Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][NH:6][CH2:5][C:4]2[NH:8][C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])=[N:10][C:3]1=2.C(O)(=O)C.[Na].[CH3:41][C:42]([CH3:44])=O>CN(C=O)C>[CH:42]([N:6]1[CH2:7][C:2]([CH3:35])([CH3:1])[C:3]2[N:10]=[C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)=[O:17])[NH:8][C:4]=2[CH2:5]1)([CH3:44])[CH3:41]
Reactant: CC(C)=O
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3(C)C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc3c([nH]2)CN(C(C)C)CC3(C)C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
4-(1-(5-(7,7-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (0.12 g, 0.26 mmol) (intermediate prepared in the synthesis of compound 451), DMF (4 mL), acetic acid (69 μL, 1.21 mmol), sodium triacetoxyborohydide (0.11 g, 0.52 mmol) and acetone (0.50 mL, 6.8 mmol) were mixed and stirred at room temperature for 2 hours. The reaction was carefully quenched with water (10 mL) and the mixture was extracted with ethyl acetate (60 mL) and the organics was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by preparative TLC (DCM/10% MeOH) followed by a second preparative TLC (ethyl acetate/5% MeOH) to obtain the title compound as a white powder (4.1 mg, 8.1%). m/z (ES+) 510 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([CH2:17][C@H:18]3[CH2:23][N:22]([S:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)(=[O:26])=[O:25])[CH2:21][CH2:20][NH:19]3)[CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:33]1[N:38]=[CH:37][C:36]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([CH2:17][C@H:18]3[CH2:23][N:22]([S:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)(=[O:26])=[O:25])[CH2:21][CH2:20][N:19]3[C:33]3[N:34]=[CH:35][C:36]([C:39]([OH:45])([CH3:44])[C:40]([F:41])([F:42])[F:43])=[CH:37][N:38]=3)[CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCN[C@@H](CN2C3COCC2C(OCc2ccccc2)C3)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(c1cnc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)nc1)C(F)(F)F
Temperature: 120 °C
Yield: 48.2 %

Procedure:
A 20-mL vial was charged with 6-(benzyloxy)-8-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octane (endo) (250 mg, 0.54 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1-trifluoropropan-2-ol (244 mg, 1.078 mmol, Intermediate E), Hünig's base (0.29 mL, 1.62 mmol) and dioxane (5 mL). The reaction was heated to 120° C. for 12 h. The mixture was then concentrated onto silica gel and purified via column chromatography (120 g silica gel, 0 to 100% EtOAc in hexanes) to give 2-(2-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (endo) (170 mg) as a mixture of four isomers.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[N:4]([CH3:15])[N:3]=1.Br[C:17]1[N:22]=[C:21]2[C:23]([C:34]([O:36][CH3:37])=[O:35])=[CH:24][N:25]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]2=[N:19][CH:18]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>CN(C=O)C.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>[CH3:37][O:36][C:34]([C:23]1[C:21]2=[N:22][C:17]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=4)[N:4]([CH3:15])[N:3]=3)=[CH:18][N:19]=[C:20]2[N:25]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])[CH:24]=1)=[O:35]
Reactant: Cn1nc(I)c2cc(S(C)(=O)=O)ccc21
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(S(C)(=O)=O)cc34)nc12
Temperature: 100 °C
Yield: 70.7 %

Procedure:
To a solution of 3-iodo-1-methyl-5-(methylsulfonyl)-1H-indazole (127 mg, 0.37 mmol), methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (128 mg, 0.34 mmol) and Pd(PPh3)4 (20 mg, 0.017 mmol) in DMF (8 mL) was added hexa-N-butylditin (299 mg, 0.51 mmol). The reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 100° C. for 15 hours under nitrogen. After cooling to room temperature, water (40 mL) was added and product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc/petroleum ether=2:1) to give methyl2-(1-methyl-5-(methylsulfonyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (120 mg, 69.7%) as an off-white solid. LCMS: (M+H)+=500; 1H NMR (300 MHz, DMSO): δ 9.43 (d, 1H, J=1.2 Hz), 9.21 (s, 1H), 8.95 (d, 1H, J=1.2 Hz), 8.77 (s, 1H), 8.01 (s, 1H), 6.33 (s, 2H), 4.24 (s, 3H), 4.04 (s, 3H), 3.28 (s, 3H), 1.09 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:19](=[O:36])[C@@H:20]([NH:28]C(=O)OC(C)(C)C)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]([N:8]1[C:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:12]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=2[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(C(N)=O)cc(-c3ccncc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(-c2ccncc2)cc2c1CCN2C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a 20 ml vial was added crude (S)-tert-butyl 1-(4-carbamoyl-6-(pyridin-4-yl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate 60.B (75 mg, 0.1 mmole), 20 ml of DCM and 10 ml of TFA. The reaction was stirred at room temperature for 12 hours at which time the crude was partitioned between 600 ml DCM and 100 ml saturated sodium carbonate. The organic layer was extracted once more with 100 ml of water, the organic layer dried with sodium sulfate and the solvent removed to give (S)-1-(2-amino-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxamide 60.0 as an off white solid. (49 mg, 82% yield).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:21][CH2:20][C:19]2[CH:18]3[O:22][CH:7]([C:8]4[C:17]3=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=4)[C:6]=2[CH2:5]1)=[O:3].FC(F)(F)C(O)=[O:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:2]([CH:4]1[CH2:21][CH2:20][C:19]2[C:18](=[O:26])[C:17]3[C:8](=[CH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7](=[O:22])[C:6]=2[CH2:5]1)(=[O:3])[CH3:1]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)C1CCC2=C(C1)C1OC2c2cc3ccccc3cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)C1CCC2=C(C1)C(=O)c1cc3ccccc3cc1C2=O
Reaction time: 20 h
Yield: 38 %

