Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20])(=[O:13])=[O:12])([O-:4])=[O:3].[CH2:21]([O:28][C:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH2:41][C:42](O)=[O:43])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH2:41][C:42]([N:17]1[CH2:18][CH2:19][N:14]([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N+:2]([O-:4])=[O:3])(=[O:12])=[O:13])[C:15](=[O:20])[CH2:16]1)=[O:43])=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Agent: Cl
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(=O)C1)OCc1ccccc1
Yield: 61.5 %

Procedure:
The title compound (731 mg, 61%) was synthesized by reaction of 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (644 mg, 2.0 mmol) with [6-N-(benzyloxycarbonyl)-adenin-9-yl]-acetic acid (655 mg, 2.0 mmol) as per the procedure of example 77. 1H NMR (DMSO-d6) δ 10.69 (s, 1H), 9.00 (m, 1H), 8.71 (m, 1H), 8.63˜8.58 (m, 2H), 8.31 (s, 0.6H), 8.29 (s, 0.4H), 7.47˜7.33 (m, 5H), 5.39 (s, 1.2H), 5.29 (s, 0.8H), 5.21 (s, 2H), 4.57 (s, 0.8H), 4.29 (s, 1.2H), 4.15˜4.09 (m, 2.4H), 3.93˜3.86 (m, 1.6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
3.9 g of 5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is dissolved in 70 ml of dichloromethane with 1.84 ml of triethylamine and 0.54 g of dimethylaminopyridine. The solution is cooled to 0° C. and then mixed by portions with 2.54 g of tosyl chloride. After stirring for 2 hours at room temperature and standing overnight, it is shaken out three times with sodium hydrogen carbonate solution, the organic phase is concentrated and recrystallized from acetic acid. 4 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 149°-150° C. is obtained. This 4 g is dissolved in 40 ml of tetrahydrofuran under argon and mixed at room temperature with 17 ml of a 1.7 molar solution of calcium diisopropoxy aluminum hydride in tetrahydrofuran (Capal); after refluxing for one hour, 17 ml of Capal is added once more and refluxing is continued for 2 hours. After cooling, it is mixed with 2N sodium hydroxide solution and shaken out with acetic acid. The organic phase is concentrated and 3.1 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-3-hydroxymethyl-beta-carboline is obtained, which is suspended in 57 ml of toluene and mixed with 1 ml of azodicarboxylic acid ester. After refluxing for 12 hours, it is concentrated and chromatographed over silica gel with cyclohexane:acetic acid=1:1 as eluant, 1.8 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carbaldehyde with a melting point of 125°-127° C. is obtained.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[C:2]([CH3:4])=[O:3].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5])(=[O:17])[CH3:16]
Reactant: CCCCCCCCOC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: C=C(OC(C)=O)C(=O)OCCCCCCCC
Temperature: 120 °C
Reaction time: 27 h
Yield: 59.2 %

Procedure:
Next, in a mixture of the obtained octyl pyruvate (300 g, 1.5 mol) and acetic anhydride (306 g, 3.0 mol), p-toluenesulfonic acid monohydrate (5 g) was added. Then, the mixture was stirred under a nitrogen gas stream at 120° C. for 27 hours, thereby obtaining a second reaction solution. Next, acetic acid generated by a reaction with excess acetic anhydride under reduced pressure (5 mmHg) was removed from the second reaction solution. Thereafter, the residue was purified by reduced pressure distillation (1 mmHg or less, 80 to 102° C.), thereby obtaining octyl α-acetoxyacrylate (215 g, yield 59%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>CN(C)C=O>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[C:18]=[S:19]
Reactant: Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-[4-(cyclopropylmethyl)-1-piperazinyli]benzenamine (3.7 g, 16 mmol) (from Step B above) in N,N-dimethylformamide (50 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyidiimidazole (2.87 g, 16.1 mmol) (Aldrich) in N,N-dimethylformamide (25 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water (1000 mL) was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water and dried under vacuum. (4 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(-c2nc3ccccc3s2)cc1
Yield: 87.7 %

