Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:41]([NH:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)(C)C#Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (12 mg, 0.026 mmol) in CH2Cl2 (1 mL) was added triethylamine (50 μL) and acetic anhydride (10 μL) and trace DMAP. After 30 min, the reaction mixture was filtered and purified by reverse phase HPLC (MeCN/H2O w/0.1% TFA) to give 10 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 7.27 (s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.90 (s, 3H), 1.61 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33ClNO4: 506.2; found: 506.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9](O)[CH:10]=1)[C:5]([OH:7])=[O:6].[Cl-].[NH4+:14]>N>[NH2:14][C:9]1[CH:10]=[C:2]([OH:1])[C:3]([CH3:12])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1c(O)cc(O)cc1C(=O)O
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Product: Cc1c(O)cc(N)cc1C(=O)O
Temperature: 180 °C
Yield: 35.9 %

Procedure:
A mixture of 7.00 g of 3,5-dihydroxy-2-methylbenzoic acid, 5.40 g of ammonium chloride, and 20 ml of 25% aqueous ammonia was heated to 180° C. for 40 hours in a pressure vessel. After cooling, the mixture was evaporated in vacuo. The residue was taken up in 230 ml of 6N hydrochloric acid, and the mixture was heated at reflux for 16 hours. After cooling, unsoluble material was removed by filtration, and the filtrate was evaporated in vacuo. The residue was supended in 100 ml of water, the pH of the suspension was adjusted to 4.5 by the addition of 3N sodium hydroxide, and the mixture was cooled to 0° C. for 30 minutes. The precipitate was isolated by filtration and dried to give 2.50 g of 5-amino-3-hydroxy-2-methylbenzoic acid as white crystals, m.p. >250° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(B(O)O)c21
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(-c3ccccn3)c21
Yield: 58.2 %

Procedure:
A mixture of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440 mg, 1.28 mmol), 2-bromopyridine (0.14 ml, 1.50 mmol), Pd(PPh3)2Cl2 (10 mg, 2 mmol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) were refluxed under N2 for 24 h. The solvents were removed under reduced pressure and the residue was treated with saturated NH4Cl (10 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with water (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (2:1, v/v) as eluent, yielding 280 mg (58%) of 5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([CH3:14])[CH:12]=3)[C:7]([C:16]#[N:17])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:16]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:6]=1[B:18]([OH:23])[OH:19])#[N:17]
Reactant: Cc1cc2c(cc1F)c(C#N)cn2C1CCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1F)c(C#N)c(B(O)O)n2C1CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 1-cyclobutyl-5-fluoro-6-methyl-1H-indole-3-carbonitrile (1.2 g, 5.3 mmol) and triisopropyl borate (2.18 mL, 9.47 mmol) in THF (20 mL) at −78° C. was added LDA (1.5 M in cyclohexane, 4.6 mL, 6.84 mmol). The mixture was stirred at −78° C. for 30 min and quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with 2 N aq. HCl to pH 5 and then extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-cyano-1-cyclobutyl-5-fluoro-6-methyl-1H-indol-2-ylboronic acid as a solid (1.44 g, 98% pure by LCMS) that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:17][CH2:14][CH2:15][CH3:16])=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCN
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCNCc1ccc(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.178 g (0.1 mmol) of the product of Step A and 0.206 g (3.5 mmol) of n-propylamine dissolved in 10 mL of CH2Cl2 was added 0.5 g of finely powdered 4 Å molecular sieves. The reaction mixture was stirred under a nitrogen atmosphere at room temperature overnight, then 0.53 g (2.5 mmol) of sodium triacetoxyborohydride was added. The reaction was then stirred an addition 8 h at room temperature, then diluted with CH2Cl2 and MeOH. The mixture was filtered through a pad of Celite filter aid eluted with CH2Cl2, and the filtrate was washed with saturated aqueous NaHCO3. The organic layer was the