Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]2[C:26]3=[CH:27][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]4[O:37][C:14]([NH:15][C@@H:16]([CH:34]([CH3:36])[CH3:35])[C:17](=[O:33])[N:18]5[CH2:28][C@H:21]([O:22][C:23]3=[N:24][CH:25]=1)[CH2:20][C@H:19]5[C:29]([O:31][CH3:32])=[O:30])=[N:13][N:12]=4)=[CH:5][CH:4]=2.[CH2:38]([Sn](CCCC)(CCCC)C=C)[CH2:39]CC>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH:34]([C@@H:16]1[NH:15][C:14]2[O:37][C:11](=[N:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:27]=[C:26]3[C:3](=[CH:4][CH:5]=2)[C:2]([CH:38]=[CH2:39])=[CH:25][N:24]=[C:23]3[O:22][C@H:21]2[CH2:28][N:18]([C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:20]2)[C:17]1=[O:33])([CH3:36])[CH3:35]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCc1ccc3c(I)cnc(c3c1)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a 0.1 M solution of methyl (3R,5S,8S)-22-iodo-8-isopropyl-7-oxo-2,27-dioxa-6,9,11,12,24-pentaazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24), 10,12,18,20,22,25-heptaene-5-carboxylate (Example 12, Step 2) in dry toluene was added tetrakis(triphenylphosphine)palladium(0) (0.05 eq.). N2 was bubbled through the reaction mixture for 5 minutes and tributylethenylstannane (1.5 eq) was added. The mixture was stirred at 100° C. for 1 h, allowed to cool to RT, diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (20% to 40% EtOAc/PE) to give the compound as a white solid. MS (ES+) C28H33N5O5 requires: 519. Found: 520 (M+H+).
Reaction SMILES: [CH3:1]I.[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[N:5]=1.O>CN(C=O)C>[Br:3][C:4]1[C:9]([O:10][CH3:1])=[CH:8][CH:7]=[C:6]([I:11])[N:5]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(I)nc1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Add K2CO2 (6.22 g, 45.1 mmol) and methyl iodide (24.6 g, 10.77 mL, 173.3 mmol) to 2-bromo-6-iodopyridin-3-ol, 2 (14.9 g, 49.5 mmol), dissolved in DMF (30 mL). Heat the reaction medium at 100° C. for 2 h, then leave it to cool to room temperature. Then stop the reaction with H2O and stir it for a further 30 min. The precipitate is then filtered, washed with H2O and dried in air to give 3 (15.7 g, 100%) in solid form, light brown: 1H NMR (CDCl3) δ 7.61 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=8.4 Hz), 3.93 (s, 3H); m/z obs.=314 (M+1), 315.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10]=2[CH:11]=1)#[N:2]>C(O)(=O)C.CO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:10]=2[CH:11]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(CN)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 40 °C

Procedure:
6-cyano-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.10 g, 0.257 mmol) was suspended in acetic acid (8 mL). The contents were placed heated at 40° C. under an atmosphere of hydrogen (50 psi; H-cube reactor) at a flow rate of 1 mL/min with recirculation 2 h. Then contents were diluted with MeOH, concentrated in vacuo, and dried under hi vacuum for 18 h. The crude product was dissolved in DCM and purified by silica gel chromatography (eluent: 10-100% gradient of chloroform (containing 10% 2M ammonia in methanol) and dichloromethane. The product was concentrated from MTBE and dried in a vacuum oven at 45° C. for 4 h. The title compound was collected as 68 mg (66%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.75 (m, 2H), 1.82-1.93 (m, 2H), 1.94-2.04 (m, 2H), 2.06-2.17 (m, 6H), 2.21 (s, 3H), 3.85 (s, 2H), 4.35 (d, J=5.05 Hz, 2H), 5.14 (t, J=7.07 Hz, 1H), 5.89 (s, 1H), 7.54 (s, 1H), 7.76 (s, 1H), 8.27 (s, 1H), 8.32 (t, J=5.05 Hz, 1H);
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: COC(C(=O)O)c1cccc2ncccc12
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(C(=O)N(C)OC)c1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
To an ice-cold solution of 2-methoxy-2-(quinolin-5-yl)acetic acid (2.8 g, 12.9 mmol) in anhydrous CH2Cl2 (50 mL) and NMM (3.1 mL, 29 mmol) under argon was added isobutyl chloroformate (1.9 mL, 14 mmol) dropwise. After stirring over an ice bath for 40 min, N,O-dimethylhy droxylamine hydrochloride (1.63 g, 16.8 mmol) was added in three aliquots over a period of 15 min. The mixture was stirred for 15 min then the ice bath was removed. After 24 hrs, saturated aqueous NaHCO3 was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-100% EtOAc-hexanes) gave N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide as an oil which became crystalline upon standing (1.8 g, 60% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:28]([OH:30])=[O:29])[CH3:39])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)OCc4ccccc4)cc3)cc2)CC1
Reactant: CI
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(C)C(=O)O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 82, Step 1, using 1-[4′-(4-benzyloxycarbonylmethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and iodomethane.
