Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([CH3:17])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][O:31][C:32]1[CH:38]=[C:37]([C:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH:44]=2)[C:36]([N+:46]([O-:48])=[O:47])=[CH:35][C:33]=1[NH2:34]>CC(O)CCC>[CH3:30][O:31][C:32]1[CH:38]=[C:37]([C:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH:40]=2)[C:36]([N+:46]([O-:48])=[O:47])=[CH:35][C:33]=1[NH:34][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([CH3:17])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1-c1cnn2ccccc12
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cnn3ccccc23)n1
Yield: 63.2 %

Procedure:
A solution of 3-(2-chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 5, 271 mg, 1.00 mmol), p-toluene sulphonic acid monohydrate (271 mg, 1.43 mmol) and 2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) were heated in 2-pentanol (12 mL) at reflux under N2 for 30 h. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. Purification by ion exchange chromatography (SCX column), eluting with 7M methanolic ammonia, gave the title compound (283 mg, 63%) as an orange powder after trituration with CH3CN. 1H NMR: 2.28-2.36 (5H, m), 2.44 (3H, s), 2.60 (2H, t), 3.00 (2H, d), 4.00 (3H, d), 5.64 (1H, s), 6.97 (1H, s), 7.13 (1H, m), 7.40 (1H, m), 8.27 (1H, s), 8.39 (1H, s), 8.53 (1H, d), 8.61 (1H, s), 8.83 (1H, d), 8.87 (1H, s); m/z: ES− MH− 470.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.O1CCCC1.O1CCCC1.[Br-].[CH2:19]([Zn+])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>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.O>[CH2:19]([C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1csc(Br)n1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: Brc1csc(Cc2ccccc2)n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A flask containing 267 mg of tetrakis(triphenylphosphine)palladium and 1.00 g of 2,4-dibromothiazole was subjected to nitrogen substitution. To this flask, 9 ml of dry tetrahydrofuran and 9.9 ml of a 0.5 M benzylzinc bromide tetrahydrofuran solution were added. The obtained mixture was stirred at 70° C. for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and 30 ml of water was then added thereto, followed by extraction with 30 ml of ethyl acetate twice. The organic layer was washed with 30 ml of water twice and then with 30 ml of a saturated brine once. The resultant was dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; hexane:ethyl acetate=14:1), so as to obtain 0.36 g of 2-benzyl-4-bromothiazole.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15](O)=[C:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:25])=[C:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(O)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Product: Cc1c(Cl)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O

Procedure:
3-Benzyl-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (5.5 g, 18.5 mmol) was dissolved in excess POCl3 (50 mL) and heated at reflux for 1 hour. POCl3 was removed in vacuo and the residue dissolved in DCM then quickly washed with saturated sodium bicarbonate solution until neutral pH was observed. The organic layer was dried over MgSO4 and evaporated to dryness to give 7.3 g of the title compound as an impure reddish brown solid. [M+H] calc'd for C16H14ClN3O2, 315; found, 315.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:17]1[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[S:20][CH:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:19]1[S:20][CH:21]=[C:17]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=1)(=[O:23])=[O:24]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(CCc2ccccc2)cs1
Product: Cc1noc(NS(=O)(=O)c2cc(CCc3ccccc3)cs2)c1Br
Yield: 32 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenethylthiophene-2-sulfonamide was prepared in the same manner as described in Example 1 0 from 5-amino-4-bromo-3-methylisoxazole and 4-phenethyl-2-thiophenesulfonyl chloride in 32% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]1([N:22]2[CH2:31][CH2:30][C:25]3(OCCO3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:25]3([CH2:30][CH2:31][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[NH:1][C:2]=2[CH:6]=1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCN(c3ccccc3)CC1)N2
Temperature: 100 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (100 mg, 0.45 mmol), 8-phenyl-1,4-dioxa-8-azaspiro[4.5]decane (109 mg, 0.50 mmol), CSA (125 mg, 0.54 mmol), MgSO4 (108 mg, 0.90 mmol) and DMA (1 mL) was stirred at 100° C. for 1 h. Then, saturated aqueous NaHCO3 was added to quench the reaction. The organic materials were extracted with EtOAc/THF. The combined extracts were dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, NH, 80:20 hexane/EtOAc to EtOAc then to 95:5 EtOAc/MeOH), then crystallized from MeOH/EtOAc/heptane to give the title compound (46 mg, 27%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:12]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:16]=[CH:17][CH:18]=3)=[CH:11][N:10]=[C:9]([NH:32][CH2:33][CH2:34][N:35]3[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:36]3=[O:43])[N:8]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:12]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][NH:22][CH3:23])[CH:16]=[CH:17][CH:18]=3)=[CH:11][N:10]=[C:9]([NH:32][CH2:33][CH2:34][N:35]3[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:36]3=[O:43])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)Nc1cccc(-c2cnc(NCCN3C(=O)NC(=O)C3(C)C)nc2-c2ccc(Cl)s2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCC(=O)Nc1cccc(-c2cnc(NCCN3C(=O)NC(=O)C3(C)C)nc2-c2ccc(Cl)s2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 15 mg (0.024 mmol) of tert-Butyl 2-(3-{4-(5-chlorothiophen-2-yl)-2-[2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino]pyrimidin-5-yl}phenylamino)-2-oxoethyl(methyl)carbamate in 1 mL of 1,4-dioxane was treated with 2 mL of a 4 M solution of HCl in 1,4-dioxane and stirred 1 h at rt, then concentrated in vacuo to give the desired product as the hydrochloride salt. MS (M+H)+ 528.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=4[O:25][CH3:26])=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1(CN)CCCC1>C(O)C>[CH:1]1([CH:6]([N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[CH:18][C:17]=4[O:25][CH3:26])=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:27])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C)C)cc1-c1cnc2[nH]c(=O)n(CC3CCCC3)c2n1
Reactant: NCC1CCCC1
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1cnc2[nH]c(=O)n(C(C)C3CCCC3)c2n1
Yield: 75 %