separated, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a flash chromatography column eluted with CH2Cl2-MeOH—NH4OH (95:4:1) to afford the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[S:13][C:14]([CH2:26][CH3:27])=[CH:15][C:16]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]([CH3:28])=[N:9][N:8]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[S:13][C:14]([CH2:26][CH3:27])=[CH:15][C:16]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]([CH3:28])=[N:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CCl)s1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Four grams of thionyl chloride is added dropwise to a solution of 10 g of 3-hydroxymethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole in 50 ml of dioxane. The mixture is stirred at 70° - 80°C for 2 hours. The reaction mixture is poured into 200 ml of water and made alkaline with potassium carbonate. The oil liberated is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is treated with ligroin containing 5% ethyl acetate to cause crystallization. The crystals are collected by suction filtration and recrystallized from ligroin containing 5% ethyl acetate to give 9.3 g of 3-chloromethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole as colorless pillars melting at 109° - 110°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([NH:23][C:24](=[O:26])[CH3:25])[CH:10]=1)=[O:8].[Na].[S:28](Cl)([Cl:31])(=[O:30])=[O:29]>C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([N:23]([S:28]([Cl:31])(=[O:30])=[O:29])[C:24](=[O:26])[CH3:25])[CH:10]=1)=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Agent: [Na]
Solvent: c1ccccc1
Product: CC(=O)N(c1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1)S(=O)(=O)Cl

Procedure:
An anhydrous benzene solution of 3-acetamido-4-benzyloxyphenyl 2-pyridyl ketone is heated at reflux with sodium until a suspension is formed. To this suspension is added sulfuryl chloride in benzene and the resulting mixture is filtered to remove sodium chloride. The filtrate is evaporated to give 4-benzyloxy-3-(N-chlorosulfonylacetamido)phenyl 2-pyridyl ketone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29]>C(O)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:21]1[CH3:29]
Reactant: COCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: CC(=O)O
Product: COCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Yield: 112 %

Procedure:
Proceeding in a manner similar to that described in part A of Example 8 above, 30.0 g of tetrachlorophthalic anhydride was interacted with 40.0 g of 1-(2-methoxyethyl)-2-methylindole in 75.0 ml of glacial acetic acid at approximately 110° C. for approximately one hour to obtain 55.83 g of 2-[1-(2-methoxyethvl)-2-methylindol-3-yl]carbonyl-3,4,5,6-tetrachlorobenzoic acid, (Formula V: R=CH3OC2H4 ; R1 =CH3 ; X=Cl4 ; Y=H), a pale yellow solid which melted at 182°-184° C. A significant infrared maximum appeared at 1750 (C=O;s).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[CH:13]=[C:12]([Cl:18])[S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2sccc2c(=O)n1CCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCCCc1nc2sc(Cl)cc2c(=O)n1CCC
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
In a sulfonation flask, 2.0 g (8 mmol) of 2-n-butyl-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are added, with stirring, to 15 ml of absolute pyridine. The internal temperature is then raised to 80° C. and then 1.87 g (14 mmol) of N-chlorosuccinimide (NCS) are added in smallish portions. After stirring for 3 hours at 90° C. 1.0 g of NCS is added and the mixture is stirred another 3 hours at 90° C. The pyridine is removed in a water-jet vacuum and the crude product so obtained is purified by column chromatography over silica gel (eluant:n-hexane/tert.butylmethylether=3:1), giving 0.9 g of 2-n-butyl-6-chloro-3-propyl-3H-thieno-[2.3-d]pyrimidin-4-one in the form of a beige powder having a melting point of 67-69° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](F)[CH:12]=2)[CH:7]=[N:6][CH:5]=1.NC1C=CC(O)=CC=1[F:28]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:28])[CH:7]=[N:6][CH:5]=1
Reactant: Nc1ccc(O)cc1F
