Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[NH:6][C:5]2=O.C(N(CC)CC)C.C(OC([N:31]1[CH:36]2[CH2:37][CH2:38][CH:32]1[CH2:33][CH:34]([NH2:39])[CH2:35]2)=O)C>P(Cl)(Cl)(Cl)=O.CN(C=O)C>[CH:32]12[NH:31][CH:36]([CH2:37][CH2:38]1)[CH2:35][CH:34]([NH:39][C:5]1[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[N:6]=1)[CH2:33]2
Reactant: CCOC(=O)N1C2CCC1CC(N)C2
Reactant: O=c1[nH]c(=O)n(CC(F)(F)F)c2ccc(Cl)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1nc(NC2CC3CCC(C2)N3)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione (1.10 g, 3.97 mmol) in phosphorous oxychloride (15 mL) was added 1 mL triethylamine. The reaction was heated to 100° C., stirred for 4 hrs and concentrated. The crude residue was dissolved in chloroform, washed with 1 N aq sodium hydroxide, dried over Na2SO4, filtered, and concentrated. To a solution of the crude residue in DMF (50 mL), was added triethylamine (1 mL) and 3-amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.0 g, 5.50 mmol). The solution was heated to 50° C. and stirred for 12 hrs. The reaction was partitioned between ethyl acetate and water and the organic phase was washed an additional 2× with water and brine, dried over Na2SO4, filtered, and concentrated. The resultant yellow foam was treated with HBr solution (6 mL, 30 weight % in AcOH) in a pressure vessel at 100° C. After 4 hrs the solution was cooled and concentrated (1.1 g). 1H NMR (300 MHz, CD3OD) δ ppm 2.20 (m, 8H), 4.16 (m, 2H), 4.65 (m, 1H), 5.04 (q, J=8.6 Hz, 2H), 7.62 (d, J=9.0 Hz, 1H), 7.83 (dd, J=2.2, 9.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H); MS (ESI+Q1MS) m/z 388 [M+2H]+
Reaction SMILES: CO.[CH3:3][NH2:4].[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13](=[N:16][N+:17]([O-:19])=[O:18])SC)=[CH:9][N:10]=1>C(#N)C>[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13]([NH:4][CH3:3])=[N:16][N+:17]([O-:19])=[O:18])=[CH:9][N:10]=1
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CN
Solvent: CO
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 1.5 h

Procedure:
349 mg of a 40% methylamine methanol solution was dropwise added to a mixture consisting of ! g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea and 30 ml acetonitrile, at room temperature, over 5 minutes. After stirring for 1.5 hours, the resultant white precipitate was collected by filtration and then dried to afford 410 mg of N-(2-chloro-5-thiazolylmethyl)-N'-methyl-N"-nitroguanidine (compound No. 14) as a white powder. The mother liquor after the filtration was concentrated, then 20 ml of ethanol was added, followed by stirring thoroughly, and the crystals formed were collected by filtration to obtain additional 330 mg of compound No.14 (mp 172°-173° C). Upon recrystallization from acetonitrile, this product exhibited mp 173°-174° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)#[N:4].Cl[C:27]1[CH:28]=[C:29]2[N:36]([CH3:37])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1>C1COCC1>[C:3]([C:5]1[CH:23]=[C:22]([CH2:24][O:25][C:27]2[CH:28]=[C:29]3[N:36]([CH3:37])[CH2:35][CH2:34][N:30]3[C:31](=[O:33])[N:32]=2)[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:17])[F:19])[CH:9]=1)#[N:4]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C#N)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.37 mg, 0.234 mmol), 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile (49.7 mg, 0.156 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one (29 mg, 0.156 mmol).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17]O)=[C:14]([CH3:19])[C:13]=2[CH:20]=1)=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][Cl:3])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)=[O:8]
Reactant: COC(=O)c1ccc2oc(CO)c(C)c2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2oc(CCl)c(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.25 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid methyl ester (0.20 g) and pyridine (2 drops) in chloroform (5 ml). The solution was stirred at room temperature for 30 minutes and then washed successively with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave crude 2-chloromethyl-3-methylbenzofuran-5-carboxylic acid methyl ester (0.18 g), m.p. 114°-115° which was used directly in the next stage.
