Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([OH:34])=O)=[CH:4][N:3]=1.[CH2:35]([N:37]([CH2:40]C)[CH2:38]C)[CH3:36].C[N:43](C)C=O>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:43][CH2:36][CH2:35][N:37]([CH3:40])[CH3:38])=[O:34])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Product: COc1cc(-c2csc3c(C(=O)NCCN(C)C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 90 °C
Yield: 36 %

Procedure:
In a 3-necked round bottom flask were combined 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (0.100 g, 0.180 mmol) and trans-dichloro[bis(triphenylphosphine)]palladium (II) (0.012 g, 0.018 mmol). The flask was filled and evacuated with nitrogen gas 4 times, followed by the addition of N,N-dimethylformamide (2.5 mL), triethylamine (0.050 mL, 0.361 mmol), and the appropriate amine (0.032 mg, 0.361 mmol). The flask was then filled and evacuated with carbon monoxide gas 3 times and the reaction mixture heated to 90° C. under an atmosphere of carbon monoxide for 4 hours. The reaction was cooled to room temperature, diluted with methylene chloride (50 mL), and washed with water and brine (50 mL each). The organic layer was separated and dried over magnesium sulfate, filtered, and the solvents removed. The crude product was purified by trituration with ethanol to give the title compound (0.034 mg, 36%) as a tan powder. LCMS (Conditions a): Rt 3.00 minutes, 543.3 (MH+); 1H NMR DMSO-d6 δ 9.50 (s, 1H), 8.54 (s, 1H), 8.43 (t, J=5.9 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.19 (s, 1H), 7.15 (t, J=7.0 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.40 (m, 2H), 2.43 (m, 2H), 2.20 (s, 6H).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][CH2:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=1>O.C(O)(=O)C>[CH2:24]([NH:23][C:18]1[C:19]([O:21][CH3:22])=[CH:20][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:16][C:17]=1[O:26][CH3:27])[CH3:25]
Reactant: CCNc1c(OC)cc(C(=O)OC)cc1OC
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCNc1c(OC)cc(C(=O)CS(C)(=O)=O)cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A suspension of 58.4 g. of dimethylsulfone and 21.1 g. of sodium hydride (50% dispersion in oil) in 200 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for a period of 4 hours. Then, 42.6 g. of 4-(ethylamino)-3,5-dimethoxy-benzoic acid methyl ester were added. The resulting mixture was stirred at 80° C. for 10 minutes and subsequently dissolved in 1 liter of water. The solution was neutralized with glacial acetic acid. The precipitate was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-(ethylamino)-3',5'-dimethoxy-2-(methylsulfonyl)-acetophenone having a melting point of 129°-130° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][C:22]1([CH3:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24](=O)[O:23]1>C1COCC1>[CH3:21][C:22]1([CH3:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2/[C:24](=[C:3]2\[C:2](=[O:10])[NH:1][C:9]3[C:4]\2=[CH:5][CH:6]=[CH:7][CH:8]=3)/[O:23]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CC1(C)OC(=O)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3ccccc32)c2ccccc21
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 41.5 %

