Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C1C=CN=CC=1)C.CC#N.CCOC(C)=O>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61.2 mg, 0.165 mmol) (see following Steps B, C, D, E, F, G and H for preparation), was added to a solution of diethylamine (0.2 mL, 1.93 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (60 mL), washed with NH4Cl (2×5 mL), NaCl (2×5 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 20.5 mg (30%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.13 (t, J=7.13 Hz, 6 H), 1.46-1.63 (m, 4 H), 1.66 (s, 9 H), 2.25-2.48 (m, 1 H), 3.22-3.29 (m, 4 H), 3.31-3.41 (m, 2 H), 3.94 (m, 2 H), 4.50 (d, J=7.42 Hz, 2 H), 7.89 (dd, J=8.79, 1.76 Hz, 1 H), 7.96-8.04 (m, 1 H), 8.14 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=408.0; Anal. Calcd for C21H33N3O3S+1.00 TFA+0.1H2O+0.30 EtOAc (549.84): C, 52.86; H, 6.71; N, 7.64. Found: C, 52.91; H, 6.52; N, 7.61.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)F)[CH2:13][CH:14]=[CH2:15]>C1COCC1>[CH2:12]([Si:16]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C=CCC[Si](F)(c1ccccc1)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Reaction time: 2 h

Procedure:
To a solution of 1,3-dithiane (6.77 g, 56.3 mmol) in THF (120 mL) at -78° C. was added dropwise over 10 min n-butyllithium (1.6M in hexane, 50 mmol), and the solution was stirred for 2 h under argon. A solution of 31 (11.1 g, 43.3 mmol) in THF (100 mL) was added, the mixture was stirred for 3 h at -78° C., and overnight at rt. The reaction mixture was quenched with water (100 mL) and the organic layer isolated. The aqueous layer was extracted with two 100-mL portions of ethyl ether. The combined organic extracts were washed with saturated aqueous NaCI, dried over Na2 SO4, and concentrated. Flash chromatography over silica gel (1/9EtOAc:hexane) gave 32 contaminated with 3-dithiane. The latter was removed by sublimation (54° C., 8.0 mm Hg). Recrystallization from Et2O provided pure 32 as a colorless solid (14.8 g, 96%): R.function. =0.40 (1/49 EtOAc:hexane); mp 47°-49° C.; 1H NMR (300 MHz, CDCl3) δ7.66 (d, J=7.8 Hz, 4H), 7.43 (m, 6H), 5.90 (m, 1H), 5.02 (dd, J=17.1, 1.7 Hz, 1H), 4.91 (dd, J=10.2, 1.7 Hz, 1H), 4.26 (s, IH), 2.92 (t, J=11.8 Hz, 2H), 2.71 (m, 2H), 2.19 (m, 2H), 2.07 (m, 2H), 1.37 (m, 2H); 13C NMR (75 MHz, CDCl3) δ141.1, 135.9, 132.4, 130.2, 128.0, 113.2, 32.3, 31.5, 27.5, 25.8, 10.5; IR (film) 3068 (m), 3047 (m), 2897 (s), 2840 (m), 1961 (w), 1890 (w), 1826 (w), 1639 (m), 1490 (w), 1429 (s), 1275 (m), 1112 (s), 1003 (m), 911 (s), 785 (m), 744(s), 703 (s) cm-1 ; MS (FAB) m/e (rel. intensity) 357 (M+, 11), 356 (11), 355 (25), 301 (18), 279 (13), 237 (36), 227 (11), 225 (18), 221 (14), 215 (14), 213 (18), 212 (12), 211 (100), 209 (9), 207 (15); HRMS (FAB) calcd for C20H23S2 Si: 355.1010 (MH+ -2), found: 355.1020. Anal. Calcd for C20 H24S2Si: C, 67.36; H, 6.78. Found: C, 67.08; H, 6.78.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=[O:28])[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].[NH4+].[Cl-]>CN(C=O)C.C1COCC1>[OH:28][CH:26]([CH3:27])[CH:25]([N:22]1[C:21](=[O:30])[N:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)=[CH:19][CH:18]=2)[CH:24]=[N:23]1)[CH3:29]
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.120 mol) in DMF (700 ml) was cooled on ice. Potassium tri-sec-butylborohydride, 1M solution in THF (300 ml) was added dropwise. The mixture was allowed to warm to room temperature, then poured out into an aqueous NH4Cl solution. The precipitate was filtered off, dried and crystallized from 2-propanol. This fraction was separated into its enantiomers over CHIRALPAC AD [(amylose 3,5 dimethylphenyl carbamate) purchased from Daicel Chemical Industries, Ltd, in Japan] (eluent: 100% ethanol). Two pure fraction groups were collected and their solvent was evaporated. The desired fraction was recrystallized from methanol. The precipitate was filtered off and dried, yielding 0.9 g of [R-(R*,R*)]-2,4-dihydro-2-(2-hydroxy-1methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 14a; [α]20D=+10.35° @ 48.61 mg/5 ml in DMF) and 0.8 g [S-(R*,R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 14b).
