Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]2[CH2:23][CH:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:20]2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[F:46])=[O:18])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]2[CH2:23][CH:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:20]2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[F:46])=[O:18])[CH2:10][CH2:9]1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC1CN(C(=O)NCCC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)NCCC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (piperidin-4-ylethyl)-amide trifluoroacetic acid prepared in Example 51 (30 mg, 0.04 mmol) was reacted with triethylamine and methanesulfonyl chloride (5.5 mg, 0.05 mmol) in dichloromethane to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-methanesulfonyl-piperidin-4-ylethyl)-amide as a white solid (Yield, 27 mg, 959%).
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[C:13]([F:17])[C:14]([F:16])=[CH:15][C:6]=2[N:5]=1)C.[C:18]([NH:26][NH2:27])(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[F:17][C:13]1[C:14]([F:16])=[CH:15][C:6]2[N:5]3[C:4]([CH2:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1)=[N:27][N:26]=[C:18]3[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC1=Nc2cc(F)c(F)cc2NC(=O)C1
Solvent: CC(=O)O
Product: O=C1Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc2N1
Temperature: 120 °C

Procedure:
To a solution of 4-ethoxy-7,8-difluoro-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(B) (5.38 g, 22.4 mmol) in acetic acid (100 mL) was added benzoic hydrazide (3.11 g, 22.85 mmol). The reaction was heated to 120° C. for 18 hours and the volatiles were concentrated in vacuo. The residue was dissolved in CH2Cl2 and the organic solution was washed with aqueous NaHCO3 (1×), dried (Na2SO4), filtered and concentrated. The solid residue was triturated with a warm mixture of EtOAc and hexanes and was filtered. The solids were triturated in 50% hexanes in Et2O and filtered to provide 3.97 g of 8,9-difluoro-1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one. 1H NMR (DMSO-d6) δ 7.52-7.36 (m, 6H), 7.06 (m, 1H), 3.91 (d, 1H), 3.76 (d, 1H); MS 313.1 (M+1), 311.1 (M−1).
Reaction SMILES: CC1C=CC([CH2:6][NH:7][CH2:8][C:9](O)([CH2:16][C:17]2C=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=CC=1.S(=O)(=O)(O)O.F[C:36](F)(F)C(O)=O>>[CH3:24][O:23][C:20]1[CH:21]=[C:16]([CH:9]2[C:10]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:36])[CH:15]=3)[CH2:6][NH:7][CH2:8]2)[CH:17]=[CH:18][C:19]=1[O:25][CH3:26]
Reactant: COc1ccc(CC(O)(CNCc2ccc(C)cc2)c2ccccc2)cc1OC
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: COc1ccc(C2CNCc3ccc(C)cc32)cc1OC

Procedure:
530 mg of α-[[(4-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl benzyl alcohol was dissolved in 4 ml of trifluoroacetic acid, and after adding thereto 0.12 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, was washed with water once, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 490 mg of 4-(3,4-dimethoxyphenyl)-6-methyl-1,2,3,4tetrahydroisoquinoline (melting point: 94°-96° C.)
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.CO.[C:12]([O:16][C:17]([N:19]1[CH2:51][CH2:50][C:21]2([CH2:49][N:24]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:31]([C:32]4[C:33](=O)[O:34][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]3[CH2:22]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:51][CH2:50][C:21]2([CH2:49][N:24]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:31]([C:32]4[C:33](=[O:34])[NH:3][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]3[CH2:22]2)[CH2:20]1)=[O:18])([CH3:14])([CH3:13])[CH3:15]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CC3(CCN(C(=O)OC(C)(C)C)C3)C4)C(=O)OC2=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC3(CCN(C(=O)OC(C)(C)C)C3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 72 h

