Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[CH3:20][O:21][C:22]([CH3:24])=[CH2:23]>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:20][O:21][C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: C=C(C)OC
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC(C)(C)OC

Procedure:
2-methoxy-2-(octadecyloxy)propane was prepared by reacting stearic alcohol (0.025 mole) with 2-methoxypropene (4 equivalents) for 2 hours at 20° C. in the presence of one drop of phosphoryl chloride (POCl3) then adding 5 drops of triethylamine and distilling the excess enol ether.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.S([O-])([O-])(=O)=[O:15].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.O>[O:15]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11](=[O:13])[CH3:12])[CH2:1][CH2:2]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)Nc1cccc2c1CCC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)CC2
Temperature: 0 °C

Procedure:
147 mg (0.84 mmol) N-indan-4-yl-acetamide are dissolved in 10 ml acetone and combined with 770 μl of a 15% aqueous magnesium sulphate solution. The solution is cooled to 0° C. and 397 mg (2.490 mmol) potassium permanganate are added batchwise. After 2 h the mixture is diluted with 50 ml of water, and extracted three times with 20 ml chloroform. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (85:15).
Reaction SMILES: N1C=CC=CC=1[C:7]1[CH:12]=[CH:11]C=CN=1.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C(Br)C)C=CC=CC=1>C1COCC1>[CH:13]([O:17][CH2:18][CH:12]([CH3:11])[CH3:7])=[CH2:14].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15]
Reactant: c1ccc(-c2ccccn2)nc1
Agent: CC(Br)c1ccccc1
Solvent: C1CCOC1
Solvent: C=CC(=O)OC
Product: C=COCC(C)C
Temperature: 50 °C

Procedure:
To 0.11 g (6.68×10−4 mole) 2,2′-bipyridyl and 0.036 g (2.34×10−4 mole) CuBr in a glass tube, were added 1.8 ml (1.65×−10−2 mole) IBVE, 0.5 ml (0.55×10−2 mole) methyl acrylate and 0.034 ml (2.34×10−4 mole) 1-phenylethyl bromide under argon atmosphere. The glass tube was sealed under vacuum, and the reaction mixture was warmed at 50° C. for 12 hours. The reaction mixture was then dissolved in THF, and the conversion of MA and IBVE as determined by GC were 100%. The polymer was then precipitated in methanol (three times), filtered, dried at 60° C. under vacuum for 48 h and weighed. The content of IBVE in the copolymer was 75%, and Mn=8710, Mw/Mn=2.00 (Mth=9090). The glass transition temperatures of the product as determined by DSC were −44.3° C. and 7.1° C.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[CH2:11][C@@H:12]([NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])(=O)=O.O>CN(C=O)C>[C:1](=[O:4])([S:3][CH2:11][C@@H:12]([NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:2]
Reactant: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 78 °C
Reaction time: 1 h

Procedure:
Potassium thioacetate (1.30 g, 11.51 mmol) was added to a stirring solution of (S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.50 g, 7.67 mmol) in dry DMF (50 mL). The resulting brown solution was heated with stirring at 78° C. for 1 hour. The brown suspension was poured into water and extracted with EtOAc (3×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 2.1 g of compound 76a as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 5.12 (m, 1H), 4.21 (t, J=9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 306.02 (M+H) RT=3.32 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3I)=[C:13]([C:26]#[N:27])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[C:13]([C:26]#[N:27])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1I
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1-c1cn[nH]c1
Temperature: 90 °C

Procedure:
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide (Preparation 240, 50 mg, 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27 mg, 0.14 mmol) palladium (0) tetrakis(triphenylphosphine) (10 mg, 0.009 mmol) and sodium carbonate (30 mg, 0.28 mmol) were dissolved in dimethylformamide:water (2:1, 1.5 ml) and heated to 90° C. for 18 hours. The reaction was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to afford a brown oil. Purification by preparative HPLC afforded the title compound. Yield 12.5 mg 30%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[H-].[Na+].I[CH2:39][CH3:40]>CN(C)C=O>[CH2:39]([N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2)[CH3:40]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.2 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give a yellow solution, then cooled to 0° C. under a nitrogen atmosphere. Sodium hydride, 60% in oil (10 mg, 0.254 mmol) was added and the mixture stirred at 0° C. for 15 minutes. Iodoethane (10 μl, 0.127 mmol) was added and the mixture stirred at 0° C. for 30 minutes, allowed to warm to room temperature then stirred for one hour. Further sodium hydride, 60% in oil (10.18 mg, 0.254 mmol) was added and the reaction mixture was heated to 40° C. under a nitrogen atmosphere for one hour. Further iodoethane (10 μl, 0.127 mmol) was added and the mixture stirred at room temperature for 30 minutes. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (5 mL) and extracted into ethyl acetate (3×5 mL). The organic phase was washed with 50:50 water:brine (2×10 mL) then brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as a pale yellow solid (7 mg, 13% yield). 1H-NMR (500 MHz, CDCl3) δ 7.10-7.28 (10H, m), 4.93 (1H, br s), 4.81 (2H, s), 3.94 (2H, q), 2.10-2.55 (4H, m), 1.90-2.08 (1H, m), 1.65-1.80 (1H, m), 1.00-1.40 (9H, br m), 1.14 (3H, t). LCMS (Method A) RT=7.29 min, M+H+=500.12.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[CH:8]1([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1C2C(=CC=CC=2)C(CCCC(O)=O)=C1>O1CCCC1>[C:15]([NH:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Oc1ccccc1
Agent: O=C(O)CCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Yield: 17 %

