Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[F:23][C:24]([F:34])([F:33])[C:25]1[N:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:50]>CO>[ClH:50].[F:34][C:24]([F:23])([F:33])[C:25]1[N:30]=[CH:29][C:28]([CH2:31][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[CH:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:6][CH2:7]2)=[CH:27][CH:26]=1
Reactant: ClCCl
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc(C(F)(F)F)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (see Example 1 step (j) above: 400 mg, 1.33 mmol) and 6-(trifluoromethyl)-3-pyridinecarbaldehyde (233 mg, 1.33 mmol, from Apollo) in a mixture of DCM (5 ml) and MeOH (5 ml) was stirred at room temperature for 2 hour. NaBH(OAc)3 (1.7 g, 7.99 mmol) was then added and the mixture was stirred at room temperature. The reaction was monitored by LCMS. More aldehyde (47 mg, 0.27 mmol), and NaHB(OAc)3 (421 mg, 1.98 mmol) were added and when full conversion was observed, it was quenched with 10% NaHCO3 and extracted with DCM. The organic layer was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography using a 70 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded 463 mg (75%) of the expected product as the free base. It was dissolved in MeOH (50 ml). HCl (4M solution in 1,4-dioxane, 0.25 ml, 1 mmol) was added dropwise. After stirring at room temperature for 20 min, the solvent was evaporated. (1R)-1-{[4-({[6-(Trifluoromethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]methyl}-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione hydrochloride (238 mg, 0.480 mmol, 36%) was obtained as a beige solid.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[CH:10]=[N:11][NH:12][C:6]=2[N:5]=[C:4]1[S:13][CH3:14])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>CN(C=O)C>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[CH:10]=[N:11][N:12]([CH2:29][C:28]3[CH:27]=[CH:26][C:25]([C:23](=[O:24])[C:22]4[CH:33]=[CH:34][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)=[CH:32][CH:31]=3)[C:6]=2[N:5]=[C:4]1[S:13][CH3:14])[CH3:2].[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[CH:10][N:11]([CH2:29][C:28]3[CH:27]=[CH:26][C:25]([C:23](=[O:24])[C:22]4[CH:33]=[CH:34][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)=[CH:32][CH:31]=3)[N:12]=[C:6]2[N:5]=[C:4]1[S:13][CH3:14])[CH3:2]
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: CCn1c(SC)nc2[nH]ncc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(SC)nc2c(cnn2Cc2ccc(C(=O)c3ccc(OC)cc3)cc2)c1=O
Product: CCn1c(SC)nc2nn(Cc3ccc(C(=O)c4ccc(OC)cc4)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-ethyl-6-methylthio-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (900 mg) in DMF (20 ml) was added 60% sodium hydride (207 mg) and the mixture was stirred at room temperature for 10 minutes. Then, 4-(4-methoxybenzoyl)benzyl bromide (1.31 g) was added and the mixture was further stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate-chloroform=3:2:1) to provide the title compounds (A) (400 mg) and (B) (366 mg) both as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[CH3:12][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.CCCCCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 mg (0.68 mmol) of 3-cyanobenzoic acid are initially charged in 4 ml of toluene and 3.5 ml of methanol, and 0.51 ml (1.02 mnmol) of a 2 M solution of trimethylsilyldiazomethane in n-hexane is added at RT. The reaction mixture is stirred at RT for 1.5 h. After removal of the solvent on a rotary evaporator the residue is dried under reduced pressure. The product is obtained in pure form and is directly reacted further.