Procedure:
A mixture of 0.59 ml of 1,1,1,3,3,3-hexamethyldisilazane and 45 mg of methanol was added to a solution of 150 mg of 3-[1-(tert.butoxy-carbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione in 10 ml of DMF and stirred for 72 hours. The solvent was removed by evaporation and the residue was treated with 10 ml of methanol. After evaporation, the residue was subjected to chromatography on silica gel using dichloromethane/ethyl acetate (4:1) for the elution. There were obtained 120 mg of 3-[1-(tert.butoxycarbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 232°-235° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH:9]([CH2:24][CH2:25]O)[CH2:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:74]=[N+:75]=[N-:76])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8][CH:9]2[CH2:24][CH2:25][N:74]=[N+:75]=[N-:76])=[O:14])=[CH:18][CH:19]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)CC1CCO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(2-hydroxyethyl)piperazine (0.134 g, 0.33 mmol) and triphenylphosphine (0.100 g) in THF (6 mL) at 0° C. was added diethyl azodicarboxylate (0.060 mL) and diphenylphosphoryl azide (0.081 mL). The mixture was stirred at ambient temperature for 2 days, then concentrated of volatiles in vacuo. Purification by flash column chromatography on silica gel afforded 0.047 g of 1-((4-chlorophenoxy)methyl)carbonyl-2-(2-azidoethyl)-4-(4-fluorobenzyl)piperazine as a clear, colorless oil; NMR (CDCl3) 7.3 (m, 4), 7.0 (t, 2), 6.9 (d, 2), 4.7 (m, 3), 4.4 (br d, 1), 4.3 (m, 1), 4.1 (m, 1), 3.5-3.1 (m, 4), 2.8 (d, 1), 2.7 (d, 1), 2.1 (m, 2), 1.8 (m, 1) ppm.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[N:9][CH:10]=1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O
Reactant: CS(N)(=O)=O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 151 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.50 (s, 1H), 8.59 (s, 1H), 8.25 (s, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.34-7.28 (m, 1H), 7.20-7.13 (m, 1H), 6.90 (t, J=8.8 Hz, 1H), 3.54 (s, 3H), 3.35 (s, 3H). LCMS: 459.0 (M+1)+
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH2:8]([N:10]([CH2:31][CH3:32])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2([NH2:30])[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])=[CH:13][CH:12]=1)[CH3:9].C(N(CC)CC)C>O1CCCC1>[CH:5]([O:4][C:2](=[O:3])[NH:30][C:20]1([C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([N:10]([CH2:31][CH3:32])[CH2:8][CH3:9])=[CH:16][CH:15]=2)=[O:19])[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OC(C)C)CCc3ccccc3C2)cc1
Temperature: -40 °C
Reaction time: 8 h

Procedure:
The isopropyl chloroformate (18.4 mg, 0.15 mmol) was dissolved in anhydrous tetrahydrofuran (0.05 mL) and cooled at −40° C. A solution of amine from Example 8A (33.7 mg, 0.1 mmol) and triethylamine (0.021 mL, 0.15 mmol) in anhydrous tetrahydrofuran (0.5 mL) was added at −40° C. and reaction allowed to warm at room temperature, shaken overnight, then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to provide the title compound. Yield: 10.7 mg (25%). 1H NMR (500 MHz, DMSO-d6) δ 1.05 (m, 12H), 2.11 (m, 1H), 2.33 (d, J=17.15 Hz, 1H), 2.50 (m, 1H), 2.73 (m, 2H), 2.99 (d, J=16.53 Hz, 1H), 3.44 (m, 4H), 4.70 (m, 1H), 7.07 (m, 4H), 7.67 (d, J=15.0 Hz, 4H), 9.88 (s, 1H), 10.95 (s, 1H); MS (ESI): 424 (M+H)+, 422 (M−H)−.
Reaction SMILES: C[Si](Cl)(C)C.[CH2:6]1[C:11]2([CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7]1.[CH:19]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)=O.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O.C(#N)C.O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH:19]([C:14]2[C:15](=[O:17])[CH2:16][C:11]3([CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH2:12][C:13]=2[OH:18])[NH:40][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:41])([F:42])[F:29])[CH:32]=2)=[O:39])=[CH:22][CH:23]=1)#[N:26]
Reactant: O=C1CC(=O)CC2(CCOCC2)C1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC3(CCOCC3)CC2=O)cc1
Temperature: 50 °C

Procedure:
Trimethylsilyl chloride (275 μL, 2.17 mmol) is added to a solution of 3-oxaspiro[5.5]un-decane-8,10-dione (360 mg, 1.98 mmol), 4-formylbenzonitrile (259 mg, 1.98 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (403 mg, 1.98 mmol) in a mixture of N,N-dimethyl-formamide (1.5 mL) and acetonitrile (2.5 mL), and the mixture is heated at 50° C. for 1 h. The reaction mixture is cooled to room temperature and poured into a mixture of water and ice. The precipitate is filtered and dried under reduced pressure. Yield: 712 mg; ESI mass spectrum [M+H]+=500, Retention time HPLC: 1.12 min (V012_S01).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.Br[CH2:11][CH2:12][CH2:13]Br.[C:15](=[O:18])([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][CH2:13][O:18][C:15]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[I:9])=[C:4]([I:9])[CH:3]=1
Reactant: BrCCCBr
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(F)cc1I
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCCCOc2ccc(F)cc2I)c(I)c1
Temperature: 25 °C