Procedure:
Phenol (0.46 g., 0.005 mole), dicyclohexylcarbodiimide (1.01 g, 0.005 mole) and indole-3-butyric acid (1.00 gm. 0.005 mole) were dissolved in minimal amounts of tetrahydrofuran in individual glass-stoppered Erlenmeyer flasks. Indole-3-butyric acid and dicyclohexylcarbodiimde solutions were mixed together and allowed to react for 15 minutes. The phenol solution was then added and the mixture allowed to react for 48 hours at room temperature. The mixture was then cooled in a refrigerator (0° C.). Dicyclohexylurea crystals which formed were filtered, washed with cold tetrahydrofuran, and the filtrate reduced in volume. Filtration, washing, and volume reduction were repeated four times.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.Br[C:30]1[CH:31]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=1>C(Cl)Cl.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>[NH2:23][C:14]1[CH:15]=[C:16]([C:30]2[CH:31]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=2)[CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Temperature: 120 °C
Yield: 19.8 %

Procedure:
Four identical reactions were carried out in a 20 ml microwave vial, each using one quarter of the quantities stated. They were then combined for work-up and purification. A solution of a quarter of 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (4.329 g, 9.93 mmol) in a quarter of DMF (24 ml) was treated with a quarter of N-(5-bromo-2-chloro-3-pyridinyl)methanesulfonamide (3.26 g, 11.42 mmol) followed by a quarter of Pd(PPh3)4 (1.032 g, 0.893 mmol). Each vial was heated at 120° C. for 50 mins in a Biotage Initiator. The orange solutions were combined and loaded onto a 20 g silica cartridge, and the vials washed with methanol (10 ml) which was also loaded onto the cartridge which was then eluted with methanol. Then eluants were evaporated to leave an orange oil. This was diluted with DCM (10 ml) and loaded directly and evenly onto 2×100 g silica cartridges. These were eluted with 0-100% ethyl acetate/cyclohexane over 80 mins using the Flashmaster II. Appropriate pure fractions were combined and evaporated to give the title compound as a yellow solid (0.939 g).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]1[N:27]([CH2:34][C@:35]2([CH3:38])[CH2:37][O:36]2)[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[N:30]=1>CN(C=O)C>[CH3:37][C@@:35]1([CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]3)=[O:7])=[CH:21][CH:22]=2)[O:36][C:26]2=[N:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][N:27]2[CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(O)cc2)CC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
Tert-butyl 4-(4-hydroxybenzoyl)piperazine-1-carboxylate (6.6 g, 21.5 mmol) was dissolved in DMF (50 ml). To the solution, sodium hydride (991 mg, 24.8 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (5.16 mg, 23.7 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water, dissolved in methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and then crystallized from methylene chloride-diisopropyl ether to afford tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)benzoyl]piperazine-1-carboxylate (7.35 g, yield 70%) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O1CCCC1.O>[OH:16][N:15]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=NO)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of methyl 4-formyl-2-methylbenzoate (1.3 g) in tetrahydrofuran (50 mL) was added dropwise to a solution of hydroxylamine hydrochloride (1.0 g), sodium acetate (1.2 g) in tetrahydrofuran (50 mL) and water (50 mL) under ice cooling, and after finishing the dropwise addition, the mixture was stirred for one hour at room temperature. The reaction mixture was diluted with water and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of methyl 4-[(hydroxyimino)methyl]-2-methylbenzoate (1.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]=[O:18])[CH2:6][CH2:7][CH3:8])[CH3:2].[CH2:20](O)[CH2:21][OH:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]1[O:22][CH2:21][CH2:20][O:18]1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A mixture of 2-(4-chloro-2-formyl-phenoxy)-pentanoic acid ethyl ester (15 g, 53 mmol), ethylene glycol (25 mL, 440 mmol) and p-toluenesulfonic acid (0.8 g, 4.65 mmol) in toluene (150 mL) was refluxed with a Dean-Stark trap attached to remove water. After 3 h, the reaction was cooled and washed with water, saturated NaHCO3 solution and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow oil (16 g).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Br[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].N12CCCNC1C=CCCC2>CN(C)C=O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[N:4]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: C1=CC2NCCCN2CCC1
Solvent: CN(C)C=O
Product: Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-thiocytosine (0.51 g.), dimethylformamide (5 ml.), N-(2-bromoethyl)phthalimide (1.12 g.) and 1,8-diazabicyclo[5,4,0]undec-5-ene (0.67 g.) was stirred at room temperature for 6 hours and then evaporated to dryness. The residue was stirred with a mixture of water and ethyl acetate and the unsoluble material collected to give 4-amino-2-(2-phthalimidoethylthio)pyrimidine which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:24].[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:11]([C:12]([NH2:13])=[O:24])=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(N)=O
Temperature: 80 °C

