Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:15][S:14][C:9]2=[C:10]([C:12]#[CH:13])[N:11]=1)=[O:5])[CH3:2].[CH2:25]([N:32]=[N+:33]=[N-:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[N:15][S:14][C:9]2=[C:10]([C:12]2[N:34]=[N:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1nc(C(=O)OCC)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1nc(-c2cn(Cc3ccccc3)nn2)c2snc(-c3ccc(Cl)cc3)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
To a mixture of 3-(4-chloro-phenyl)-7-ethynyl-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (0.106 mmol) and CH2Cl2/H2O (1/1, 0.70 mL) was added benzylazide (0.117 mmol), CuSO4.5H2O (0.0053 mmol) and sodium L-ascorbate (0.0159 mmol). The mixture was stirred at rt for 16 h before it was partitioned between H2O (20 mL) and CH2Cl2 (20 mL). The aqueous phase was then extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with brine and water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 0-20% EtOAc/CH2Cl2, to give the title compound (40 mg) as a white solid: MS (m/z) 492.1 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[CH3:12][C:13]1S[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[S:30]([O-:33])(O)=[O:31].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:12][C:13]1[S:30](=[O:33])(=[O:31])[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]=1[C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1
Reactant: O=S([O-])O
Reactant: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
M-chloroperbenzoic acid (content, 65% or more, 200 mg) was added to a chloroform (2 mL) solution of 4-(3-methyl-1,4-benzoxathiin-2-yl)phenol (100 mg, 0.39 mmol) synthesized in Reference Example 1-2, and stirred at room temperature for 90 minutes. Aqueous saturated sodium hydrogensulfite solution and aqueous saturated sodium hydrogencarbonate solution were added to the reaction solution, and stirred. The organic layer was collected, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the entitled compound (106 mg, 94%).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[C:21]([CH3:25])[C:22]([CH3:24])=[CH:23][C:17]=2[N:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[ClH:1].[CH3:24][C:22]1[C:21]([CH3:25])=[CH:20][C:18]2[NH:19][C:15]([CH2:14][N:11]3[CH:4]=[C:3]([CH2:2][C:5]4[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=4)[N:13]=[N:12]3)=[N:16][C:17]=2[CH:23]=1
Reactant: Cc1cc2nc(CN=[N+]=[N-])[nH]c2cc1C
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Cc1cc2nc(Cn3cc(Cc4c[nH]c(N)n4)nn3)[nH]c2cc1C
Yield: 49.7 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.047 g, 0.295 mmol) was reacted with 2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.071 g, 0.354 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(5,6 Dimethyl-1H-benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine dihydrochloride (0.029 g, 25%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.09 (s, 1H), δ 7.45 (s, 2H), δ 6.52 (s, 1H), δ 6.08 (s, 2H), δ 3.93 (s, 2H), δ 2.35 (s, 6H) ppm; 13C (75 MHz, CD3OD) δ 142.2, 136.9, 136.6, 124.5, 124.3, 113.8, 113.4, 110.0, 100.4, 85.8, 80.6, 75.3, 74.1, 45.0, 20.9, 19.28 ppm; HRMS (ESI) calcd for C16H18N8 (M+) 323.1727. found 323.1734.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]([O:14][CH3:15])[NH:8][CH:9]=[C:10]([C:11]([NH2:13])=O)[C:5]=2[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]([O:14][CH3:15])[NH:8][CH:9]=[C:10]([C:11]#[N:13])[C:5]=2[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: COC1NC=C(C(N)=O)c2c1c(Br)cn2C1CCCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: O
Product: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (654 mg) in THF (8 mL) was added Burgess reagent (1152 mg at 0° C.), and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (522 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][S:9][CH2:10]2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:24][C:25]([F:34])([F:33])[C:26](C1NC=CN=1)=[O:27].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH:8]([C:26](=[O:27])[C:25]([F:34])([F:33])[F:24])[S:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CSCC2=O
Reactant: O=C(c1ncc[nH]1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CSC(C(=O)C(F)(F)F)C2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
7-Methoxyisothiochroman-4-one from Step 3 (0.58 g, 3.0 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to -78° C. A solution of sodium bistrimethylsilylamide (3.0 mL of a 1.0M tetrahydrofuran solution) was added and the reaction stirred for 0.5 hours at -78° C. Trifluoroacetyl imidazole (0.41 mL, 3.6 mmol) was added and the reaction was warmed to room temperature and stirred under a nitrogen atmosphere for 16 hours. At this time, 1N hydrochloric acid (200 mL) was added to the reaction followed by extraction with ether (250 mL). The organics were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil (0.42 g, 48%) was used without further purification.