Procedure:
To a solution of 15.00 g (63.03 mmol) of 4-fluoro-2-iodophenol (P7), Preparation 7 and 6.40 g (31.68 mmol) of 1,3-dibromopropane in 200 mL of acetone add 26.00 g (188.4 mmol) of potassium carbonate. Reflux the resulting reaction mixture for 24 hours. Cool the reaction mixture to room temperature, filter it, and concentrate the filtrate by rotary evaporation. Crystallize the resulting solid from acetonitrile to yield 12.00 g (74%) of (P8) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:46])=[N:4][O:5][C:6]=1[N:7]([CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](OC(=O)C)[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:46])=[N:4][O:5][C:6]=1[N:7]([CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(OC(C)=O)c2cc3c(cc2CCOC(C)=O)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2CCOC(C)=O)OCO3)sc2ncccc12
Yield: 99 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-{α-acetoxy-2-[2-(acetoxy)ethyl]-4,5-(methylenedioxy)benzyl}thieno[2,3-b]-pyridine-3-sulfonamide (0.1 3 g, 0.19 mmoles), CH2Cl2 (3 ml), triethylsilane (0.30 ml, 1.9 mmoles) and boron trifluoride etherate (0.12 ml, 0.95 mmoles), giving 0.12 g (96%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH:13]4[CH2:19][CH2:18][N:16]([CH2:17][C:7]=3[C:6]=2[CH:5]=1)[CH2:15][CH2:14]4.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[N:28][CH:29]=1)#[CH:23]>>[CH3:30][C:27]1[N:28]=[CH:29][C:24](/[CH:22]=[CH:23]\[N:9]2[C:10]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:5][C:6]=3[C:7]3[CH2:17][N:16]4[CH2:15][CH2:14][CH:13]([C:8]2=3)[CH2:19][CH2:18]4)=[CH:25][CH:26]=1
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc(/C=C\n2c3c(c4cc(OC(F)(F)F)ccc42)CN2CCC3CC2)cn1

Procedure:
The coupling of 9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (140 mg, 0.473 mmol; Example 175) and 5-ethynyl-2-methylpyridine (111 mg, 0.945 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.66-1.80 (m, 2H), 1.84-1.98 (m, 2H), 2.40 (s, 3H), 2.95-3.23 (m, 5H), 4.24 (s, 2H), 6.83 (d, J=8 Hz, 1H), 6.92-6.99 (m, 2H), 7.06-7.16 (m, 3H), 7.28 (s, 1H), 7.85 (s, 1H); MS (DCI/NH3) m/z 414 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]([CH3:29])[CH3:28])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>>[ClH:1].[ClH:1].[CH2:34]([N:36]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]([CH3:29])[CH3:28])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1)[CH2:37][CH3:38])[CH3:35]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1
Product: Cl

Procedure:
According to the same manner as that described in Example 14, ethyl 2-chloromethyl-4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 2-(N,N-diethylaminomethyl)-4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate dihydrochloride. This compound was recrystallized from ethyl acetate - ether. Yellow powder, mp. 122°-124° C.
Reaction SMILES: [N-:1]=[C:2]=[S:3].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[NH:5][NH2:6]>>[C:4]([NH:5][NH:6][C:2]([NH2:1])=[S:3])([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)NN
Reactant: [N-]=C=S
Product: CCOC(=O)NNC(N)=S

Procedure:
For the synthesis of compounds of formula (I) wherein E=--S--, Reaction Schemes 13 and 14 may be utilized. In Reaction Scheme 13, the isothiocyanate 22 is reacted with ethyl carbazate (8) to give the 1-(carbethoxy)thiosemicarbazide 48. By standard conditions, 48 is S-alkylated to yield 49, which can be cyclized to the triazolinone 50 by heating, optionally in the presence of base or acid [F. Kurzer and D. R. Hanks, Chem. Ind. (London), 1143 (1966)]. Finally, alkylation of the triazolinone as in Reaction Scheme 1 provides the fully substituted product 51. ##STR22##
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]([NH2:28])([CH3:27])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][CH:25]([CH3:27])[CH3:26])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)C
Yield: 89.3 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 2.2 ml (0.026 mol) of isopropylamine in 30 ml of DMF were reacted at room temperature affording a residue which was kugelrohr distilled at 80 Pa, pot temperature 112° C., to give 4.86 g (89.3%) of product as a yellow solid; mp 43.5°-45° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([O:6][N:7]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:2]1.[ClH:21]>CCO>[ClH:21].[ClH:21].[NH:1]1[CH2:5][CH2:4][C@@H:3]([O:6][NH2:7])[CH2:2]1
Reactant: c1ccc(C(=NO[C@@H]2CCNC2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: NO[C@@H]1CCNC1