Procedure:
1-Cyclopentylmethyl-6-(5-isopropyl-2-methoxy-phenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one. N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxy-phenyl)-pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), cyclopentylmethylamine (0.287 mL, 2.9 mmol) and ethanol (4 mL) were heated according to General Procedure E. The product was purified using reverse-phase semi-preparatory HPLC (5-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Product fractions were concentrated and then triturated with 50% methanol in H2O to give a white solid (77 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.36 (s, 1H), 7.60 (d, J=2.5, 1H), 7.26 (dd, J=8.7, 2.6, 1H), 7.08 (d, J=8.5, 1H), 3.82 (s, 3H), 3.78 (d, J=7.4, 2H), 2.45 (d, J=7.1, 1H), 1.58-1.70 (m, 4H), 1.53 (d, J=9.3, 2H), 1.38 (d, J=4.4, 2H), 1.22 (d, J=6.9, 6H); MS (ESI) m/z 367.5 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11]4=[C:12]([O:18][CH2:19][CH:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:10]4[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:13]=[CH:14][CH:15]=3.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([CH2:37][NH2:38])[OH:36]>CN(C=O)C>[C:21]1([CH:20]2[N:10]3[C:11]4[C:16]([C:17]5[C:5]([O:4][CH2:3][CH2:2][NH:38][CH2:37][CH2:35][OH:36])=[CH:6][CH:7]=[CH:8][C:9]=53)=[CH:15][CH:14]=[CH:13][C:12]=4[O:18][CH2:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCO
Reactant: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCNCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Reaction time: 5 h
Yield: 42.2 %

Procedure:
To a mixture of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole (0.273 g, 0.751 mmol) in dry DMF (10 mL) is added sodium iodide (0.113 g, 0.751 mmol), potassium carbonate (0.207 g, 1.5 mmol), and ethanolamine (0.046 g, 0.751 mmol). The mixture is heated at 85° C. for 17 h. The temperature is then increased to 90° C. and the mixture is allowed to stir for another 5 h. The mixture is then cooled to room temperature and partitioned between water and ether. The organic layer is washed twice with water (50 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (50 mL silica gel) using 5% methanol in CH2Cl2 gave 0.123 g (42%) of 2-({2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}amino)-1-ethanol.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: O=C1CCCCN1
Reactant: COc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CN2CCCCC2=O)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 108.9 %