Reaction SMILES: CN1C=CN=C1.[Cl:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:11]=[C:12]([F:16])[C:13]=1[C:14]#[N:15].[CH:34]([C:36]([CH3:38])=[O:37])=[CH2:35].O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH3:33])[N:31]([CH2:35][CH2:34][C:36](=[O:37])[CH3:38])[CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:11]=[C:12]([F:16])[C:13]=1[C:14]#[N:15]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1
Reactant: C=CC(C)=O
Agent: Cn1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)nc1C
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 42.3 %

Procedure:
1-Methylimidazole (1.030 μl, 0.013 mmol) and DMSO (3 ml) were added into a flask. (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.259 mmol) dissolved in 3 ml of DMSO was added. Lastly methyl vinyl ketone (0.065 ml, 0.776 mmol) was added and the resulting mixture was stirred in 70° C. for 2.5 h. The mixture was stirred at RT during the night and in the next morning the temperature was again raised to 70° C. for 3.5 h. During the last part of the reaction a total of 0.195 ml of methyl vinyl ketone and 16.48 μl of 1-methylimidazole were added and the mixture was stirred at 70° C. for three days. 10 ml of water was poured into the mixture and the resulting white solution was extracted with ethyl acetate. Combined ethyl acetate phases were dried, filtered and evaporated. The product was purified by flash-chromatography and recrystallization from ACN/water, respectively. Yield 42.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.05 (d, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 2.97 (t, 2H), 4.04 (t, 2H), 4.23-4.45 (m, 3H), 7.01 (d, 1H), 7.48 (s, 1H), 7.85 (d, 1H), 7.93 (dd, 1H), 8.00 (s, 1H), 8.05 (d, 1H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:25]1N(C2CCCCO2)C2C(N=1)=C(N)N=C(OC1CCCC1)N=2>>[CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:2][CH2:25][CH2:3][CH2:4]1
Reactant: Nc1nc(OC2CCCC2)nc2c1nc(Br)n2C1CCCCO1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Product: COc1nc2c(N)nc(OC3CCCC3)nc2n1C1CCCCO1

Procedure:
Prepared similarly to Intermediate 57 from 8-bromo-2-(cyclopentyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:8]2=[O:31])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:44]([NH:46][NH2:47])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:16][C:17]1[O:18][CH:44]=[N:46][N:47]=1)[C:8]2=[O:31])([CH3:3])([CH3:2])[CH3:4]
Reactant: NNC=O
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC

Procedure:
5-(t-Butyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione was prepared as described for Example 8 from 3-[5-(tert-butyl)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (0.81 g, 5.0 mmol), formic hydrazide (0.35 g, 5.8 mmol), and phosphorus oxychloride (1.0 mL, 10.7 mmol) in acetonitrile (20 mL). The product was isolated as a white solid (800 mg, 38% yield): mp, 136.0-138.5° C.; 1H NMR (CDCl3) δ 1.35 (s, 9H, CH3), 1.44 (t, J=6.9 Hz, 3H, CH3), 3.79 (dd, J=5.9, 16.1 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.11 (q, J=7.1 Hz, 2H, CH2), 4.38 (dd, J=10.3, 15.8 Hz, 1H, CHH), 5.80 (dd, J=5.9, 10.4 Hz, 1H, NCH), 6.82 (d, J=8.2 Hz, 1H, Ar), 7.11-7.17(m, 2H, Ar), 7.70 (br s, 2H, Ar), 7.82 (br s, 1H, Ar), 8.29 (s, 1H, Ar); 13C NMR (CDC3) δ 14.71, 27.73, 31.08, 35.72, 51.78, 55.92, 64.44, 111.36, 112.58, 120.31, 120.63, 123.26, 128.94, 130.33, 131.14, 131.84, 148.41, 149.42, 153.02, 158.82, 164.07, 168.25, 168.39; Anal Calcd for C25H27N3O5+0.11 H2O: C, 66.51; H, 6.08; N, 9.31; H2O, 0.43. Found: C, 66.42; H, 5.83; N, 9,18; H2O, 0.43.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCBr)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
