Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8](Cl)[C:9]=1[F:10].S1(CCCC1)(=O)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([F:1])[C:9]=1[F:10]
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(C(F)(F)F)cc(Cl)c1F

Procedure:
A mixture of 55 parts of anhydrous potassium fluoride and 45.32 parts of 3,5-dichloro-4-fluorobenzotrifluoride in 291 parts of sulfolane was heated and maintained at about 216° to 256° for a period of about 55 hours, while product vapors were removed through a distillation column at a head temperature of about 130°-150° C. A total of 32.02 parts of distillate was collected and analyzed by gas chromatography/mass spectrometry. The distillate was found to be 25.1 percent 3,5-dichloro-4-fluorobenzotrifluoride; 65.9 percent 3-chloro-4,5-difluorobenzotrifluoride; 8.6 percent 3,4,5-trifluorobenzotrifluoride and trace amounts of 4-chloro-3,5-difluorobenzotrifluoride. The desired 3-chloro-4,5-difluorobenzotrifluoride was isolated by distillation (b.p. 122° C.) to recover it in essentially pure form (greater than 99 percent pure). The 3,5-dichloro-4-fluoro isomer is recycled.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:12][N:13](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[Cl:11][C:9]1[CH:10]=[C:2]([C:12]#[N:13])[C:3]2[CH:4]=[N:5][NH:6][C:7]=2[CH:8]=1
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)c2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Cl)cc2[nH]ncc12
Temperature: 120 °C
Yield: 86.9 %

Procedure:
A mixture of 4-bromo-6-chloro-1H-indazole (3.0 g, 12.9 mmol), Pd(PPh3)4 (2.24 g, 1.94 mmol), and Zn(CN)2 (9.22 g, 25.8 mmol) in DMF (50 mL) under nitrogen was heated at 120° C. for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (50 mL×5). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 6-chloro-1H-indazole-4-carbonitrile as white solid (2.0 g, 86.9%).
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4](O)=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:8])=[CH:11][CH:12]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CCC(=O)O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CCC(=O)N1c1ccncc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The starting material is prepared as follows: The mixture of 500 g of succinic acid anyhydride, 471 g of 4-amino-pyridine and 5,200 ml of xylene is heated to reflux while stirring and separating the water formed. After 30 minutes 15 ml of methane sulfonic acid are added and refluxing is continued until 5 moles of water are collected, requiring about 4 days. The mixture is cooled to room temperature, the supernatant is decanted off and the suspension combined with 1000 ml of isopropanol. It is stirred for 5 minutes, filtered, the residue washed with 250 ml of isopropanol and dried for 3 days under reduced pressure at room temperature and shortly at 50° , to yield the 1-(4-pyridyl)-pyrrolidin-2, 5-dione melting at 232°-235° .
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br

Procedure:
2.8 g of 2-bromo-5-nitroaniline are dissolved in 18 mL of acetic anhydride in a microwave oven reactor. After hermetically closing the reactor and reacting for one hour at 60° C. under microwave irradiation, the solid is filtered off and then washed with three times 10 mL of diethyl ether and dried to give 3 g of N-(2-bromo-5-nitrophenyl)acetamide in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH2:18]1[O:26][C:25]2[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=2[O:19]1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[CH:21][C:20]4[O:19][CH2:18][O:26][C:25]=4[CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3ccc4c(c3)OCO4)cc2)on1
Yield: 67 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesul-fonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 3,4-methylenedioxyphenylboronic acid resulting in a 67% yield of final product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:20][OH:21])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: NO
Agent: Cl
Product: ON=Cc1cn(Cc2ccccc2)c2ccccc12
Yield: 60 %

Procedure:
1-Benzyl-1H-indole-3-carbaldehyde oxime (1.752 g, 60%) was prepared from 1-benzyl-1H-indole-3-carbaldehyde and hydroxylamine hydrochloride using a procedure similar to Step 6 of example 1. 1H NMR (400 MHz, DMSO-d6); δ 11.30 (s, 1H), 8.40 (s, 1H), 7.88 (d, 1H), 7.80 (s, 1H), 7.50 (d, 1H), 7.22 (m, 7H), 5.50 (s, 2H).
Reaction SMILES: [C:1](Cl)(=O)C.[NH:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8].CCN(CC)CC.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1>CO>[CH3:1][O:8][C:7](=[O:9])[C@@H:6]1[CH2:10][CH2:11][CH2:12][N:5]1[CH2:26][C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)Cl
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Reaction time: 15 h
Yield: 66.9 %