Procedure:
A solution of 2-(4'-aminophenyl)benzothiazole (0.5 g, 2.21 mmol) in benzene (30 ml) and acetic anhydride (0.5 g) was stirred at reflux for 4 hours and then cooled. The white precipitate was filtered off and washed with benzene. Recrystallisation from ethyl acetate gave a white powder (0.52 g, 88%), m.p. 227.2-229.1° C.
Reaction SMILES: Cl.Br[C:3]1[C:4]([F:10])=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>O1CCOCC1.CCOC(C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:10][C:4]1[C:3]([CH:11]=[CH2:12])=[CH:8][N:7]=[C:6]([NH2:9])[CH:5]=1
Reactant: Nc1cc(F)c(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1cnc(N)cc1F
Temperature: 120 °C

Procedure:
5-Bromo-4-fluoro-pyridin-2-ylamine mono HCl salt (xvii) (368 mg, 1.62 mmol), tributyl(vinyl)stannane (0.52 mL, 1.78 mmol) and palladium tetrakis(triphenylphosphine) (19 mg, 0.016 mmol) in dioxane (6 mL) under argon were heated under microwave irradiation at 120° C. for 45 min. Were then added tributyl(vinyl)stannane (0.2 mL, 0.685 mmol) and palladium tetrakis(triphenylphosphine) (7 mg, 0.006 mmol) and the RM was placed under argon and heated once more under microwave irradiation at 120° C. for 45 min. The RM was diluted with EtOAc and washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by chromatography with hexane and EtOAc to yield the title product as a yellow solid (tR 1.76 min (conditions 8), MH+=139).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[S:10](=[O:13])(=[O:12])=[O:11]>>[F:1][C:2]([F:9])([F:8])[C:3]1([F:7])[C:4]([F:6])([F:5])[O:13][S:10]1(=[O:12])=[O:11]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=S(=O)=O
Product: O=S1(=O)OC(F)(F)C1(F)C(F)(F)F
Reaction time: 96 h

Procedure:
A mixture of commercial liquid sulfur trioxide (10 ml) and hexafluoropropene (45 g, 0.30 mol) was sealed in a Carius tube at liquid nitrogen temperature, mixed well at 25° C., allowed to stand for 4 days at 25° C., and finally heated in a steam bath for 6 hours. From two such tubes, there was obtained by distillation, 3-(trifluoromethyl)-3,4,4-trifluoro-1-oxa-2-thiacyclobutane 2,2-dioxide (2-hydroxy-1-trifluoromethyl-1,2,2-trifluoroethane sulfonic acid sultone, D. C. England, M. A. Dietrich and R. V. Lindsey, Jr., J. Amer. Chem. Soc., 82, 6181 (1960)) (25 g, 22%) bp 44° C., and pentafluoro-2-propenyl fluorosulfate (hereinafter referred to as perfluoroallyl fluorosulfate) (73 g, 63%), bp 58°-60° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:34][C:33]4[CH:35]=[CH:36][C:37]5[O:38][CH2:39][CH2:29][O:30][C:31]=5[CH:32]=4)[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 65 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol) gave N4-[4-(N-benzylpiperazino)phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (40 mg, 63%). 1H NMR (CDCl3): δ 2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8 Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H, NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28-7.36 (m, 5H), 7.47 (d, J=8.7 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −168.66; LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[O:6][CH2:7][CH2:8][N:9]1[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:18].CCN(C(C)C)C(C)C.[S:33]1[C:37]2[CH:38]=[C:39]([S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:41][C:36]=2[N:35]=[CH:34]1>C(Cl)Cl>[S:33]1[C:37]2[CH:38]=[C:39]([S:42]([N:17]3[CH:15]4[CH2:14][CH2:13][CH2:12][CH:11]3[C:10](=[O:18])[N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16]4)(=[O:43])=[O:44])[CH:40]=[CH:41][C:36]=2[N:35]=[CH:34]1
Reactant: COc1ccc(OCCN2CC3CCCC(N3)C2=O)cc1OC
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCCN2CC3CCCC(C2=O)N3S(=O)(=O)c2ccc3ncsc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxyl)ethyl)-3,9-diazabicyclo[3.3.1]nonan-2-one (32 mg, 0.1 mmol) in 3 ml DCM was treated with DIPEA (15 mg, 0.12 mmol) and stirring for 30 min at room temperature followed by addition of 1,3-benzothiazole-6-sulfonyl chloride (28 mg, 0.12 mmol). The reaction was stirred overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-TLC in 10% MeOH in CHCl3.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:41][O:40][C:39](=[O:42])[O:38]3)=[CH:33][CH:32]=2)O1>>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:31]3[CH:32]=[CH:33][C:34]([CH:37]4[CH2:41][O:40][C:39](=[O:42])[O:38]4)=[CH:35][CH:36]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: CC1(C)OB(c2ccc(C3COC(=O)O3)cc2)OC1(C)C
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C4COC(=O)O4)cc3)cc2N=C(N)C1
Yield: 9 %