Reaction SMILES: [NH2:1][C:2]1[N:3]=C(SC)[S:5][C:6]=1[C:7]#[N:8].ClC1C=CC=C(C(OO)=[O:19])C=1.[CH3:22][S:23]([CH3:25])=[O:24]>ClCCl>[NH2:1][C:2]1[N:3]=[C:22]([S:23]([CH3:25])(=[O:19])=[O:24])[S:5][C:6]=1[C:7]#[N:8]
Reactant: CSc1nc(N)c(C#N)s1
Reactant: CS(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1nc(N)c(C#N)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.7 g (15.8 mmol) of 4-amino-2-(methylsulfanyl)-1,3-thiazole-5-carbonitrile were dissolved in 500 ml of dichloromethane, and 12 g (34.7 mmol) of 50% strength 3-chloroperbenzoic acid were added. The mixture was stirred at RT for 30 min. 6 ml of DMSO were added, and the reaction mixture was washed with saturated sodium bicarbonate solution and water. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. This gave 2.2 g (46% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=3[NH2:14])=[CH:10][N:9]([CH3:23])[C:8]=12.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1.[Na].C(O)(=O)C>ClCCl>[CH:24]1([CH2:27][NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:12]=2[C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:23])[CH:10]=2)[CH2:26][CH2:25]1
Reactant: O=CC1CC1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N)cn(C)c12
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CC3)cn(C)c12
Yield: 99.6 %

Procedure:
The product from Example 44A (0.1 g, 0.302 mmol), cyclopropanecarboxaldehyde (0.063 g, 0.905 mmol) and sodium triacetoxyhydroborate (0.192 g, 0.905 mmol) were combined in dichloromethane (1.0 mL) and acetic acid (1.0 mL) under nitrogen, stirred for 6 hours and partitioned into water/ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.116 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: COc1cc(Br)c2cn[nH]c2c1
Reactant: C1=COCCC1
Solvent: C1CCOC1
Product: COc1cc(Br)c2cnn(C3CCCCO3)c2c1
Yield: 111.7 %

Procedure:
A round-bottom flask was charged with 4-bromo-6-methoxy-1H-indazole (1.00 g, 4.40 mmol), TsOH monohydrate (39 mg, 0.22 mmol), 3,4-dihydro-2H-pyran (1.48 g, 17.6 mmol), and THF (40 mL). The reaction mixture was degassed with nitrogen and refluxed for 18 h, and the solvent was then removed in vacuo. The residue was purified by SiO2 chromatography to afford 4-bromo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.53 g, quantitative) as a yellow solid. MS (ESI) m/z: 311.2 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[CH2:32][CH2:33][N:34]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:35][CH2:36]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CCNCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 54 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[4-(2-pyridyl)phenylsulphonyl]piperazine to give 1-[4-(2-pyridyl)phenylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 54% yield, m.p. 224-226° C.;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[I:10]I>FC(F)(F)C([O-])=O.[Ag+].ClCCCl>[NH2:1][C:2]1[C:3]([I:10])=[CH:4][C:5]([C:8]#[N:9])=[CH:6][N:7]=1
Reactant: II
Reactant: N#Cc1ccc(N)nc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1cnc(N)c(I)c1
Yield: 33.3 %

Procedure:
6-Amino-3-pyridinecarbonitrile (10.0 g, 0.081 mol), silver trifluoroacetate (25.5 g, 0.115 mol) and 160 ml of 1,2-dichloroethane are combined in a flask and heated under reflux for 5 h. Iodine (29.5 g, 0.116 mol) is added, and the mixture is heated for a further 18 h. After cooling, the mixture is filtered and partitioned between water and dichloroethane. Organic and aqueous phase are filtered through Celite. The aqueous phase is extracted to exhaustion, and the combined organic phases are combined, dried and evaporated. The residue is dissolved in ethyl acetate and washed with sodium thiosulfate solution. Removal of the solvent gives 6.6 g of yellowish crystals product. These are reacted further without further purification; HPLC: 2.57 min; LCMS: 246 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:14]=[CH:13][N:12]=[C:11]2[O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:37])=[CH:31]2.CCN(C(C)C)C(C)C.CO>ClCCl>[Cl:1][CH2:2][C:3]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][O:18][C:17]2[CH:16]=[C:15]3[C:10]([C:11]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][C:32]([CH3:37])=[CH:31]5)=[N:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:7][CH3:6])[CH2:26][CH2:25]1)=[O:4]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)CCl)CC1
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (0.09 ml) was added dropwise to a solution of 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]quinazoline (0.45 g), prepared as described in Example 13, and PS-DIEA resin (0.66 g) in dichloromethane (15 ml). After 1 hour at ambient temperature, methanol was added and the reaction mixture was filtered. Solvents were removed by evaporation in vacuum and the residue was triturated under diethyl ether, filtrated and dried to give 7-{2-[4-(chloroacetyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (0.36 g) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN(C=O)C.CCOC(C)=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(O)c1C
