Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](O)=[N:21]3)=[CH:16][CH:15]=2)[CH2:6]1)(=[O:4])=[O:3].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:59][C:60]1[CH:65]=[CH:64][C:63]([CH:66]2[CH2:69][N:68]([CH2:70][C:71]([NH2:73])=[O:72])[CH2:67]2)=[CH:62][CH:61]=1>>[CH3:1][S:2]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([NH:59][C:60]4[CH:65]=[CH:64][C:63]([CH:66]5[CH2:67][N:68]([CH2:70][C:71]([NH2:73])=[O:72])[CH2:69]5)=[CH:62][CH:61]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(O)nn34)c2C1
Reactant: NC(=O)CN1CC(c2ccc(N)cc2)C1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(Nc5ccc(C6CN(CC(N)=O)C6)cc5)nn34)c2C1
Yield: 7.7 %

Procedure:
7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (80 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (95.1 mg, 0.266 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.726 mmol), and N,N-Dimethylformamide (2 mL, 30 mmol) and stir at room temperature for half an hour. Add 2-[3-(4-Amino-phenyl)-azetidin-1-yl]-acetamide (71 mg, 0.34 mmol) and stir at 60° C. overnight. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were collected, basified with sat sodium bicarbonate extracted with EtOAc, dried, filtered and concentrated to give a yellow solid (8 mg, 6%). MP 216-218° C. LCMS (E/I+) 518 (M+H). NMR 1H (DMSO-d6)-9.48 (s, 1H), 9.02 (s, 1H), 7.97 (d, 1H, J=7.81 Hz), 7.64 (d, 2H, J=8.55 Hz), 7.56 (t, 1H, J=7.80 Hz), 7.44 (d, 1H, J=7.74 Hz), 7.21 (d, 2H, J=8.34 Hz), 7.12 (bs, 1H), 7.05-7.08 (m, 2H), 6.99 (d, 1H, J=4.69 Hz), 4.74 (s, 4H), 3.69 (t, 2H, J=7.40 Hz), 3.53-3.61 (m, 1H), 3.15 (t, 2H, J=6.86 Hz), 3.02 (s, 2H), 2.92 (s, 3H).
Reaction SMILES: [C:1](Cl)(=O)[O:2]C(Cl)(Cl)Cl.[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=1[C:12]([OH:14])=[O:13].C(OCC)C>O1CCOCC1>[CH3:19][C:15]1[C:11]2[C:12](=[O:14])[O:13][C:1](=[O:2])[NH:9][C:10]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cccc2[nH]c(=O)oc(=O)c12
Yield: 56 %

Procedure:
Trichloromethyl carbonochloridate (2.04 mL, 16.9 mmol) was added to 2-amino-6-methylbenzoic acid (2.13 g, 14.1 mmol) in anhydrous dioxane (32 mL) under nitrogen, then refluxed for 30 minutes. Diethyl ether (100 mL) was added, and the precipitated solid was collected by filtration to give 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.4 g, 56%) which was used without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].C(N)C>C(O)C.C(N)CCC>[N+:12]([C:15]([CH3:16])=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)([O-:14])=[O:13]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc2nccn2c1
Agent: CCN
Solvent: CCCCN
Solvent: CCO
Product: CC(=Cc1ccc2nccn2c1)[N+](=O)[O-]
Yield: 11.9 %

