Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:29][C:30]([NH2:32])=[O:31]>O1CCCC1.C(OCC)(=O)C>[NH2:32][C:30](=[O:31])[CH2:29][O:27][CH2:26][C:23]1[N:22]=[C:21]([C@H:12]([CH2:11][CH2:10][CH2:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:25][N:24]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COCC(N)=O)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 268.6 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (51 mg, 1.28 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (105 mg, 0.30 mmol) in anhydrous tetrahydrofuran (3 ml) and stirred under a nitrogen atmosphere for 30 minutes. 2-Bromoacetamide (235 mg, 1.70 mmol) was added and the mixture was allowed to warm to room temperature and then heated at 40° C. for 15 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (0:100) to afford the title compound as a colourless oil (330 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][Cl:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:8]([CH2:9][Cl:10])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:19])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ncccc1CCl
Solvent: ClC(Cl)Cl
Product: CCc1c(CCl)ccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 2-ethyl-3-chloromethylpyridine (2.4 g, 15.4 mmol) was dissolved in CHCl3 (100 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 4.2 g) was added in small portions. The reaction was stirred for 2 hours. The reaction was extracted twice with saturated aqueous sodium bicarbonate (100 mL). The organic phase was dried with MgSO4, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel packed in 98:2 CH2Cl2 :MeOH and eluted with the same. The appropriate fractions were combined and the solvent removed under reduced pressure the give the desired 2-ethyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22]C(O)=O)[CH:9]=2)=[CH:4][CH:3]=1.CC[N:28](CC)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][NH2:28])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(-n2nc(CCN)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the acid 12 (1.0 g, 2.8 mM) in benzene (25 ml) was added Et3N (0.39 ml, 2.8 mM) and diphenylphosphoryl azide (0.60 ml, 2.8 mM). After stirring overnight at room temperature, the reaction mixture was heated to 70° C. for 1.5 hours, cooled and concentrated in vacuo. Dioxane (2 ml), followed by a solution of concentrated HCl (0.3 ml) in dioxane (2 ml) was added, and the reaction mixture was heated to reflux for 2 hours, cooled and diluted to 50 ml with EtOAc. The organic solution was washed with a 0.25N NaOH solution, and extracted with 1N HCl. The extracts were combined, basified with 5N NaOH, and extracted with EtOAc, dried, filtered and concentrated in vacuo. Crystallization from Et2O afforded pure 42 (0.62 g, 68%) as a light yellow crystalline solid, mp=95°-97°. MS, m/e 327 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14]>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: COC(=O)c1ccc(CO)cc1NC(C)=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1NC(C)=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
To a suspension of 2-acetylamino-4-hydroxymethyl-benzoic acid methyl ester (1.7 g, 7.62 mmol) in DCM (40 mL) was added MnO2 (1.32 g, 2 equiv) and the resulting mixture was stirred at 50° C. for 18 h. MnO2 (0.66 g, 1 equiv) was added and the mixture was stirred at 50° C. for 2 h. The mixture was cooled down, filtered through a pad of celite and washed with DCM. The solvent was removed in vacuo to afford a crude yellow solid. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 50:50)) to provide the title compound as a light yellow solid (1.15 g, 68%) (ES-MS: m/z 263.2 [M+CH3CN+H]+, rt 4.29 min).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31]N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1ccccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccn3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and pyridin-2-yl-hydrazine according to example 43 gave the desired product. MS: M=393.9 (M+H)+
