Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=S)SC)=[CH:6][CH:5]=1)[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][C:28]=1[NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20].CO>CN(C=O)C.C(Cl)Cl.[Hg]=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:28]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=3[N:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(NC(=S)SC)cc1
Reactant: CCN(CC)C(=O)c1ccc(NCCC(C)C)c(N)c1
Agent: O=[Hg]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(Nc2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Reaction time: 5.5 h
Yield: 56.6 %

Procedure:
A solution of methyl 4-ethoxyphenyldithiocarbamate (0.0274 g, 0.121 mmol) in DMF (0.2 mL) was added to a mixture of 3-amino-N,N-diethyl-4-(isopentylamino)benzamide (0.0334 g, 0.120 mmol) and red mercury(II) oxide (0.0261 g, 0.121 mmol) in DMF (0.2 mL). The resulting suspension was stirred vigorously for 5.5 h, and an additional portion of red mercury(II) oxide (0.0130 g, 0.0600 mmol) was added. After stirring an additional 16 h, the reaction was diluted with 9:1 CH2Cl2:MeOH, loaded onto a small plug of silica gel, and eluted with the same solvent system. The eluant was concentrated, and the residue was purified by reverse phase HPLC (gradient 20–70% CH3CN in H2O) to provide the title compound (0.0287 g, 45%) as its TFA salt. This material was lyophilized from H2O/dioxane to produce a white solid. 1H-NMR (CD3OD): δ 7.60 (d, J=8.4 Hz, 1H), 7.44–7.38 (2 overlapping d; 3H), 7.35 (s, 1H), 7.11 (d, J=9.2 Hz, 2H), 4.32 (br t, J=7.2 Hz, 2H), 4.12 (q, J=7.6 Hz, 2H), 3.56 (br s, 2H), 3.32 (br s, 2H), 1.85–1.76 (br m, 3H), 1.43 (t, 7.6 Hz, 3H), 1.25 (br s, 3H), 1.14 (br s, 3H), 1.08 (d, J=6.4 Hz, 6H). 13C-NMR(CD3OD): δ 172.51, 160.57, 151.15, 134.20, 132.87, 130.29, 128.70, 128.44, 123.46, 117.18, 111.54, 111.23, 65.02, 45.07, 43.16, 41.13, 37.49, 27.26, 22.76, 15.07, 14.35, 13.07. Anal. Calcd for MS (ESI) (M+H)+=423.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:12])=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[F:22][C:23]([F:29])([F:28])[CH2:24][C:25](Cl)=[O:26]>ClCCl>[F:22][C:23]([F:29])([F:28])[CH2:24][C:25]([NH:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[C:8]=1[CH3:12])=[O:26]
Reactant: Cc1c(N)nc2ccc(F)cn12
Reactant: O=C(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)CC(F)(F)F)nc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine (0.033 g, 0.00020 mol) was dissolved in dichloromethane (3.0 mL) and N,N-diisopropylethylamine (0.070 mL, 0.00040 mol) was added. The reaction was cooled to 0° C. and 3,3,3-trifluoropropionyl chloride (29 uL, 0.00024 mol) was added. The mixture was warmed to room temperature and was stirred for 1 hour. Solvent removed and residue was chromatographed on silca (70% ethyl acetate/hexanes) to give 3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamide Rf 0.43, 70% ethyl acetate/hexanes; MS m/z 276 (M+H). SH-SY5Y_EC50 (μM): 10.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([O:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:14][CH3:15]>>[C:9]([OH:11])(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][O:19][CH2:18][CH2:17][O:16][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCOCCO
Reactant: O=C(O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCOCCOCCCCCC(=O)O
Yield: 50 %