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[O:6][CH:7]=1.[H-].[K+].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[O:30]1CCCC1>>[CH2:18]([O:30][C:3]1[CH:4]=[C:5]([Si:8]([CH2:9][CH3:10])([CH2:11][CH3:12])[CH2:13][CH3:14])[O:6][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCI
Reactant: CC[Si](CC)(CC)c1cc(CO)co1
Agent: [H-]
Agent: [K+]
Product: CCCCCCCCCCCCOc1coc([Si](CC)(CC)CC)c1
Reaction time: 96 h

Procedure:
A solution of 4-hydroxymethyl-2-triethylsilylfuran (Compound 1, 160 mg, 0.75 mmol) in tetrahydrofuran (0.5 ml) was added to a suspension of potassium hydride (33 mg, 0.83 mmol) in tetrahydrofuran (1 ml) at room temperature. When all the potassium hydride disappeared, 1-iodododecane (0.37 ml, 1.5 mmol) was added. Stirring was continued for 4 days at room temperature. The reaction mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 5% ethyl ether/hexane. Fractions with Rf of about 0.65 on evaporation gave the titled ether as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([NH2:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:26](=[O:27])C1.C(N(CC)C(C)C)(C)C.[NH:51]1[CH2:56][CH2:55][CH:54]([N:57]2[CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[NH:59][C:58]2=[O:67])[CH2:53][CH2:52]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([C:19]([O:21][CH3:22])=[O:20])[NH:23][C:26]([N:51]3[CH2:52][CH2:53][CH:54]([N:57]4[CH2:66][C:65]5[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=5)[NH:59][C:58]4=[O:67])[CH2:55][CH2:56]3)=[O:27])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COC(=O)C(N)Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
A solution of 5-(2-amino-2-methoxycarbonyl-ethyl)-indazole-1-carboxylic acid tert-butyl ester (307 mg, 0.96 mmol), N,N-disuccinimidyl carbonate (246 mg, 0.961 mmol), and N,N-diisopropylethylamine (0.67 mL, 3.84 mmol) in methylene chloride was stirred for 30 min at room temperature. 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (238 mg, 1.03 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue subjected to flash chromatography using methylene chloride/methanol/triethylamine (93:5:2) as eluent, giving the product (259 mg, 47%). 1H-NMR (CDCl3, 300 MHz) δ 8.13-8.10 (m, 2H), 7.48 (br s, 1H), 7.31 (dd, J=8.8, 1.6 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.82 (s, 1H), 6.66 (d, J=8.0 Hz, 1H), 4.98 (d, J=7.7 Hz, 1H), 4.87-4.81 (m, 1H), 4.58-4.49 (m, 1H), 4.26 (s, 2H), 4.05-3.97 (m, 2H), 3.74-3.67 (m, 4H), 3.29-3.23 (m, 2H), 2.93-2.84 (m, 2H), 1.76-1.62 (m, 1H), 1.70 (s, 9H), 1.48-1.42 (m, 1H). Mass spec.: 577 (MH)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:29]([C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=3[CH:10]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)c(Cl)c2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(Cl)c(Cl)c4)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-3′,4′-dichloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G21) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (150 mg).