Procedure:
Acetylchloride (9.26 mL, 130.28 mmol) was added dropwise to a stirred and cooled (0° C.) solution of (S)-proline (5 g, 43.42 mmol) in MeOH (86 mL). After the addition, the ice bath was removed and the stirring was continued for 15 h at room temperature. The solvent was then evaporated and the residual oil redissolved in dry CH3CN (70 mL). Et3N (18 mL, 130 mmol) and BnBr (6.20 mL, 52.10 mmol) were added to obtain a white suspension. After 12 h of stirring at room temperature, the CH3CN was evaporated, and the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL). The phases were separated, the aqueous layer was extracted with Et2O (40 mL×2), and the combined organic phases were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified over silica gel using 5 to 10% EtOAc/pet ether to give a clear oil (6.37 g, 69%): 1H NMR (300 MHz, CDCl3) δ 1.70-2.20 (m, 4 H), 2.32-2.46 (m, 1 H), 3.00-3.10 (m, 1 H), 3.20-3.30 (m, 1 H), 3.56 (d, J=12.7 Hz, 1 H), 3.64 (s, 3 H), 3.88 (d, J=12.7 Hz, 1 H), 7.25-7.35 (m, 5 H). The spectroscopic data agrees with literature values (Corey, E. J., Link, J. O.; J. Org. Chem. 1991, 56, 442).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][CH2:46][CH2:47][NH2:48].F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: COCCN
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COCCNC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and 2-methoxyethanamine (212 mg) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the solid was recrystallized from diisopropyl ether/heptane to give the title compound (31 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:13][N:14]([CH3:18])[C:15](=[S:17])[S-:16].C[NH2+]C>C(=S)=S>[CH3:13][N:14]([CH3:18])[C:15](=[S:16])[S:17][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])C=Cc1ccccc1Cl
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1Cl

Procedure:
As in Example 17, reaction of o-chloro-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave o-chloro-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 102° C.-103.5° C. when recrystallized without heating from acetone-methanol solution.
Reaction SMILES: [Cl-].[P:2]([O-:10])([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[S:3].O[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[P:2]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])([O:10][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)=[S:3]
Reactant: On1cccn1
Reactant: CCOP([O-])(=S)OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=S)(OCC)On1cccn1
Reaction time: 12 h
Yield: 91 %

Procedure:
112 part of diethyl thiophosphate chloride were added to 55 parts of 1-hydroxypyrazole and 50 parts of sodium carbonate in 600 parts of acetonitrile at 25° C., with stirring. Stirring was continued for another 12 hours. The solid product was filtered off with suction and washed with two portions of 50 parts of acetonitrile. The filtrate was concentrated in a rotary evaporator at from 20° to 40°C. under 20 mbar. The residue as dissolved in 300 parts by weight of methylene chloride, the organic phase was extracted with three portions of 50 parts by weight of saturated aqueous NaHCO3 solution, the methylene chloride solution was dried with magnesium sulfate and the solvent was stripped off in a rotary evaporator at from 20° to 40° C. under 20 mbar to give 127.5 parts by weight (91% of theory) of O-pyrazol-1-yl O,O-diethyl thiophosphate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:27][S:28]([C:31]1[CH:40]=[CH:39][C:34]([O:35][CH2:36][CH2:37]O)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:37][CH2:36][O:35][C:34]2[CH:33]=[CH:32][C:31]([S:28]([NH2:27])(=[O:30])=[O:29])=[CH:40][CH:39]=2)=[CH:7][CH:6]=1
Reactant: NS(=O)(=O)c1ccc(OCCO)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.905 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.218 g), stirred for 15 minutes and treated with the tosylate of 2-(4-aminosulfonylphenoxy)ethanol (1.67 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from ethyl acetate extraction was purified by HPLC (dichloromethane-ethyl acetate; 4:1) and crystallized from dichloromethane-hexane to provide 0.9 g of 4-[[2-[4-(amino-sulfonyl)phenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 136°-137° C.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([O-])=O.C[O-:9].[Na+].[CH3:11][N:12]([CH:14]=[N:15][CH:16]=[N+](C)C)C.[Cl-]>C(COC)OC>[OH:9][C:16]1[C:2]([C:1]([O:6][CH3:7])=[O:5])=[CH:11][N:12]=[CH:14][N:15]=1
Reactant: COC(=O)C(=O)[O-]
Reactant: CN(C)C=NC=[N+](C)C
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cncnc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl oxalate (0.2 eq.) and malonomonoamide monomethyl ester (58.55 g, 0.50 mol) were added to an initial charge of sodium methoxide (279.4 g, 1.5 mol, 29% in methanol). 350 ml of dimethoxyethane were added. The solid Gold's reagent prepared as in Example 1 (89.35 g, 0.55 mol) was then added using a spatula. The suspension was then stirred at room temperature for 18 hours. The yellow suspension was poured on to an aqueous, ice-cold hydrochloric acid solution (2 eq. of HCl). Following filtration at pH 9-10, the moist sodium salt of the title product was taken up in HCl-saturated methanol, stirred for 15 min, filtered and dried. The yield of the title product in the form of its hydrochloride was 52.3 g (55%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:8][C:7]1[C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][CH:4]=[C:3]([OH:13])[C:2]=1[NH:1][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1c(O)ccc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1c(O)ccc(C(F)(F)F)c1Cl)c1ccncc1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of 0.17 g of 2-amino-3-chloro-4-trifluoromethylphenol, 0.99 g of isonicotinic acid, 0.19 g of WSC and 3 ml of pyridine was stirred while heating at 80° C. for two hours. The mixture was cooled to room temperature, and then water was poured, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.15 g of N-[2-chloro-6-hydroxy-3-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:8].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17].O>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Yield: 70.8 %