Procedure:
In 40 ml of ethanol, 6.9 g of 6-imidazo[1,2-a]pyridinecarbaldehyde was stirred under reflux for 14 hours, together with 10.6 g of nitroethane and 30 drops of n-butyl amine. Then, a small quantity of ethyl amine was added thereto and the mixture was stirred under reflux for further 18 hours. After insoluble matters were removed by filtration upon heating, 50 ml of ethanol and 150 ml of ether were further added to remove insoluble matters by filtration. The solvent was removed by distillation under reduced pressure and the residue was recrystallized twice from ethanol to obtain 1.14 g of 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13]O.S(=O)(=O)(O)O>>[C:1]([O:12][CH3:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CO
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCC(C)(C)C
Temperature: 55 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
neo-Decanoic acid (1,376 g, 8.0 mol) and methanol (1,280 g, 40 mol) were placed in a 5-liter four-neck round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. To the mixture at ambient temperature was added conc sulfuric acid (548 g, 5.6 mol) in a dropping funnel for 15 min, raising the pot temp to 55° C. at the end of the addition. The resulting mixture was kept overnight (20-24 h) under reflux with vigorous stirring and then cooled to ambient temperature. The aqueous phase separated, and the remaining organic layer was washed with water until the pH of the last washing was >4. One gram of the organic phase was withdrawn and titrated with 1.0 N NaOH. The calculated amount of NaOH was added to remove the unreacted neo-decanoic acid present in the crude ester. Then the ester was washed with water (88 mL×3) followed by brine (NaCl-saturated, 500 mL). About 100 mL methanol was added into the crude ester and then the resulting mixture was distilled to obtain methyl neodecanoate (749 g, 4.03 mol) at 175-205° C. at atmospheric pressure. The purity of the ester was >99%, and the yield 50% yield.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[C:18]([CH3:27])=[N:19][CH:20]=[C:21]([CH:26]=2)[C:22](OC)=[O:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[AlH4-].[Li+]>O1CCCC1>[OH:23][CH2:22][C:21]1[CH:26]=[C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[N:8]=[CH:9]3)=[CH:14][CH:13]=2)[C:18]([CH3:27])=[N:19][CH:20]=1
Reactant: COC(=O)c1cnc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncc(CO)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of Methyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylnicotinate (11.9 mg, 0.0329 mmol) in tetrahydrofuran (3 mL, 40 mmol) was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was then quenched with water and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 4.5 mg (41%) of N-(7-(5-(hydroxymethyl)-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=2.995, M+H=334.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.64 (s, 1H), 5.30 (t, J=5.4 Hz, 1H), 4.58 (d, J=5.2 Hz, 2H), 2.47 (s, 3H), 2.08 (s, 1H), 0.91-0.78 (m, 4H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21][CH:22]=[O:23])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>ClCl>[CH3:30][CH:29]([CH3:31])[C:28]([O:27][C@@H:26]1[C@@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[O:34][C@@H:24]([N:12]2[C:13]3[N:14]=[C:15]([NH:21][CH:22]=[O:23])[N:16]=[C:17]([O:19][CH3:20])[C:18]=3[C:10]([Cl:9])=[C:11]2[Cl:1])[CH2:25]1)=[O:32]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: ClCl
Product: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
N-Chlorosuccinimid e (117 mg, 0.9 mmol) is added to a solution of compound (45) (200 mg, 0.4 mmol in 5 ml of DMF). After it had been stirred (at room temperature for 16 h), the solution is added to a mixture of CH2 Cl2 /5% aq. NaHCO3 (50 ml, 9:1). The organic phase is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2 /acetone, 95:5). The main zone is separated off. Colorless crystals (149 mg, 72%) are obtained after evaporating off the solvent and crystallizing from cyclohexane. Melting point: 127°-128° C. 1H-NMR ([D6 ] DMSO): δ=1.01 (dd, CH3), 1.14 (d, J=7.0, CH3), 2.44, 2.47, 2.60, 3.53 (4 m, CH and Hα, ○ --C(2')), 4.05 (s, OCH3), 4.17 (m, H--C(5')), 4.30 (m, H--C(4')), 5.56 (m, H--C(3')), 6.41 (m, H--C(1')), 9.44 (d, J=9.1, NH), 10.94 (d, J=9.8, HCO). Anal. calculated for C21 H26Cl2N4O7 (517.4): C 48.75, H 5.07, N 10.83; found: C 49.04, H 5.09, N 10.66.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19](=[O:25])[C:18]=1[CH3:26])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][C:19](=[O:25])[C:18]=1[CH3:26]
Reactant: CC(=O)OCCCCCCCCCCCCC1=C(C)C(=O)CCC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1=C(CCCCCCCCCCCCO)C(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a solution of 3-(12-acetoxydodecyl)-2,4,4-trimethyl-2-cyclohexene-1-one (132 mg, 0.36 mmol, 1 eq.) in dry methanol (8 ml) was added water (3 drops) and K2CO3 (74 mg, 0.54 mmol, 1.5 eq.). After stirring at room temperature for 2.5 hours the solution was neutralized at pH 7 with HCl 5%, extracted with ether, dried with MgSO4 and concentrated in vacuo. The residue was purified by chromatography over silica gel, eluting with hexane-AcOEt (8-2 to 7-3) to give 3-(12-hydroxydodecy)-2,4,4-trimethyl-2-cyclohexen-1-one as a colorless oil (94 mg, 81%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH:20]=[CH:19][C:18]=2[C:22]=1[C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN(C)[CH:30]=[O:31]>>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH:30]=[O:31])=[CH:19][C:18]=2[C:22]=1[C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2occc12
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Under ice-cooling, 26.2 ml of phosphorus oxychloride was added dropwise to 17 ml of N,N-dimethylformamide, followed by a solution of 40.0 g of 5-benzyloxy-4-t-butylbenzofuran in 10 ml of N,N-dimethylformamide. After stirring at room temperature for 20 minutes, the mixture was heated at 80° C. for 2 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution and then water, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10%ethyl acetate) to give 16.2 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran as a pale yellow solid (yield 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Br:20][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:17])[C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(COc2ccc(Cl)cc2)c(Br)c2ccccc21
Reaction time: 3.5 h

