Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[C:13]1[N:18]=[CH:17][NH:16][C:15]2=[N:19][CH:20]=[CH:21][C:14]=12>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:13]2[C:14]3[CH:21]=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:6][CH:5]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(COc2ncnc3[nH]ccc23)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
To a 0.375 M solution of aqueous potassium hydroxide (26.2 mL, 9.83 mmol) was added (4-chlorophenyl)methanol (464 mg, 3.26 mmol) and the mixture was heated to 80° C. for 30 min. Then 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (500 mg, 3.26 mmol) was added and the mixture was refluxed at 130° C. After 6 h, additional (4-chlorophenyl)methanol (100. g, 0.701 mmol) was added and the solution was heated to 115° C. overnight. The reaction was cooled to rt and diluted with water. The solution was then extracted with EtOAc (2×) and DCM (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude oil was purified by silica gel chromatography eluting with a gradient of 5 to 30% EtOAc in DCM to afford the product as a white solid (210 mg, 25%). LC/MS: Rt=1.72 min, ES+ 260. (FA standard).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:24][C:25]1[N:30]=[C:29]([O:31][C@H:32]([CH3:37])[C:33]([CH3:36])([OH:35])[CH3:34])[C:28]([I:38])=[CH:27][N:26]=1>C(Cl)Cl>[Cl:24][C:25]1[N:30]=[C:29]([O:31][C@H:32]([CH3:37])[C:33]([CH3:34])([O:35][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH3:36])[C:28]([I:38])=[CH:27][N:26]=1
Reactant: C1=COCCC1
Reactant: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89 %

Procedure:
2.64 ml (29.0 mmol) dihydropyran and 0.36 g (1.5 mmol) pyridinium tosylate were added to a solution of 4.96 g (14.5 mmol) (R)-3-(2-chloro-5-iodo-pyrimidin-4-yloxy)-2-methyl-butan-2-ol in 30 ml DCM and stirred for 22 hours at room temperature. The mixture was diluted with DCM and washed with saturated sodium hydrogencarbonate solution. The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 4:1). 5.50 g (12.9 mmol; yield: 89%) of the mixture of diastereomers was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1C(C)=CC=C[C:38]=1C.CN.O1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:23])[NH:37][CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, a 2.0 M solution of methylamine in tetrahydrofuran (121 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-methylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (28 mg, 28%) as a white solid: ESI-LRMS m/e calculated for C21H27ClN4O4S [M+] 466.1, found 467.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.24 (m, 2H, CH2), 1.43-1.97 (m, 8H, 4×CH2), 2.18-2.29 (m, 1H, CH), 2.78 (d, J=4.9 Hz, 3H, NCH3), 3.27 (s, 3H, SO2CH3), 3.60 (t, J=7.5 Hz, 1H, CH), 4.67 (s, 2H, NCH2), 5.83-5.91 (m, 1H, NH), 6.77 (d, J=2.4 Hz, 1H, Ar), 7.33 (d, J=2.4 Hz, 1H, Ar), 7.49 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.06 (s, 1H, NH), 8.11 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[SH:5])(C)C.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:25](=[O:26])[C@@H:24](OS(C(F)(F)F)(=O)=O)[C@H:23]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:18][CH:17]=1>C1COCC1>[SH:5][C@H:24]1[C:25](=[O:26])[N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C@@H:23]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: CCOC(=O)[C@@H]1[C@H](OS(=O)(=O)C(F)(F)F)C(=O)N1c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1[C@@H](S)C(=O)N1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triisopropylsilane thiol (0.91 mmol) in anhydrous THF (2 ml) was added sodium hydride (0.68 mmol, 60% in mineral oil) and the reaction mixture was stirred at room temperature for 15 min. Afterwards, compound 109 (0.45 mmol, dissolved in 2 ml THF) was added to the reaction and the mixture was stirred at room temperature for 1 h. Then it was concentrated in vacuo, diluted with ethyl acetate and washed with sodium bicarbonate. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated in vacuo. Column chromatography purification (12 g pre-packed silica column, hexane/ethyl acetate) afforded the protected thiol. The thiol (0.126 mmol) was then diluted with anhydrous methanol (2 ml) and ammonium fluoride (0.15 mmol, 0.5 M in methanol) and acetic acid (0.454 mmol) were added to the reaction and the mixture was stirred at room temperature for 2 h. Afterwards, it was concentrated in vacuo and the residual acetic acid was azeotroped with toluene. The solid was diluted with dichloromethane and was filtered through a syringe filter. The solution was concentrated in vacuo to give compound 110 as a clear oil (23% yield for both steps). LS/MS M+H 282.3, calc. 282.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:18][C:17]=3[F:32])=[C:12]([C:33]([F:36])([F:35])[F:34])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[F:32])=[C:12]([C:33]([F:34])([F:35])[F:36])[S:11][N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)OC(C)(C)C)cc2F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (520 mg, 0.99 mmol, 1.00 equiv), CF3COOH (2.0 mL), dichloromethane (8.0 mL). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The solid was washed by EtOAc and hexane. The mixture was filtered and the solid was dried under vacuum. This resulted in 0.37 g (80%) of 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl) propanoic acid as a white solid. 1H-NMR (300 Hz, CD3OD): δ 7.67 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 6.86 (d, J=9.6 Hz, 2H), 5.21 (s, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.74 (q, J1=7.5 Hz, J2=15.2 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.30 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H18F5NO3S, 472.1 (M+H). found 472.1.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>CN(C)C=O>[N:21]1([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]2=3)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Add 4.0 gm of methyl 6,11-dihydro-11-chlordibenz[b,e]oxepin-2-carboxylate to a 78° C. solution of 2.0 gm of imidazole in 15 ml of dimethylformamide. Stir under a nitrogen atmosphere for 1 hour. Cool to room temperature and pour into 25 ml of water. Extract twice with 125 ml of ether. Wash the combined ether extracts twice with 50 ml of water and with 25 ml of saturated aqueous sodium chloride. Dry over anhydrous sodium sulfate and evaporate to dryness to obtain the title product (Yield 3.12 gm).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=O)=[N:4][N:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:9])=[N:4][N:3]=1
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: NC1CC1
Solvent: CO
Product: Nc1nnc(C(=O)NC2CC2)s1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
To a suspension of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (2 g, 11.55 mmol) in methanol (15 mL) was added cyclopropylamine (1.5 mL, 21.65 mmol). The mixture was stirred at room temperature for 1 h and at 40° C. for 1.5 h. Additional cyclopropylamine (2 mL) was added. After 3 h at 40° C., 1 h at 50° C. and 20 min at 70° C., the mixture was concentrated to half the volume, diluted with water (2.5 mL), heated to boil to give a clear solution and cooled to room temperature. The solid was filtered, washed with cold methanol, and dried to give 5-amino-N-cyclopropyl-1,3,4-thiadiazole-2-carboxamide as yellow crystals (1.52 g, 72% yield). MS (ES+) m/z: 185 (M+H); LC retention time: 0.87 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17]>>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=1[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17]
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCCC(=O)c1c(C)cc(C)c(C)c1O