Reaction SMILES: [CH2:1]([CH:8]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]2)=[C:12]([O:24]CC2C=CC=CC=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Pd]>[CH2:1]([CH:8]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]2)=[C:12]([OH:24])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(c2ccc(CC(Cc3ccccc3)C(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1CN(c2ccc(CC(Cc3ccccc3)C(=O)c3ccccc3)cc2O)S(=O)(=O)N1
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(2-benzyl-3-oxo-3-phenylpropyl)-2-benzyloxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.069 mmol) and 7 mg of Degussa 5% Pd/C in 4 mL of ethanol/water (1:1) is hydrogenated at 1 atm for 8 h at RT. The catalyst is filtered through Celite, washed with 1:1 ethanol/water and the filtrate concentrated under reduced pressure. The resulting residue is stripped four times with ethanol and the resulting solid is triturated with ether and dried to afford the title compound as a solid: (M−1)−=449. HPLC retention time=0.88 min (Method C).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:18](N)=[NH:19]>COC(O)C>[N+:11]([C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:18][N:19]=[C:4]2[OH:6])([O-:13])=[O:12]
Reactant: N=CN
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: COC(C)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ncnc(O)c2c1
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-5-nitrobenzoic acid (1000 g, 5 mol) and formamidine acetate (1000 g, 10 mol) were dissolved in methoxyethanol (4 L) and heated to 115° C. for 16 hours. After cooling the mixture to room temperature, ice water (5 L) was added and the mixture was stirred for 30 minutes before collecting the product (125 g, 14%) by filtration.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:15])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Product: CN(C)C1CCc2oc3ccc(C(=O)NC4CC4)cc3c2C1
Yield: 33.5 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol cyclopropylamine, 0.004 gm (32%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:17][C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:16]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:33]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[Cl:33][C:8]1[N:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]2[CH:16]=[C:2]([Cl:1])[C:3]([S:17][C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:4][C:5]=2[N:9]=1
Reactant: COCCOCn1cnc2cc(Sc3cccc(C)c3)c(Cl)cc21
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: COCCOCn1c(Cl)nc2cc(Sc3cccc(C)c3)c(Cl)cc21
Temperature: 23 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A solution of 6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazole (1.89 g, 5.21 mmol) and THF (13 mL) was cooled to −78° C. in an acetone/dry ice bath. Buthyllithium (2.2M solution in hexanes, 2.60 mL, 5.73 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 1 h. (Lithium diisopropylamide as a 2.0M solution in THF/heptane/ethylbenzene can also be used as a base.) A solution of N-chlorosuccinimide (765 mg, 5.73 mmol) and THF (11.5 mL) was added. The reaction mixture was warmed to 23° C. and stirred for 2 h. Saturated aqueous NH4Cl (20 mL) was added and the crude product was extracted into CH2Cl2 (3×75 mL). The organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-100% EtOAc/hexanes) to provide the titled compound (1.46 g, 71%) as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C18H18Cl2N2O2S, 396.0; m/z found, 397.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.74 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.23-7.18 (m, 3H), 7.18-7.14 (m, 2H), 7.12-7.07 (m, 3H), 5.58 (s, 2H), 5.48 (s, 2H), 3.64-3.60 (m, 2H), 3.54-3.48 (m, 4H), 3.43-3.40 (m, 2H), 3.34 (s, 3H), 3.29 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [N+:1]1([O-])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.CS([Cl:15])(=O)=O>CN(C=O)C>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:4]2[NH:3][CH:2]=[N:1][C:5]=12
