Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][OH:10])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl.O>[CH3:11][S:12]([O:10][CH2:9][CH2:8][C:3]1([CH2:1][CH3:2])[O:7][CH2:6][CH2:5][O:4]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(CCO)OCCO1
Solvent: O
Solvent: ClCCl
Product: CCC1(CCOS(C)(=O)=O)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 140.2 %

Procedure:
To a solution of 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 1.59 mmol) and TEA (327 mg, 3.2 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.23 ml, 2.92 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (500 mg, 100%) as yellow oil that was used without purification. Product tlc [DCM/methanol (100:1) developed with potassium permanganate, Rf 0.6]
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[OH:11][C:12]1[C:21]2[C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:17]([CH3:25])([CH3:24])[C:16]=2[CH:15]=[C:14]([CH3:26])[CH:13]=1.[C:27](O)(=[O:29])C.Cl>C(OCC)C.O>[CH:27]([C:13]1[C:14]([CH3:26])=[CH:15][C:16]2[C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][C:20]([CH3:22])([CH3:23])[C:21]=2[C:12]=1[OH:11])=[O:29]
Reactant: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 20 °C

Procedure:
Formylation. Hexamethylenetetramine (21 g, 0.15 mol) and 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene were added in one portion with stirring to acetic acid (250 mL) and the mixture was heated at 95°-100° C. for 2 h. After cooling to 80°-85° C., water (250 mL) and concentrated hydrochloric acid (60 mL) were added and the mixture was heated at 95°-100° C. for a further 2 h. The reaction product was then cooled to 20° C., diethyl ether (150 mL) was added and the mixture was stirred vigorously. The organic layer was separated, washed with brine (2×50 mL), neutralized with 5% sodium bicarbonate solution (100 mL), and dried (Na2SO4). The solvent was removed by distillation and the residue was distilled to yield 2-formyl-1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (4a) (18 g), mp 91°-92° C., GLC purity 99%+. 1H-NMR (CDCl3) δ12.92 (1H, s), 10.21 (1H, s), 6.73 (1H, s), 1.68 (3H, s), 1.67 (4H, s), 1.48 (6H, s), 1.32 (6H, s). 13C-NMR (CDCl3)67194.4 (1C, d), 163.5 (1C, s), 156.5 (1C, s), 138.0 (1C, s), 130.8 (1C, s), 120.1 (1C, d), 116.2 (1C, s), 37.7 (1C, t), 35.3 (1C, s), 34.6 (1C, t), 33.9 (1C, s), 31.0 (2C, q), 27.7 (2C, q), 17.8 (1C, q). IR (KBr) 1615, 1628 cm-1, MS (m/e) 246.2 (M+, 23.9) 231.2 (100.0), 189.1 (19.9), 161.2 (19.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:7]([CH2:19]O)=[CH:6]2.O=S(Cl)[Cl:23]>C(Cl)Cl>[ClH:23].[Cl:23][CH2:19][C:7]1[C:8]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CO)cc2c1
Solvent: ClCCl
Product: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of (6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methanol SLA 41068 (1.45 g, 5.07 mmol) in dry CH2Cl2 (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (7.35 mL, 101.3 mmol). The mixture was stirred for 2 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 as a yellow solid (1.74 g, >100% yield).
Reaction SMILES: [CH2:1]([NH2:5])[C@@H:2]([NH2:4])[CH3:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.ClCCl>CC(C)CC(O)C>[NH2:4][C@@H:2]([CH3:3])[CH2:1][NH:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C[C@H](N)CN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)CC(C)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC[C@H](C)N)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To 62.9 parts of (S)-1,2-propanediamine under a nitrogen atmosphere (temp. 0°-5° C.) was added dropwise over 7 hours a solution of 80.84 parts of 4-methylbenzenesulfonyl chloride in 1689 parts of dichloromethane. After stirring overnight at 20° C., the reaction mixture was washed with 250 parts of water (3x). The organic layer was separated, dried, filtered and evaporated. About 1 gram of the thus obtained product was recrystallized from 2-propanol. After cooling to 0° C., filtering and drying, about 0.30 parts of crystals suitable for seeding were obtained. The remainder of the product was dissolved in 4-methyl-2-pentanol by heating just below the reflux temperature. The mixture was allowed to cool slowly and at about 30° C. was seeded with the previously obtained crystals. After further cooling to 0° C., the precipitate was filtered off and triturated with 2,2'-oxybispropane. The crystals were filtered off, dried in vacuo, yielding 50.75 parts (52.4%) of (S)-N-2-aminopropyl-4-methylbenzenesulfonamide; mp. 82°-86° C.; [α]D20 =-1.10° (c=1% in methanol) (interm. 1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([SH:17])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:25]([CH2:34][CH3:35])[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([S:17][CH:25]([CH2:34][CH3:35])[C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: CCC(Br)C(=O)N1CCCCC1
Reactant: Fc1ccccc1-c1nnc2ccc(S)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(Sc1ccc2nnc(-c3ccccc3F)n2n1)C(=O)N1CCCCC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-thiol (1 mmol) and cesium carbonate (1.5 equiv.) in DMF (5 mL) was added 2-bromo-1-(piperidin-1-yl)butan-1-one (1.5 equiv.) and the mixture was stirred at 70° C. for 3 hours. The reaction was monitored by thin-layer chromatography and was shown to be complete at this time. The solvent was removed in vacuo and the residue was flash chromatographed to give 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)-1-(piperidin-1-yl)butan-1-one.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].C(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[NH:18].C(=O)=O>O>[C:6]([C@@H:4]([C@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[NH2:15][NH:16][C:17]([NH2:19])=[NH2+:18].[NH2:15][NH:16][C:17]([NH2:19])=[NH2+:18]
Reactant: N=C(N)NN
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NNC(N)=[NH2+]
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
L-Tartaric acid (20.00 g, 133.25 mmol) was dissolved in 200 ml of distilled water. Aminoguanidine bicarbonate (36.27 g, 266.51 mmol) was added in portions at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 24 hours. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was isolated as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:26])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[C:17]4[CH3:23])[C:11]([CH3:24])=[C:10]([F:25])[CH:9]=2)[CH2:5][CH2:4]1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33].O>CN(C=O)C.C(Cl)(Cl)Cl>[CH:3]1([NH:6][C:7](=[O:26])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[N:18]=[C:17]4[CH3:23])[C:11]([CH3:24])=[C:10]([F:25])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]nc(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(c1)c(C)nn2S(=O)(=O)c1cccs1
Reaction time: 2 h
Yield: 50.1 %

