, 2H), 4.7 (m, 1H), 4.3 (m, 1H), 3.63 (m, 1H), 3.42 (m, 1H), 2.8-3.1 (m, 7H), 2.6 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH2:8]1[O:10][C@H:9]1[CH2:11]Cl.[OH-:13].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C)C=O>[CH2:11]([O:7][CH2:1][CH:6]1[O:13][CH2:5]1)[CH:9]1[O:10][CH2:8]1
Reactant: ClC[C@H]1CO1
Reactant: Oc1ccccc1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(OCC1CO1)C1CO1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The starting phenol derivative (2.50 g) of the following formula: ##STR25## and R-(-)-epichlorohydrin (chemical purity: 98.5% or more, optical purity: 99% or more, 4.25 g) and benzyltriethylammonium chloride (20 mg) are dissolved in dimethylformamide (3 ml) and thereto is added dropwise 24 wt. % aqueous sodium hydroxide (1.2 equivalent) at 60° C. After reacting at the same temperature for 40 minutes, the reaction mixture is cooled to room temperature and extracted with ether. The extract is distilled under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography to give S isomer of glycidyl ether (1.62 g) of the following formula: ##STR26##
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([N:12]2[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]2)[N:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:21][C:20]([F:23])([F:22])[C:6]([C:5]1[C:4]([N:12]2[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]2)=[N:3][C:2]([CH3:1])=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)c1ccc(C)nc1-n1ccc(C)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C(F)(F)F)c(-n2ccc(C)n2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate (3.7 g, 16 mmol) and trimethyl(trifluoromethyl)silane (11.4 g, 80.2 mmol) in toluene (60 ml), was added dropwise at −78° C. and then the solution of tetrabutyl ammonium fluoride (1.6 mL, 1.0 M in THF) was added dropwise to the reaction mixture at −78° C. After addition, the mixture was warmed slowly up to RT and stirred for 12 h. The reaction mixture was concentrated and the resulting residue was dissolved in methanol (30 mL). 6 N HCl (30 mL) was added to the reaction mixture and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated, adjusted to pH 6 with sat.NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/hepate) to provide 2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone as a brown semi-solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([N:11]([CH2:14][CH3:15])CC)C.[C:16]1([C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:11][C:14]3[CH:15]=[CH:6][CH:7]=[CH:2][C:3]=3[OH:8])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Nc1ccccc1O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccccc1O)c1ccc(-c2ccc(S(=O)(=O)Nc3ccccc3O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A flask with a stirrer was charged with 3.10 g of 2-aminophenol, 2.87 g of triethylamine and 50 ml of tetrahydrofuran, and a solution of 5.00 g of 4,4′-biphenyldisulfonyl chloride in 10 ml of tetrahydrofuran was dropwise added with cooling with ice over 10 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethanol/n-hexane mixed solvents, to give 3.7 g of an end product. Decomposition point 185° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:26][NH2:27]>>[C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH2:19][CH2:20][C:21](=[O:22])[NH:26][N:27]=4)=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=O)c1ccc(-n2ccnc2-c2ccccc2)cc1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(-n3ccnc3-c3ccccc3)cc2)=NN1

Procedure:
Similarly, reaction of 4-(2-phenyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-phenyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.CCCCC.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](F)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(F)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)n1ccc2ccccc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)n1c(S(=O)(=O)c2ccc(F)cc2)cc2ccccc21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43.1 %

Procedure:
A solution of 1-indole carboxylic acid tert-butyl ester (1.88 g, 8.65 mmol) in 100 mL of anhydrous THF was cooled to −78° C. in a dry ice/acetone bath under an argon gas blanket. A fresh commercial (Aldrich) 1.7 M solution of t-BuLi in pentane (10.2 mL, 17.3 mmol, 2.0 eq) was slowly added to the stirring mixture via syringe. During the addition, the solution turned from a light amber-red color to a dark, orange-burgundy color. After the addition was complete, the reaction mixture was allowed to stir for 45 minutes at −78° C. and then 4-fluorobenzenesulfonyl fluoride was slowly added to the reaction mixture while carefully maintaining an internal temperature of <−65° C. The reaction mixture was kept at −75 to −78° C. for a period of 20 minutes after the addition was complete then was allowed to warm to room temperature, where it remained for 2 h. The reaction mixture was poured into 500 mL of saturated NH4Cl solution, diluted with 500 mL of EtOAc and mixed well. The pale, amber-orange organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a dark amber oil which was silica-gel chromatographed, gradient eluting with 10% EtOAc/Hexane followed by CHCl3 to give 1.40 g, 3.73 mmol, 43.1% yield of the 2-(4-Fluoro-benzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester as an amber oil which solidified on standing to a pale reddish-tan solid which had a melting point range of 88–93° C.