Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:20])[C@H:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH2:8])[CH3:4].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:20])[C@H:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1cnc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](Cc1cnc2ccccc2c1)NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a mixture of 0.637 g (2 mmol) of 3-(3-quinolyl)alanine ethyl ester dihydrochloride, 0.35 g (2 mmol) of N-(tert-butoxycarbonyl)glycine, 0.56 mL (4 mmol) of triethylamine and 16 mL of chloroform was added at 0° C., in one portion, 0.42 g (2 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred overnight and the precipitate which formed was removed by filtration. The filtrate was washed twice with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, using first 1:1 methylene chloride/ethyl acetate and then 1:3 methylene chloride/ethyl acetate as eluents, to give 0.73 g (9.9%) of the title compound as a colorless oil. TLC Rf =0.52 (ethyl acetate); NMR (CDCl3) δ 8.64 (1H, d), 7.9-8.1 (2H, m), 7.9-7.4 (4H, m), 7.1 (1H, bd), 5.46 (1H, bt), 4.9 (1H, m), 4.15 (2H, q), 3.8 (2H, bd), 3.3 (2H, m), 1.37 (9H, s) 1.2 (3H, t). The product has the formula: ##STR115##
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[NH:15][C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OCc2ccccc2)c2cc(OCCCl)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a suspension of NaH (0.959 mmol, 0.038 g, 60% in mineral oil, rinsed twice with hexanes) in 5 mL of DMF at 0° C. under N2 was added a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 3.73 mL of DMF. The ice bath was removed and the solution was stirred for 2 hours at room temperature. Benzyl bromide (0.959 mmol, 0.114 mL, Aldrich) was added dropwise via syringe and the solution was stirred for 19 hours. Water (10 mL) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off, the filtrate was extracted with ethyl acetate (3×10 mL), and the extracts were washed with brine (1×10 mL), dried over MgSO4, and concentrated. The residue was combined with the solid and purified by silica gel flash column chromatography (10-20% ethyl acetate/hexanes) to give an off-white solid (0.236 g, 62%): 1HNMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H, ArCH3),3.86-3.89 (m, 2H, CH2Cl), 4.09-4.12 (m, 2H, CH2OAr), 5.30 (s, 2H, CO2CH2Ph), 5.46 (s, 2H, NCH2Ph), 6.78 (dm, J=8.79 Hz, 1H, ArH), 6.96 (d, J=7.33 Hz, 2H, ArH), 7.18-7.30 (m, 3H, ArH), 7.32-7.40 (m, 4H, ArH), 7.44-7.49 (m, 3H, ArH); MS(APCI+): m/z 434.1 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (624 mg, 1.5 mmol; prepared as shown in Scheme 2, and according to US 2004/0254215 A1, 1H NMR (CDCl3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08 to 7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H)), CuCN (271 mg, 3 mmol) and dimethylformamide (6 mL) was refluxed with stirring under nitrogen for 15 min. After cooling to ambient temperature the mixture was diluted with ethyl acetate (100 mL). The resulting suspension was filtered through a pad of celite. The filtrate was washed with water (2×250 mL), and dried over MgSO4 before silica gel was added. Subsequently, the mixture was concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with dichloromethane gave the title compound as a white solid (313 mg); MS-(−)-ion: M−1=361.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH:9]=2)=[N:6][CH:7]=1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C>[Si:19]([O:14][CH:10]1[CH2:11][CH2:12][CH2:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:9]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cnc(C2=CC(O)CCC2)cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1C=C(c2cnc(N)cn2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-(5-aminopyrazin-2-yl)cyclohex-2-enol (149 mg, 0.779 mmol) in DMF (5.5 mL) at 0° C. were added tert-butylchlorodimethylsilane (294 mg, 1.95 mmol)) and 1H-imidazole (212 mg, 3.12 mmol). The reaction mixture was stirred at room temperature overnight. After quenched with sat NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layers were dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was purified with flash chromatography eluting with 0-100% of EtOAc/heptane to provide 238 mg of crude product which was used as it was. LCMS (m/z): 306.9 (MH+), 1.04 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCO)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(SCCCCl)cc1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
To a stirred suspension of 5.62 g (0.025 mole) of 3-(4'-acetamidophenylthio)propanol in 25 ml of methylene chloride and 2.03 ml of pyridine (0.025 mole) is added 3.7 g of thionyl chloride (0.031 mole) in 10 ml of methylene chloride. After the exothermic reaction subsides, the mixture is heated at reflux for 0.5 hr. The reaction mixture is poured into 100 ml of ice-water with stirring. The organic layer is separated, dried and concentrated to a dark red solid. Extraction of the latter with ether in a Soxlet apparatus yields 3.5 g of 3-(p-acetamidophenylthio)propyl chloride having the correct IR and NMR spectra.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([Mg]Br)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[CH:15][CH:14]=1>O1CCCC1>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([OH:23])([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:18](=[O:22])[NH:19]2)=[CH:15][CH:14]=1
Reactant: CC(C)c1ccc([Mg]Br)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: -25 °C
Reaction time: 3 h