Procedure:
In 6 ml of N,N-dimethylformamide was suspended 0.8 g of 60% sodium hydride and thereto was added dropwise a solution of 1.98 g of 2-piperidone in 8 ml of N,N-dimethylformamide under a stream of argon and with ice cooling. Then, to the mixture was added dropwise a solution of 2.82 g of 3-methoxybenzyl chloride in 8 ml of N,N-dimethylformamide at room temperature. The mixture was stirred at 65° C. for 8 hours. After cooling, to the reaction mixture were added ice-cold water and the mixture was extracted with diethyl ether. The extract was purified by a silica gel column chromatography (chloroform:methanol=20:1) to give 4.3 g of 1-(3-methoxybenzyl)-2-piperidone. This compound was heated in 10 ml of 47% hydrobromic acid for 12 hours. The mixture was made alkaline with addition of sodium carbonate and extracted with chloroform. After removing the solvent at a reduced pressure, 2.3 g (yield 57%) of 1-(3-hydroxybenzyl)-2-piperidone was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>C1(C)C=CC=CC=1.O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)=[CH:31][N:30]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ncc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1
Yield: 46.9 %

Procedure:
Procedure SS: To a stirred solution of (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (100 mg, 0.297 mmol), sodium carbonate (94.4 mg, 0.890 mmol) and 2-Methoxy-5-pyrimidine boronic acid (230 mg, 1.48 mmol) in toluene (5 ml), water (1 ml) and ethanol (1.5 ml) under nitrogen was added Tetrakis (triphenylphosphine) palladium (0) (34.3 mg, 0.030 mmol). The reaction was then heated to reflux for 48 h. The reaction was allowed to cool and bound to a SCX-2 cartridge (5 g). The cartridge washed with two cartridge volumes of dimethylformamide and one volume of methanol. The product was eluted using 2M ammonia in methanol. The ammonia/methanol solution was evaporated on a Genevac HT4. The sample was further purified by prep-LCMS. The resulting acetonitrile/water fractions were combined and evaporated using a Genevac to give 51 mg of a colourless oil (47%). MS (ES+) 367.3
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClCCl>CN.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CN
Solvent: ClCCl
Product: CCOC(=O)/C=C(\c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (E)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (0.728 g, 2.2 mmol), dimethyl-prop-2-ynyl-amine (0.56 ml, 6.58 mmol), bis(triphenylphosphine) palladium(II) chloride (0.061 g, 0.088 mmol), copper(I) iodide (1.25 mg, 0.0065 mmol) in dry Methylamine (7 ml) were heated to 100° C. by microwave irradiation for 20 min. To the cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (5 g) and the reaction mixture was evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]Br>C(OCC)C>[Br:12][CH:8]([CH2:9][CH3:10])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: CCCC(=O)c1ccccc1
Reactant: BrBr
Solvent: CCOCC
Product: CCC(Br)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
To a solution of 1-phenylbutan-1-one (10.0 g, 67.5 mmol) in diethyl ether (200 ml) was slowly added dropwise bromine (10.8 g, 67.5 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure to give the desired product (11.1 g, 72.3%) as an oil.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH2:12][CH2:11][CH:10]([CH:13](C)[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH2:9][CH:8]=1)(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1>C1COCC1>[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH2:9][CH2:8]1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NCCC1CCC(=O)CC1
Reaction time: 0.5 h
Yield: 26 %

Procedure:
N-[2-[4-[[(trifluoromethyl)sulfonyl]oxy]-3-cyclohexen-1-yl]propyl] 2-propanesulfonamide: To a −78° C. solution of 1.0 g (3.82 mmol) of the material prepared in Preparation 2 in 6 ml of THF was added 8.4 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF (8.4 mmol). The bath was removed and the mixture was stirred for 30 min and then 1.46 g (4.09 mmol) of N-phenyltrifluoromethane sulfonimide was added at ambient temperature. The mixture was stirred for 24 h. The reaction was quenched with NH4Cl saturated solution and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (125 g of silica gel, 15% ethyl acetate/hexane) of the residue afforded 395 mg (26%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:16]([S-:18])#[N:17].[K+].BrBr>C(O)(=O)C>[NH2:17][C:16]1[S:18][C:12]2[CH:13]=[C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
A solution of 4-(4′-fluorophenoxy)aniline (0.305 g, 1.50 mmol) and KSCN (0.29 g, 3.00 mmol, 2.0 eq) in 3 mL acetic acid was cooled at about 5° C., and was treated dropwise with a solution of bromine (0.077 mL, 1.50 mmol, 1.0 eq) in 2 mL acetic acid. The mixture was stirred at room temperature for about 2 hours. The precipitate was filtered off and washed with Et2O. The mother liquid from the filtration was concentrated, and the residue was combined with the precipitate. The obtained solid was neutralized with saturated sodium carbonate solution, and a new precipitate was formed. It was filtered off, washed with water, and dried under vacuum to give the desired compound 0.403 g (90%). LC/MS 261.2 (M+1); LC retention time 2.44 min.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:16])#[C-:14].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:16][C:15]1[N:13]=[CH:14][O:8][C:7]=1[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Yield: 68.4 %

