Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])(=O)=O.Cl>C1(C)C=CC=CC=1.C(NCC(C)C)C(C)C.S(Cl)(Cl)(=O)=O>[Cl:22][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:10][CH2:11][C:12]=2[C:2]=1[OH:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Agent: CC(C)CNCC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Temperature: 24 °C
Reaction time: 0.83 h
Yield: 88.8 %

Procedure:
Heat a mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 g, 0.4629 mol) and toluene (14.4 L) to 70° C. for 45 min until most of the starting material is dissolved. Add diisobutylamine (1.197 g, 1.62 mL, 9.26 mmol) followed by addition of sulfuryl chloride (62.48 g, 37.19 mL, 0.463 mol) in toluene (360 mL) over 20 min. Stir the reaction mixture for 50 min and then add additional sulfuryl chloride (4.536 g, 2.70 mL, 0.0336 mol) neat and stir the reaction mixture for 15 min at 70° C. Cool the reaction mixture to 24° C. over 30 min and then add 1N hydrochloric acid (2 L). Separate, wash the organic layer with saturated aqueous NaHCO3 (2 L), brine (2 L) and then dry over Na2SO4. Filter and remove the solvent with a rotary evaporator at 70° C. until about 672.5 g remains using the minimum effective vacuum in order to maintain a vapor phase sufficient to prevent drying above the solvent line and self-seeding, thus preventing crystallization under these conditions. Using toluene heated to 70° C., transfer the light-yellow solution to a preheated (70° C.) 3-neck flask equipped with a mechanical stirrer. Lower the temperature to 58° C. over 1 h. If available, seed the solution with crystals of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine from a prior synthesis to enhance crystallization. After 30 min, reduce the temperature further to 55° C. and observe the initiation of the crystallization process. Hold the temperature at 55° C. for 2 h. followed by 4 h. at 45° C., then turn off the heat allowing the mixture to slowly reach 24° C. (ambient temperature). After stirring for 8 h. with the heat off, cool the mixture to 0° C. for 2 h. followed by 2 h. at −10° C. Collect the resulting dense, white, granular crystals by vacuum filtration at −10° C. Rinse the crystals twice with cold (−10° C.) toluene and vacuum dry at 50° C., 5 Torr, for 12 h., to obtain the desired intermediate as a white solid (120.7 g, 99.5% purity, 88.8%): mp 133-134° C. MS (ES+) m/z 294 (M+H)+. Anal. Calc'd for C12H11ClF3NO2: C, 49.08; H, 3.78; N, 4.77; Cl, 12.07. Found: C, 49.01; H, 3.63; N, 4.72; Cl, 12.32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:21])([CH3:20])/[CH:16]=[CH:17]/[C:18]#[N:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>CO.[Ni]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:21])([CH3:20])/[CH:16]=[CH:17]/[CH2:18][NH2:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(/C=C/C#N)c1cccc(OCc2ccccc2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(/C=C/CN)c1cccc(OCc2ccccc2)c1
Reaction time: 12 h
Yield: 90.9 %

Procedure:
Nitrile derivative XXXIV (120 g, 0.43 mol), Raney Ni (30 mL) and ammonia in methanol (750 mL) were placed in a hydrogenator, 15 psi pressure of H2 gas was applied at 60° C. for 12 h. Reaction mass was filtered and the filtrate was concentrated under reduced pressure to give 110 g crude amine XXXV (92%). M+1=282
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[O:17]1[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18]1>O>[O:17]1[CH:21]=[CH:20][C:19]([C:22]([NH:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:23])=[CH:18]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(Cl)c1ccoc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2[nH]1)c1ccoc1
Temperature: 25 °C