Procedure:
NaH (2.2 g, 0.045 mol) was allowed to react with 2-butoxyethanol (50 mL) during 1 h. 6-Bromohexanoic acid (4.2 g, 0.0215 mol) was added, the mixture was heated at reflux for 24 h, cooled, and the solvent was removed in vacuo. The residue was dissolved in ether (50 mL), washed with water (3×40 mL), the aqueous phase was acidified (pH 1.0, 6 M HCl), washed with ether, and the solvent removed in vacuo. The yellow oil was chromatographed (silica gel, 10%-30% Et2O/CH2Cl2) and distilled (Kugelrohr) to yield the title product (2.0 g, 50%, bp 120° C./0.02 torr). IR: 1740 cm-1. 1H NMR: 0.98 (t, 3H), 1.4 (m, 4H) 1.6 (m, 6H), 2.4 (t, 2H), 3.4 (t, 4H), 3.6 (s, 4H). Anal. Calcd for C12H24O4 : C, 62.04; H, 10.41%. Found C, 61.99; H, 10.47%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:21])[CH3:20]>>[CH2:19]([N:21]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:20]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Product: CCN(CC(CC1CCCCC1)NC(=O)OC(C)(C)C)CC(CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product from Example 15A and ethylamine were processed as described in Example 7B to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1([O-])OO1.[OH2:29].[OH2:30].O.O.[Na+]>CC(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([S:17]([C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)(=[O:30])=[O:29])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Br)cc2)CC1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
4-(4-bromo-phenylsulfanyl)-piperidine-1-carboxylic acid benzyl ester (1.2 g, 2.96 mmol, 1 equiv) and sodium perborate tetrahydrate (NaBO3.4H2O) (1.36 g, 8.87 mmol, 3 equiv) were heated to 55° C. in HOAc and stirred for 18 h. The reaction was cooled to room temperature and poured onto water. The aqueous phase was extracted with EtOAc (3×100 mL). The organic phases were combined and washed carefully with saturated sodium bicarbonate solution (CAUTION: copious gas evolution), dried over sodium sulfate, filtered and evaporated to yield a white solid (1.2 g, 93% yield). Rf=0.16 (20% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O.S(=O)(=O)(O)O>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)c1c(F)cccc1Cl
Temperature: 60 °C
Yield: 59.6 %

Procedure:
A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and a heating mantle attached to a temperature controller. The flask was charged with 2-chloro-6-fluorobenzoic acid (8.30 g, 47.55 mmol), methanol (15 g), and concentrated sulfuric acid (1 g). The reaction mixture was heated to 60° C. for seven days, then cooled to room temperature. Ethyl ether (50 mL) was added; the reaction mixture was transferred to a separatory funnel and washed with 1M sodium hydroxide solution (3×40 mL), then with water (40 mL). The organic layer was dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was dried under vacuum to give 5.34 g of methyl 2-chloro-6-fluorobenzoate as a yellow oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=1)[C:23]#[N:24]>C(#N)C>[C:23]([C:22]1[CH:21]=[N+:20]([O-:9])[CH:19]=[C:18]([O:17][CH2:16][C:15]2[CH:26]=[C:27]([F:29])[CH:28]=[C:13]([F:12])[CH:14]=2)[CH:25]=1)#[N:24]
Reactant: N#Cc1cncc(OCc2cc(F)cc(F)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)c[n+]([O-])c1
Reaction time: 20 h
Yield: 75.1 %

Procedure:
224 mg of m-CPBA is added at 0° c. to a solution in acetonitrile of 250 mg of 5-(3,5-difluorobenzyloxy)nicotinonitrile. The reaction medium is stirred for 20 hours while a precipitate is formed progressively. this solid is then filtered and washed to yield 200 mg (75%) of 3-cyano-5-(3,5-difluorobenzyloxyl)pyridine 1-oxide in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1[NH2:8].[H-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH:9]([CH3:10])[CH3:11])[N:5]=[CH:6][C:7]=1[NH:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)n1ncc(N)c(Cl)c1=O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)n1ncc(NCc2ccccc2)c(Cl)c1=O
Reaction time: 0.5 h