Procedure:
2,3,5-Trimethylphenol (formula VII wherein R=H3C, X=H, Y=OH)(0.9 part,) aluminum chloride (2.1 parts) and ethyl 6-chloroformylhexanoate (1.3 part) were treated as in Example 1 (1). The procedure provided colorless needles of ethyl 6-(2'-hydroxy-3', 4', 6'-trimethylbenzoyl)hexanoate (formula II-1 wherein R=H3C, X=H, Y=OH, n=5, in the form of ethyl ester) (1.5 part) melting at 47°-48° C.
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1.C1(C)C=CC(S([C:30]#[N:31])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:30]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1)#[N:31]
Reactant: CSc1nc(I)n2ccsc12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc(C#N)n2ccsc12
Temperature: -5 °C
Yield: 49.1 %

Procedure:
A 1 M ethylmagnesium bromide/THF solution (2.0 ml) was added in an argon atmosphere at −40° C. to a solution of 405 mg of 5-iodo-7-methylthioimidazo[5,1-b]thiazole in 12 ml of dry THF. The mixture was stirred at the same temperature for 30 min. p-Toluenesulfonyl cyanide (372 mg) was added thereto. The temperature of the system was raised to −5° C. over a period of one hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate:hexane=3:1:1) to give 131 mg of 5-cyano-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([O:23]C)[CH:14]=3)[O:10][N:9]=2)=[C:6]([CH3:25])[C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([OH:23])[C:16]([OH:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=3)[O:10][N:9]=2)=[C:6]([CH3:25])[C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1
Reactant: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1nc(Cl)c(-c2noc(-c3cc(O)c(O)c([N+](=O)[O-])c3)n2)c(C)c1Cl
Temperature: 60 °C
Yield: 81.1 %

Procedure:
To an ice-cooled solution of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol (2.40 g, 5.84 mmol) in NMP (19 mL) was added aluminium chloride (0.977 g, 7.33 mmol) followed by addition of pyridine (1.93 mL). The reaction mixture was heated to 60° C. for 1 hour. It was cooled to room temperature and poured into 2 N HCl-solution (ca. 40 mL). The precipitate was filtered off, washed with water and dried under vacuum. Recrystallization from acetic acid yielded 1.88 g (81%) of 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]=[C:12]=[S:13])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)Oc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol), in 150 mL of CHCl3 was added dropwise thiophosgene (2.81 mL, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 mL, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 mL of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate. The crude 3-isopropoxyphenyl isothiocyanate was dissolved in 150 mL of acetic acid, and anthranilic acid (6.04 g, 44 mmol) was added. The resulting reaction mixture was refluxed for 16 hours and then cooled to room temperature. The white solid was separated which was filtered to yield 9.0 g of the title compound (72.1%), mp 288°-290° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c2ccccc12
Temperature: 80 °C
Yield: 96 %