Procedure:
A solution of 20 g. of 2-aminobenzimidazole (II) in 150 ml. of pyridine is cooled to -20°C. and 20 g. of 3-furoyl chloride is added thereto. The thus-obtained reaction mixture is allowed to warm slowly to between 20°-30°C. (room temperature), and maintained at this temperature for 15 hours, diluted with water and filtered to give a residue which is recrystallized from acetic acid to yield 2-(3-furylcarbonylamino)-benzimidazole [(III), R = 3-furyl].
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][C:20]1([CH3:27])[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24](=[O:26])[CH2:25][C:20]([CH3:27])([CH3:19])[C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1)C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), 2,2-dimethylsuccinic anhydride (400 mg), triethylamine (1.39 mL), and tetrahydrofuran (20 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (1.03 g, 95%) as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:9](=[O:12])[CH2:10][CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:18]([N:22]([CH3:24])[CH3:23])N(C)C)(C)(C)C>>[CH3:24][N:22]([CH3:23])[CH:18]=[C:10]([CH3:11])[C:9](=[O:12])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: CCC(=O)C(C)c1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CC(=CN(C)C)C(=O)C(C)c1ccccc1
Yield: 117.6 %

Procedure:
A mixture of 2-phenyl-3-pentanone (106 mg, 0.54 mmol) and of tert.-butoxy-bis(dimethylamino)methane (146 mg, 0.75 mmol, 90%) was stirred at 110° C. for 16 h. The reaction was evaporated to dryness, treated twice with toluene and the solvent was evaporated under reduced pressure to give the crude title compound (138 mg, 97%) as a dark brown solid which was used directly in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23](O)=[O:24])[CH3:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:23](=[O:24])[C@H:21]([CH3:22])[NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-leucine methyl ester hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the tide compound was prepared as a solid (mp=120-132° C.). The reaction was monitored by tlc (Rf=0.49 in 1:1 EtOAc:Hexanes) and the product was purified by flash chromatography using 1:1 EtOAc:Hexanes as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:6]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].Cl.C1C=C2C=CC3OP(O)(=O)OC4C=CC5C(C=4C=3C2=CC=1)=CC=CC=5.Cl>>[CH3:1][O:2][C:3]([C@@H:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C@@H:6]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: COC(=O)[C@@H](c1ccccc1)[C@@H]1CCCCN1
Agent: Cl
Agent: O=P1(O)Oc2ccc3ccccc3c2-c2c(ccc3ccccc23)O1
Product: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1

Procedure:
As alluded to above, racemic threo methylphenidate hydrochloride is known and commercially available, as is the resolving agent employed in Steps 2 and 1A, viz., (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate. In the latter connection, another advantage of the process of the invention is that the resolving agent is recyclable. Thus, the (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate may be recovered by: 1) combining the sodium salt thereof obtained by basifying the filtrate from Step 2, collecting the solid by filtration, and extracting the solid with isopropyl acetate, with the sodium salt and aqueous layer obtained in Step 3; 2) allowing the mixture to react at reflux temperature for between 30 and 45 minutes; and 3) treating the mixture with concentrated hydrochloric acid, initially at the reflux temperature for between 30 and 60 minutes, and then at a temperature of between 15° and 30° C. for a period of between 3 and 5 hours. The recovered (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate is of comparable purity to that of the commercially available material. A resolution of the free base form of racemic threo methylphenidate with the recovered material yielded the desired phosphate salt enriched with the d-threo isomer of methylphenidate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[N:3][CH:2]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>COC(C)(C)C>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[N:9]/[CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[N:3][CH:2]=1
Reactant: O=Cc1ccncn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(/N=C/c2ccncn2)CC1
Reaction time: 2.5 h