Reactant: CS(=O)(=O)Cl
Reactant: [O-][n+]1c[nH]c2ncccc21
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]cnc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A 50 mL round bottom flask set up with a reflux condenser under nitrogen atmosphere was charged 4-azabenzimidazole N-oxide (1.2 g, 8.88 mmol) and 11 mL of DMF. This was heated to 50° C. and methanesulfonyl chloride (1.86 ml, 23.98 mmol) was added dropwise via syringe. The resulting mixture was heated to 80° C. and stirred at this temperature for 16 hours. This was cooled to room temperature and quenched with water (approximately 10 mL) and reaction mixture brought to pH 7 by adding 6N NaOH aqueous solution. The reaction was extracted four times with dichloromethane (50 mL). Some product was present in aqueous layer; this was concentrated and residue set aside. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g column, gradient elution 0-10% MeOH:DCM) to afford 7-chloro-3H-imidazo[4,5-b]pyridine (450 mg, 33.0% yield). MS [M+H]=154.2. Calc'd C6H4ClN3=153.56.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:7]=1)=O)C.[BH4-].[Na+]>CO.O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:7]=[C:6]([CH2:4][OH:3])[N:11]3[N:12]=[CH:13][CH:14]=[C:10]3[N:9]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2ccnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid ethyl ester (60 mg, 0.2 mmol) in MeOH/tetrahydrofuran (1:1 v/v, 1 mL) was added at 0° C. over 5 min sodium borohydride (75 mg, 2.0 mmol). The mixture was stirred at 0° C. for 1 h and then poured into ice-cold 3 N HCl (3 mL). The mixture was extracted with AcOEt and the organic layer was washed with H2O, dried (Na2SO4), and evaporated in vacuo. The residue was chromatographed on silica gel using AcOEt/cyclohexane (1:2 v/v) as eluent to give [5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-methanol (45 mg, 87%). Pale yellow solid. MS (ISN) 258.1 [(M−H)−]; mp 185-186° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:18][C@H:15]1[CH2:16][CH2:17][C@@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1)(=[O:21])[CH3:20]
Reactant: O=C(NCc1nccnc1Cl)[C@H]1CC[C@@H](O)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To (cis)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (57.4 mmol, 15.47 g) and 4-dimethylaminopyridine (5.74 mmol, 0.701 g) in pyridine (125 ml) at 0° C. was added dropwise acetic anhydride (60.2 mmol, 5.69 ml) and the mixture was stirred at room temperature for one hour. Then the reaction was quenched with 4 N hydrochloric acid to a pH of four and extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was taken up in toluene and concentrated in vacuo again. The residue was dissolved in dichloromethane (100 ml) and washed with 1 M hydrochloric acid (100 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give (cis)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl acetate (16.5 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]([O:21]C)=[O:20])[C:5](=[O:18])[NH:6][C:7]=1[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11].[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[C:5](=[O:18])[NH:6][C:7]=1[C:8]([F:16])([F:17])[C:9]([F:15])([F:14])[C:10]([F:12])([F:13])[F:11]
Reactant: COC(=O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O