Procedure:
To a solution of oxindole (127 mg, 0.956 mmol) in THF (2.0 ml) cooled at 0° C. was added 1.0M LiHMDS in THF (1.91 ml). The mixture was stirred for 4 minutes at 0° C., then allowed to warm to room temperature for an additional 6 minutes. The solid 3,3-dimethyl-2-benzofuran-1(3H)-one (140 mg, 0.86 mmol) was added in one portion and the reaction rapidly stirred for 1.5 hours. The reaction was quenched into 30 ml 10% HCl aqueous solution. The resulting mixture was stirred 5 minutes, and then extracted into EtOAc. The combined organic layers were washed with water, brine, dried with anhydrous Na2SO4, and rotary evaporated to a yellow oil. The yellow oil was chromatographed through silica gel column (20% to 30% EtOAc/hexane gradient) to give (3E)-3-(3,3-dimethyl-2-benzofuran-1(3H)-ylidene)-1,3-dihydro-2H-indol-2-one as a yellow solid (99 mg, 41%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11](N2CCCC2)[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[OH2:30]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[C:11](=[O:30])[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O
Reactant: CC1CN(Cc2ccccc2)CC=C1N1CCCC1
Solvent: c1ccccc1
Product: CC1CN(Cc2ccccc2)CC(CC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred, cooled solution of 1-benzyl-1,2,3,6-tetrahydro-3-methyl-4-pyrrolidinopyridine (14 g) in dry benzene (50 ml) was added dropwise, in an atmosphere of nitrogen, a solution of phenacyl bromide (10 g) in dry benzene (50 ml). The resulting solution was stirred at room temperature, under nitrogen for 40 hours. Water (100 ml) was added and stirring continued for 1 hour. The organic layer was collected, dried over magnesium sulphate and evaporated to give 17.3 g of the crude product as a red oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12.[CH:20]([N:23](CC)C(C)C)(C)C.[CH2:29]1[CH2:33][O:32]CC1>C(OCC)(=O)C.O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]2[C:4](=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=2[NH:23][CH2:20][C@@H:33]([OH:32])[CH3:29])[NH:10][N:11]=1
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)n[nH]c2n1
Reactant: C1CCOC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nc(NC[C@H](C)O)c2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 0.964 mmol) and N,N-diisopropylethyl amine (0.34 mL, 2 eq) in THF (5 mL) was added dropwise a solution of (S)-(+)-1-amino-2-propanaol (Aldrich) (0.217 g, 3 eq) in THF. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC analysis. The reaction mixture was diluted with ethyl acetate (150 mL) and water (70 mL). The organic layer was separated, washed with water (2×70 mL) and brine (1×70 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as an off-white solid (328 mg, (M+H)+=350).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:33])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[C:13]([F:32])[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[F:32][C:13]1[CH:12]=[C:11]([N:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([O:41][C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)=[CH:3][CH:4]=2)=[O:9])[CH3:33])[CH:16]=[CH:15][C:14]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2F)CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(F)cc1
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2F)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-2-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate (D70) and 4-fluorophenol using a method similar to that described for D55 in Description 55 although the reaction temp./time was 130° C. for 8 h and purification was carried out by column chromatography. δH (CDCl3, 400 MHz) 8.07 (1H, dd), 7.70 (1H, dd), 7.33 (1H, t), 7.05 (4H, m), 6.78 (3H, m), 4.19 (1H, br.s), 3.81 (1H, d), 3.47 (5H, m), 3.07 (1H, td), 2.71 (1H, d), 2.53 (1H, d), 2.18 (1H, dd), 2.04 (1H, m), 1.46 (9H, s), 1.20 (3H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]>C(OC(=O)CCC)(=O)CCC>[OH2:9].[CH2:2]([C:7]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1)[CH2:3][CH3:4]
Reactant: Nc1ccncc1S(N)(=O)=O
Agent: CCCC(=O)OC(=O)CCC
Product: CCCC1=NS(=O)(=O)c2cnccc2N1
Product: O
Temperature: 180 °C

Procedure:
A mixture of 1 g of 4-aminopyridine-3-sulfonamide (Preparation 2) and 10 cm3 of butyric anhydride is heated to 180° C. for 18 hours. After cooling, the crystals obtained are collected on a filter, washed with a small amount of butyric anhydride and with diethyl ether and then dried. The product is recrystallized from hot water.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:19]([NH:20][C:21](=[O:50])[NH:22][C@@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C@H:26]([O:33][C:34]4[CH:35]=[CH:36][C:37]5[N:38]([C:40]([N:43]6[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]6[CH3:49])=[N:41][N:42]=5)[CH:39]=4)[CH2:25][CH2:24]3)=[CH:18][C:17]([C:51]([CH3:72])([CH3:71])[CH2:52][O:53][Si:54]([C:67]([CH3:70])([CH3:69])[CH3:68])([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[N:16]2)[CH:10]=1)(=O)=O.[CH3:73][NH:74][CH3:75]>C1COCC1>[Si:54]([O:53][CH2:52][C:51]([C:17]1[CH:18]=[C:19]([NH:20][C:21]([NH:22][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:26]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]5[CH3:49])=[N:41][N:42]=4)[CH:39]=3)[CH2:25][CH2:24]2)=[O:50])[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][N:74]([CH3:75])[CH3:73])[CH:10]=2)[N:16]=1)([CH3:71])[CH3:72])([C:67]([CH3:68])([CH3:69])[CH3:70])([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CNC
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A solution of Intermediate 153i (131 mg, 0.13 mmol) in THF (0.8 mL) was treated with a 2M solution of dimethylamine in THF (1.3 mL, 2.6 mmol) and the mixture was stirred at 60° C. for 18 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-8% (2N NH3/MeOH) in DCM, to give the title compound as a white foam (93 mg, 75%). LCMS (Method 3): Rt 3.91 min, m/z 960.6 [MH+].
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1)=[O:4].ClCC(Cl)=O.C(C1C=CC=CC=1N1CCNCC1)#[N:24].C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:24])[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: N#Cc1ccccc1N1CCN(C(=O)CCl)CC1