Procedure:
Reaction of (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dioxolan-2-one as follows yielded (1E,4E)-2-amino-8-(4-(2-oxo-1,3-dioxolan-4-yl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (9%). (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. 1H NMR (400 MHz, DMSO-d6) δ 7.74-7.80 (m, 2H), 7.55-7.60 (m, 2H), 7.26-7.42 (m, 3H), 6.78 (s, 1H), 5.89-5.96 (m, 1H), 4.88-4.95 (m, 1H), 4.45-4.52 (m, 1H), 2.78 (s, 2H), 1.50-1.63 (m, 4H), 0.71-0.93 (m, 6H); m/z (APCI-pos) M+1=448.2. (1E,4E)-2-amino-8-(4-(1,2-dihydroxyethyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (19%) was obtained as the more polar product. (19%). 1H NMR (400 MHz, DMSO-d6) δ 7.59-7.64 (m, 2H), 7.39-7.44 (m, 2H), 7.33-7.38 (m, 1H), 7.26-7.28 (m, 1H), 7.20-7.24 (m, 1H), 6.84 (br s, 1H), 6.74 (s, 1H), 5.23-5.27 (m, 1H), 4.71-4.75 (m, 1H), 4.54-4.62 (m, 1H), 3.44-3.50 (m, 2H), 3.28-3.35 (m, 4H), 2.74 (s, 2H), 1.51-1.61 (m, 4H), 0.73-0.90 (m, 6H); m/z (APCI-pos) M+1=422.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.[CH:11]([NH2:13])=O>C(Cl)Cl>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:9])[NH:13][CH:11]=1
Reactant: COC(=O)c1ccsc1N
Reactant: NC=O
Solvent: ClCCl
Product: O=c1[nH]cnc2sccc12
Yield: 40 %

Procedure:
A solution of methyl 2-aminothiophene-3-carboxylate (602.1 mg, 3.83 mmol) in formamide (5 mL) is heated at 200° C. for 12 h. The resulting tar is dissolved in CH2Cl2 (10 mL) then placed on a silica plug and eluted with 10% MeOH in CH2Cl2. The filtrate is stripped under reduce pressure and the resulting solid is washed with EtOH to yield 3H-thieno[2,3-d]pyrimid-4-one (231.4 mg, 40%) as an orange solid. 1H NMR (DMSO) δ 12.50 (1H, brs), 8.13 (1H, s), 7.60 (1H, d, J=5.8 Hz), 7.41 (1H, d, J=6.0 Hz).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(OCC)(=O)C.O>[OH-].[Na+]>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2nnn(O)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)On2nnc3ccc([N+](=O)[O-])cc32)cc1
Yield: 56.1 %

Procedure:
In 1 N aqueous sodium hydroxide (45 ml) is dissolved 1-hydroxy-6-nitro-1,2,3-benzotriazole (7.2 g). To the solution is gradually added p-toluenesulfonyl chloride (7.7 g) with stirring under ice-cooling and further are added thereto ethyl acetate (100 ml) and water (50 ml) and the mixture is stirred for 1 hour. The ethyl acetate layer is separated, dried over magnesium sulfate-charcoal, and concentrated until it becomes about 30 ml. n-Hexane (about 50 ml) is added thereto and the mixture is allowed to stand. The precipitated crystals are separated and dried to give faint yellow needles of 1-(p-toluenesulfonyl-oxy)-6-nitro-1,2,3-benzotriazole (7.5 g), melting point: 142°-144° C. The product is recrystallized from ethyl acetate-n-hexane to give a pure product, melting point: 144° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.CC(O)=O.[Fe]>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1c(N)cccc1F
Temperature: 25 °C