Procedure:
In 6 ml of dry dimethylformamide, 1.875 g of 4-chloro-5-amino-2-i-propyl-3(2H)pyridazinone was dissolved. 0.48 g of sodium hydride (50% mineral oil suspension) was added thereto at a temperature of from 5° to 10° C., and the mixture was stirred for about 30 minutes. Then, 1.4 g of benzyl chloride was dropwise added thereto at the same temperature. After the dropwise addition, the mixture was stirred at room temperature for 2 hours. To the reaction solution, 50 ml of benzene and 30 ml of a 10% hydrochloric acid aqueous solution were added, and the mixture was vigorously shaken. The organic layer was washed with water, and dried, and then the solvent was distilled off. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 2.3 g of the above identified compound having a melting point of from 131° to 132° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16](=[O:17])[N:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:10]3[CH:9]2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=2)=[CH:4][CH:3]=1.[CH3:28][C@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](=[O:17])[N:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:36][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[N:19]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(C2C(c3ccc(F)cc3)C(=O)N3CC=CCN23)n1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC=CC3)n1)c1ccccc1
Temperature: 140 °C
Yield: 80 %

Procedure:
2-(4-Fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-2,3,5,8-tetrahydro-pyrazolo[1,2-a]pyridazin-1-one, 12, (0.9 g, 2.3 mmol) is dissolved in toluene (18 mL) and (S)-(−)-α-methylbenzylamine (10.5 mL, 81.6 mmol) added. The resulting mixture is heated to 140° C. for 12 hours, cooled, and the solvent removed in vacuo. The resulting crude product is purified over silica (1:1 EtOAc/hexanes) to afford 0.8 g (80% yield) of the desired product as a red sticky solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.[OH-].[NH4+].Cl>O.CO.N1C=CC=CC=1>[OH:8][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:23]([C:13]23[CH2:22][CH:17]4[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]4)[CH2:20]2)[CH2:14]3)=[O:24])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: O=C(NCCc1ccc(O)c(O)c1)C12CC3CC(CC(C3)C1)C2
Reaction time: 5 h

Procedure:
Dissolve 15.0 g. of dopamine hydrochloride in 200 ml. of pyridine. With stirring, add 47.8 g. of 1-adamantane carboxylic acid chloride portionwise over a 2-hour period at room temperature. Stir at room temperature overnight. Add methanol (200 ml.), water (75 ml.) and concentrated ammonium hydroxide solution (50 ml.) to the reaction mixture and allow the clear solution to stand for 5 hours at room temperature. Pour the solution into 2 liters of 2N hydrochloric acid and ice with vigorous agitation. Extract the oily precipitate with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate solution, dry over sodium sulfate and evaporate to a residue. Remove the last traces of ethyl acetate in vacuo and crystallize the product from acetone-ether to obtain the title product, m.p. 198°-200° C.
Reaction SMILES: [Br:1][C:2]1(N)[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:16])[CH:8]=2)[NH:3]1.[CH3:18][N:19](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Br:1][C:2]1([C:18]#[N:19])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:16])[CH:8]=2)[NH:3]1
Reactant: NC1(Br)C=C(C(F)(F)F)c2cc(Cl)ccc2N1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#CC1(Br)C=C(C(F)(F)F)c2cc(Cl)ccc2N1
Temperature: 140 °C
Reaction time: 1.33 h
Yield: 51 %

Procedure:
2-Bromo-6-chloro-4-(trifluoromethyl)-quinolineamine (5, 476 mg, 1.46 mmol) was dissolved in anhydrous DMF (5 mL) under N2. Zn(CN)2 (103 mg, 0.88 mmol) was added and the solution was degassed with a stream of N2. Pd(PPh3)4 (34 mg, 0.029 mmol) was added and the solution was degassed again and then heated to 140° C. The reaction was complete by TLC after 80 min. The reaction mixture was cooled to rt and diluted with EtOAc (100 mL), The organic phase was washed with H2O (2×20 mL) and brine (1×20 mL) then dried over MgSO4. Concentration and chromatography (SiO2, 40 g, 10% EtOAc-hexane) provided the desired material 6 as a yellow crystalline solid (202 mg, 51%). mp 188° C. Rf 0.34 (10% Ethyl acetate-hexane). 1H NMR (CDCl3, 300 MHz) δ 7.95 (d, J=8.8 Hz, 1H), 7.94 (m, 1H), 7.52 (dd, J=2.2, 8.8 Hz, 1H), 5.34 (br s, 2H, NH2); 19F NMR (CDCl3, 300 MHz) δ −54.51; 13C NMR (CDCl3, 75 MHz) δ 140.21, 139.00, 138.39, 132.27, 128.25, 126.65, 126.10, 122.98, 121.90, 121.84, 114.43; IR (KBr) υmax 3485, 3410, 3386, 2230, 1650, 1639, 1574, 1492, 1430, 1352, 1322, 1221, 1158, 1130, 1121, 1095, 975, 822 cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:15]1([C@H:21]([NH2:24])[CH2:22][CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:15]1([C@H:21]([NH2:24])[CH2:22][CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)CC1COc2cc(O)ccc21
Agent: CC[C@@H](N)c1ccccc1
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21