Reactant: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(Oc2ccc(N)cc2F)c1

Procedure:
The title compound was prepared in the same manner described 5-(4-Amino-3-fluorophenoxy)nicotinic acid methyl ester, substituting 4-amino-2-fluorophenol for 4-amino-3-fluorophenol. 1H NMR (DMSO-d6) δ 7.96 (d, J=1.5 hz, 1H), 7.64 (d, J=3.0 Hz, 1H), 6.88 to 6.87 (m, 1H), 6.16 (t, J=8.7 Hz, 1H), 5.79 to 5.69 (m, 2H), 4.07 (s, 2H), 3.09 (s, 3H); TLC (50% EtOAc/Hex), Rf=0.31.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)CCc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)CCc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of the product of Example 7A (505 mg, 2.447 mmol) in THF (19 mL) at 0° C. was added a 1M solution (in THF) of lithium aluminum hydride (12.2 mL, 12.237 mmol) dropwise. After completion of addition the ice bath was removed and the reaction was stirred at room temperature for 1 hour under nitrogen atmosphere. Then, in succession, was added water (183 μL), 15% NaOH solution (183 μL), and water (548 μL). The reaction stirred for an additional 15 minutes before it was filtered and washed with THF. The filtrate was then concentrated under reduced pressure to obtain 4-(4-hydroxymethyl-phenyl)butan-2-ol as a brown oil (314 mg, 71% yield). Then to a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (234 mg, 1.155 mmol) in THF (45 mL) was added 4-(4-hydroxymethylphenyl)butan-2-ol (312 mg, 1.732 mmol), triphenylphosphine (454 mg, 1.732 mmol), and then diisopropyl azodicarboxylate (DIAD, 335 μL, 1.732 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Thin layer chromatography (100% ethyl acetate) indicated consumption of the pyridazinone starting material and the reaction was concentrated. The crude material was purified by flash column chromatography (4:1 hexane:ethyl acetate to 100% ethyl acetate) to obtain a clear oil (200 mg, 48% yield). 1H NMR (600 MHz, CDCl3): δ 7.73 (s, 1H), 7.32 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 5.30 (s, 1H), 5.27 (s, 2H), 3.83 (m, 1H), 2.80-2.76 (m, 1H), 2.71-2.66 (m, 1H), 1.63 (s, 9H), 1.23 (d, 3H, J=6.2); 13C (CDCl3 159.3, 153.9, 143.2, 132.5, 129.2, 127.6, 125.4, 150 MHz): δ HRMS calcd for C, 118.5, 73.4, 67.6, 66.6, 40.9, 32.0, 28.1, 23.9.19H25ClN2O3: 365.162647, found 365.1624.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([NH2:32])([C:30]#[N:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][C:27]([C:30]#[N:31])([NH:32][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])=[CH:15][CH:14]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 85.5 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uoronium hexafluorophosphate (1.60 g, 4.20 mmol) was added to a solution of 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoic acid (1.00 g, 4.20 mmol), 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (995 mg, 4.42 mmol) and N,N-diisopropylethylamine (1.46 ml, 8.39 mmol) in DMF (8.8 ml) at 0° C. The mixture was gradually warmed to room temperature and stirred for 28.5 hours. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate three times. The organic layers were sequentially washed with H2O (×2) and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:AcOEt=90:10→30:70) to give 4-cyano-4-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester as a light brown powder (1.60 g, 86%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.I[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:31]([O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1)[CH3:32]
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), iodoethane (0.040 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) to give the title compound (94.1 mg, 88% yield) as an off-white
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH2:7])=[O:5])[CH3:2].C(O)(=O)C.[CH:12]([C:15]([CH3:17])=O)([CH3:14])[CH3:13]>O>[CH2:1]([O:3][C:4]([NH:6]/[N:7]=[C:15](/[CH3:17])\[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CC(=O)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N/N=C(/C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazinecarboxylic acid ethyl ester (4.40 g, 42.2 mmol) and acetic acid 60 um, 1.0 mmol) were added to 20 mL (excess) of methyl isopropyl ketone, and the mixture was stirred at room temperature for 18 hours. Water (40 mL) was added, and the mixture was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 7.25 g of crude N′-[1,2-dimethyl-prop-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester as an oil, which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCl)c(OC)c1