Procedure:
Sodium hydride (60% oil dispersion, 0.008 g) was added to a stirred solution of N-cyclopropyl-3-fluoro-4-methyl-5-(3-methyl-1H-indazol-5-yl)benzamide (Example 121) (0.033 g) in dry DMF (1.5 ml) under nitrogen. After 5 min a solution of 2-thiophenesulphonyl chloride (0.038 g) in DMF (0.75 ml) was added and stirring was continued for a further 2 h. Water (1 ml) and chloroform (10 ml) were added, the mixture was passed through a hydrophobic filter and the solvent was evaporated. The residue was purified by preparative Hplc to give the title compound as a clear glass (0.024 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[C:18]1([CH2:24][N:25]([CH2:37][CH:38]=[CH2:39])[C:26](=[O:36])[CH2:27][NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]3[C:26](=[O:36])[N:25]([CH2:24][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:37][CH:38]3[CH2:39]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(OCc2ccccc2F)cc1
Reactant: C=CCN(Cc1ccccc1)C(=O)CNCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C2C(CC(c3ccc(OCc4ccccc4F)cc3)N2Cc2ccccc2)CN1Cc1ccccc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
A solution of 4-{[(2-fluorophenyl)methyl]oxy}benzaldehyde (D92, 920 mg, 4.0 mmol), prepared by an analogous procedure to that described hereinabove, N1,N2-bis(phenylmethyl)-N1-2-propen-1-ylglycinamide (D90, 588 mg, 2.0 mmol) and DIPEA (0.68 ml, 4.0 mmol) in dry toluene (8 ml) were stirred at 120° C. for 72 h. After the reaction was terminated, it was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The residue was purified via flash chromatography affording the title compound (503 mg, 50%) as a racemate. Rf (cyclohexanes:ethyl acetate 1:1): 0.57.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=O)[C:8]([OH:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[ClH:17].[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([OH:19])=[C:7]([CH2:20][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)cc2Cl)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(Cl)cc2Cl)c1O
Product: Cl