Procedure:
480 mg (1.642 mmol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinonitrile were treated with 3.8 ml sulfuric acid (90%) and heated at 80° C. for 1 hour. The mixture was cooled down to 20-25° C. and treated with 20 ml ethyl acetate. 2.0 g sodium hydroxide solution (28%) was added and the organic phase was washed with 6 ml water. Evaporation in vacuo gave 380 mg of 6-(4-methylpiperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)P(=O)(N(C)C)N(C)C.C(=O)(O)[O-].[Na+].[CH2:38](Br)[CH:39]=[CH2:40]>C(OCC)(=O)C>[CH2:40]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=1)[CH:39]=[CH2:38]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
In a three necked 1 liter round bottom reaction vessel equipped with a mechanical stirrer and reflux condenser were placed 48.8 g (0.15 mol) of the compound of Example 8 and 125 ml of hexamethylphosphorictriamide. The mixture was heated with stirring under nitrogen to 80°-85° C. To this solution 126 g (1.5 mol) of sodium bicarbonate powder was added portionwise followed by 20 g (0.17 mol) of allyl bromide. After 2.25 hours an additional 1.8 g (0.015 mol) of allyl bromide was added. After 29 hours of heating the reaction mixture was cooled to room temperature diluted with 700 ml of ethyl acetate, and the slurry was cross washed with water and diluted brine. The ethyl acetate was separated, dried with magnesium sulfate, clarified and taken to dryness under vacuum. The crude reaction mixture was crystallized from chloroform yielding 26.2 g of analytically pure product mp 99°-101° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1([CH3:40])[O:17][N:16]=[C:15]([S:18][CH:19]([C:24]2[C:25]([C:36]([F:39])([F:38])[F:37])=[N:26][N:27]([CH3:35])[C:28]=2[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]([F:23])([F:22])[F:21])[CH2:14]1>ClCCl>[CH3:12][C:13]1([CH3:40])[O:17][N:16]=[C:15]([S:18]([CH:19]([C:24]2[C:25]([C:36]([F:39])([F:37])[F:38])=[N:26][N:27]([CH3:35])[C:28]=2[O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[C:20]([F:23])([F:22])[F:21])=[O:6])[CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(C(F)(F)F)c(C(SC2=NOC(C)(C)C2)C(F)(F)F)c1OCC(F)(F)F
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)c(C(S(=O)C2=NOC(C)(C)C2)C(F)(F)F)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (70% by weight) (305 mg, 1.24 mmol) was added in portions to a solution of 5,5-dimethyl-3-{2,2,2-trifluoro-1-[1-methyl-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethylsulfanyl}-4,5-dihydro-isoxazole (190 mg, 0.41 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction was quenched by addition of saturated aqueous sodium metabisulfite solution, followed by addition of saturated aqueous sodium hydrogencarbonate solution. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: hexane/dichloromethane) to give the product (Compound No. 2.35 of Table 28) as a colourless gum (105 mg, 51% yield).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].CCN(C(C)C)C(C)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:19])=[O:18]
Reactant: CSCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCCCOS(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(methylthio)propan-1-ol in dichloromethane (0.2 M) was added sequentially at −78° C. Hunig's base (1.3 eq.) and methanesulfonyl chloride (1.3 eq.). The resulting reaction mixture was stirred at −78° C. for 1 h and then warmed slowly to RT. The reaction was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Li])CCC.[C:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>O1CCCC1>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C(F)(F)F)n2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A mixture of 2-bromo-6-(trifluoromethyl)pyridine (300 mg, 1.33 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere cooled to −78° C. was treated with n-butyl lithium (2M solution in tetrahydrofuran, 0.83 mL, 1.33 mmol). The mixture was stirred at −78° C. for 15 min. At this time, the reaction was treated with 1-boc-4-piperidone (265 mg, 1.33 mmol). The mixture was then allowed to slowly warm to 25° C. and was stirred at 25° C. for 1 h. At this time, the reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4′-hydroxy-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (450 mg, 98%) as a yellow oil; LRMS for C16H21F3N2O3 (M+H)+ at m/z=346. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=O)[C:13](=[N:15][OH:16])[CH3:14])[CH:8]=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2].[NH2:18][NH:19][C:20]([NH2:22])=[S:21]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[N:18][NH:19][C:20]([NH2:22])=[S:21])[C:13](=[N:15][OH:16])[CH3:14])[CH:8]=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1cc(C(=O)C(C)=NO)ccc1Cl
Product: CC(=O)Nc1cc(C(=NNC(N)=S)C(C)=NO)ccc1Cl
Yield: 92.6 %

Procedure:
3'-Acetamido-4'-chloro-2-hydroxyiminopropiophenone (70.75 g) was reacted with thiosemicarbazide (28.4 g) in the same manner as Example 1-(1) to give 3'-acetamido-4'-chloro-2-hydroxyiminopropiophenone thiosemicarbazone (84.36 g).