Procedure:
Compound 17A is prepared according to the same procedure as that for 12A, using the following reactants: chloroacetyl chloride (670 μl, 8.4 mmol), 1-(2-cyanophenyl)piperazine (1.32 g, 7 mmol), calcium carbonate (2.1 g, 21 mmol), methyl ethyl ketone (30 ml).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Bi+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]2[O:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C:35]32[O:37][CH2:36]3)[CH:30]=[CH:31][C:32]=1[Cl:33].C(=O)([O-])[OH:51].[Na+]>C1COCC1.O>[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]2[O:42][CH2:41][CH2:40][NH:39][CH2:38][C:35]2([CH2:36][OH:51])[OH:37])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C2(CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cl
Product: OCC1(O)CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Bismuth(III)trifluoromethanesulfonate (228 mg) was added to a mixed solution of tert-butyl (3RS,4SR)-4-(3,4-dichlorophenyl)-1,5-dioxa-8-azaspiro[2.6]nonane-8-carboxylate (59 mg) in THF/water (v/v=4/1, 5 mL), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To the residue was added a solution (4 M, 4 mL) of hydrogen chloride in ethyl acetate. The solvent was evaporated under reduced pressure. To a solution of the residue in THF (4 mL) were added triethylamine (0.033 mL) and di-tert-butyl dicarbonate (52 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To the residue was added a solution (4 M, 3 mL) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, 8 M aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To the residue was added a solution (4 M, 3 mL) of hydrogen chloride in ethyl acetate. The solvent was evaporated under reduced pressure to give the title compound (7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O.[C:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])[CH3:23]>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:22](=[O:24])[CH3:23])=[CH:16][CH:17]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)c1c(C)nc2ccc(OC(F)(F)F)cc2c1-c1ccc(Cl)cc1
Yield: 61 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-chloro-phenyl)-methanone [example A3] and acetylacetone according to the method of example 1, except that heptane/ethyl acetate (1:2) was used. Yield: 61%. MS: m/z=379 (M).
Reaction SMILES: CO[C:3]1[CH:8]=[C:7](OC)[CH:6]=[CH:5][C:4]=1[CH:11]1[C:20]2[C:15](=[CH:16][C:17]([N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[C:13](=[O:14])[O:12]1.C[C:25]1[NH:26][C:27]2C(C=1)=CC=CC=2>>[CH3:25][N:26]([CH3:27])[C:7]1[CH:6]=[CH:5][C:4]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[O:12]2)=[CH:3][CH:8]=1.[CH3:22][N:21]([CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=1
Reactant: COc1ccc(C2OC(=O)c3cc(N(C)C)ccc32)c(OC)c1
Reactant: Cc1cc2ccccc2[nH]1
Product: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Product: CN(C)c1ccccc1