Procedure:
Under an argon atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole (5.0 g, 18.40 mmol) was dissolved in 46 ml of tetrahydrofuran. To this solution was added N-bromosuccinimide (3.28 g, 18.4 mmol of a freshly recrystallized lot), dissolved in 46 ml of tetrahydrofuran. The resulting mixture was stirred over an ice bath for about 3.5 hours, after which time the reaction mixture was poured into about 500 ml of water in which 5.0 grams of sodium sulfate had been dissolved.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[CH2:37][NH2:38].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:38][CH2:37][CH:29]3[CH2:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCC1Cc2ccccc2C1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC4Cc5ccccc5C4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 99.2 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (50 mg, 0.133 mmol), suspended in 1.3 ml of dichloromethane, was treated sequentially with (2,3-dihydro-1H-inden-2-yl)methanamine hydrochloride (26.8 mg, 0.146 mmol), N-ethyl-N-isopropylpropan-2-amine (32.4 μl, 0.186 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) at ambient temperature. After 16 hours, the reaction was applied directly to a silica gel column and eluted with a gradient (20% to 80%) of ethyl acetate-hexanes to provide the title compound (67 mg, 0.132 mmol, 99.8% yield) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:6]1[CH:5]=[C:4]([C:1](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NNC(N)=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Yield: 62.8 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g), semicarbazide hydrochloride (0.5 g), and pyridine (0.35 g) in ethanol (20 ml) was stirred and refluxed for 2 hours. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtered, and recrystallized from methanol to give a powder of 3'-(2,4-difluorophenoxy)-4'-methanesulfonamidoacetophenone semicarbazone (1.1 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:29])(=O)=O>>[Cl:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(CO)cc1)c1ccccn1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCl)cc1)c1ccccn1
Yield: 95.1 %