Procedure:
A mixture of 0.68 g of (1,2,3,4,5,12-hexahydro-5,12-epoxynaphthacen-2-yl) methyl ketone, 15 ml of chloroform and 0.9 ml of trifluoroacetic acid was left to stand at room temperature for 20 hours, neutralised with sodium hydrogen carbonate and extracted with methylene chloride. The extract was dried over sodium sulphate and concentrated to dryness. The residue was treated with 50 ml of methylene chloride, 1 ml of diethyl ether and 12 g of silicic acid and the mixture was stirred in the air for 48 hours. After concentration to dryness, the residue was chromatographed on silicic acid. There were obtained 475 g (38%) of crude 2-acetyl-1,2,3,4-tetrahydro-5,12-naphthacenedione which, after washing with methanol, had a melting point of 189°-192° C. (from ethanol).
Reaction SMILES: [Na].[C:2]1([S:16](O)(=O)=O)[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.C1(S(Cl)(=O)=O)C2C(=CC3C(C=2)=CC=CC=3)C=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[C:2]1([SH:16])[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1cccc2cc3ccccc3cc12
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S(=O)(Cl)c1cccc2cc3ccccc3cc12
Solvent: ClP(Cl)Cl
Solvent: C1CCOC1
Product: Sc1cccc2cc3ccccc3cc12

Procedure:
The reaction of anthracene (Tokyo chemical industry Co., Ltd) with sulfur trioxide (Tokyo chemical industry Co., Ltd) was conducted in the presence of the piperidine catalyst to synthesize β-anthracenesulfonic acid, followed by a treatment with a sodium hydroxide solution to obtain anthracenesulfonic acid sodium. The obtained anthracenesulfonic acid sodium was allowed to react with phosphorous trichloride and phosphorous pentachloride (Tokyo chemical industry Co., Ltd) in a solvent of phosphorous dichloride (Tokyo chemical industry Co., Ltd) at the temperature of 120° C., thereby obtaining anthracenesulfonyl chloride. In THF, anthracenesulfonyl chloride was allowed to react with lithium aluminum hydride, followed by a treatment with hydrochloric acid to yield anthracene thiol.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[N:13]=[C:12]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C.[OH-].[Na+].Cl>O1CCCC1.CO.O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[C:12]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(F)cc2)n1
Agent: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.1 g (5.7 mmol) of ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate in 20 mL of tetrahydrofuran, 1 0 mL of water and 1 0 mL of methanol was added 2.0 mL (10 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a pale yellow foam. LC/MS 341.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][OH:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:19])[CH:3]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:19])[C:16]=3[O:15]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1cc(Cl)ccc1-c1cccc2c1OC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4C)c3O2)cc1
Yield: 93.2 %

Procedure:
Treatment of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (2.78 g, 10.11 mmol) with p-toluenesulfonyl chloride (2.31 g, 12.14 mol) generally according to the procedure described for Intermediate 10 gave 4.04 g (93%) of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C23H21ClO4S: C, 64.4; H, 4.93. Found: C, 64.24; H, 4.93.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.[N:12]1C=CC=C[CH:13]=1.CN>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:12][CH3:13])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Agent: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-pyridinesulfonyl chloride (500 mg, 1.949 mmol) was added to a 0° C. solution of pyridine (0.315 ml, 3.90 mmol), methylamine (0.975 ml, 1.949 mmol, 2M in THF) and CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature for 1 hr, then quenched with brine. The contents were extracted with DCM, dried, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: 50%, EtOAC/CH2Cl2). The product was collected as a clear oil, 225 mg (75%). LCMS E-S (M+H)=251.1. 1H NMR (400 MHz, Chloroform-d) δ ppm 8.77 (s, 1H), 8.07 (dd, J=8.34, 2.27 Hz, 1H), 7.92 (d, J=8.34 Hz, 1H), 5.45 (d, J=5.05 Hz, 1H), 2.76 (d, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
159 g of oxalic acid chloride was dissolved in one liter of dichloromethane, in to which 195.8 g of dimethyl sulfoxide was dropped at -67° C., followed by agitation for 30 minutes. Thereafter, 200 ml of dichloromethane dissolving 66 g of 1-benzyloxycarbonyl-4-(2-hydroxyethyl)-piperidine was dropped at -67° C. Subsequently, 380 g of triethylamine was dropped at -67° C., followed by agitation for about 1 hour. After removal of the solvent by distillation, ethyl acetate was added and insoluble matters were removed by filtration, and the resultant filtrate was washed with water and dried with anhydrous magnesium sulfate, followed by filtration and removal of the solvent by distillation. The resultant residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:hexane=20:80) to obtain 55.0 g of the captioned compound (yield 84%).
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][O:11][C@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([NH:35][S:36]([N:39]([CH2:41][CH:42]([O:45][CH3:46])[O:43][CH3:44])[CH3:40])(=[O:38])=[O:37])=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:47]=[CH:48][CH:49]=[CH:50][C:15]=2[O:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([NH:35][S:36]([N:39]([CH2:41][CH:42]([O:45][CH3:46])[O:43][CH3:44])[CH3:40])(=[O:38])=[O:37])=[O:34])=[CH:21][C:20]=3[N:18]3[C:17]=2[C:16]2[CH:47]=[CH:48][CH:49]=[CH:50][C:15]=2[O:14][CH2:13][C@@H:12]([O:11][CH2:10][CH2:9][NH:8][CH3:1])[CH2:19]3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)Cc1ccccc1)COc1ccccc1-3)OC
Agent: [Pd]
Solvent: CO
Product: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc3n2C1
Reaction time: 12 h