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:10].[Na+]>S(=O)(=O)(O)O>[C:2]1([CH2:1][C:8]([NH2:9])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Benzyl cyanide (5 g, 42.7 mmol) was added slowly to concentrated sulfuric acid (20 ml) cooled by water-ice bath. The solution was stirred overnight. The reaction mixture was poured into ice water and neutralized with 20% NaOH. The aqueous phase was extracted by ethyl acetate (3×15 mL). The combined organic layers were washed with water (3×10 mL) and brine (3×10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound (4.5 g, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.20-7.32 (m, 5H), 6.87 (s, 1H), 3.38 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[CH2:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH3:23]C(C)(C)C(C(OC(C(=O)C(C)(C)C)=O)=O)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:19]([O:20][CH2:21][CH3:23])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[CH2:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(N)c(OC)cc4[C@H]3CC[C@]12C
Reactant: CC(C)(C)C(=O)C(=O)OC(=O)C(=O)C(C)(C)C
Solvent: ClC(Cl)Cl
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(N)c(OCC)cc4[C@H]3CC[C@]12C
Reaction time: 0.67 h
Yield: 42.1 %

Procedure:
Representative preparation of 3-formamide estrane derivatives: Preparation of 3-formamide-17-methylene-2-methoxyestra-1,3,5(10)-triene (Compound #88): 3-Amino-17-methylene-2-methoxyestra-1,3,5(10)-triene (293 mg, 0.99 mmol) was dissolved in chloroform (1 mL) and trimethylacetyl formic anhydride (170 mg, 1.30 mmol, prepared as in Vlietstra et al Recueil, 1982, 101, 460) was added. The mixture was stirred 40 min, after which, the solvent was removed under reduced pressure. The product was purified by titurating with hexanes and isolating the precipitate by decanting after the precipitate was centrifuged. Obtain 150 mg white powder (0.417 mmol, 42% yield). 1H NMR (300 MHz, CD3OD) δ 8.27 (s, 1H), 7.88 (s, 1H), 6.94 (s, 1H), 4.72-4.67 (m, 2H), 3.88 (s, rotamer 1) and 3.86 (s, rotamer 2, total 3H), 2.87-2.76 (m, 2H), 2.66-1.19 (m, 13H), 0.87 (s, 3H).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=O)[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:18])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: -30 °C
Reaction time: 4 h

Procedure:
To the solution of 2-biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid amide (0.24 g, 0.76 mmol) in pyridine (10 mL) was added imidazole (0.11 g, 1.53 mmol). The reaction mixture was cooled to −30° C. and phosphorous oxy chloride (0.3 mL, 3.1 mmol) was added drop wise. The reaction mixture was then stirred at −10° C. for 4 h. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated to dryness and water was added. This mixture was extracted with ethyl acetate and the combined organic layers were concentrated. The resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to get the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)O)[C:5]1=[O:24])(=[O:3])[CH3:2].C(Cl)(Cl)(Cl)[Cl:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([Cl:26])[C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc2c(c1)C(=C(O)c1cnccn1)C(=O)N2C(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)C(=C(Cl)c1cnccn1)C(=O)N2C(C)=O

Procedure:
1.2 g (3.7 mmol) 1,5-diacetyl-3-[pyrazin-2-yl-hydroxy-methylidene]-2-indolinone (Ex. V.23) are dissolved in 50 ml dioxane and refluxed with 2 ml carbon tetrachloride and 2 g triphenylphosphine for 5 h. Then the mixture is left to cool and evaporated down. The residue is chromatographed through a silica gel column with methylene chloride/methanol 25:1, the corresponding fractions are combined and concentrated by rotary evaporation.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].CCCP(=O)=O.[N:29]1[CH:30]=[CH:31][N:32]2[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][C:33]=12.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH:15][C:38]([C:36]2[CH:35]=[CH:34][C:33]3[N:32]([CH:31]=[CH:30][N:29]=3)[CH:37]=2)=[O:39])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (81 mg, 0.238 mmol, Intermediate 6) and EtOAc (3 mL) was added 50% propylphosphonic anhydride in EtOAc (0.28 mL, 0.470 mmol), imidazo[1,2-a]pyridine-6-carboxylic acid (47 mg, 0.290 mmol) and DIPEA (0.12 mL, 0.689 mmol). The solution was stirred at room temperature. After 16 h, the reaction product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with 0 to 100% EtOAc in hexane, to provide the title compound as a white solid. 