Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:22]([CH3:23])[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of N-(benzyloxycarbonyl)-4-(mesyloxy)butylamine (2.51 g) in anhydrous dimethylformamide (28 ml) are added dimethylamine (12.5 ml), anhydrous potassium carbonate (1.72 g) and sodium iodide (3.74 g), and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 1.59 g (76%) of N-(benzyloxycarbonyl)-4-(dimethylamino)butylamine.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[C@@H:18]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>N1C=CC=CC=1>[C:42]([O:15][CH2:14][C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)[O:16][C@H:17]1[CH2:25][CH2:24][C@H:23]2[C@@H:19]([CH2:20][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]2)[C@@H:18]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
To a solution of the (1S) isomer of EXAMPLE 1 (tert-Butyl (3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate, 8.61 g, 14.65 mmol) in 50 mL pyridine was added benzoyl chloride (3.40 mL, 29.3 mmol). The mixture was stirred at 50° C. for 16 hr. The volatiles were removed in vacuo. The residue was dissolved in 200 mL ethyl acetate, washed with sodium bicarbonate aqueous and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexane, 15% to 30% for 2900 mL, then 30% to 50% for 1250 mL) to give 10.38 g (102% yield) of the title compound. M++1: 588.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:48])[NH:17][C:18]3[S:19][C:20]4[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=4[C:22]=3[C:23](=[O:43])[NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=4)=[CH:27][CH:26]=3)[CH:11]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(O)(C(F)(F)F)=O>>[OH:1][CH2:2][CH:3]1[CH2:4][NH:5][CH2:6][CH2:7][N:8]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)=[O:43])=[O:48]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN5CCN(C(=O)OC(C)(C)C)CC5CO)c4)sc4c3CCCC4)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN5CCNCC5CO)c4)sc4c3CCCC4)cc2)cc1
Yield: 92.8 %

Procedure:
By using 1.71 g of tert-butyl 3-(hydroxymethyl)-4-[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]piperazine-1-carboxylate and 17 mL of TFA, a reaction was performed under the conditions similar to Preparation Example 12, thereby obtaining 1.38 g of methyl 4-(2-{4-[({2-[(3-{[2-(hydroxymethyl)piperazin-1-yl]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:33]([F:36])([F:35])[F:34])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=2[F:32])[C:21]([NH:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])=[O:22])([CH2:16][F:17])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:33]([F:36])([F:35])[F:34])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=2[F:32])[C:21]([NH:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])=[O:22])([CH2:16][F:17])[N:15]=1
Reactant: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
To a solution of 3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-N-((S)-1-methoxypropan-2-yl)benzamide (0.0591 g, 0.115 mmol) in MeOH (1.15 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.021 ml, 0.138 mmol) and allowed to stir at 65° C. for 15 h. The reaction mixture was concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP Ultra silica gel column (25 g), eluting with a gradient of 20-100% EtOAc in hexane, to provide 3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-N-((S)-1-methoxypropan-2-yl)benzamide (0.0246 g, 0.060 mmol, 52.2% yield). MS m/z=410.0 [M+H]+. Calculated for C17H20F5N3O3: 409.14
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:22]=[C:23]([CH:35]=O)[NH:24][C:25]=1[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:23]4[NH:24][C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])=[C:21]([CH3:20])[CH:22]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C=O)[nH]c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 4-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.6 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 89.1 mg (72%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.13 (br s, 1H, NH), 11.74 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.27 (s, 1H), 7.75 (dd, J=2.7 & 6.5 Hz, 1H), 7.71 (s, 1H), 7.52 (m, 1H), 7.38 (t, J=8.85 Hz, 1H), 6.74 (s, 1H), 3.52 (m, 4H, 2×CH2), 2.37 (m, 4H, 2×CH2), 2.21 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]#[N:9].C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1>C(OCC)(=O)C.C1CCCCC1>[C:8]([C:2]1([CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2)#[N:9]
Reactant: N#CC1CC2CCC1C2
Reactant: BrCC1OCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: N#CC1(CC2OCCO2)CC2CCC1C2
Yield: 92.1 %