Procedure:
Pd/C (1 eq) was added to a solution of (7S)-7-{2-[benzyl(methyl)amino]ethoxy}-14-cyclohexyl-N-{[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide (0.06 M) in MeOH. The resulting mixture was stirred for 12 h under H2 atmosphere. The mixture was filtered and then concentrated in vacuo to afford the title compound. The product was used in the next step without further purification. (ES+) m/z 629 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1I
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(C)nn3c(-c4ccc(F)cc4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
(S)-(1-(7-(4-Fluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (56 mg), 4-methoxyphenylboronic acid (30 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (5 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (27 mg).
Reaction SMILES: C(O)(=O)C.C[O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH:10]1[OH:16])=O>C1(C)C=C(C)C=C(C)C=1>[OH:16][CH:10]1[CH2:11][CH:12]2[CH2:13][CH2:14][CH:9]1[C:7](=[O:6])[NH:15]2
Reactant: COC(=O)C1CCC(N)CC1O
Solvent: CC(=O)O
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1NC2CCC1C(O)C2
Temperature: 25 °C
Yield: 72.6 %

Procedure:
4-Amino-2-hydroxy-cyclohexanecarboxylic acid methyl ester acetic acid salt (6.6 g) was heated to reflux in mesitylene (60 ml) for 3 h. After cooling to rt, solvent was decanted and the crystals were washed with hexane three times to provide 2.9 g of 5-hydroxy-2-aza-bicyclo[2.2.2]octan-3-one (M+: 141).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][O:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCO)CC1
Product: CS(=O)(=O)OCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O

Procedure:
In analogy to the procedure described in example 5C, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(3-hydroxy-propyl)-[1,4]diazepan-5-one and methanesulfonyl chloride gave the crude title compound as white foam and as a mixture of mainly mesylate and some chloride.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CCC2(CC1)OCCO2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCC2(CC1)OCCO2
Reaction time: 18 h
Yield: 101.4 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (8.60 g, 49.9 mmol) and imidazole (8.50 g, 125 mmol) in DMF (50 mL) was added tert-butyldimethylsilyl chloride (9.03 g, 59.9 mmol), and the mixture stirred at room temp. for 18 hours. The mixture was concentrated in vacuo and the residue redissolved in ethyl acetate (20 mL), washed with water followed by brine, then dried (Na2SO4), and concentrated in vacuo to provide the title compound (14.5 g, 50.6 mmol, 101% yield) as a clear oil: LCMS: m/z 287 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 0.01 (6H, s), 0.86 (9H, s),1.14-1.26 (2H, m), 1.45-1.54 (3H, m), 1.67-1.82 (4H, m), 3.40 (2H, d, J=6.7 Hz), 3.91 (4H, s); 13C NMR (126 MHz, CDCl3) δ ppm-5.25, 18.5, 26.1, 26.9, 34.3, 39.2, 64.3, 68.0, 109.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18]CC)=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[OH-].[Na+].N1C=CC=C(C2N3N=CC(C([O-])=O)=C3N=CC=2)C=1.[Na+].Cl>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Agent: Cl
Agent: O=C([O-])c1cnn2c(-c3cccnc3)ccnc12
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 6.0 g. of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate, 125 ml. of ethanol and 50 ml. of 1 N sodium hydroxide is heated on a steam bath for 4 hours. The mixture is chilled and filtered to give 5.85 g. of sodium 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate, m.p. 360°-363° C. dec. The preceding compound is stirred with 1 N hydrochloric acid and the mixture is filtered to give 5.0 g. of the product of the example, m.p. 286°-287° C. dec. (gas evolution).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:16]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C1COCC1>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Temperature: 70 °C

Procedure:
To 77 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 ml THF was added 85 mmol CDI, and the mixture heated at 70° C. for 1 h. 770 mmol methanol was then added and the mixture was heated at 70° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant:ethyl acetate/heptane/dichloromethane 45:45:10) to afford the title compound. MS (m/e): 244.1 ([M−H]−, 100%)