Reaction SMILES: [H-].[Na+].[CH2:3]=[CH:4][CH2:5][CH2:6][CH:7]([OH:12])[CH2:8][CH2:9][CH:10]=[CH2:11].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:12][CH:7]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: BrCCCCCCCCCCBr
Reactant: C=CCCC(O)CCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(CCC=C)OCCCCCCCCCCBr
Reaction time: 21 h
Yield: 31.3 %

Procedure:
2.1 g of 60% sodium hydride was suspended in 50 ml of THF, and 6.6 g of 1,8-nonadien-5-ol was dropped therein in an atmosphere of argon. 28 g of 1,10-dibromodecane was further dropped therein, and reflux was then carried out for 21 hours in an atmosphere of argon. After the generated precipitate was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography, to obtain 5.3 g of the compound (7). (Yield: 31%)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=2)=[O:20])=[CH:7][CH:6]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:1][N:2]([CH3:3])[C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])/[CH:18]=[CH:17]/[C:12]2[CH:13]=[N:14][N:15]([CH3:16])[C:11]=2[C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)=[CH:23][CH:24]=1
Reactant: CNC
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
A mixture of dimethylamine (2M tetrahydrofuran solution, 1.7 mL), [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-N-{4-[2-(dimethylamino)-2-oxoethyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.36 g, yield 49%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization thereof from acetone-diisopropyl ether gave colorless prism crystals. melting point: 209-210° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C@H:28]([C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:38]=3[OH:45])[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[O:34][CH3:35])[CH2:23]2)=[O:21])[CH2:9][N:10](C)[C:11](OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:7][C@H:8]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C@H:28]([C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:38]=3[OH:45])[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[O:34][CH3:35])[CH2:23]2)=[O:21])[CH2:9][NH:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)NCCO[C@@H](c1cc(F)cc(F)c1O)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cc(F)cc(F)c2O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
methyl 2-((R)—((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)(3,5-difluoro-2-hydroxyphenyl)methoxy)ethylcarbamate (100 mg, 0.131 mmol) was dissolved in MeOH (1 mL) and Pd/C (20 mg) was added to it. The reaction mixture was stirred in 30 psi at room temperature for 2 h. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to afford methyl 2-((R)—((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)(3,5-difluoro-2-hydroxyphenyl)methoxy)ethylcarbamate (20 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.O.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cc[nH]n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Brc1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 3-bromo-pyrazole (2.0 g, 13.6 mmol) in anh. CH2Cl2 (40 mL), at r.t., under N2, were added triphenylmethyl chloride (4.17 g, 1.1 eq) and Et3N (2.1 mL, 1.1 eq). The reaction mixture was stirred at r.t. for 4 hr. It was poured into water/CH2Cl2. The phases were separated and the aqueous layer was further extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 100% CH2Cl2) to give the title compound as a white solid (3.39 g, 64%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:16][CH2:15][CH2:14][S:13][CH2:2][C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Reactant: OCCS
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NO)C(=O)CSCCO
Temperature: 20 °C
Reaction time: 15 h

Procedure:
Ethyl 4-chloro-2-hydroxyimino-3-oxo-butyrate (340 g.) is dissolved in chloroform (1.5 liters) and 2-mercapto-ethanol (126 cc.) is then added. Triethylamine (248 cc.) dissolved in chloroform (1 liter) is added to the resulting solution at about 20° C., over the course of 30 minutes. The reagents are left in contact for 15 hours whilst stirring at about 20° C. Then the reaction mixture is washed with water (200 cc.) followed by 2 N hydrochloric acid (200 cc.) and finally four times with water (a total of 1 liter). The organic phase is dried over sodium sulphate treated with decolourising charcoal, filtered and concentrated to dryness under reduced pressure (20 mm.Hg). Ethyl 4-(2-hydroxy-ethylthio)-2-hydroxyimino-3-oxo-butyrate (321 g.) is thus obtained in the form of an oil which gradually solidifies.