Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](OCC)(OCC)OCC.[N-:23]=[N+:24]=[N-:25].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH:13]=[N:25][N:24]=[N:23]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(-n2cnnn2)ccc1C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Combine methyl 2-methyl-5-aminobenzoate (4.5 g, 27.2 mmol) and triethyl orthoformate (16.2 g, 109 mmol) in glacial acetic acid (25 mL). After 12 hours, add portionwise sodium azide (7.08 g, 109 mmol). Heat to 70° C. After 2 hours, cool the reaction mixture to ambient temperature, dilute with water (250 mL). Collect the solid by filtration, rinse with water, and dry to give methyl 2-methyl-5-(1H-tetrazol-1-yl)benzoate: Rf=0.13 (silica gel, ethyl acetate/hexane 1/4).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH3:32]>>[ClH:1].[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1)[CH3:32]
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CCl)cc2)C1
Reactant: CNCCOC
Product: COCCN(C)Cc1ccc(SC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Product: Cl

Procedure:
Using a similar protocol as described in Example 60 employing 60B (0.16 g, 0.41 mmol) and 2-methoxy-N-methylethanamine (0.037 g, 0.41 mmol) as starting materials afforded the desired compound in neutral form as a gum. The residue was then dissolved in MeOH (2 ml) whereupon HCl in MeOH (1.25 M, 2 ml) was added. After a little while, it was evaporated to dryness. The residue was triturated with MeOH/diethyl ether. There was obtained 0.16 g (80%) of 61 as a solid. 1H NMR (500 MHz, DMSO-d6): δ 2.64 (s, 3H), 3.15 (m, 1H), 3.23 (m, 1H), 3.27 (s, 3H), 3.73 (m, 2H), 3.98 (m, 1H), 4.25 (dd, 1H), 4.34 (dd, 1H), 4.47 (m, 2H), 4.68 (m, 1H), 5.15 (m, 1H), 7.35 (d, 2H), 7.5-7.7 (m, 5H), 8.04 (d, 2H), 11.0 (m, 1H), MS (APCI+) m/z 439 [M+H]+, LC purity: 88%.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][C:16]([P:19]([O:22][P:23]([OH:30])(NP(O)(O)=O)=[O:24])([OH:21])=[O:20])([F:18])[F:17])[CH2:12][CH2:11]2)[CH:3]=1.[O-:31][P:32](OP([O-])([O-])=O)(=[O:34])[O-:33].C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.[O-:92]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].P(=O)([O-])OC1NC=CN=1>>[CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][C:16]([P:19]([O:22][P:23]([O:30][P:32]([OH:34])([OH:33])=[O:31])([OH:24])=[O:92])([OH:21])=[O:20])([F:17])[F:18])[CH2:12][CH2:11]2)[CH:3]=1
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Reactant: Cc1cn([C@H]2CC[C@@H](CC(F)(F)P(=O)(O)OP(=O)(O)NP(=O)(O)O)O2)c(=O)[nH]c1=O
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=[PH]([O-])Oc1ncc[nH]1
Product: Cc1cn([C@H]2CC[C@@H](CC(F)(F)P(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O

Procedure:
Following the procedure for the compound 63, starting from 102 mg (0.19 mmol) of the product 61 from Step C, using tri(n-butyl)ammonium pyrophosphate (246 mg), after 18 h (25% of the target triphosphate in mixture with 41% of the imidazolyl phosphonate intermediate as judged by LCMS) 12 mg of the titled compound 64 was isolated.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29]S[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O[O:32][S:33]([O-:35])=O.[K+]>C1COCC1.CO.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][S:33](=[O:35])(=[O:32])[CH2:29][CH2:30]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCSCC3)cs2)c1-c1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCS(=O)(=O)CC3)cs2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a mixed solution of 4-({2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetyl)thiomorpholine (100 mg, 0.22 mmol) in THF (2 mL), MeOH (2 mL) and water (2 mL) was added Oxone (290 mg, 0.47 mmol) at 0° C., and the mixture was stirred at 0° C. for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (82 mg, 0.172 mmol, 76%) as a white powder.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][N:11]=2)[N:6]=1.[ClH:20].N([O-])=O.[Na+].NC(N)=O>C(O)(=O)C.O>[Cl:20][C:2]1[S:3][C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][N:11]=2)[N:6]=1
Reactant: COCCn1ccnc1-c1nc(N)sc1C(=O)OC