Reaction SMILES: C(OCC)C.O=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[C-:20]#[N:21].[Na+].C(=O)([O-])O.[Na+]>O>[C:20]([C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC=C(C#N)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
Diethyl ether (15 ml) and 8 ml of water were added to 790 mg of tert-butyl 4-oxopiperidine-1-carboxylate, 216 mg of sodium cyanide and 672 mg of sodium hydrogen carbonate and the solution was stirred at room temperature for 1.5 hours. The resulting product was extracted with ether, washed with water and a saturated saline solution and dried over sodium sulfate. After the solvent was evaporated in vacuo, 10 ml of chloroform, 0.84 ml of triethylamine and 0.34 ml of methanesulfonyl chloride were added to the resulting residue followed by stirring at room temperature for 20 minutes. The reaction was stopped by water, the product was extracted with chloroform and the organic layer was washed with a saturated sodium hydrogen carbonate and a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo, 10 ml of pyridine was added to the resulting residue and the mixture was stirred for one night under heating to reflux. After cooling to room temperature, the solvent was evaporated in vacuo followed by adding ethyl acetate and water. The organic layer washed with a saturated saline solution and dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=6/1) to give 650 mg of the title compound as a white solid.
Reaction SMILES: Cl/[C:2](/[N+]([O-])=O)=[CH:3]\[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][CH:5]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[N:19]=[CH:18][N:17]=1.N12CCCN=C1CCCCC2>C(O)C>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]2[C:21]3[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=3[O:15][CH:2]=2)=[CH:5][CH:6]=1)[CH3:11]
Reactant: CCc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Reactant: Oc1cc(O)ncn1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(-c2coc3nc[nH]c(=O)c23)cc1
Reaction time: 15 h

Procedure:
Analogously to the literature method [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 11.9 g (85% purity, 47.6 mmol) of 1-[(Z)-2-chloro-2-nitrovinyl]-4-ethylbenzene and 5.9 g (52.3 mmol) of 4,6-dihydroxypyrimidine in 200 ml of ethanol at 60-70° C. for 30 minutes. Then slowly add 14.4 ml (14.6 g, 96.1 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir the resulting reaction solution under reflux for six hours and then at 60° C. for 15 hours. After concentration under reduced pressure, take up the residue in dichloromethane and chromatograph it on silica gel (eluent: cyclohexane/ethyl acetate 1:1→1:5). Stir the resulting solid in diethyl ether and filter. 5.0 g (44% of theory) of the target compound are obtained.
Reaction SMILES: C1(N)CCCCC1.[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+:49]>O>[Na+:49].[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C:16]([O-:18])=[O:17])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)[O-]
Temperature: 22.5 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acid cyclohexylamine salt (6.8 g, 17 mmol) and ethyl acetate (100 ml) were added to an aqueous solution of citric acid (10%, 100 ml) and the organic phase was separated and washed with water (100 ml). Iso-propyl alcohol (20 ml) and 5% rhodium on alumina (51.69) were added and the mixture was stirred at 20-25° C., under hydrogen (10 atmospheres, 150 p.s.i.) for 48 hours and then filtered through celite. To the filtrate was added a solution of sodium hydroxide (0.67 g, 17 mmol) in water and the mixture was stripped and replaced with acetonitrile by distillation at atmospheric pressure to a volume of 30 ml. The mixture was allowed to cool to 20-25° C. and was stirred for 24 hours. The mixture was cooled to 0° C. and then filtered. The residue was washed with acetonitrile (2×10 ml) and then dried in vacuo at 45° C. for 2 hours to leave the title compound as a colourless solid (3.8 g, 69% yield, 95% pure by NMR).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1.Cl>ClCCl.CO.O1CCOCC1>[F:1][CH:2]([F:17])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(CC(F)F)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(CC(F)F)C1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 407A (525 mg) in a mixture of dichloromethane (3 mL) and methanol (2.0 mL) was added hydrogen chloride, 4M in dioxane (5.24 mL). The reaction was stirred for 3 hours, and concentrated to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:10]([CH3:36])=[C:11]([CH3:35])[C:12]2[O:17][C:16]([CH2:19][CH2:20][CH2:21]OS(C3C=CC(C)=CC=3)(=O)=O)([CH3:18])[CH2:15][CH2:14][C:13]=2[C:33]=1[CH3:34].O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[C:10]([CH3:36])=[C:11]([CH3:35])[C:12]2[O:17][C:16]([CH2:19][CH2:20][CH2:21][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)([CH3:18])[CH2:15][CH2:14][C:13]=2[C:33]=1[CH3:34]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCOS(=O)(=O)c1ccc(C)cc1)O2
Reactant: C1CNCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCN1CCNCC1)O2
Yield: 91.7 %

Procedure:
To a refluxing solution of 7.2 g (0.085 mol) of piperazine in 50 ml of toluene was added 3.8 g (8.5 mmol) of the 3,4-dihydro-6-methoxy-2-[3-(p-toluenesulfonyloxy)propyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained in the above manner, followed by refluxing for 6 hours. After cooling, the reaction mixture was poured into water and extracted with diethyl ether. The ether layer was dried over anhydrous sodium sulfate and low-boiling substances were distilled off therefrom under reduced pressure and the excess piperazine was then removed by sublimation under reduced pressure. The thus-obtained residue was purified by silica gel column chromatography to give 2.7 g (91.8% yield) of 3,4-dihydro-6-methoxy-2-[3-(piperazin-1-yl)propyl]-2,5,7,8-tetramethyl-2H-benzopyran.