1H NMR (300 MHz, MeOH-d4) δ ppm 9.06-9.16 (m, 1H), 8.44-8.55 (m, 1H), 7.96 (s, 1H), 7.76 (dd, J=9.5, 1.8 Hz, 1H), 7.56-7.71 (m, 3H), 7.42-7.51 (m, 2H), 7.32-7.42 (m, 2H), 6.68-6.76 (m, 1H). MS (ESI pos. ion) m/z: 449.0 (M+H).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:19])=[O:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26]([C:2]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:5]=[C:4]([CH3:13])[CH:3]=3)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:18])=[O:19])([CH3:16])[CH3:15]
Reactant: Cc1cc(Br)n(-c2ccccc2)n1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)n(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 5-(bromo)-3-(methyl)-1-(phenyl)-pyrazole (264 mg, 1.11 mmol) in 6 mL DME add 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (694 mg, 2.45 mmol). Add sodium carbonate (354 mg, 3.34 mmol) dissolved in 0.5 mL of water and trans-dichlorobis(triphenylphosphine) palladium (II) (234 mg, 0.33 mmol). Heat the mixture to 100° C. with stirring under nitrogen. After 2 hours, cool and filter over a pad of Celite® and sodium sulfate. Purify the crude product by radial chromatography eluting with 4% methanol in CH2Cl2 to yield 201 mg (46%) of the title compound. MS(ES+): m/z=396.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cc(-c2cc(-c3nnc(CN4CCOCC4)o3)c3cn[nH]c3c2)cnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (30 mg, 0.051 mmol) and morpholine (1 ml, 11.48 mmol) were placed a vial and heated in a microwave at 90° C. for 15 mins. The morpholine was blown off under a stream of nitrogen and the residue suspended in isopropanol (2 ml) and 2M sodium hydroxide (1 ml) added. The mixture was stirred at room temperature for 2 h. The solvent was blown off and the residue purified by chromatography on a silica gel (20 g) cartridge, eluting with 0-25% methanol in dichloromethane over 30 mins. The solvent was removed in vacuo and the residue loaded onto a SCX (10 g) cartridge and eluted with methanol and then 2M ammonia in methanol. The residue was purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound as a white solid (5 mg).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:23])=[CH:8][C@H:9]2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:23])=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of (2S,5R)-6-(allyloxy)-2-((tert-butyldimethylsilyloxy)methyl)-4-methyl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 13, 1.76 g, 5.20 mmol) in THF (20 mL) at 0° C. was added tetrabutylammonium fluoride (1M in THF) (6.76 mL, 6.76 mmol). Stirred at 0° C. for 1 hour. The reaction mixture was concentrated onto silica gel. Silica gel chromatography (50%-100% ethyl acetate/hexanes) afforded the desired product (1.070 g, 92%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[C:31]([F:38])[N:30]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:32]=[C:31]([F:38])[N:30]=1
Reactant: OB(O)c1cc(F)nc(F)c1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cc(F)nc(F)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine was reacted with 2,6-difluoropyridine-4-boronic acid in General Procedure A. Purification on silica yielded 2-(2,6-difluoro-pyridin-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH:11]=2)=[C:6]([CH3:25])[C:5]([OH:26])=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([CH3:25])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH:11]=1
Reactant: Cc1cc(C(=O)Nc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 60 °C
Yield: 86 %

Procedure:
To a solution of N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-3-(3-fluorophenyl)-5-methyl-benzamide (394 mg, 1.11 mmol, 1.0 eq) in THF (15 mL) under N2 was added a solution of BH3 (1M in THF, 6.7 mL, 6.7 mmol, 6.0 eq) dropwise The reaction mixture was heated at 60° C. overnight. After cooling, the reaction was quenched by addition of water and the aqueous layer was extracted with EtOAc. The extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 30:1 to 20:1) to give the title compound as a brown oil (324 mg, 86%).