Reactant: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCn1ccnc1-c1nc(Cl)sc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methyl 2-amino-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate (Intermediate 55; 0.55 g, 2.2 mmol) was suspended in glacial acetic acid (20 ml) and concentrated HCl (30 ml). The solution was cooled to 0° C. and a solution of sodium nitrite in water (15 ml) was added dropwise. After stirring at 0° C. for 10 min, the reaction was slowly warmed to room temperature and stirred for 1 hour. The reaction was followed by LCMS and once complete, a solution of urea (0.25 g) in water (10 ml) was added dropwise. After stirring at room temperature for 30 min, solvent was removed under reduced pressure. The residue was partitioned with sat. NaHCO3 (aq) and EtOAc. Extraction with EtOAc (×3), drying with MgSO4 and concentrating yielded an orange oil which was used without purification (0.20 g). MS (ES) (M+H)+: 302 for C11H12ClN3O3S; NMR: 3.34 (s, 3H), 3.62 (m, 2H), 3.81 (s, 3H), 4.22 (m, 2H), 7.24 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].O>C(OCC)(=O)C.[Cu]I.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>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:20])[CH3:19]
Reactant: Brc1cccnc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccnc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A flask was charged with 3-bromopyridine (1.22 mL, 12.66 mmol) and triethylamine (40 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (1.97 mL, 13.92 mmol) and the reaction purged 15 min longer. To this was added copper(I) iodide (0.121 g, 0.633 mmol), and Pd(PPh3)2Cl2 (0.444 g, 0.633 mmol). The reaction was stirred at room temperature for 72 h. The reaction was diluted with ethyl acetate (60 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->15% EtOAc/Hex) gave 1.70 g (77%) as a dark oil. 1H-NMR (CDCl3, 500 MHz) δ 8.71 (m, 1H), 8.55 (dd, J=4.9, 1.5, 1H), 7.76 (ddd, J=7.9, 1.8, 1.8, 1H), 7.26 (ddd, J=7.9, 4.9, 0.6, 1H), 0.29 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 152.8, 148.8, 138.9, 123.0, 120.4, 101.6, 98.3, −0.1. Mass spec.: 176.14 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:12]=1)=[O:10]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccc(C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
1.65 g (11.9 mmol) of potassium carbonate are added at 25° C. under an argon atmosphere to 0.9 g (4.75 mmol) of 3-methoxycarbonyl-5-methyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 25° C. for 0.5 hour, 0.623 cm3 (4.75 mmol) of 4-chloroquinoline is added. After stirring at 100° C. for 48 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and then washed with 3 times 50 cm3 of water and 25 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.4 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume)]. After concentrating the fractions under reduced pressure, 1.2 g of 3-methoxycarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a white solid melting at 168° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][CH2:6]2)[O:4]CC1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.[H-].[Na+]>CN(C=O)C>[N:16]1([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(n2cncn2)CC1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A solution of methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (567 mg, 2.40 mmol) and 1,2,4-triazole (232 mg, 3.36 mmol) in dry DMF (5.00 mL) was treated with sodium hydride 60% (125 mg, 3.12 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 65° C. for 72 h. It was poured in ice water (75 mL), extracted 3 portions of 75 mL of EtOAc. The organic portions were combined, dried over anhydrous Na2SO4 and concentrated. The solid was purified by silica gel column chromatography using a gradient from 100% EtOAc to 5% MeOH:EtOAc as eluent to furnished the final compound I-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,4]triazole as a white solid (247 mg, 49%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([CH2:15][NH2:16])[OH:14]>C1COCC1.CC(=O)OCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH2:15][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: NCCO
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(=O)(=O)NCCO)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 112.3 %

Procedure:
To a solution of 4-cyano-benzenesulfonyl chloride (1.00 g, 4.96 mmol) in THF, ethanolamine (454 mg, 7.44 mmol) is added. The mixture becomes slightly warm (30° C.) and turbid. The mixture is stirred at rt for 3 h before it is diluted with EA, washed with sat. aq. NH4Cl solution and water, dried over MgSO4, filtered and concentrated to give crude 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.26 g) as a white solid; LC-MS: tR=0.34 min, [M+1+CH3CN]+=268.13. b) A mixture of 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.25 g, 5.56 mmol), hydroxylamine hydrochloride (773 mg, 11.1 mmol) and NaHCO3 (934 mg, 11.1 mmol) in methanol is stirred at 60° C. for 7 h. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in EA (250 mL) and washed with water (5 mL). The organic extract is dried over MgSO4, filtered, concentrated and dried to give the title compound (720 mg) as a white solid; LC-MS: tR=0.23 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[CH:29]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:29]([CH:25]3[CH2:26][CH2:27][CH2:28][O:24]3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: O=CC1CCCO1
Product: Nc1cc(Br)cc2nc(C3CCCO3)nn12

Procedure:
The title compound, MS m/e (%): 283 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and tetrahydro-furan-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([Cl:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:4]1[CH:3]=[C:2]([CH3:26])[CH:7]=[CH:6][C:5]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Temperature: 100 °C
Yield: 16.3 %

Procedure:
To a degassed solution of 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.4 g, 0.92 mmol, see Ex. #3 step D) in 1,4-dioxane (10 mL) was added potassium carbonate (0.4 g, 2.9 mmol), trimethylboroxine (0.200 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.18 mmol). The resulting mixture was heated, in a sealed microwave vessel, for about 1 h at about 100° C. in a microwave. After cooling to rt, the mixture was concentrated in vacuo. The residue was treated with water (25 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1) to give 4-(2-chloro-4-methyl-phenyl)-1-methyl-3-(2 pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.055 g, 0.15 mmol, 60%) as an off white solid: LC-MS (Table 1, Method e) Rt=8.02 min; m/z 371 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.27 (3 H, s) 2.72 (1 H, ddd, J=15.0, 6.0, 2.5 Hz) 2.86 (1 H, ddd, J=15.0, 9.0, 2.5 Hz) 3.22-3.29 (1 H, m) 3.54-3.63 (1 H, m) 3.80 (1 H, br s) 3.84 (3 H, s) 6.75 (1 H, s) 6.89 (1 H, br.d, J=7.5 Hz) 7.07 (1 H, ddd, J=7.5, 5.0, 1.0 Hz) 7.16 (1 H, d, J=8.0 Hz) 7.22 (1 H, br.d, J=1.0 Hz) 7.58 (1H, td, J=7.5, 2.0 Hz) 7.70 (1 H, dt, J=8.0, 1.0 Hz) 8.53 (1 H, ddd, J=5.0, 2.0, 1.0 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[O:2].[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:68](O)[CH2:69][OH:70]>C(OCC)(OCC)OCC.C(OCC)(=O)C.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[O:2]1[CH2:68][CH2:69][O:70][CH:1]1[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-formylphenyl)acetate (1.72 g, 9.66 mmol) was dissolved in ethylene glycol (2.3 mL) and triethyl orthoformate (1.8 mL). Tetrabutylammonium tribromide (0.048 g) added and the reaction stirred at RT for 1 hour. Further tetrabutylammonium tribromide (0.434 g) added and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0-15% ethyl acetate in iso-hexane to afford impure methyl 2-(4-(1,3-dioxolan-2-yl)phenyl)acetate (0.84 g). This material was dissolved in THF (15 mL) and cooled to −78° C. A solution of lithium aluminium hydride (1.0 M in THF, 6.00 mL, 6.00 mmol) was added drop-wise. The reaction mixture was allowed to warm to RT over 18 hours. The mixture was sequentially treated with water (0.228 mL), 2M aqueous sodium hydroxide (0.228 mL) and water (3×0.228 mL). The mixture was diluted with ethyl acetate and magnesium sulfate added. The mixture was stirred at RT for 1 hour and then filtered through celite. The filter cake was washed with further ethyl acetate and the filtrates combined. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (0.315 g, 17%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Br[CH2:42][CH:43]1[CH2:46][CH2:45][CH2:44]1>C(#N)C>[CH:43]1([CH2:42][N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=2)[S:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:28])=[CH:14][CH:13]=2)(=[O:17])=[O:16])[CH2:46][CH2:45][CH2:44]1