Procedure:
A solution of 4-isopropyl-phenyl magnesium bromide in tetrahydrofuran (0.5 M, 3.3 mL, 1.65 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.2 g, 1.1 mmol) in tetrahydrofuran (5 mL) with cooling in a −25° C. bath. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 3 hours, 15% aqueous ammonium chloride solution was added and mixture extracted with ethyl acetate. The combined organic layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one as a pale yellow solid. This was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:15][C:11]=2[C:10]=1[CH2:23][CH2:24][CH3:25])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:22]=[CH:21][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:15][C:11]=2[C:10]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1c(OCc2ccccc2)ccc2cc(C(=O)OCC)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2cc(C(=O)OCC)oc12

Procedure:
The ester product of step (d) was dissolved in ethyl acetate and reduced under hydrogen with palladium/charcoal catalyst until uptake of hydrogen was complete. The solution was filtered and evaporated to leave ethyl 6-hydroxy-7-propylbenzofuran-2-carboxylate (2.8 g) as a pink solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[NH:12][N:11]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(N(CC)CC)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[O:21])=[CH:16][CH:17]=2)[NH:12][N:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (208 mg, 0.7 mmol) in dry dimethylformamide (6 mL) was added 4-aminophenol (82 mg, 0.7 mmol) followed by HATU (312 mg, 0.8 mmol) and then triethylamine (20 drops) was added. The reaction was stirred overnight at room temperature. LC/MS showed desired product as major component. The solvent was removed by vacuum. The residue remaining was taken up in water and ethyl acetate. The layers were separated and the organic layer was concentrated under vacuum. The residue was dissolved in methanol (10 mL) and half of this solution was purified by HPLC using a gradient of 5% acetonitrile/water to 55% acetonitrile/water over 60 minutes with 0.1% trifluoroacetic acid in the water. The tide compound was isolated as a solid (20 mg). 1H NMR (methanol-d4) δ 6.87 (2H, d, 8.8 Hz), 7.55 (2H, d, 8.7 Hz), 7.61 (2H, m), 7.87 (2H, br s), 8.00 (1H, d, 8.4 Hz), 8.35 (1H, s), 8.52 (1H, d, 8.6 Hz). MS (APCI pos) 370.1. The starting material was prepared as follows: To 1H-indole-6-carboxylic acid (2.0 g, 12.42 mmol) in water (100 mL) was added NaNO2 (856 g, 124.2 mmol). To this suspension was then slowly added dropwise via addition fuel 6N HCL (16 mL). The resulting slurry was allowed to stir at room temperature overnight The solid precipitate was filtered and washed with water (50 mL) to provide 2.35 g (100%) of 3-formyl-1H-indazole-5-carboxylic acid. 1H NMR (DMSO-d6) δ 14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=8.3 Hz). MS (APCI positive) 205 (methyl ester). To 3-formyl-1H-indazole-6 carboxylic acid (2.35 g, 12.42 mmol) in DMF (60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) and sulfur powder (1.1 eq, 13.66 mmol). This mixture was then heated to reflux for 6 hours. The reaction was followed by TLC and LC-MS. After cooling, water (50 mL) was added to the reaction and the brown precipitate which formed was filtered and collected to provide 3.1 g (90%) of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) δ 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, l=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:31]3[CH:32]=[N:33][C:28]([NH2:27])=[CH:29][CH:30]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: Nc1ccc(B(O)O)cn1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Yield: 90.5 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxa zinan-2-one (1.6 g, 3.84 mmol) and 6-aminopyridin-3-ylboronic acid (1.0 g, 4.61 mmol), Pd(Ph3P)2Cl2 (150 mg), and aq Cs2CO3 solution (3.84 mL, 2 M) in 1,4-dioxane (150 mL) was stirred and heated to reflux for 2 h. The mixture was filtered and the filtrate was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.5 g, 90%), which was used for the next step without purification. 1H NMR (CDCl3): δ=1.51 (d, 3H), 2.17-2.31 (m, 3H), 2.54-2.60 (m, 2H), 2.90 (m, 1H), 4.46 (s, 2H), 4.99-5.09 (m, 2H), 5.65-5.71 (m, 2H), 6.54 (m, 2H), 6.88 (d, 2H), 7.03 (t, 2H), 7.21-7.27 (m, 3H), 7.58 (d, 1H), 8.22 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:6]([NH2:8])=[NH:7].C(ON=[CH:17][C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1)C>CO>[C:6]([C:5]1[CH:9]=[CH:10][C:11]2[NH:12][C:17]([C:18]3[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=3)=[N:2][C:3]=2[CH:4]=1)(=[NH:8])[NH2:7]
Reactant: CCON=Cc1cc(C(=O)OC)ccn1
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccnc(-c2nc3cc(C(=N)N)ccc3[nH]2)c1
Yield: 82.3 %