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-2′,4′-dichloro-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a gray solid using the procedure described in Example 9 from 5-(tert-butyl)-2′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:13])=[CH:10][N:11]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>CO.C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]([C:9]1[S:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)(=[O:28])=[O:27])=[N:11][CH:10]=1)=[O:13]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1cnc(NCCCNS(=O)(=O)c2cccs2)s1
Yield: 27 %

Procedure:
A mixture of 31.1 mg (0.1 mmol) [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone hydrochloride in 1 ml methanol, 18.2 mg (0.1 mmol) Thiophene-2-sulfonyl chloride in 1 ml DCM and 0.15 ml NEt3 was stirred for 16 h at 50° C. After evaporation to dryness the residue was taken up in 1.5 ml MeOH/formic acid 1/1 and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of product fractions yielded 11.4 mg (27%) of the title compound.
Reaction SMILES: CN(C)CCCN[C:7]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[CH:11][CH:10]=1)=[O:8].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][OH:34].CCOCC>C1COCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][O:34][C:7]([C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[CH:13][CH:14]=1)=[O:8]
Reactant: CN(C)CCCO
Reactant: CN(C)CCCNC(=O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCCOC(=O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1

Procedure:
The acid chloride (25 g) of Example 29 above was dissolved in THF (1250 ml) and 3-dimethylaminopropanol (250 ml) was added dropwise. After stirring overnight at room temperature ether (2 l) was added and the resulting precipitate was filtered. The crude ester (13.6 g) was purified via the hydrochloride salt, mp 288° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>C(OCC)C.C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH3:21])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Yield: 58.8 %

Procedure:
An acetonitrile (15 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.78 g, 2.63 mmol), potassium carbonate (0.27 g, 1.97 mmol) and methyliodide (0.33 mL, 5.26 mmol) was stirred for 6.5 hours under reflux. A saturated ammonium chloride solution (15 mL) and diethyl ether (15 mL) were added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (15 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/1) to obtain a white solid of 2-(4-chloro-2-fluoro-5-methyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.36 g, yield:44.3%).
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH2:16][CH:17]([CH3:19])[O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[C:6]([C:10]1[C:15]2[CH2:16][CH:17]([CH3:19])[O:18][C:14]=2[C:13]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC1Cc2c(ccc(O)c2C(C)(C)C)O1
Agent: CS(=O)(=O)O
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CC1Cc2c(c(C(C)(C)C)cc(O)c2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 112.3 %