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 3-hydroxy-2-methylbenzoate (Step A, 3.1 g, 17.22 mmol), K2CO3 (3.09 g, 22.38 mmol) in dry DMF (15 ml) was added 2,6-Dimethylbenzyl chloride (3.19 g, 20.66 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours, diluted with EtOAc (40 ml), washed with water (20 ml) and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.CCO.[C:17]([O:21][C:22](=[O:53])[N:23]([CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]2[S:43][C:42]3[C:37](=[N:38][CH:39]=[CH:40][C:41]=3[O:44][C:45]3[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][C:46]=3[F:52])[CH:36]=2)=[CH:33][CH:34]=1)[CH2:24][CH2:25][O:26][CH3:27])([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([O:21][C:22](=[O:53])[N:23]([CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]2[S:43][C:42]3[C:37](=[N:38][CH:39]=[CH:40][C:41]=3[O:44][C:45]3[CH:50]=[CH:49][C:48]([NH:51][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:47][C:46]=3[F:52])[CH:36]=2)=[CH:33][CH:34]=1)[CH2:24][CH2:25][O:26][CH3:27])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of isothiocyanate 2 (5.50 g, 28.2 mmol) in a mixture of toluene (20 mL)/EtOH (20 mL) in a 500 mL round-bottom flask was added aniline 13 (10 g, 19.06 mmol) in a mixture of toluene (50 mL)/EtOH (50 mL). After 30 min, additional amount of isothiocyanate 2 (1 g, 5.12 mmol) in a mixture toluene (5 mL)/EtOH (5 mL) was added to the reaction mixture which was stirred at r.t. for an additional 45 min. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with MeOH (40 mL) to dryness. Finally MeOH (80 mL) was added to the dry residue to produce a precipitate that was stirred at room temperature for 14 h, collected by filtration, dried for 2 h under vacuum to afford 14 as beige solid (7 g, 51% yield). MS (m/z): 720.3 (M+1)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1C=C(O)C=CC=1C.[F:21][C:22]([F:45])([F:44])[C:23]1[O:27][C:26]([CH2:28][N:29]2[C:37]3[CH:36]=[C:35]4[O:38][CH2:39][CH2:40][O:41][C:34]4=[CH:33][C:32]=3[C:31](=[O:42])[C:30]2=[O:43])=[CH:25][CH:24]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:42][C:31]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:32]2[CH:33]=[C:34]3[O:41][CH2:40][CH2:39][O:38][C:35]3=[CH:36][C:37]=2[N:29]([CH2:28][C:26]2[O:27][C:23]([C:22]([F:44])([F:45])[F:21])=[CH:24][CH:25]=2)[C:30]1=[O:43]
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc21)OCCO3
Reactant: Oc1ccc2c(c1)OCCO2
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCCO2)OCCO3

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3,4-dimethylphenol, and 6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 8-hydroxy-8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one was obtained (80%): 1H NMR (300 MHz, CDCl3) δ8.78 (s, 1H), 7.07-6.97 (m, 1H), 6.71-6.65 (m, 1H), 6.60-6.55 (m, 1H), 6.51-6.47 (m, 1H), 6.40-6.35 (m, 1H), 6.31-6.25 (m, 1H), 4.89-4.69 (m, 2H), 4.34-4.04 (m, 9H); MS (ES+) m/z 487.9 (M−17).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@@H](O)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 83.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (66.5 mg, 0.0975 mmol) prepared in Example 162h, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (39.2 mg, 83%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:12]=[N:11][C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].CN1C=NC(=O)NC1=O>>[CH2:1]([N:5]1[CH2:12][NH:11][C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc(=O)[nH]c1=O
Agent: Cn1cnc(=O)[nH]c1=O
Product: CCCCN1CNC(=O)NC1=O
Yield: 67 %

Procedure:
Following the procedure described in Preparation 2, Part C, above, but substituting the 1-n-butyl-5-azauracil prepared in Part B, above, for the 1-methyl-5-azauracil, there is prepared 40 gm. (67% yield) of the desired new precursor 5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione having a melting point of 205° C. to 207° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][OH:16].O>O1CCOCC1>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:15][OH:16])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(O)cc1O
Reactant: NO
Solvent: C1COCCO1
Solvent: O
Product: O=C(NO)c1cc([N+](=O)[O-])c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dihydroxy-5-nitrobenzoyl chloride (17.0 g, 78.1 mmol) in dioxane (70 mL) is added to an ice cold solution of 50% aqueous hydroxylamine (35 mL) and water (35 mL). After the addition is complete, the ice bath is removed and the mixture is stirred at room temperature for 30 min. The resulting thick precipitate is filtered, washed once with 1:1 water/dioxane and dried to obtain 2,4,N-trihydroxy-5-nitrobenzamide. After standing in the refrigerator for 18 h, the 1:1 water/dioxane solution affords additional 2,4,N-trihydroxy-5-nitrobenzamide: (M+H)+=215.1.