Procedure:
Benzophenone O—[(R)-3-pyrrolidinyl]oxime (13.0 g) was suspended in 6N HCl (250 mL) and the mixture was refluxed for 2 h. After cooling, the reaction was extracted with Et2O. The aqueous layer was evaporated to give a crude brown solid which was treated with 0.34 g of activated carbon in absolute EtOH (255 mL) at reflux for 2 h. The solid obtained after evaporation was crystallized with 96% EtOH (40 mL) to give the title compound III-e (2.98 g, 72%), as an off white solid. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 11.22 (3H, bb), 9.74 (1H, bb), 9.54 (1H, bb), 4.98 (1H, m), 3.60-3.00 (4H, m), 2.40-2.00 (2H, m).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]>[Ni]>[CH2:2]([OH:1])[C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: [Ni]
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
In the presence of the Raney-nickel catalyst, L-rhamnose (10 w/v %) was completely reduced at a temperature of 50° C. and a pressure of 1.2 MPa, to produce 6-deoxy L-mannitol. Using the resulting 6-deoxy L-mannitol as a substrate, 6-deoxy L-fructose was produced. A freshly separated Enterobacter sp. 230S was used for selectively oxidizing the carbon in 6-deoxy L-mannitol at position 2 to prepare 6-deoxy L-fructose. The microorganism was cultured in a mineral salt-added culture medium supplemented with D-sorbitol (0.8 w/v %) and glycerol (0.2 w/v %) under agitation at a temperature of 30° C. and 300 rpm, for 24 hours. The culture was centrifuged at 12,000 rpm for 30 minutes, to harvest the bacterial cells, which were then washed twice with 50 mM Tris-HCl buffer (pH 10). The washed bacterial cells were suspended in the same buffer for use in converting 6-deoxy L-mannitol to 6-deoxy L-fructose. The reaction was done in various substrate concentrations in a 5-liter bioreactor (ABLE DPL-2, Japan), using the bacterial cells of OD600=40, a handling volume of 0.5 liter, an agitation speed of 200 rpm, an air flow rate of 0.2 liters/min and a temperature of 30° C.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[CH:11]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][C:4]1[N:3]=[C:2]([C:11]#[C:10][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: C#Cc1cccnc1
Reactant: Cc1ccc(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cccnc2)n1
Yield: 44.9 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted with (PPh3)2PdCl2 (37 mg, 0.05 mmol), Cul (10 mg, 0.05 mmol) and 3-ethynyl-pyridine (110 mg, 1.07 mmol) in triethylamine (1.6 ml). The crude residue was purified by flash chromatography (DCM-DCM/MeOH 97:3) to yield 100 mg (0.48 mmol, 49%) of (6-methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine as a yellow powder. The hydrochloride of (6-methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine was prepared as described in Example 1 to yield after trituration with pentane 145 mg (100%) of the title hydrochloride as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([CH2:24][CH2:25][CH3:26])C(=O)C(F)(F)F)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[OH-].[Li+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([NH:17][CH2:24][CH2:25][CH3:26])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCN(C(=O)C(F)(F)F)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCNN(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Reaction time: 5 h
Yield: 63.8 %

Procedure:
5.64 g (15.187 mmol) of crude product 403 are dissolved in 100 ml of methanol and treated at RT with 10 ml of completely deionized water and 1.08 g (45.24 mmol) of lithium hydroxide. The reaction mixture is then stirred for 5 h. After customary work-up, 2.67 g (63.8%) of 404 are thus obtained as an oil; MS(FAB)=276.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:10]=2[N:9]=[C:8]1[S:33][CH3:34])(=O)C.COCCOC.[OH-].[Na+].Cl>CO>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:16]3[C:10]4[N:9]=[C:8]([S:33][CH3:34])[N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[C:11]=4[CH:14]=[CH:15]3)=[CH:19][CH:20]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1CCO
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of 3-acetoxyethyl-7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (410 mg) in methanol (8 ml)-DME (4 ml) was added 1N-aqueous sodium hydroxide solution (1.64 ml) and the mixture was stirred for 2 hours. This reaction mixture was neutralized with 1N-hydrochloric acid (1.64 ml) and the precipitate was collected by filtration, washed serially with water, methanol and ether, and dried to provide the title compound (295 mg).