Procedure:
Under ice-cooling, 3 ml of methanesulfonic acid was added dropwise to a solution of 0.77 g of 4-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran in 1.5 g of t-butyl alcohol and 6 ml of chloroform. After stirring at 0° C. for 10 minutes, the mixture was poured into ice water and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in chloroform) to give 0.55 g of 4,7-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a white crystal (yield 57%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.CCN(CC)CC.[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>C1COCC1.CCOC(C)=O>[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([N:6]2[CH2:7][CH2:8][CH2:9][C@H:5]2[C:4]([O:3][CH3:2])=[O:10])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccc(CBr)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
To a mixture of (S)-proline methyl ester hydrochloride salt (1.6 g, 9.65 mmol) in THF (20 mL) was added Et3N (1.34 mL, 9.65 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min and cooled back down to 0° C. 3-Bromomethyl-benzenesulfonyl chloride (2.6 g, 9.65 mmol) and Et3N (1.34 mL, 9.65 mmol) were then added to the slurry. The resulting mixture was stirred at room temperature for 3 h and then diluted with EtOAc (100 mL). The organic phase was washed with water (2×50 mL), brine (20 mL) and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by chromatography via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to give 550 mg of (S)-methyl 1-((3-(bromomethyl)-phenyl)sulfonyl)pyrrolidine-2-carboxylate that was used in the next step without further purification. This residue was taken up in acetone (20 mL) and transferred to a microwave vial. (S)-tert-butyl ((3-hydroxyphenyl)(phenyl)methyl)carbamate (I8, 251 mg, 1.82 mmol) and K2CO3 (546 mg, 1.82 mmol) were added, and the mixture was heated to 130° C. under microwaves irradiation for 1 h. The mixture was stirred at room temperature for 18 h and partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (30 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to give the title compound (636 mg, 60%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10])(=[O:6])=[O:5].[Cl:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[C:19](Cl)[N:18]=[C:17]([S:25][CH3:26])[N:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C.C1COCC1>[Cl:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[C:19]([NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([S:4]([CH3:3])(=[O:5])=[O:6])[CH:8]=2)[N:18]=[C:17]([S:25][CH3:26])[N:16]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CSc1nc(Cl)c(C(N)=O)c(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)n1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a mixture of 55% sodium hydride in oil (733 mg) and DMF (20 mL), a mixture of 3-(methylsulfonyl)aniline (1.44 g) and THF (20 mL) were added under ice cooling and stirred for 30 minutes under ice cooling. After dropwise addition of a mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxamide (2.0 g) and DMF (30 mL) over 15 minutes, the reaction liquid was further stirred under ice cooling for 15 minutes. After addition of 10% aqueous citric acid (300 mL) and extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was concentrated, and the precipitated solid was collected by filtration and dried to give 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (1.95 g) as a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Cl:13][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCCc1ccncc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a stirred solution of 3-(4-pyridyl)propanol (22.05 g, 0.16 mol) in 100 mL of dry chloroform (CHCl3) at 0° C. was added dropwise a CHCl3 solution of thionylchloride (SOCl2, 17.5 mL, 0.24 mol). The reaction was allowed to warm to room temperature, stirred for 1 hour, and then brought to reflux for 1 hour. After cooling the reaction to room temperature, it was stripped of all solvent under reduced pressure and the residue was partitioned between CH2Cl2 and water that had been made basic with concentrated NH4OH. The aqueous phase was washed 2x with CH2Cl2 and the combined organic phase was dried (Na2SO4), filtered, and stripped of solvent to yield 24 g of crude product. This material was vacuum distilled at 68°-71° C. (0.3 mm) to give 24 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].F[B-](F)(F)F.[CH3:21][O+](C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:21])[N:7]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(Br)c(F)cc2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)c(F)cc2nn(C)cc12
Reaction time: 2.5 h
Yield: 77.6 %

Procedure:
To a solution of methyl 5-bromo-6-fluoro-1H-indazole-4-carboxylate (700 mg, 2.56 mmol) in ethyl acetate (26 mL) was added trimethyloxonium tetrafluoroborate (569 mg, 3.85 mmol) at room temperature, and the mixture was stirred for 2.5 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (570 mg, yield 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][CH2:14]S)[CH2:11][C@@H:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:29]=1)#[N:2].[C:30](=[O:33])([O-])[O-].[K+].[K+].[OH2:36]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][CH2:14][N:9]([O:33][CH2:30][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:29]=3)[S:23]([CH3:26])(=[O:24])=[O:36])[CH2:11][C@@H:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:29]=1)#[N:2]
Reactant: O
Reactant: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCS)C[C@H]1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCN(OCc2ccccc2)S(C)(=O)=O)C[C@H]1Cc1ccccc1

Procedure:
A mixture of Compound B of Example 27 (95.2 mg, 0.2 mmol) and N-phenylmethoxyl methanesulfamide (44 mg, 0.22 mmol) was stirred with potassium carbonate (69 mg, 0.5 mmol) in DMF (1 mL) at 70-80° C. for 2 hours. Water (10 mL) was added and the precipitates were collected. The solids were dried in vacuo and redissolved in DCM. The DCM solution was filtered and the filtrate solution was concentrated to afford the title compound as a colorless foam, 119.0 mg (100%) MS m/e 597 (M+H)+.