Procedure:
To a stirred solution of methyl 4-methyl-1-naphthoate (22.5 g, 0.112 mol) in CCl4 (500 mL) was added NBS (22 g, 0.123 mol) and benzoylperoxide (10% w/w). The reaction mixture was allowed to reflux at 80° C. for 7 h. The reaction mixture was cooled to rt and filtered off. The solid and concentrated under vacuum and the obtained crude product (30 g) was used for further reaction.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:15][O:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCc1c(O)cccc1C(=O)OC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCc1c(OC)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To methyl 3-hydroxy-2-prop-2-en-1-ylbenzoate (10.3 g, 53.6 mmol, M. A. Eissenstat et al., J. Med. Chem. 1995, 38, 3094-3105) and cesium carbonate (26.2 g, 80.4 mmol) in DMF (100 ml) was added methyl iodide (15.2 g, 102.2 mmol). The reaction mixture was stirred at room temperature for 18 h, then filtered and concentrated. The residue was partitioned between ethyl acetate (250 mL) and water (100 mL). The layers were separated, the organic layer was washed with 5% lithium chloride (2×100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to provide methyl 3-(methyloxy)-2-prop-2-en-1-ylbenzoate (10.3 g, 93% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.41 (m, 1H), 7.24 (m, 1H), 7.02 (m, 1H), 6.97 (m, 1H), 4.97 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.73 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Yield: 67.1 %

Procedure:
A solution of [(S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (292 mg, 0.82 mmol) in TFA (4 mL) and DCM (12 mL) was stirred for 1 h at RT. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford the title compound as a pale yellow oil (141 mg, 67%). Marfey's test: 76% de. LCMS (Method C): RT 1.34 min [M+H]+ 257. 1H NMR (CDCl3, 400 MHz): δ 8.80 (1H, dd, J=5.0, 1.5 Hz), 8.73-8.72 (1H, m), 7.81 (1H, ddd, J=8.0, 2.5, 1.5 Hz), 7.71 (1H, ddd, J=9.0, 4.5, 0.5 Hz), 7.56 (1H, ddd, J=8.0, 5.0, 1.0 Hz), 7.04 (1H, ddd, J=9.5, 9.0, 2.5 Hz), 6.75 (1H, ddd, J=8.5, 2.5, 0.5 Hz), 4.08 (1H, q, 6.5 Hz), 1.87 (2H, bs), 1.48 (3H, d, J=6.5 Hz).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CS(C)=O>[N:32]([C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N=[N+]=[N-])n2Cc1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.28 g, 0.4 mmol, intermediate 14) in DMSO (10 mL) was added sodium azide (65 mg, 1 mmol). The reaction was heated at 65° C. for 2.5 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.800 min; LCMS MH+-THP 390.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[CH:20][N:19]=1>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[N:19][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1cncc2ccccc12
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Product: FC(F)(F)c1ccc(-c2cc(Oc3cncc4ccccc34)ncn2)cc1

Procedure:
The title compound was prepared from 4-fluoro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 169(a) and isoquinolin-4-ol (MonomerChem) analogous to the conditions described in Example 169(b). Mp: 206-211° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) were added tert-butyl (3S)-3-(aminooxy)pyrrolidine-1-carboxylate 7 (0.164 g, 0.814 mmol, WO 2008/67481 A1), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 8 (0.22 g, 88%) as a white foam.
Reaction SMILES: Br[CH:2]([S:4]([O-:7])(=[O:6])=[O:5])[CH3:3].[Na+].[CH2:9]([CH2:11][NH2:12])[OH:10]>O.C(O)C>[OH:10][CH2:9][CH2:11][NH:12][CH2:3][CH2:2][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: NCCO
Reactant: CC(Br)S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCNCCO
Reaction time: 17.5 h

Procedure:
A solution in 2 liters of water of 315 g of sodium bromoethanesulphonate (Organic Synthesis, Coll. Vol. II, p. 558) and 450 g of ethanolamine was heated to 60°-70° C. for 30 minutes. Excess ethanolamine and water were then distilled off under vacuum, and the residue dissolved in 250-270 ml of water. 2.2 Liters of concentrated hydrochloric acid was added and the solution kept in a refrigerator for 15-20 hours. The precipitated sodium chloride was filtered off using a filter pump, and the solution concentrated until a viscous oil was obtained. The oil was diluted with 60 ml of water and ethanol (about 500 ml) then added to precipitate the reaction product. After the mixture has been left one night in a refrigerator, precipitation was almost complete. The product obtained was filtered off with a filter pump. About 130-140 g of crystalline product was obtained, having a melting point of 180°-183° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[N:10][C:11]([Br:15])=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].[H-].[Na+].[CH2:26](Br)[CH3:27]>>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:9]2=[N:10][C:11]([Br:15])=[C:12]([O:14][CH2:26][CH3:27])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCBr
Reactant: CCOC(=O)c1cc2cc(O)c(Br)nc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2cc(OCC)c(Br)nc2n1C(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 1, intermediate d) from 6-bromo-5-hydroxy-pyrrolo [2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester, sodium hydride and ethyl bromide.