Aniline 1 (12.69 g, 0.052 mol) was stirred in dichloromethane at 0° C. and 5-bromovaleryl chloride (8.9 mL, 0.052 mol) added followed by diisopropylethylamine (9 mL, 0.052 mol). The resulting white suspension was allowed to warm to room temperature and stirred for 3 h. The white solid was collected by filtration and recrystallised from ethyl acetate to give 2 as a white fluffy powder (10.22 g, 50%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCc1ccccc1Cl
Solvent: CO
Product: N#CNC(=NCCc1ccccc1Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.9 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-(2-chlorophenyl)ethylamine (0.45 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanolhexane to give the title compound (0.56 g, 2.0 mmol, yield: 75%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23]Cl)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[CH3:28][NH:29][CH3:30].C(O)C>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23][N:29]([CH3:30])[CH3:28])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(COCCCl)c1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: CNC
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCOCC(O)c1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
A mixture of 4.5 g of 1-(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol, 1 g of potassium iodide, 10 ml of a 50% aqueous dimethylamine solution and 20 ml of ethanol was refluxed for 3 hours. To the reaction mixture was added 10 ml of a 50% aqueous dimethylamine solution. The resulting mixture was further refluxed for 6 hours. The reaction mixture was cooled and concentrated to about a half volume under reduced pressure. To the concentrate were added 100 ml of ethyl acetate and 100 ml of water. The mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 30 ml of diethyl ether. The resulting crystals were collected by filtration and dried to obtain 3.9 g of 1-(6-benzyloxy-2 -naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol (compound No. 284).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N[CH2:33][CH2:34][SH:35].C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]4[S:35][CH2:34][CH2:33][N:28]=4)[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCS
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NCCS2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carbonitrile (100 mg, 0.24 mmol) in methanol (20 mL) was added 2-aminoethanethiol hydrochloride (41 mg, 0.36 mmol) and triethylamine (0.1 mL, excess). The reaction mixture was heated to reflux for 14 h and cooled to room temperature. After concentration, the residue was purified by prep. HPLC to yield the title compound (76 mg, 66%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.10 (1H, s), 7.71 (1H, s), 7.66 (1H, s), 7.25–7.53 (4H, m), 6.33 (1H, d, J=7.6 Hz), 5.01 (1H, dd, J=4.2, 7.0 Hz), 4.58 (2H, t, J=8.6 Hz), 3.91 (2H, t, J=8.6 Hz), 3.73 (1H, dd, J=4.2, 13.7 Hz), 3.63 (1H, dd, J=7.0, 13.7 Hz), 2.64 (3H, s). LCMS (M+H)+ m/z 480 (t=1.70 min.).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6]/[C:7](/[CH3:16])=[CH:8]/[CH2:9][CH2:10]/[C:11](/[CH3:15])=[CH:12]/[CH:13]=[O:14])[CH3:3].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>>[CH3:15][CH:11]([CH2:10][CH2:9][CH:8]=[C:7]([CH3:16])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])[CH2:12][CH:13]([OH:14])[CH:20]([N+:17]([O-:19])=[O:18])[CH3:21]
Reactant: CC[N+](=O)[O-]
Reactant: C/C(=C\C=O)CC/C=C(\C)CCCC(C)C
Product: CC(C)=CCCC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Yield: 90 %

Procedure:
To 2.93 g of 3 was added 5 mL of nitroethane with stirring. Approximately 5-6 g of Amberlyst A-21 was added, and the mixture was stirred at room temperature overnight. The mixture was filtered and the ion exchange resin was rinsed four times with 25 mL of dichloromethane. The filtrate was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation, which afforded 3.53 g (90%) of a mixture of stereoisomers of the desired nitro alcohol 4. 1H NMR δ (ppm) 5.2 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 4.4 (m, CHNO2), 2.2 (br s, CHOH), 2.0 (m, C═CHCH2CH2C(CH3)═CHCH2), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.9 (d, CH2CH(CH3)CH2).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([CH:7]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]([CH3:22])=[N:11]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1cc(F)ccc1-n1cc(C(O)C2CCCCC2)c(C)n1
Product: Cc1cc(F)ccc1-n1cc(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)c(C)n1
Yield: 63.8 %

Procedure:
Using cyclohexyl[1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.52 g, 70%) was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].N12CCCN=C1CCCCC2>C(OCC)(=O)C>[C:12]([S:15][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)S
Reactant: OCCOCCOCCCl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)SCCOCCOCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a mixture of 2-[2-(2-chloroethoxy)ethoxy]ethanol (11.0 g, 65.24 mmol) and tert-butylthiol (7.35 mL, 65.23 mmol) cooled in an ice bath was slowly added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 9.75 mL, 65.23 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. This mixture was then diluted with ethyl acetate and filtered. The crude product in the filtrate was purified on a filter column eluted with ethyl acetate to give yellowish oil (14.4 g, 64.6 mmol, 99%): 1H NMR (300 MHz, CDCl3): d 3.73 (br s, 2H), 3.69-3.60 (m, 8H), 2.75 (t, J=7.4, 2H), 2.62 (br s, 1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3): d 72.47, 71.08, 70.33, 70.27, 61.71, 42.09, 30.95, 27.87; MS (ESI): m/e (M+1) Calcd. for C10H23O3S: 223, obsd.: 223.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCI
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CCC)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-iodopropane (0.16 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.5 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6]1)[CH2:8][CH3:9]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CCCn1nnc(N)n1
Product: CCCn1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid,, m.p. 208-209° and MS: (neg. ions): m/e=334.1 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-propyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])C1C=CC(B(O)O)=CC=1>>[F:21][C:22]([F:33])([F:32])[C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(C(F)(F)F)cc3)[nH]c3cccc1c23

Procedure:
In a manner analogous to the method described above for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-trifluoromethylphenylboronic acid (322 mg, 1.70 mmol) were coupled to yield 2-(4-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 261 mg (70%), as an off-white solid. mp 208-209° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.09 (m, 2H), 3.40 (m, 2H), 7.27 (app t, 1H, J=7.8 Hz), 7.60 (dd, 1H, J=8.1, 0.9 Hz), 7.71 (dd, 1H, J=7.5, 0.6 Hz), 7.88 (m, 4H), 8.13 (br t, 1H), 11.77 (br s, 1H); MS (FAB, MH+) 331; Anal. (C18H13F3N2O.1.0 H2O) C, H, N.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([C:13]1[O:14][C:15]([CH:18]2[CH2:20][CH2:19]2)=[N:16][N:17]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:13]1[O:14][C:15]([CH:18]2[CH2:20][CH2:19]2)=[N:16][N:17]=1)[OH:12]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)c1nnc(C2CC2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)[C@H](O)c1nnc(C2CC2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {1-[(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (2.83 g, 9.95 mmol), trifluoro acetic acid (5 mL) in dichloromethane (20 mL) is stirred at room temperature for 2 hrs and concentrated to dryness under reduced pressure to give (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-butan-1-ol: compound with trifluoro-acetic acid.