Procedure:
A mixture comprising 3,4-diaminobenzamidine hydrochloride (1.16 g, 6.2 mmol), methyl 2-(C-ethoxyiminomethyl)pyridine-4-carboxylate (1.8 g, 7.4 mmol) and anhydrous methanol (6 mL) was stirred for 20 hours. The mixture was concentrated and the residue was trituated with hot methanol (5 mL). The solid was isolated and dried to provide methyl 2-(5-amidino-1H-benzimidazol-2-yl)pyridine-4-carboxylate (1.8 g, 5.1 mmol); Calculated for C15H13N5O2 : 295.3, Found (MH+): 295.7.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Solvent: CCO
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.8 %

Procedure:
72.15 g (0.3 mol) of 2-(4-chlorophenoxy-methyl)-2-tert.-butyl-oxirane and 24.15 g (0.35 mol) of 1,2,4-triazole were heated under refulx in 120 ml of ethanol for 48 hours. The mixture was then concentrated, and the residue was taken up in 200 ml of ethyl acetate and the solution heated. The solution was thereafter cooled in an ice bath, and the solid material was filtered off under suction and was washed with ethyl acetate. The filtrate was concentrated and the residue was dissolved in ether/hexane, and the solution was treated with gaseous hydrogen chloride. The precipitate was filtered off under suction and washed with ether, and the free base was obtained by the addition of ethyl acetate/1 N sodium hydroxide solution. 60.2 g (65% of theory) of 2-(4-chlorophenoxy-methyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 84°-87° C. were obtained.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][N:24]([C:60](=[O:62])[CH3:61])[CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Reaction time: 0.5 h

Procedure:
(1H-Indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine hydrochloride (60 mg, 0.137 mmol), HATU (63 mg, 0.164 mmol) and Hunigs base (100 μL, 0.576 mmol) were combined in DMF (4 mL) and stirred for 30 min. Acetic acid (8 μL, 0.168 mmol) was added and the solution was stirred overnight. Another portion of acetic acid (8 μL, 0.168 mmol) was added and the stirred for a further 4 h. The DMF was removed in vacuo and the residue was loaded onto silica. Purification on silica by elution with dichloromethane:methanol (95:5) yielded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.03 & 2.07 (2s, rotamers, 3H), 2.44 & 2.53 (2s, rotamers, 2H), 3.62-3.67 (m, 2H), 4.11 & 4.18 (2s, rotamers, 2H), 6.39 (s, 1H), 6.72 & 6.76 (2s, rotamers, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 8.24 (s, 1H), 8.33 (brs, 1H), 9.35 (brs, 1H), 11.90 (brs, 1H). MS (ES+): m/z 374.5 (100) [MH+].
Reaction SMILES: C(OC([N:6]=[C:7]=[S:8])=O)C.C[O:10][C:11](=[O:20])[CH2:12][CH2:13][C:14]1[S:15][C:16]([NH2:19])=[N:17][N:18]=1>ClCCl>[NH:19]([C:16]1[S:15][C:14]([CH2:13][CH2:12][C:11]([OH:10])=[O:20])=[N:18][N:17]=1)[C:7]([NH2:6])=[S:8]
Reactant: COC(=O)CCc1nnc(N)s1
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: NC(=S)Nc1nnc(CCC(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethoxycarbonyl isothiocyanate (0.656 ml, 5.61 mmol) is added dropwise to a stirred suspension of 3-(5-amino-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester (56a) in dichloromethane (30 ml). The reaction is at room temperature for 18 hours. After removing the solvent, aqueous sodium hydroxide (2M, 10 ml) is added and the stirred mixture is heated at reflux for 3 hours. The solution is allowed to cool to room temperature and brought to pH 3 by the addition of 6M aqueous HCl. The titled compound which precipitates is removed by filtration, washed with ethyl acetate and dried in vacuo.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]1[O:4][CH2:3]1.C(=O)(O)[O-:19].[Na+]>O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]([CH2:3][OH:19])[OH:4]
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCOCC(O)CO
Temperature: 200 °C
Reaction time: 8 h