Procedure:
A mixture of 4-(trifluoromethyl)benzaldehyde (3.45 mL, 25.8 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (5.40 g, 25.8 mmol), and K2CO3 (4.28 g, 31.0 mmol) in methanol (125 mL) was heated to reflux. After 2.5 hours the volatiles were evaporated, and the residue was partitioned between diethyl ether and H2O. The aqueous phase was extracted with diethyl ether, and the combined organic extract was washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (Analogix Intelliflash 280; 10% to 30% ethyl acetate/hexanes eluant; SF65-400 g column), which yielded 4.01 g (68% yield) of the title compound as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.85 (m, 4H), 2.42 (s, 3H). MS (DCI+) m/z 228 (M+H)+.
Reaction SMILES: C1(S(O[C@H:11]2[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)(=O)=O)C=CC=CC=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[N:19]([C@@H:11]1[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: COC(=O)[C@H]1C[C@H](OS(=O)(=O)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 105 °C
Reaction time: 2.75 h

Procedure:
A solution of trans 3-carbomethoxycyclobutyl benzenesulfonate* (6.1 g, 22.6 mmol) in hexamethylphosphoramide (35 ml) was treated with sodium azide (289 g, 44.5 mmol) and stirred at 105° C. for 2.75 h. The reaction mixture was cooled to 23° C., diluted with water (350 ml) and extracted with ether (4×125 ml). The organic extracts were combined, washed with water (2×15 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to a slightly yellow liquid which was distilled under high vacuum; bp 66°-7° C. (0.6 mm); 2.8 g; 80%; ir (neat) νmax : 2100 (N3) and 1735 cm-1 (C=O); Hmr (CDCl3) δ: 40.34 (m, H-1), 3.7 (s, methyl) and 2.9-2.1 ppm (5H, 2H-2, H-3 and 2H-4).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ncccn1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ncc(Sc2ncccn2)s1
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 2-acetamido-5-chlorothiazole (14.3 g), 2-mercaptopyrimidine (10 g) and potassium carbonate anhydrous (22.4 g) in N,N-dimethylformamide (280 ml) was stirred at 150° C. an hour. The reaction mixture was poured into water with stirring under ice cooling. The mixture was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give solid. The solid was triturated with water, and the precipitates were collected by filtration, washed with water and dried in vacuo no give 2-acetamido-5-(2-pyrimidinylthio)thiazole (12.30 g, yield: 60.2%). mp: 225° C. (dec.) IR (Nujol): 3170, 1645, 1555, 1310 cm-1NMR (DMSO-d6, 60 MHZ, ppm): 2.20 (3H, s), 7.33 (1H, t, j=4 Hz), 7.70 (1H, s), 8.68 (2H, d, J=4 Hz), 12.33 (1H, br s) Mass: M+2 254, M+1 253, M 252, m/e 210, 168
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=3)=[CH:18][N:19]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)cc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)cc1
Yield: 81.5 %

Procedure:
The title compound was prepared from methyl 4-(2-(7-phenylheptanoyl)oxazol-5-yl)benzoate (10 mg, 0.026 mmol) following General Procedure E. Preparative thin layer chromatography (EtOAc) yielded the title compound as a white solid (8 mg, 83%): 1H NMR (THF-d8, 500 MHz) δ 8.21 (d, 2H, J=8.5 Hz), 8.00 (d, 2H, J=8.5 Hz), 7.90 (s, 1H), 7.32-7.18 (m, 5H), 3.15 (t, 2H, J=7.5 Hz), 2.70 (t, 2H, J=7.5 Hz), 1.80-1.71 (m, 2H), 1.52-1.50 (m, 2H), 1.44-1.38 (m, 4H); 13C NMR (THF-d8, 500 MHz) δ 187.3, 165.4, 158.2, 153.2, 142.9, 132.2, 131.1, 130.7, 128.5, 128.4, 126.9, 125.7, 125.1, 38.9, 36.1, 31.6, 31.6, 29.4, 24.1; MALDI-FTMS m/z 378.1697 (M+H+, C23H24NO4, requires 378.1700).