Procedure:
7.2 g of norbornane-2-carbonitrile are reacted with 60 mmoles of lithium diisopropylamide (prepared from 8.2 ml of diisopropylamine and 40 ml of n-butyllithium) and with 7 g of 2-bromomethyl-1,3-dioxolane in analogy to Example 1a. After chromatography on silica gel with ethyl acetate/cyclohexane (1:6) as the mobile phase, 8.0 g of the title compound are obtained as an oil.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:20])[CH3:19]>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:20][CH2:18][CH3:19])=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: C[n+]1ncc(N)cc1Cl
Reactant: CCS
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCSc1cc(N)cn[n+]1C

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 250 parts of acetonitrile is stirred with 10 parts of ethylmercaptan and 10 parts of triethylamine for four hours at 50° to 60°C. After the solvent has been distilled off the residue is washed with 100 parts of water. 18.3 parts (67.9% of theory) of 1-methyl-4-amino-6-ethylmercaptopyridazinium perchlorate is obtained; C7H12O4N3SCl, melting point 136° to 137°C after having been recrystallized from alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([O:33]/[CH:34]=[CH:35]/B1OC(C)(C)C(C)(C)O1)[CH3:32].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2/[CH:32]=[CH:31]/[O:33][CH2:34][CH3:35])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCO/C=C/c1cc2c(cc1NC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of 3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (12.7 g, 26.4 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.85 g, 39.7 mmol), Pd(dppf)Cl2.CH2Cl2 adduct (4.32 g, 5.29 mmol) and K2CO3 (7.31 g, 52.9 mmol) in dioxane (210 mL) and water (35 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20-50% EtOAc in petroleum ether) to give 3-[(R)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (9 g, 72%). 1H NMR (CD3OD, 400 MHz): δ 6.88 (s, 1H), 6.81 (d, J=12.5 Hz, 1H), 5.99 (brs, 1H), 5.85 (d, J=12.5 Hz, 1H), 4.97-4.93 (m, 1H), 4.70 (m, 2H), 4.06 (m, 2H), 3.93 (m, 4H), 1.61 (s, 3H), 1.48-1.44 (m, 12H), 1.33 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][OH:8])([O-:3])=[O:2].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2[N+](=O)[O-])cc1
Yield: 92 %

Procedure:
2-Nitrophenethyl tosylate was prepared according to the general method as outlined in Preparation 1 starting from 2-nitrophenethyl alcohol (15 g, 89.7 mmol) and tosyl chloride (20.52 g, 110 mmol). The residue was triturated with hexanes and 26.44 g of off white crystals were collected. Yield 92%; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=9.7 Hz, 1H), 7.91 (d, J=9.7 Hz, 2H), 7.64 (t, 1H), 7.39 (m, 2H), 7.24 (s, 2H), 4.32 (t, J=6 Hz, 2H), 3.24 (t, J=6 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCNC(=O)OC(C)(C)C)s1
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A solution of 5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.06 g) and 10% Pd/C (1.03 g) in 50 mL MeOH was placed in a Parr shaker and was hydrogenated at 50 psi H2 for 16 h. The reaction was filtered through Celite® with the aid of MeOH and the filtrate was concentrated in vacuo to afford the title compound of Step B as a solid (1.93 g). MS 317 (M+18).
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].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12].N1CCCC1>C1(C)C=CC=CC=1>[C:14]1([C:11](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)c1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(=C1C(=O)Nc2ccccc21)c1ccccc1
Yield: 85 %

Procedure:
Oxindole (0.1332 g, 1 mmol) and acetophenone (1.4 ml, 1.2 mmol) were mixed in toluene; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture refluxed for 3 hand monitored by TLC. When the reaction was finished the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 10-25% ethyl acetate in petroleum ether) to give 3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one as yellow powder (200 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 5.96 (d, J=7.83 Hz, 1H) 6.51-6.57 (m, 1H) 6.77 (d, J=7.58 Hz, 1H) 7.00-7.10 (m, 1H) 7.30-7.37 (m, 2H) 7.44-7.58 (m, 3H) 10.54 (br. s., 1H). MS calcd. for C16H13NO 235, obsd. (ESI+) [(M+H)+] 236.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:17][CH:18]=1.[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:17][CH:18]=1
Reactant: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2N)cn1
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cn1
Reaction time: 1 h