Procedure:
Pyrimidine-4-carbaldehyde (C12) (23.00 g, 212.8 mmol) was added to a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (42.61 g, 212.8 mmol) in tert-butyl methyl ether (1.52 L). After 2.5 hours, the reaction was filtered, and the filtrate was concentrated in vacuo to provide an amber oil, which was generally taken directly to the following step. Yield: 56.30 g, 193.9 mmol, 91%. 1H NMR (400 MHz, CDCl3) partial spectrum, characteristic peaks: δ 1.49 (s, 9H), 7.95 (dd, J=5.2, 1.5 Hz, 1H), 8.36 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 9.28 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH:17][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C#N)C1
Product: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)c3ccccc3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid 1,1-dimethylethyl ester (compound A2) and benzoyl chloride.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1.[C:12]1(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[O:13]1.CCN(C(C)C)C(C)C>C1(C)C(C)=CC=CC=1>[O:11]=[C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][N:2]2[C:12](=[O:13])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:21])[CH:10]=[CH:9][NH:8]1
Reactant: NCCc1cc[nH]c(=O)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Br
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCc1cc[nH]c(=O)c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
A mixture of 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (400 mg, 1.83 mmol), isobenzofuran-1,3-dione (271 mg, 1.83 mmol) and DIEA (472 mg, 3.66 mmol) in 30 mL of xylene was stirred at 140° C. for 6 hours. The solvent was removed under reduce pressure. The residue was purified by silica gel chromatography, eluting with DCM/MeOH (30/1) to give 2-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (370 mg, 76%) as a white sold. LC-MS: 269 [M+H]+, tR=1.23 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl.[NH2:27][CH2:28][C:29](N)=[O:30]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:27][CH2:28][CH:29]=[O:30])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCC(N)=O
Agent: Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC=O)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and glycinamide hydrochloride.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][C:20]=2[CH3:28])[N:15]=[N:16][C:17]=1[Cl:18].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C1COCC1>[CH3:28][C:20]1[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=1[C:14]1[N:15]=[N:16][C:17]([Cl:18])=[C:12]([NH:11][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(N)c(Cl)nn2)s1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2cc(NS(=O)(=O)c3ccccc3)c(Cl)nn2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium hexamethyldisilazane (1M solution in THF; 0.81 mL) was added to a mixture of N-[5-(5-amino-6-chloropyridazin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (77 mg) and THF (1.3 mL) that had been cooled to 0° C. The reaction mixture was allowed to warm and was stirred at room temperature for 30 minutes. Benzenesulfonyl chloride (0.069 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. Water (2 drops) was added to the reaction mixture. The mixture was evaporated and the residual solid was purified by preparative HPLC. The material so obtained was purified further by column chromatography on silica using a solvent gradient of 0% to 20% methanol in dichloromethane as eluent. There was thus obtained the title compound as a solid (2.5 mg); 1H NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.40 (s, 3H), 7.05 (s, 1H), 7.45 (m, 3H), 7.80 (m, 2H); Mass Spectrum: M+H+ 424.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]1N2CN3CN(C2)C[N:18]1C3.Cl.[C-]#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[C:17]([CH:6]([OH:7])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)#[N:18]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1