Procedure:
Powdered potassium carbonate (5.18 g, 37.7 mmol) is added to a stirred solution of 4-cyanophenol (2.00 g, 16.8 mmol) and bromoacetaldehyde diethyl acetal (4.53 mL, 30.3 mmol) in anhydrous DMF (20 mL). The resultant mixture is stirred at 85° C. under nitrogen for 3 days. The mixture is cooled to ambient temperature; then water (100 mL) and EtOAc (100 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The oil is chromatographed on silica (gradient 5-20% EtOAc in hexane) to give 2.80 g (11.9 mmol, 71% yield) of the title compound. 1H NMR (CDCl3): δ1.24 (t, J=7.1 Hz, 6H), 3.60-3.68 (m, 2H), 3.73-3.81 (m, 2H), 4.04 (d, J=5.2 Hz, 2H), 4.83 (t, J=5.2 Hz, 1H), 6.97 (br d, J=9.2 Hz, 2H), 7.58 (br d, J=9.2 Hz, 2H); Analysis for C13H17NO3: calcd: C, 66.36; H, 7.28; N, 5.95; found: C, 66.41; H, 7.34; N, 6.01.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]2[CH3:29])=[N:13][C:14]([Cl:18])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:18].[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]2[CH3:29])=[N:13][C:14]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1cc(F)ccc1N
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3[C@H]2C)c1C
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccccc3[C@H]2C)n1
Product: Cl
Yield: 55.5 %