Reactant: BrCC1CCC1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC2CCC2)c2ccc(C(C)C)cn2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (150 mg, 0.374 mmol) in acetonitrile (4 mL) stirred in air at 20° C., was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (128 mg, 0.747 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then (bromomethyl)cyclobutane (0.084 ml, 0.747 mmol) was added. The reaction was heated by microwaves to 150° C. for 30 minutes. After cooling the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with water (5 mL) and dried using a hydrophobic frit. The solvent was removed in vacuo to give the crude product as an orange oil. The crude product was purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product (42 mg) as a colourless oil. LCMS (2 min, High pH) Rt 1.48 mins, m/z (ES+) 470, (M+H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:20])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[CH2:15][O:16][CH2:17][CH3:18])=[CH:8][CH:7]=1.[C:21]1([CH3:32])[CH:26]=[CH:25][C:24]([S:27]([O:30]C)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[CH3:33]COCC>C(Cl)Cl>[C:21]1([CH3:32])[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:17]([O:16][CH2:15][CH:14]([OH:19])[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:4]([CH2:3][S+:2]([CH3:33])[CH3:1])=[O:20])=[CH:11][CH:10]=1)[CH3:18]
Reactant: CCOCC(O)COc1ccc(NC(=O)CSC)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCOCC
Solvent: ClCCl
Product: CCOCC(O)COc1ccc(NC(=O)C[S+](C)C)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
Dissolved in 20 ml of methylene chloride was 2.99 g of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethyl methyl sulfide. To the solution was added 5.50 g of methyl p-toluenesulfonate. The mixture was stirred at room temperature for 24 hours and ether was added to the reaction mixture. The insoluble solid was filtered off and recrystallized from methylene chloride-ether, giving 4.75 g of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethyldimethylsulfonium p-toluenesulfonate (Compound 1) in 97.7% yield, M.P. 139° to 141° C.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:21]1[N:25]2[N:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[N:29][C:24]2=[N:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1([C:10]2[CH:9]=[C:8]([C:21]3[N:25]4[N:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[N:29][C:24]4=[N:23][CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC1(C)COB(c2cccc(-n3cncn3)c2)OC1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cnn2c(-c3cccc(-n4cncn4)c3)cnc2n1
Yield: 54.7 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 1-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-1H-[1,2,4]triazole (192 mg, 0.75 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.1 g, 0.375 mmol), 2 M Na2CO3 (0.75 ml) and tetrakis(triphenylphosphine)palladium(0) (0.022 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and triturated with Et2O to yield the title compound (68 mg, 55%): 1H NMR (360 MHz, CDCl3) δ 7.72 (1H, t, J 7.8 Hz), 7.76-7.80 (1H, m), 8.09-8.13 (1H, dt, J 7.8, 1.3 Hz), 8.17 (1H, s), 8.57 (1H, t, J 1.9 Hz), 8.67 (1H, s), 8.71 (1H, s), 8.87 (1H, s); MS (ES+) m/z 332 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([O:16][CH3:26])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1
Reactant: O=C(O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Yield: 31 %

Procedure:
To a solution of Example 26 (15 mg, 0.05 mmol) in MeOH (10 mL) was added thionyl chloride (1 mL) at rt. The reaction was stirred at reflux for 2 days. The solution was concentrated and purified by prep-HPLC to give 5 mg (31%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 0.70-0.73 (2H, m), 1.0-1.04 (2H, m), 2.0-2.04 (1H, m), 3.96 (2H, s), 4.74 (3H, s), 7.08 (1H, d, J=1.6 Hz), 7.14 (1H, dd, J=2.0, 8.4 Hz), 7.25 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=4.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.13 (1H, s). [M+H] Calc'd for C17H17ClN2O2, 317. Found, 317.