Temperature: 0 °C
Yield: 72 %

Procedure:
A solution was prepared from 15.3 g of 2,4-dimethoxyaniline and 10.1 g of triethylamine in 300 ml of methylenedichloride. The solution was cooled to about 0° C. Eleven and three tenths grams of chloroacetylchloride were added in dropwise fashion with stirring under a nitrogen blanket. After the addition had been completed, the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then extracted successively with equal volumes of 1N hydrochloric acid and of water. The organic solution was next extracted with cold saturated aqueous sodium bicarbonate followed by a second extraction with water. All these aqueous extracts were discarded. The organic solution was dried, and the solvent removed in vacuo. A residue consisting of 23 g of a purple colored solid was obtained. Twenty-one grams of this residue were chromatographed over silica gel using ethyl acetate as the eluant in order to remove a colored impurity. Fractions containing the desired product, N-chloroacetyl-2,4-dimethoxyaniline were combined and the solvent removed therefrom to yield a tan solid residue. Recrystallization of the residue from an ethyl acetate/hexane solvent mixture gave 16.5 g of N-chloroacetyl-2,4-dimethoxyaniline melting at 90°-91° C. (yield=72%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1)[CH3:6]>S(=O)(=O)(O)O>[CH2:5]([N:7]1[C:11]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([C:13]([F:15])([F:14])[F:16])=[N:8]1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCn1nc(C(F)(F)F)cc1C
Agent: O=S(=O)(O)O
Product: CCn1nc(C(F)(F)F)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 30 mL of concentrated sulfuric acid and 30 mL of concentrated nitric acid was added slowly with stirring at 0° C. to a solution of 18.9 g (106 mmol) of 1-ethyl-5-methyl-3-(trifluoromethyl)pyrazole in 70 mL of concentrated sulfuric acid. When the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 72 hours. It was then poured slowly onto 500 g of ice. The resultant mixture was extracted twice with 100 mL portions of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 20.4 g (86 percent of theory) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(C=O)ccc1OS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 3-ethoxy-4-hydroxybenzaldehyde (3.0 g, 18.1 mmol, 1.0 equiv) and N,N-dimethylaminopyridine (2.87 g, 23.5 mmol, 1.3 equiv) in dichloromethane (10 mL) under Ar at 0° C. was added methanesulfonyl chloride (1.68 mL, 2.48 g, 21.7 mmol, 1.2 equiv). After the reaction mixture was stirred for 1 h, water (100 mL) was added, the solution extracted with dichloro-methane (3×50 mL) and the combined organic phases dried over MgSO4. Removal of the solvent by evaporation under reduced pressure provided the title compound in quantitative yield (4.8 g). 1H NMR (300 MHz, CDCl3): δ 1.42 (t, J=7.0 Hz, 3H), 3.19 (s, 3H), 4.14 (q, J=7.0 Hz, 2H), 7.41 (s, 2H), 7.45 (s, 1H), 9.89 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.53, 38.94, 64.99, 112.20, 124.38, 125.17, 136.01, 142.92, 151.63, 190.65. MS (ISP): 245.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[N:6]3)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: BrCc1ccc2nccnc2c1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ccc3nccnc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 6-(bromomethyl)quinoxaline (900 mg, 4.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (440 mg, 3.1 mmol), and triethylamine (1.1 mL, 7.8 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The reaction mixture was evaporated and then co-evaporated with EtOAc. The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (3×20 mL), and hexanes (3×20 mL), and then dried in vacuo, affording 6-methyl-2-[(quinoxalin-6-ylmethyl)sulfanyl]pyrimidin-4-ol (658 mg, 75% yield). The product was used without further purification.