Procedure:
Methyl 2-fluoro-6-nitrobenzoate (715 mg, 3.59 mmol) was dissolved in EtOH/HOAc/(10 mL/10 mL), followed by addition of iron powder (602 mg, 10.8 mmol) at room temperature. The resulting mixture was refluxed under N2 for 2 hrs. After cooling down to room temperature, the brown suspension was partitioned between H2O (30 mL) and Et2O (100 mL). After separation, the aqueous solution was extracted with Et2O (50 mL). The combined organic layers were washed with 1N NaOH (3×50 mL), brine (50 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product, methyl 2-amino-6-fluorobenzoate, an colorless oil which became wax-type solid on standing. The crude compound was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3H), 5.67 (s, 2H), 6.34 (ddd, J=11.58, 8.06, 1.01 Hz, 1H), 6.41 (d, J=8.31 Hz, 1H), 7.13 (td, J=8.18, 5.79 Hz, 1H); Mass spec. 170.06 (MH+), Calc. for C8H8FNO2 169.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.[CH2:16]([NH2:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([N:28]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCN
Reactant: COc1ccc(C(=O)CCC(C)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1c(C)ccc1-c1ccc(OC)cc1
Yield: 78 %

Procedure:
A solution of 1-(4-methoxyphenyl)-1,4-pentanedione (3.00 g, 14.5 mol), dodecylamine (3.24 g, 17.5 mmol) and p-toluenesulfonic acid (150 mg, 0.871 mmol) in toluene (100 ml) was refluxed for 10 hours under heating using Dean-Stark's apparatus. The insoluble matter was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 4.01 g (yield: 78%)
Reaction SMILES: [C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40].O>CN(C)C=O>[C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])#[N:2]
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(C#N)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
72 mg of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 9) was dissolved in 1.0 ml of N,N-dimethylformamide, and to this was added 31 mg of anhydrous potassium carbonate, and 31 mg of methyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 1 hours at 70° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into water, 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 80 mg of methyl 2-[3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 5-7 of the present invention].
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: ClCCN1CCNCC1
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(CCN2CCNCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=626.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-piperazine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: CCCCCCCCCCCC(O)OC1CCCCO1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
The above-mentioned dodecanediol monotetrahydropyranyl ether (7.882 g) and 11.437 g of carbon tetrabromide were dissolved in 78 ml of dichloromethane. Triphenylphosphine (10.843 g) was added thereto under ice-cooling and the mixture was stirred at 0° C. for 5 minutes. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography to give 4.029 g of 1-bromo-12-tetrahydropyranyloxydodecane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.O.[H-].[Na+].[CH3:22]OS(OC)(=O)=O>OS(O)(=O)=O.CN(C=O)C>[Br:1][C:2]1[C:3]2[C:11](=[O:13])[C:10]3[C:9](=[CH:17][C:16]([Cl:18])=[CH:15][CH:14]=3)[N:8]([CH3:22])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cc1Nc1cccc(Br)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2cc(Cl)ccc2c(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
(Method E-3) 2-(3-Bromo-phenylamino)-4-chlorobenzoic acid, 14 (4 g, 12.2 mmol) was heated in conc. H2SO4 (50 ml) for 30 min then allowed to cool to room temperature. Water was added slowly and the precipitate filtered off, washed with water and dried over phosphorous pentoxide. The crude material was suspended in DMF (50 mL) and added under nitrogen to NaH (1.2 g, 50 mmol) in DMF (50 mL). After 30 min dimethylsulphate (3 ml, 18 mmol) was added and stirring continued for 1 hr. Addition of water gave a precipitate the title compound (625 mg, 2.02 mmol, 17%) as the more polar product after separation by column chromatography (ethyl acetate:hexane 1:4)