Reaction SMILES: [NH2:1]N.[C:3]1([NH:9][C:10]([NH2:12])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([NH:9][C:10](=[O:11])[NH:12][NH2:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: NC(=O)Nc1ccccc1
Product: NNC(=O)Nc1ccccc1

Procedure:
Other known methods for the preparation of 4-aryl-1,2,4-triazol-3-ones involve the use of hydrazine as a raw material. In one such method, phenylurea is reacted with hydrazine to give a 4-phenylsemicarbazide. The semicarbazide is then condensed with ethyl formate to give the 4-phenyltriazolone. The overall yield from this method is about 20%. In another method, a 4-phenylsemicarbazide is reacted with formic acid to form the 1-formyl-4-phenylsemicarbazide intermediate, followed by intramolecular condensation to the 4-phenyltriazolone. The yield obtained by this method is about 40%. In yet another method, a substituted aniline is converted to the phenylcarbamate derivative. The phenylcarbamate is treated with hydrazine to give the phenylsemicarbazide derivative, followed by condensation with formamidine acetate to give the 4-phenyltriazolone. Each of these methods requires the use of the toxic compound hydrazine. In addition, the methods suffer from low overall yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1.N1C=CC=CC=1.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.C(OCC)(=O)C>[C:20]1([CH2:19][O:26][C:27]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C1CCNN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 3-pyrazolidinecarboxylic acid, 1,1-dimethylethyl ester (10.935 g., 63.5 mmol.) in dry acetonitrile (90 ml.) was cooled to 0° C. (ice-salt bath) and treated with dry pyridine (11.0 ml.) followed by a solution of benzylchloroformate (12.54 g., 10.5 ml., 69.9 mmol.) in dry acetonitrile (25 ml.). The reaction was stirred at 0° C. for 3 hours, evaporated to dryness and the syrup obtained was redissolved in ethyl acetate (250 ml.). The solution was washed with 5% sodium bicarbonate (2×25 ml.) and brine (25 ml.), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product mixture was chromatographed on a silica gel column (Merck), eluting the column with ethyl acetate:hexane mixtures (1:4; 1:2) to give 11.144 g. of title product as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([Cl:17])=[N:10][C:11]([CH:14]([F:16])[F:15])=[N:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.C(O)C>CC(C)=O>[Cl:17][C:9]1[C:8]([CH:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)[OH:7])=[CH:13][N:12]=[C:11]([CH:14]([F:15])[F:16])[N:10]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cnc(C(F)F)nc1Cl
Solvent: CCO
Solvent: CC(C)=O
Product: OC(c1ccc(Cl)cc1)c1cnc(C(F)F)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
12 g of 5-(4-chlorobenzoyl)-4-chlorodifluoromethylpyrimidine and 6 g of a t-butylamine borane complex were added to 100 ml of ethanol, and the resulting mixture was stirred at 0° C. for 2 hours. Then, 20 ml of acetone was added thereto, and the mixture was stirred at 0° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform) to obtain 11.1 g of the desired product as a pale yellow viscous liquid. nD20.3 1.5563
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH2:51])[CH2:45][CH2:46][CH3:47]>C(Cl)(Cl)Cl.O>[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH:51][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[O:23][CH3:24])=[O:42])[CH2:45][CH2:46][CH3:47]
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCN(CCN)CCCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (81 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (56 mg, yield 34%).