Reaction SMILES: [CH3:1][C:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:5][CH2:6][N:7]1[C@H:12]2[CH2:13][CH2:14][C@@H:8]1[CH2:9][CH:10]([N:15]1[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][N:17]=[C:16]1[CH3:23])[CH2:11]2)[CH2:3][NH2:4].C(N(C(C)C)CC)(C)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:1][C:2]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH2:5][CH2:6][N:7]1[C@H:8]2[CH2:14][CH2:13][C@@H:12]1[CH2:11][CH:10]([N:15]1[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][N:17]=[C:16]1[CH3:23])[CH2:9]2)[CH2:3][NH:4][S:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:47])=[O:46]
Reactant: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of intermediate 24 (158 mg, 0.4 mmol) in CH2Cl2 (4 mL) was added diisopropylethylamine (0.175 mL, 1.0 mmol) followed by phenylsulfonyl chloride (0.065 mL, 0.5 mmol) and the solution stirred at room temperature under nitrogen atmosphere for 18 h. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with 0-5% methanol/CH2Cl2 to give the title compound (150 mg, 70%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1)(=[O:18])=[O:17]
Reactant: OCCC1(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(O)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(2-hydroxyethyl)cyclopropanol (86 mg, 0.843 mmol) and triethylamine (136 mg, 1.35 mmol, Shantou Xilong chemical factory) in 10 mL of dichloromethane was stirred at −10° C. for 30 min. Methanesulfonyl chloride (106 mg, 0.927 mmol, Shanghai Haiqu chemical Ltd.) was then added via a syringe. The reaction was stirred at −10° C. for 1 hr at rt and then quenched with 1 mL ice-water. The resulted mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 2-(1-hydroxycyclopropyl)ethyl methanesulfonate as yellow oil (used in the next step without further purification).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.[OH:29][C:30]1[CH:31]=[C:32]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[C:33](=[CH:44][CH:45]=1)[C:34](OCC1C=CC=CC=1)=[O:35]>>[OH:29][C:30]1[CH:31]=[C:32]2[C:33]([C:34](=[O:35])[N:28]([S:25]([C:14]3[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=3)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:47](=[O:48])[NH:46]2)=[CH:44][CH:45]=1
Reactant: O=C(Nc1cc(O)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(O)ccc3c2=O)ccc1C(=O)O
Yield: 4 %

Procedure:
620 mg (1.53 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 550 mg (1.51 mmol) of benzyl 4-hydroxy-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 25 mg (yield 4%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.48 (1H, s), 6.61 (1H, d), 7.14 (1H, d), 7.51 (1H, s), 7.70 (1H, d), 7.90 (1H, d), 10.80 (1H, s), 11.39 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:34]1([CH2:40][CH2:41]O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:41][CH2:40][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCCC1CCCCC1
Reactant: Clc1nccc(Nc2ccccc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1nccc(N(CCC2CCCCC2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
2-Chloro-4-anilinopyrimidine (Reference Example A-9, 700 mg, 3.4 mmol) was dissolved in DCM (70 ml), triphenyl phosphine (1.07 g, 4.1 mmol) and 2-cyclohexyl ethanol (0.57 ml, 4.1 mmol) were added followed by dropwise addition of DEAD (0.646 ml, 4.1 mmol). After 1 hour additional triphenyl phosphine (0.5 g, 2 mmol), 2-cyclohexyl ethanol (0.28 ml, 2 mmol) and DEAD (0.320 ml, 2 mmol) were added and the reaction mixture was stirred overnight at ambient temperature. The solvent was evaporated off and the residue was purified by flash chromatography using EtOAc/petroleum ether (15/85, then 20/80) as the eluent. The solvent was evaporated to give the title product as a colourless oil (368 mg, 37%). NMR (400 MHz, 353K): 0.90 (m, 2H), 1.20 (m, 3H), 1.30 (m, 1H), 1.65 (m, 7H), 3.90 (t, 2H), 4.05 (m, 1H), 6.10 (d, 1H), 7.34 (d, 2H), 7.43 (t, 1H), 7.54 (t, 2H), 7.95 (d, 1H); m/z (ES+) 316 and 318 (MH+).