Procedure:
1.54 g (4.33 mmol) of methyl 5-chloro-6-(heptafluoropropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 23 ml of methanol, and a solution of 0.16 g (6.5 mmol) of lithium hydroxide in 13 ml of water was added. After two hours of heating under reflux, the methanol was distilled off, and the aqueous solution that remained was washed with dichloromethane. The aqueous phase was then acidified with 2N hydrochloric acid and extracted with dichloromethane. Drying and concentration of the extract gave 1.45 g (98% o of theory) of a brownish powder.
Reaction SMILES: C(OC([N:8]([C:23]1[CH:35]=[CH:34][C:26]([C:27](N2C=CN=C2)=[O:28])=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O)(C)(C)C.[OH-].[Na+].[NH2:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42]>C(Cl)(Cl)Cl>[CH:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:23]2[CH:35]=[CH:34][C:26]([C:27]([NH:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCC1CCCCC1)c1ccc(C(=O)n2ccnc2)cc1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-(t-butyloxycarbonyl)-N-(8-cyclohexyloctyl)amino]benzoyl}imidazole, 50 ml. of chloroform and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.[Cu]Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[N:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cncc(Br)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)C#Cc1cncc(Br)c1

Procedure:
3-Bromo-5-trimethylsilanylethynyl-pyridine (1.0 eq, 1.22 g, 4.78 mmol), pivaloyl chloride (1.1. eq, 0.647 ml, 5.26 mmol) and copper(I) chloride (0.2 eq, 95 mg, 0.96 mmol) are dissolved in DMF (8 ml). The resulting mixture is heated using microwave radiation at 120° C. for 30 min. The mixture is filtered and washed with EtOAc. The filtrate is concentrated in vacuo and partitioned between sat. aqueous NaHCO3 solution and EtOAc. The organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title compound; [M+H]+=266/268.
Reaction SMILES: Br[CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[C:14]([NH2:17])(=[S:16])[CH3:15].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:2]2[S:16][C:14]([CH3:15])=[N:17][C:3]=2[CH3:4])=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Reactant: CC(N)=S
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(C)c(-c2ccc(C#N)cc2)s1
Temperature: 100 °C

Procedure:
A solution of 4-(1-bromo-2-oxopropyl)benzonitrile (0.9 g, 3.83 mmol) in toluene (2 ml) was treated with thioacetamide (0.6 g, 8 mmol) followed by pyridine (0.45 ml). The mixture was warmed to 100° C. for 1 hour, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and evaporated to a yellow oil. Chromatography on silica gel, eluting with 5% ether in dichloromethane, afforded a pale yellow oil which crystallised (0.52 g, 64%), m.p. 108°-110° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:26])[NH:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18]([O:20]CC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:26])[NH:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(NC(=O)NCCCNC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc(C(=O)O)c1
Reaction time: 168 h

Procedure:
2.50 g (6.84 mmol) of ethyl 3-(3-(3-tert-butyloxycarbonylaminopropyl)ureido)benzoate are dissolved in 80 ml of ethanol and treated with 3.42 ml of 2N NaOH. After 7 d at room temperature, the mixture is concentrated in vacuo. The residue is treated with water, and the mixture is acidified with citric acid and extracted with ethyl acetate. After drying (MgSO4), solid is filtered off and the solvent is removed in vacuo.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].C(O)(=O)C.[I:14]Cl>C(Cl)Cl>[I:14][C:8]1[S:7][C:6]([NH2:9])=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: ClI
Reactant: CC(C)c1csc(N)n1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)c1nc(N)sc1I
Reaction time: 0.5 h

Procedure:
The above prepared 4-isopropyl-thiazol-2-ylamine (1.020 g, 7.17 mmol) was dissolved in 14 mL of CH2Cl2 and 2.8 mL of acetic acid and treated at 0° C. with iodine monochloride (7.53 mL of 1M in CH2Cl2, 1.05 eq.) and kept at this temperature for 0.5 h. Pouring onto crashed ice/Na2CO3, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness yielded 1.922 g of the title compound as dark brown viscous oil, sufficiently pure to be used for the next step.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]#[N:13].[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:14]1[C:12]([C:3]2[C:2](=[O:1])[N:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]3=[N:5][CH:4]=2)=[N:13][N:16]=[N:15]1
Reactant: N#Cc1cnc2ccccn2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Yield: 19.1 %

Procedure:
A stirred mixture of 4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carbonitrile (2.17 g., 0.0127 mole), sodium azide (0.911 g., 0.014 mole), and ammonium chloride (0.75 g., 0.014 mole) in N,N-dimethylformamide (20 ml.) was heated by means of an oil bath maintained at 120° for 19 hours. The solvent was removed and the residue treated with hot aqueous sodium bicarbonate. The mixture was filtered. The filtrate was acidified with acetic acid. The precipitate was collected and recrystallized from acetic acid to give the title compound (0.52 g., 19%) m.p. 308°-309° (decomp). Recrystallization from acetic acid with charcoal treatment gave analytical material, m.p. 311°-312° (decomp).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CNC1CCCCC1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O.[Cu]I.C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:11]2[CH:10]=[C:9]3[C:13]([CH:14]=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH:7]=[CH:8]3)=[N:12]2)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cc2cn[nH]c2cc1OCC1CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(COc2ccc(-n3cc4ccc(OCC5CC5)cc4n3)cc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of 6-(cyclopropylmethoxy)-1H-indazole (376 mg), 1-(benzyloxy)-4-bromobenzene (632 mg), copper(I) iodide (38.1 mg), (1RS,2RS)—N,N′-dimethylcyclohexane-1,2-diamine (114 mg), tripotassium phosphate (892 mg) and toluene (2 mL) was stirred under an argon atmosphere at 110° C. overnight. The reaction mixture was diluted with ethyl acetate and water, and filtered through celite. The organic layer separated from the obtained filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a mixture (741 mg) of the title compound and 1-[4-(benzyloxy)phenyl]-6-(cyclopropylmethoxy)-1H-indazole.