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)=[CH:5][CH:4]=1>C(OCC)(=O)C.CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(Br)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Brc1ccc([C@H]2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride in ethyl acetate solution (4N) was added to a solution of di-tert-butyl (2S)-2-(4-bromophenyl)piperazine-1,4-dicarboxylate (10 g, 22.7 mmol) in methanol (50 ml). The mixture was stirred for one hour at room temperature and the solvent was evaporated under reduced pressure to give white solid. The mixture was partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford (2S)-2-(4-bromophenyl)piperazine as white crystals. Benzylbromide (9.7 g, 56.7 mmol) was added to a solution of sodium hydride (60% in oil, 2.0 g, 50 mmol) and (2S)-2-(4-bromophenyl)piperazine in tetrahydrofuran (50 ml) at room temperature and the mixture was stirred for one hour. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish (2S)-1,4-Dibenzyl-2-(4-bromophenyl)piperazine (6.1 g, 64%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[C:5]([F:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:28]2=[N:29][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:5]1[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:10]2)=[N:7][C:2]([C:33]2[C:27]3[C:28](=[N:29][CH:30]=[C:25]([F:24])[CH:26]=3)[N:31]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:44])=[O:45])[CH:32]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: O=C(N[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1)N1CCCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)N5CCCC5)C4)n3)c3cc(F)cnc32)cc1
Temperature: 125 °C

Procedure:
A solution of N-((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)-pyrrolidine-1-carboxamide, 67e, (6.8 g, 20.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (12.5 g, 30.0 mmol) and K3PO4 (17.0 g, 80.0 mmol) in 2-methyl THF (180 mL) and water (20 mL) was degassed under nitrogen for 30 min. To the mixture was added dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (XPhos) (1.1 g, 2.4 mmol) and Pd2(dba)3 (0.5 g, 0.5 mmol). The reaction mixture was heated in a pressure bottle at 125° C. for 2.5 hr. The reaction mixture was filtered through celite, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (8% MeOH/CH2Cl2) to afford 11.5 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:12][CH3:13])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([NH:15][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:12][CH3:13])=[NH:11])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCc1cccc(N(C#N)CC)c1
Reactant: Nc1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(CC)C(=N)Nc2cccc3ccccc23)c1
Temperature: 160 °C
Yield: 67.2 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-ethylcyanamide (500 mg, 2.86 mmol) and 1-aminonaphthalene hydrochloride (520 mg, 2.86 mmol) was heated in a pre-heated oil bath at 160° C. for 2 hours and then allowed to cool to room temperature. The resulting solid was taken in dichloromethane and washed with 10% NaOH solution. The organic layer was concentrated and the resulting residue was flash chromatographed on silica gel to give N-(1-naphthyl)-N'-(m-ethylphenyl)-N'-ethylguanidine (610 mg, 67%) as a light brown liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][O:10][C:9]([CH3:12])([CH3:13])[O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1COC(C)(C)OC1
Yield: 53 %

Procedure:
To the solution of 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (19.75 g, 75.96 mmol) in dimethyl sulfoxide (80 ml) was added sodium chloride (4.4 g, 75.76 mmol) and water (2 ml). The reaction was refluxed for 7 h. After such time, it was poured into saturated sodium chloride solution (500 ml) and extracted with ether (4×200 ml). The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was distilled under reduced pressure. Three fractions collected between 100° C. and 120° C. were combined to afford 2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester (7.58 g, 53%) as a clear oil (J. Org. Chem. 1986, 51, 2637) 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H, CH3), 1.41 (s, 3H, CH3), 1.44 (s, 3H, CH3), 2.74-2.85 (m, 1H, CH), 3.96-4.30 (m, 6H, 3×OCH2).