Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OC(=O)C)(=[O:33])C>C(O)=O>[CH:31]([N:19]([CH:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:33]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: O=CO
Product: COc1cccc2c1CCC2N(C=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.13 g) in formic acid (5 ml) was added acetic anhydride (1 ml) at 0° C. After being stirred for 5 hours at room temperature, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-[N-formyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.12 g). MS (m/z): 425 (M+ +1) NMR (CDCl3, δ): 8.52 (0.25H, s), 8.43 (0.75H, s), 7.60-7.40 (4H, m), 7.38-7.24 (6H, m), 7.18-6.95 (1H, m), 6.78-6.55 (2H, m), 6.18 (0.25H, m), 5.28 (0.75H, m), 4.72 (0.75H, d, J=16.2 Hz), 4.51 (0.75H, d, J=16.2 Hz), 4.12 (0.5H, m), 3.79 (2.25H, s), 3.72 (0.75H, s), 3.20-2.94 (1H, m), 2.92-2.66 (1H, m), 2.62-2.38 (1H, m), 2.35-2.05 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[O:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:42]4[CH2:43][CH2:44][N:39]([C:37]([CH:33]5[CH2:34][CH2:35][CH2:36][O:32]5)=[O:38])[CH2:40][CH2:41]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(C(=O)C2CCCO2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(tetrahydrofuran-2-carbonyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=613.98 (M+H+); retention time=0.72 minutes.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:38](OCC)=[O:39])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2C=NC=CC=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[CH3:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:19]3[N:18]=[CH:17][C:16]([N:12]4[C:11]5([C:9](=[O:8])[NH:5][C:3](=[O:4])[NH:2][C:38]5=[O:39])[CH2:15][CH2:14][CH2:13]4)=[CH:21][CH:20]=3)=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: Cn1ncc2cc(Oc3ccc(N4CCCC45C(=O)NC(=O)NC5=O)cn3)ccc21
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-[6-(1-Methyl-1H-indazol-5-yloxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[ClH:32].CON.N1C=CC=CC=1>C(O)C>[ClH:32].[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1

Procedure:
A solution of N-[(4aR,7aS)-6-(5-fluoropyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (215 mg, 0.496 mmol), O-methylhydroxylamine hydrochloride (207 mg, 2.48 mmol), and pyridine (392 mg, 4.96 mmol) in ethanol (5 ml) is stirred at 55° C. for 4 hours. The mixture is quenched with a solution of saturated sodium bicarbonate in water, and extracted with ethyl acetate. The organic layers are combined, dried, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give a residue as the free base of the title compound. The residue is dissolved in 1 N hydrochloric acid (4 ml), and the solvent removed by a stream of nitrogen. The resulting solid is further purified by dissolving in 1/1 acetonitrile/methanol (4 ml) and precipitating with ethyl ether (2-3 ml). The solid is collected and dried under reduced pressure at 50° C. to give the title compound (0.10 g, 55%). ES/MS (m/e): 330 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.Cl[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C(=O)(O)[O-].[Na+]>O.O1CCCC1.[Cl-].[Na+].O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21](=[O:22])[CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:6]2)=[CH:24][CH:25]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C2CCN(CC(=O)c3ccc(F)cc3)CC2)cc1

Procedure:
To a solution of 3.0g (12.2 mmol) of N-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide in 10 ml of water and 100 ml of tetrahydrofuran was added 2.3 g (13.4 mmol) of 2-chloro-4'-fluoro-acetophenone followed by 2.0g (24.4 mmol) of sodium bicarbonate. This mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 500 ml of brine and extracted with chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield a solid which was recrystallized from 2-butanone/cyclohexane. 1-(4-Fluorophenyl)-2-[4-[(4-acetamidophenyl)carbonyl]-1-piperidinyl]-ethanone was obtained as an off-white solid having a mp of 168°-170° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[O:40]=[S:41]1(=[O:53])[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][N:47]([CH:44]4[CH2:43][CH2:42][S:41](=[O:53])(=[O:40])[CH2:46][CH2:45]4)[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazine dihydrochloride (prepared as described in Ding, Q. et al. WO2007063013) to give the title compound. HR-MS (ES, m/z) calculated for C38H48N5O4SCl2 [(M+H)+] 740.2799, observed 740.2802.