Procedure:
For example, 4-fluoro-3-phenoxy-toluene, when reacted with N-bromosuccinimide in the presence of a radical initiator, for example azodiisobutyronitrile, optionally using a diluent, for example carbon tetrachloride, optionally using a diluent, and 100° C., gives 4-fluoro-3-phenoxy-benzyl bromide. From this, 4-fluoro-3-phenoxy-benzaldehyde can be prepared in a Sommelet reaction, that is to say by reaction with hexamethylenetetramine in the presence of a diluent, for example methylene chloride, at temperatures between 0° and 50° C., followed by reaction with aqueous acetic acid and thereafter with hydrochloric acid, at temperatures between 80° and 120° C. The reaction of 4-fluoro-3-phenoxy-benzaldehyde with sodium cyanide in aqueous acetic acid at 20° C. gives α-cyano-4-fluoro-3-phenoxy-benzyl alcohol. The reaction sequence described above is outlined in the following equations: ##STR11##
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([NH2:18])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25]>C(Cl)Cl>[CH2:24]([O:17][C:16](=[NH:18])[CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:25]
Reactant: CC1(CC(N)=O)OCCc2c1[nH]c1ccccc21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)CC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (20.0 g., 0.817 mole), described in Example 126, is dissolved in dry methylene chloride (400 ml) and freshly prepared triethyloxonium fluoroborate (17.00 g., 0.894 mole) is added in one portion to the solution. The reaction mixture is stirred at room temperature for 2 hr.. The methylene chloride solution is washed with cold 30% aqueous potassium carbonate followed by brine and the dried organic layer is concentrated under reduced pressure. The residue is dissolved in ether (150 ml.). The solution is filtered and crystallization proceeds at room temperature to afford ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetimidate, m.p. 139.5° - 141° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:24]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)([CH3:23])[C:12](=[O:22])[NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:2]1>N1CCCCC1.CN(C=O)C>[NH2:24][C:11]([CH3:23])([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:12]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22]
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(N)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-9H-Fluoren-9-ylmethyl [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (10 g, 18.4 mmol) was dissolved in a 20% piperidine in DMF solution (50 mL) and stirred for 12 hours at room temperature. The solvent was removed in vacuo and chromatographed over silica gel using CH2Cl2 then 5% MeOH: 95% CH2Cl2 as eluants. The title compound was crystallized from ethyl acetate (4.73 g, 80%),mp 106°-110° C. (EtOAc); IR (film) 1646 cm-1 ; NMR (CDCl3) δ1.39 (3H, s), 2.56-2.74 (2H, m), 2.82 (1H, d, J 14 Hz), 3.28-3.40 (1H, m), 3.48 (1H, d, J 14 Hz), 3.44-3.53 (1H, m), 7.1-7.7 (11H, m), 8.3 (1H, s); Anal. (C20H23N3O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: Clc1ccc2cc[nH]c2c1
Product: FC(F)(F)c1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-4-(trifluoromethyl)benzene ESMS m/e: 295.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[NH2:22]>>[CH3:27][O:26][C:24]1[CH:23]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:20]=[C:19]([O:18][CH3:17])[CH:25]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(OC)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,5-dimethoxyaniline gave N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 19.61 min.; purity: 97%; MS (m/e): 357 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1>>[F:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:7]3[C:8]4[C:13](=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])[C:19]=2[CH:26]=1
Reactant: Fc1ccc2scc(CBr)c2c1
Reactant: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Product: Cc1ccc2c(c1)cc(C(=O)O)n2Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 5-methyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as white solid. MS: 338.1 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]([OH:30])=O)=[CH:23][CH:22]=2)=[O:18].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.Cl.CN(C)CCCN=C=NCC>O.O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=2)(=[O:33])=[O:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:30])=[CH:23][CH:22]=2)=[O:18]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(C(=O)N4CCOCC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazole-4-carbonyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carboxylic acid (113 mg) was dissolved in water (5 ml) and tetrahydrofuran (THF) (10 ml), and then morpholine (53.5 μl) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC-HCl) (43 mg) were added thereto. The mixture was stirred at room temperature for 24 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol/dichloromethane=0/100 to 17/100) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-(morpholine-4-carbonyl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (59 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:7]([C:8](=O)[C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].C1(Cl)C(=O)C(Cl)=C(Cl)C(=[O:19])C=1Cl>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:19])[CH:5]=[CH:4]1)[CH3:2]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CCN1CCCC2C(=O)C(F)=C(F)C=C21
Product: CCn1ccc(=O)c2cc(F)c(F)cc21
Yield: 68.3 %

Procedure:
1-Ethyl-6,7-difluoro-1,2,3,4-tetrahydro-5-oxoquinoline(10 g) and p-chloranil (23 g) were reacted in the same method as described in Preparation 1-B to give the white above-indicated compound(6.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[ClH:1].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([NH:24][CH2:23][CH2:21][OH:22])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccc(C)cc3n2)cc1
Reactant: NCCO
Product: COc1ccc(-c2cc(NCCO)c3ccc(C)cc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 233-238° C. and MS: m/e=309.2 (M+H+), was prepared from 4-chloro-2-(4-methoxy-phenyl)-7-methyl-quinoline and ethanolamine.