Procedure:
A racemate (19 mg, 0.1 mmol) of (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetic acid was charged, methanol was added, and the racemate was dissolved. The solution and ((R)-1-phenylpropylamine (13.5 mg, 0.1 mmol) were mixed and stood. The precipitated crystals were collected by filtration to give the title compound. 5.1% de
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]([C:16]([O:18]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[CH:5][CH:4]=[N:3]1.[C:24]1([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][N:2]1[C:6]([NH:7][C:16]([N:38]2[CH2:39][CH2:40][N:35]([C:32]3[S:33][CH:34]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)[CH2:36][CH2:37]2)=[O:18])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 33.3 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) (1-methyl-1H-pyrazol-5-yl)imidodicarbonate (200 mg, 0.447 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (180 mg, 0.734 mmol), diisopropylethylamine (0.129 ml, 0.734 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (54.8 mg, 33.2%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:23]([Br:28])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:11][C:12]2[C:17]([Br:18])=[C:16]([Br:19])[C:15]([Br:20])=[C:14]([Br:21])[C:13]=2[Br:22])[CH2:9][O:8][CH2:7]1.O.S(=O)(=O)(O)[OH:31]>O1CCOCC1>[Br:18][C:17]1[C:12]([O:11][CH2:10][C:6]([CH2:5][O:4][C:3]2[C:2]([Br:1])=[CH:26][C:25]([Br:27])=[CH:24][C:23]=2[Br:28])([CH2:7][OH:8])[CH2:9][OH:31])=[C:13]([Br:22])[C:14]([Br:21])=[C:15]([Br:20])[C:16]=1[Br:19]
Reactant: O=S(=O)(O)O
Reactant: Brc1cc(Br)c(OCC2(COc3c(Br)c(Br)c(Br)c(Br)c3Br)COC2)c(Br)c1
Solvent: C1COCCO1
Solvent: O
Product: OCC(CO)(COc1c(Br)cc(Br)cc1Br)COc1c(Br)c(Br)c(Br)c(Br)c1Br

Procedure:
A mixture of the oxetane derivative of Example 2 (47.5 g., 0.053 moles), dioxane (290 ml.), water (10 ml.) and 1 g. of conc. sulfuric acid was stirred and refluxed 22 hours. The cooled reaction mixture was poured into 1.5 liters of water. A gummy solid formed which became crystalline when heated with dioxane. This product was recrystallized twice from dioxane, yielding 19.4 g. of the desired product which had a melting point of 184°-187° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][N:5]=1.[C-:10]#[N:11].[Na+]>CS(C)=O>[CH3:9][N:8]1[C:4]([CH2:3][C:10]#[N:11])=[N:5][CH:6]=[N:7]1
Reactant: Cn1ncnc1CCl
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ncnc1CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
A solution of 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (1.5 g, 11.45 mmol) in dimethylsulfoxide (30 mL) was added to a stirred suspension of sodium cyanide (3.366 g, 68.70 mmol) in dimethylsulfoxide (20 mL), and the reaction mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified via column chromatography (100-200 mesh silica gel, 10-12% ethyl acetate in petroleum ether) to afford 2-(1-methyl-1H-1,2,4-triazol-5-yl)acetonitrile (1.2 g). MS (ES+APCI) (M+H) 123.2.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:22][C:23]4[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)[S:16][C:17]=3[C:18]([F:21])([F:20])[F:19])[CH:10]=[N:9]2)=CC=1.FC(F)(F)S(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[CH3:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([NH:22][C:15]2[S:16][C:17]([C:18]([F:21])([F:19])[F:20])=[C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[N:14]=2)[N:28]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4nccc(C)n4)sc3C(F)(F)F)cn2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(Nc2nc(-c3cn[nH]c3)c(C(F)(F)F)s2)n1
Yield: 5.5 %