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (from Aldrich, 690 mg, 3.7 mmol) and N,N-dimethylformamide (290 μL, 3.7 mmol) was stirred at room temperature for 10 minutes and then a solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (869 mg, 2.49 mmol) in methylene chloride (14 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography, eluting with 0 to 100% EtOAc in hexanes.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].C(O)(=O)C>C(OCCCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COCO[C@H]1C[C@H](OC(C)=O)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Solvent: CC(=O)O
Solvent: CCCCOC(C)=O
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
In 10 ml of butyl acetate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregn-6-en-5α-ol, followed by addition of 0.2 ml of acetic acid. The mixture was stirred in an atmosphere of argon gas under heating at 100° C. for 12 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 100 mg of 20-(1,3-dioxolan-2-yl)-1α--acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene showing the following physical properties.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Li][CH2:11][CH2:12][CH2:13][CH3:14].O>CCOCC>[Br:9][C:4]1[CH:3]=[C:2]([C:12]2[CH2:13][C:14]3[C:6]([CH:11]=2)=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: [Li]CCCC
Reactant: Brc1cc(Br)cc(Br)c1
Solvent: CCOCC
Solvent: O
Product: Brc1cc(Br)cc(C2=Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 12.6 g (40.0 mmol) of 1,3,5-tribromobenzene in 400 ml of ether, 160 ml (40.0 mmol) of 0.25 M nBuLi in hexanes was added for 1 h at −80° C. The mixture was stirred for 1.5 h at this temperature, and then a solution of 5.29 g (40.0 mmol) of indanone-2 in 200 ml of ether was added dropwise over 1 hour while vigorously stirring. The reaction mixture was allowed to warm to room temperature and it was stirred at this temperature for 24 h. Then, 100 ml of water was added. The organic layer was separated; the aqueous layer was extracted with 3×50 ml of dichloromethane. The combined organic layers were dried over Na2SO4 and then evaporated to dryness. The residue was dissolved in 250 ml of toluene, and 0.75 g of p-TosOH was added. The resulting solution was refluxed for 1 hours using a Dean-Stark trap to remove the water formed. Next, the mixture was evaporated to dryness, and the product was isolated by flash-chromatography on Silica Gel 60 (d 50 mm, l 400 mm, eluent: hexanes). Yield 8.54 g (61%) of white powder.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.IC>C1COCC1>[CH3:22][O:21][C:19]([C:16]1([CH3:1])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)=[O:20]
Reactant: COC(=O)C1CCOCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction is removed from the bath and stirred for 10 min. It is then cooled to −78° C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6 mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is added and the reaction allowed to reach rt. The reaction is then quenched with 1 N HCl (200 mL) and extracted with EtOAc. The organic layer is dried and evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester. MS (ESI) m/z 159.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C=O)C>[Si:38]([O:28][C@H:26]([CH3:27])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=1)[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:13])([C:35]([CH3:37])([CH3:36])[CH3:34])([CH3:40])[CH3:39]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 98.3 %

Procedure:
To a pre-cooled (0° C.) solution of N′-((2R,3R)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (1.65 g, 4.15 mmol) in DMF (100 mL) was added imidazole (2.26 g, 33.4 mmol) then TBSCl (2.50 g, 16.60 mmol). The reaction was warmed slowly to room temperature, stirred for 19 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with H2O (2×100 mL) and 5% aq. citric acid (3×80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (10-30% EtOAc in hexanes) to provide the title compound as a colourless amorphous solid (2.09 g, 98%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.06 (dm, J=8.6 Hz, 2H), 7.92 (dm, J=8.6 Hz, 2H), 7.53 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.26 (d, J=7.6 Hz, 1H), 4.42 (pentet, J=5.5 Hz, 1H), 4.31 (dd, J=5.5, 7.8 Hz, 1H), 1.35 (d, J=6.3 Hz, 3H), 0.87 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:54]O)[CH2:52][OH:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:52][OH:53])[CH2:54][O:31]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.3 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 15n (0.57 g, 0.72 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (0.22 mL, 2.88 mmol) at room temperature. The mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 15o as pale yellow oil (475 mg, 88.3%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.59 (d, 1H), 7.48 (s, 2H), 7.36-7.23 (m, 12H), 7.17 (m, 5H), 6.84 (d, 2H), 5.22 (t, 1H), 4.78 (m, 4H), 4.32 (d, 1H), 4.12 (m, 3H), 3.95 (d, 1H), 3.87 (m, 1H), 3.78 (m, 3H), 3.59 (dd, 1H), 3.52 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[N:12]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH2:18][CH2:19][OH:20])[CH2:13][CH2:14]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: OCCN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]
Temperature: 122.5 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5.0 g, 29.0 mmol), 2-piperazin-1-yl-ethanol (11.3 g, 87.0 mmol) and anhydrous potassium carbonate (4.4 g, 31 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 120-125° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (30 ml) and stirred vigorously and cooled at 5° C. overnight. The resulting yellow precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (30 mL), filtered, washed with additional diethyl ether, dried to afford 2-[4-(3-Amino-4-nitro-phenyl)-piperazin-1-yl]-ethanol (6.0 g, 77%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][O:13][CH3:14])[C:3]=1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)(=[O:27])=[O:26])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][O:13][CH3:14])[C:3]=1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1
Reactant: COCn1c(-c2nccs2)c(Cl)c2cccc(N)c21
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: COCn1c(-c2nccs2)c(Cl)c2cccc(NS(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of 3-chloro-1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indole-7-amine (0.25 g) and pyridine (8 mL) was added thiophene-2-sulfonyl chloride (0.19 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.36 g, yield 96%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 128-129° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:30][C:31](OC(C)=O)=[O:32]>C1COCC1.O>[C:31]([N:24]1[C:25]([CH:27]2[CH2:28][CH2:29]2)=[CH:26][C:22]([NH:21][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]3[S:12][C:11]([S:13]([NH:16][C:17]([CH3:19])([CH3:20])[CH3:18])(=[O:14])=[O:15])=[CH:10][CH:9]=3)[N:4]=2)=[N:23]1)(=[O:32])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Br)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (1.6 g, 3.21 mmol, 1.0 eq) in THF/H2O (30 mL/15 mL), Ac2O (0.64 g, 6.42 mmol, 2.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered to afford compound 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)-N-tert butylthiophene-2-sulfonamide (1.6 g, 92%). LC-MS (m/z)=539 [M+H]+
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-:46].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[OH:46][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(O)c2)s1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
To a solution of tert-butyl (S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (630 mg, 982 μmol) (prepared as described in Example 1) in 15 mL DMF were added cesium carbonate (3199 mg, 9819 μmol) and acetic acid (590 mg, 9819 μmol). The mixture was heated at 70° C. for 45 minutes. The reaction mixture was concentrated, and the resulting residue was diluted with 100 mL EtOAc. The organic phase was washed with water and saturated aqueous ammonium chloride twice and then dried over sodium sulfate. Removal of the solvent gave the compound as a tan solid (500 mg, 79%). LCMS (API-ES) m/z (%): 640.0 (100%, M++H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 9H) 1.54 (s, 9H) 2.84-2.94 (m, 2H) 4.23-4.31 (m, 3H) 7.47 (t, J=8.78 Hz, 3H) 7.62-7.69 (m, 3H) 8.01 (d, J=8.53 Hz, 1H).