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[CH:25]=[O:26])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[CH2:25][OH:26])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1c(C=O)c(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(CO)c(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 750 mg portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-4-formyl-2-methyl-1H-pyrrole-3-carboxylate was suspended in 15 ml of ethanol, and 158 mg of sodium borohydride was added at 0° C., followed by stirring at room temperature for 2 hours. The solvent was evaporated under a reduced pressure, chloroform and water were added, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent under a reduced pressure, 754 mg of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-4-(hydroxymethyl)-2-methyl-1H-pyrrole-3-carboxylate was obtained as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[CH:15]=[C:14]([OH:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:7]=1[C:8]([NH:10][OH:11])=[O:9].C(N(CC)CC)C.Cl>C1COCC1.O>[N+:17]([C:13]1[C:14]([OH:16])=[CH:15][C:6]2[O:11][N:10]=[C:8]([OH:9])[C:7]=2[CH:12]=1)([O-:19])=[O:18]
Reactant: O=C(NO)c1cc([N+](=O)[O-])c(O)cc1O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc2c(O)noc2cc1O
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
Thionyl chloride (20 mL) is added dropwise to a mixture of 2,4,N-trihydroxy-5-nitrobenzamide (6.7 g, 31.3 mmol) in THF (500 mL). The mixture is allowed to come to reflux during the addition and then heated at 55° C. for 18 h. The mixture is allowed to cool to room temperature. The insoluble precipitate is filtered off and the filtrate is concentrated and stripped twice with toluene to a give 4-nitro-6-(2-oxo-[1,3,2,4]dioxathiazol-5-yl)-benzene-1,3-diol as a gummy solid. To a suspension of the solid in dioxane (100 mL) is added dropwise triethylamine (16.9 mL, 121 mmol). After stirring at room temperature for 45 min, ice and water are added and the mixture is acidified with 1N HCl. The mixture is extracted twice with EtOAc and the organic layers are washed with 1N HCl and brine, and dried over MgSO4, filtered and concentrated. The crude material is purified using flash chromatography on silica gel eluting with 1:1 EtOAc/hexanes to afford 5-nitrobenzo[d]isoxazole-3,6-diol as a yellow solid: (M−H)−=195.1.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]([C:23]#[N:24])=[C:10]([CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].O>CN(C)C=O.CCOC(C)=O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][C:10]1[N:11]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:8][C:9]=1[C:23]1[NH:27][N:26]=[N:25][N:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1sc(N2CCOCC2)nc1Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc2cc(Cc3nc(N4CCOCC4)sc3-c3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
To a solution of 2-(morpholin-4-yl)-4-(2-naphthylmethyl)-1,3-thiazole-5-carbonitrile (213 mg, 0.635 mmol) in N,N-dimethylformamide (3.00 mL) was added sodium azide (61.9 mg, 0.952 mmol) and ammonium chloride (102 mg, 1.90 mmol). The mixture was heated to 100° C. and stirred for 24 hrs. The resulting mixture was cooled to rt and distributed between water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with 10% LiCl(aq) solution (×2), dried, and concentrated. Purification on HPLC (reverse phase, AA) provided 4-[4-(2-naphthylmethyl)-5-(1H-tetrazol-5-yl)-1,3-thiazol-2-yl]morpholine as a yellow solid (105 mg, 43.7% yield). LCMS: (AA) ES+ 379; 1H NMR (400 MHz, MeOD) δ 7.79-7.61 (m, 4H), 7.43-7.31 (m, 3H), 4.57-4.45 (s, 2H), 3.82-3.68 (t, J=4.9 Hz, 4H), 3.53-3.43 (t, J=4.9 Hz, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][CH:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[C:16]([O:15][C:13]([CH:11]([CH3:12])[CH2:10][C:7]1[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(CC(C)C(=O)OC(C)(C)C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1ccc(C(=O)O)o1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
5-(2-tert-Butoxycarbonylpropyl)furan-2-carboxylic acid methyl ester (1.0 g, 3.76 mmol) obtained in step 1 was dissolved in tetrahydrofuran (4.5 mL) and methanol (3 mL), 1N aqueous sodium hydroxide solution (4.5 mL) was added, and the mixture was stirred overnight. The mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the drying agent was filtered off, and the solvent was evaporated to give the title compound (0.98 g).