Procedure:
In an autoclave, 249 of the resulting dodecyl glycidyl ether, 97.2 g of water and 34.8 g of sodium bicarbonate were charged and were stirred at 200° C. for 8 hours. After completion of the reaction, the reaction mixture was dehydrated at 120° C. under reduced pressure (6.67 kPa), followed by purification by distillation under reduced pressure (13 to 26 Pa, 160 to 170° C.), whereby 117 g of monododecyl glyceryl ether was obtained. As a result of gas chromatographic analysis (hereinafter abbreviated as “GLC”), it was found that the resulting product had a purity not less than 99% and the content of a chlorohydrin ether isomer different in alcohol added position and a 2-mole adduct of epichlorohydrin (hereinafter called “organochlorine compounds”, for simplicity) was not greater than 100 ppm.
Reaction SMILES: CS(C1C=CC(C2C=CC3[N:15](N=C(N)N=3)C=2)=CC=1)(=O)=O.Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([NH2:15])=[CH:23][CH:24]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1
Reactant: Brc1ccc(N2CCOCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: Nc1ccc(N2CCOCC2)cc1

Procedure:
N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 2-amino-5-bromopyridine (10.0 g, 0.0578 mol) in a manner analogous to Step 2a. The reaction product was isolated as a yellow solid and used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 12.14 (br s, 1H), 11.72 (br s, 1H), 8.67-8.55 (m, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.13 (dd, J=9.0, 2.5 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H). MS=304, 306 (MH)+. 36b) 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea in a manner analogous to Step 2b. The reaction product was isolated as a white solid (7.84 g, 63%). MP=187-189° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.92 (d, J=1.9 Hz, 1H), 7.55 (dd, J=9.2, 1.9 Hz, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.13 (br s, 2H). MS=213, 215 (MH)+. 36c) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (200.0 mg, 0.9388 mmol) and (4-methylsulfonylphenyl)boronic acid (210.0 mg, 1.050 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.158 g, 58%). MP=301-303° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.08-9.05 (m, 1H), 8.06-7.97 (m, 4H), 7.86 (dd, J=9.2, 1.7 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 6.15 (s, 2H), 3.26 (s, 3H). MS=289 (MH)+. 36d) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 6-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(4-bromo-phenyl)-morpholine (51.0 mg, 0.211 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.011 g, 14%). MP=>300° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.41 (s, 1H), 9.28 (s, 1H), 8.09 (d, J=7.7 Hz, 2H), 8.03-7.96 (m, 3H), 7.64 (d, J=8.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 3.77-3.71 (m, 4H), 3.28 (s, 3H), 3.05-3.00 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([CH2:17][C:18]#[N:19])(=O)[C:12]([CH3:15])([CH3:14])[CH3:13]>CCO.Cl>[C:12]([C:11]1[CH:17]=[C:18]([NH2:19])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 81.5 %

Procedure:
A mixture of commercially available (4-methoxyphenyl)-hydrazine (17.4 g, 0.1 mol) and commercially available pivaloylacetonitrile (13.8 g, 0.11 mol) in EtOH (500 mL) and conc. HCl (50 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to afford 3-t-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (20 g, 82% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.38 (d, J=9.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 5.32 (s, 1H), 4.99 (brs, 2H), 3.75 (s, 3H), 1.17 (s, 9H); MS (ESI) m/z: 246 (M+H+).