Procedure:
Reaction of Pyridine-2-carboxylic acid (4-hydroxymethyl-phenyl)amide (342 mg, 1.50 mmol), Et3N (262 uL, 1.80 mmol), and methanesulfonylchloride (128 uL, 1.65 mmol) for 2 h at reflux gave the title compound (352 mg, 95%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.61 (s, 2H), 7.45 (d, 2H, J=8.4 Hz), 7.50 (ddd, 1H, J=7.5, 4.8, 0.9 Hz), 7.80 (d, 2H, J=8.7 Hz), 7.92 (ddd, 1H, J=7.8, 7.8, 1.6 Hz), 8.63 (d, 1H, J=6.0 Hz), 10.08 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[N:38][C:30]=3[CH3:29])[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: Cc1ncccc1C(=O)O
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: Cc1ncccc1C(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)C

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 2-methyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.7 (d, 1H)) 8.5 (m, 2H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (m, 1H) 7.4 (m, 3H) 7.3 (m, 1H) 7.2 (m, 1H) 6.9 (d, 1H) 5.5 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.9 (m, 6H) 1.2 (d, 6H).
Reaction SMILES: [F:1][C:2]1[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.FC(F)(F)S([O:43][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])(=O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:43][S:44]([C:47]([F:48])([F:49])[F:50])(=[O:45])=[O:46])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)C(F)(F)F)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.8 g of the compound (169) obtained in Example 46 was added to 10 ml of pyridine, and while cooling on ice, 2.35 ml of trifluoromethanesulfonic anhydride was added to the solution through 20 minutes. The solution was stirred for 24 hours at room temperature. 200 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and purified by column chromatography (silica gel, eluent solvent; chloroform:ethyl acetate=1:1). The solid matter was filtered off and washed with isopropyl ether to obtain 1.2 g of the subject compound (170).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:29](=[O:30])[CH2:28][Cl:27])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1Cl
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOc1nc(-c2ccc(NC(=O)CCl)cn2)nc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 55 (0.064 g, 0.231 mmol) in THF (4 mL), at 0° C. was added triethylamine (0.035 g, 0.346 mmol) and chloroacetylchloride (0.039 g, 0.346 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and the reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:8])[C:3]=1[CH3:9]
Reactant: Cc1c(F)cccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 1,3-difluoro-2-methylbenzene (15 g, 0.12 mol) in H2SO4 (100 mL) was treated dropwise with HNO3 (65%, 11.4 g, 0.12 mol) at −10° C. The resultant mixture was stirred for about 30 min. The mixture was poured into ice-water and extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried (NaSO4) and concentrated in vacuo to give 1,3-difluoro-2-methyl-4-nitrobenzene (16 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 6.8-7.1 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=O)[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O>C(O)C>[Cl:1][C:2]1[C:3]([C:12](=[N:30][O:29][CH2:27][CH3:28])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: CCON
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
To 214 mg of the N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-oxoethyl]phthalimide prepared in Step 2 in Synthetic Example 6 in 3 ml of ethanol, 84 mg of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), and the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 111 mg of the desired product as a brown resinous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](Cl)=[O:11].O>O1CCCC1>[CH3:16][N:15]([CH3:17])[C:13]([N:9]([CH3:8])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])=[O:14]
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 146.9 %

Procedure:
Into 50 ml of anhydrous tetrahydrofuran, 7.4 g (0.08 mol) of aniline was added thereinto and dissolved and the mixture was cooled below 0° C. under stirring. Into this cooled mixture, a solution obtained by dissolving 6.4 g (0.04 mol) of 2,4,4-trimethylallophanoyl chloride in 10 ml of anhydrous tetrahydrofuran was added drop-wise under stirring. After the reaction was continued for 1 hour at room temperature, the solvent was remvoed by distillation under reduced pressure. To the residue thus obtained, water was added and insoluble material was separated by filtration and was recrystallized from ethanol to obtain 13.0 g (yield: 73%) of 1,1,3-trimethyl-5-phenylbiuret having a melting point of 89.5°-90.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:23]([OH:28])[OH:24])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 26 (35.5 g, 0.15 mol), n-butyllithium (15 cm3, 10M in hexanes, 0.15 mol) and triisopropyl borate (56.4 g, 0.3 mol). The experimental procedure was as described in Example 28.