Procedure:
0.3 g of isoamyl nitrite was added to a mixture of 0.83 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 0.34 g of copper(I) chloride, 0.69 g of copper(II) chloride and 3 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 1 hour. 0.3 g of isoamyl nitrite was added to the mixture, and stirred for 20 minutes. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.52 g of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 7-17].
Reaction SMILES: [H-].[Na+].C1COCC1.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:19]([N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23][CH2+:22]1SCC)[CH3:20].[C:33]1([CH:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=[O:48])[CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO.O>[CH2:19]([N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23][C:22]1=[C:40]1[CH:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]1=[O:48])[CH3:20]
Reactant: CCS[CH2+]1Sc2ccccc2N1CC
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCN1C(=C2C(=O)c3ccccc3C2c2ccccc2)Sc2ccccc21
Temperature: 25 °C
Yield: 22.2 %

Procedure:
A flask was charged with 1.2 g (30 mmol) of sodium hydride (60 wt %), and 100 ml of THF was added thereto in a stream of nitrogen and stirred to make a suspension. While ice-cooling, to this was added 5.9 g (15 mmol) of 3-ethyl-2-(ethylthio)-2(3H)-benzothiazolium 4-methylbenzenesulfonate powder in small portions. Next, to this was added dropwise 50 ml of THF solution containing 6.24 g (30 mmol) of 3-phenyl-1-indanone. The reaction solution was stirred under ice-cooling for 3 hours and at room temperature for 3 hours and then mixed with 20 ml of methanol. When the reaction solution was poured in small portions into a stirred mixed solution of 100 ml of water and 100 ml of methanol, yellow crude crystals were obtained. The crude crystals were suspended in 100 ml of methanol, refluxed, purified and then collected by filtration, thereby obtaining 1.23 g (3.33 mmol) of yellow crystals of D14. Yield was 22%. Its structure was identified by nuclear magnetic resonance spectrum, infrared absorption spectrum, mass spectrometry spectrum and elemental analysis (found; carbon 78.00%, hydrogen 5.15% calcd.; carbon 78.02%, hydrogen 5.18%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH3:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)ccc1CBr
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1CN1CCOCC1
Temperature: 110 °C
Yield: 93.3 %

Procedure:
A mixture of 1-bromomethyl-4-chloro-2-methoxy-benzene (705 mg), morpholine (0.52 mL, 6 mmol) in toluene (15 mL) was heated to 110° C. for 2 hours. The solution was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 675 mg (93%) of the title compound. MS (ESI) m/e 242 (M+H)+.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.CN(C=O)C.[N+](C1C=CC([O:55][C:56](=O)[O:57][CH2:58][C:59]([CH3:62])([CH3:61])[CH3:60])=CC=1)([O-])=O.C(N(CC)CC)C>C(O)(=O)C>[CH3:60][C:59]([CH3:62])([CH3:61])[CH2:58][O:57][C:56](=[O:55])[N:37]=[C:36]([NH2:38])[C:35]1[CH:34]=[CH:33][C:32]([NH:31][CH:18]([C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[C:6]=2[F:5])[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[N:20]=2)=[CH:40][CH:39]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CC(C)(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzamidine acetic acid salt (6 g) and DMF (500 mL), carbonic acid 2,2-dimethylpropyl ester 4-nitrophenyl ester [CAS No. 158810-98-1] (3.06 g) and triethylamine (4.64 mL) were added, and the resulting mixture was stirred overnight at room temperature. Acetic acid (5 mL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (6.5 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:25]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:26])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C1CCCC1
Yield: 60.7 %

Procedure:
Using the general method of Example 205, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with cyclopentanecarbonyl chloride (1.04 g, 7.83 mmol) to provide 1.67 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclopentanecarboxamide as a solid, m.p. 207.8-208.9° C. Analysis: Calculated for C20H25N5O: % C, 68.35; % H, 7.17; % N, 19.93;
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].O1CCCC1.CO.O>C(O)(=O)C>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
130 mg (3.2 mmol, 5 eq) of sodium hydroxide are added to a solution of 245 mg (0.64 mmol, 1 eq) of methyl 3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate in 6 ml of a 9/1 tetrahydrofuran/methanol mixture. The reaction mixture is stirred for 2 hours at room temperature. The reaction is stopped by addition of 10 mL of water and 2 mL of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). The oil obtained is crystallized from pentane. 63 mg of solid are obtained (m.p.=100-102° C.). Yield=27%