Procedure:
After 2-methyl-4-fluoroaniline(1.1 ml, 9.9 mmol) was added to a mixture solution of (R)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) obtained in the above Step 1 and dimethylformamide(10 ml), 1.10 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: C1[N:6](CC2C=CC=CC=2)[C:4](=[O:5])[O:3]C1.C1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=CC=CC=2)C=CC=CC=1.C([Li])CCC.CC(C)(C)C(O[C:43](=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)=O.[Li][C@H]1COC(=O)N1CC1C=CC=CC=1>C(OCC)(=O)C.CCCCCC.O1CCCC1>[CH2:20]([C@H:21]1[CH2:26][O:5][C:4](=[O:3])[N:6]1[C:43](=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)C(=O)OC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1OCCN1Cc1ccccc1
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Agent: [Li][C@H]1COC(=O)N1Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Alternately, combine (S)-benzyl-2-oxazolidinone (25 g, 140 mmol) and tetrahydrofuran (250 ml). Add triphenylmethane (30 mg) as an indicator. Cool to about −40° C. Add n-butyl lithium (about 56 ml, 1 M in hexane, 140 mmol) until an orange color persists. After 30 minutes, cool in a dry-ice/acetone bath the a solution of 3,4-dichlorophenylacetic acid trimethylacetyl ester as obtained in Preparation 3 and add by cannula the solution of lithio (S)-benzyl-2-oxazolidinone obtained above. When the addition is complete warm to ambient temperature. After 18 hours, partition the reaction mixture between diethyl ether and a saturated aqueous sodium bicarbonate solution. Separate the layers and dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially is with 5% ethyl acetate/hexane and 10% ethyl acetate/hexane to give (S)-4-benzyl-3-(3,4-dichlorophenyl)acetyl-2-oxazolidinone.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[C:10]1([NH:16][C:17]([NH2:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>>[C:10]1([N:16]2[C:4](=[O:5])[CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:19][C:17]2=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (350 mg; 2.5 mmoles), phenylurea (353 mg; 2.6 mmoles) and acetic anhydride (2 ml) was heated at 100° C. with stirring for 1 hour. After cooling, the precipitated solid was collected by filtration to give 298 mg (yield: 46%) of 3-phenyl-5-trifluoromethyldihydrouracil. The solvent was evaporated from the filtrate, and the residue was recrystallized from chloroform/hexane to give additional 133 mg (yield: 21%) of the above product. The total yield was 67%. The physical and spectral properties of the resulting 3-phenyl-5-trifluoromethyldihydrouracil completely agreed with those of the product obtained in Example 11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][CH2:17][C:18]([C:21]([CH2:25][CH3:26])([CH3:24])[CH2:22][CH3:23])=[N:19][N:20]=1.O>ClCCl.N1C=CC=CC=1>[CH2:22]([C:21]([C:18]1[CH2:17][S:16][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:20][N:19]=1)([CH3:24])[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(C)(CC)C1=NN=C(N)SC1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)(CC)C1=NN=C(NC(=O)c2c(OC)cccc2OC)SC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.1 %

Procedure:
Two grams of 2,6-dimethoxybenzoyl chloride dissolved in about 3 ml dichloromethane was added dropwise to a stirring solution of 1.99 g of 2-amino-5-(1-ethyl-1-methylpropyl)-6H-1,3,4-thiadiazine in 10 ml of pyridine. The mixture was stirred at room temperature for approximately 72 hours and poured into water. The product was extracted into ether and washed with water. The ether phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting oil was chromatographed over silica gel eluting with a 1:4 (v:v) mixture of ethyl acetate/toluene. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 0.15 g of N-[5-(1-ethyl-1-methylpropyl)-6H-1,3,4-thiadiazin-2-yl]-2,6-dimethoxybenzamide. mp=134°-140° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[C:21](=O)([O-])O.[Na+].[C:26](O)(=O)[CH3:27]>CO.O.CC(C)=O>[CH:26]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:5][CH2:6]1)([CH3:27])[CH3:21]
Reactant: O=C([O-])O
Reactant: CC(=O)O
Reactant: c1cc2[nH]ncc2cc1OC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 18 h
Yield: 31 %

Procedure:
The 5-(piperidin-4-yloxy)-1H-indazole (80 mg, 0.368 mmol) obtained in Example 42 was suspended in methanol (2 ml), and acetone (0.031 ml, 1.10 mmol) and acetic acid (0.105 ml, 1.84 mmol) were added dropwise thereto. Then, sodium cyanoborohydride (116 mg, 1.84 mmol) was added thereto. After 18 hours, acetone, acetic acid and sodium cyanoborohydride were further added in the same amounts, respectively, as above. After 3 days, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the resulting mixture was poured into water (20 ml) and extracted with chloroform (20 ml×3). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain 5-[(1-isopropylpiperidin-4-yl)oxy]-1H-indazole (30 mg, 31%).
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:18](=[O:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>O>[CH3:20][N:10]1[C:9]2[CH2:8][CH2:7][CH:6]([CH2:5][N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])[C:18](=[O:19])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 99.8 %

Procedure:
A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (1.7 g) in water (17 ml) was treated with 2-methylimidazole (1.4 g) and then heated under reflux for 20 h. The cooled mixture was filtered and the residue washed with water (3×15 ml) to give a product (1.7 g) m.p. 221°-221.5°. This material was recrystallised from methanol to give the title compound (1.4 g) m.p. 231°-232°.