Procedure:
Example 1 was repeated except that 32 g of 3-(2',4'-dimethoxyphenyl)-6-dimethylaminophthalide and 13.5 g of 2-methylindole were used, respectively, instead of 30 g of 3-(p-dimethylaminophenyl)-6-dimethylaminophthalide and 13 g of dimethylaniline to obtain 27 g of triarylmethane having the following structure whose m.p. was 202°-203° C. in the form of colourless crystals (Recrystallized from methanol). This compound becomes bluish violet upon exposure to light on silica gel. ##STR13##
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([Br:19])([C:10](=[O:18])[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(Br)(C(=O)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of 36 g. (0.145 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 175 ml of chloroform was treated with fifteen ml. of bromine. The mixture was heated at reflux for one hour and was then allowed to stand overnight at room temperature 1-Acetyl-4-bromo-4-(p-fluorobenzoyl)piperidine hydrobromide precipitated and was collected by filtration and recrystallized from ethanol. Yield: 40.6 g., melting point 156°-159° C. In exactly the same manner, additional intermediates of this type are produced by substituting the selected starting materials from PREPARATION 2 in the procedure of PREPARATION 7.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[CH3:46][O:47][C:48](=[O:51])[CH2:49][NH2:50]>C(N(CC)CC)C>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:50][CH2:49][C:48]([O:47][CH3:46])=[O:51])[CH2:19][CH2:20]3)[N:14]=1)[CH2:2]2
Reactant: COC(=O)CN
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycine methyl ester hydrochloride (20 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 574.8 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]#[N:15])([O-:3])=[O:2].O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10]([NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH2:15])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: N#CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: O
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 8 h

Procedure:
Dissolve (5-nitro-1H-indol-3-yl)-acetonitrile (9 g, 44.7 mmol) in 250 mL dry THF and treat with 90 mL 1 M BH3 in TBF at ambient temperature. Stir overnight and quench the reaction cautiously by the dropwise addition of 10 mL water. Concentrate to dryness under vacuum and partition the residue between 5 N HCl and EtOAc. Extract the aqueous layer with EtOAc and combine with the original EtOAc layer. Treat the aqueous layer with 5 N NaOH and extract 3 times with 10% MeOH in EtOAc. Purify by flushing the extracts through a pad of 100 g SCX ion exchange resin, rinsing with 2 liters of MeOH which was discarded, and then eluting with the 2 M NH3 in MeOH and concentrating to give the title compound as a dark solid: ISMS 206 (M+1); Analysis for C20H18F6N2O2 0.3H2O 0.1C7H8: calcd: C, 57.34; H, 5.74; N, 19.29; found: C, 57.30; H, 5.38; N, 19.08; 1H NMR (DMSO-d6) 11.9–11.2 (bs, 1H), 8.50–8.49 (d, 1H), 7.95–7.92 (m, 1H), 7.47–7.45 (m, 1H), 7.38 (s, 1H), 2.79 (s, 4H), 2.2–1.3 (bs, 2H).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([OH:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:24]1/[C:23]([NH2:22])=[CH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25]/1
Reactant: COc1ccc(N)cc1O
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(N)=CC1=O

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 5-amino-2-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2O[C:8]32[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]3=O)=[CH:3][CH:2]=1.[NH2:20][NH2:21]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:21][N:20]=[C:10]3[C:11]4[C:16]([CH2:17][CH2:18][C:8]=23)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1c2ccccc2CCC12OC2c1ccncc1
Product: c1ccc2c(c1)CCc1c-2n[nH]c1-c1ccncc1

Procedure:
Following the procedure of step B of Example 1 , the above 3'-(4-pyridyl)-spiro[1,2,3,4-tetrahydronaphthalene-2,2'-oxirane]-1-one is treated with hydrazine to yield 4,5-dihydro-3-(4-pyridyl)-2H-naphtho[ 1,2-c]pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:7]=1I.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(I)c(OCC2CC2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of compound ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh3)4 (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over NaSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (4.6 g) as a yellow oil. 1H-NMR (CDCl3, 200 MHz): 0.41 (m, 2H), 0.62 (m, 2H), 1.22 (t, 3H), 1.23 (m, 1H), 3.58 (s, 2H), 3.89 (d, 2H), 4.17 (q, 2H), 6.96 (m, 2H), 7.31 (s, 1H), 7.64 (m, 4H).