Procedure:
According to Scheme 9 Step 4: A solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)-5-(trifluoromethyl)thiazol-2-amine (0.40 mmol, 180 mg) and trifluoromethanesulfonic acid (4.84 mmol, 430 μL) in TFA (1 mL) was stirred for 8 minutes at 80° C. under microwave activation. The reaction solution was neutralized with a saturated aqueous solution of Na2CO3 and extracted with AcOEt. The combined organic layers were dried over MgSO4, were filtered and were evaporated under reduced pressure to give a brown solid. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 95:5) to yield N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)thiazol-2-amine (22 μmol, 7 mg, 5.5%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>>[CH2:23]([O:8][C:7]([C:6]1[S:5][C:4]2[C:10]([N+:16]([O-:18])=[O:17])=[C:11]([OH:15])[C:12]([OH:14])=[CH:13][C:3]=2[C:2]=1[Cl:1])=[O:9])[CH3:24]
Reactant: O=C(O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl

Procedure:
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid (70 mg) from Example 4, ethanol (2 ml) and thionyl chloride (0.16 ml) were refluxed for 4 hours. Ethanol was evaporated. The residue was heated with absolute ethanol and the hot mixture was filtered. The product was dried under vacuum.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:17][N:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.3 g, 10 mmol) in MeOH (30 mL) is added 1 N NaOH (12 mL) in one portion at RT. The mixture is stirred at RT for 1 h. Most of the MeOH is removed with a rotary evaporator, and the remaining aqueous solution is diluted with water (12 mL) and neutralized with 1 N HCl to pH=5. The precipitate is collected by filtration, washed with water and dried to give the title compound. 1H NMR (CDCl): 7.26-7.82 (m, 6H), 4.26 (s, 3H); LC/MS (M+1)=203.29; RT=1.54 min
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17])[CH:6]=[CH:5][CH:4]=1.C[C:20](C)(C([O-])=O)[C:21]([O-])=[O:22].C[O-].[Na+]>CO>[OH:22][C:21]1[CH2:20][CH:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:15][C:16](=[O:18])[CH:17]=1
Reactant: COc1cccc(-c2ccsc2/C=C/C(C)=O)n1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2ccsc2C2CC(=O)C=C(O)C2)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 200 mL recovery flask was added (E)-4-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)but-3-en-2-one (30D, 4.81 g, 18.6 mmol, 1.0 eq.), MeOH (100 mL), and dimethylmalonate (30E, 2.13 mL, 18.6 mmol, 1.0 eq.). NaOMe (30% wt in MeOH, 3.66 mL, 19.5 mmol, 1.05 eq.) was added and the reaction mixture was stirred overnight at reflux. LC/MS analysis showed the desired intermediate and the mixture was concentrated and then taken up in 1N aqueous NaOH (100 mL) and refluxed for 1 h. The reaction was then cooled to 0° C. in an ice bath and acidified with 1N HCl until acidic. The reaction mixture was then stirred at 80° C. for 1 h. After cooling to room temperature, EtOAc (200 mL) was added and the organic phase was washed with saturated aqueous NaCl (100 mL). The combined aqueous phases were extracted with EtOAc (100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give a foamy brown solid 30F that was taken on to the next step without further purification. (4.9 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (m, 3H) 3.79 (s, 3H) 4.54-4.70 (m, 1H) 5.30 (s, 1H) 6.73 (d, J=8.08 Hz, 1H) 7.31 (d, J=7.33 Hz, 1H) 7.39-7.54 (m, 2H) 7.76 (t, J=7.83 Hz, 1H). ESI-MS: m/z 302.3 (M+H)+.