Reaction SMILES: CS(Cl)(=O)=O.C([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.C(O[CH2:17][CH3:18])(=O)C.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.[CH3:28][C:29]#N>CC(O)C.CC#N>[NH:8]1[C:9]2[C:10](=[CH:28][CH:29]=[CH:17][CH:18]=2)[CH:12]=[CH:11]1
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Reactant: CC#N
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Methane sulphonyl chloride (0.12 g, 1.07 mmol) was added to a solution of Intermediate 3 (0.2 g, 0.71 mmol) and triethylamine (0.143 g, 1.4 mmol) in CH2Cl2 /CH3CN (5 ml/5 ml), at 0° C. The mixture was warmed to room temperature and stirred for 1 h before adding ethyl acetate (30 ml) and washing the solution with saturated NaHCO3 solution (x1) and brine (x1). The organic was dried (MgSO4) and evaporated. To a solution of the resultant residue in IPA (25 ml) and CH3CN (3 ml) was added Intermediate 2 (0.36 g, 1.6 mmol) and Na2CO3 (0.12 g, 1.09 mmol). The mixture was heated at reflux for 8 h then cooled to room temperature and filtered. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (90:8:1) to give the title-indole (0.208 g, 57%). The 2.0 hydrogen oxalate monohydrate salt was prepared, mp 213°-215° C., (Found: C, 52.54, H, 6.04, N, 9.50. C27 H37N5SO3. 2 (C2H2O4).1H2O requires C, 52.46, H, 6.11, N, 9.87%), m/e 511 (M)+, δ(360 MHz, D6 -DMSO) 1.88-2.00 (2H, m, CH2), 2.02 (3H, s, NHCOMe), 2.54 (3H, d, J=4.1 Hz, SO2NHMe), 2.68-3.12 (16H, m, 8 of CH2), 4.34 (2H, s, CH2), 6.79 (1H, br q, SO2NHMe), 7.09 (1H, dd, J=2.0 and 8.3 Hz, Ar-H), 7.15 (2H, d, J=8.5 Hz, Ar-H), 7.18 (1H, d, J=2.0 Hz, Ar-H), 7.33 (1H, d, J=8.3 Hz, Ar-H), 7.48 (2H, d, J=8.5Hz, Ar-H), 7.51 (1H, s, Ar-H), 9.87 (1H, s, NH), 10.89 (1H, s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.[C:24](OCC)(=[O:26])C>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:24][O:26][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([O:13][CH3:12])=[O:23])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: OCc1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCCc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-chlorobenzyl alcohol (4.10 g) in N,N-dimethylformamide (110 ml), sodium hydride (60 to 72%, 952 mg) was added in an ice bath, and the mixed solution was stirred for 30 min. Then, to the resulting solution, 4-(bromomethyl)benzoic acid methyl ester (5.00 g) was added, and the mixed solution was stirred at room temperature for three hours. To the resulting solution, ethyl acetate was added. The resulting solution was washed with water and with a saturated saline solution, sequentially, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=5 to 9%) to give methyl 4-{[2-(4-chlorophenyl)ethoxy]methyl}benzoate (5.25 g).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH2:7]([N:10]1[C@H:19]2[C@@H:14]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18]2)[CH2:13][CH2:12][CH2:11]1)[CH2:8][CH3:9].C(OCC)=O.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O1CCCC1.C(O)(=O)C>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:4][CH:2]=[C:17]2[CH2:18][C@@H:19]3[C@H:14]([CH2:13][CH2:12][CH2:11][N:10]3[CH2:7][CH2:8][CH3:9])[CH2:15][C:16]2=[O:20])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN1CCC[C@@H]2CC(=O)CC[C@H]21
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC=O
Product: CCCN1CCC[C@@H]2CC(=O)C(=COS(=O)(=O)c3ccc(C)cc3)C[C@H]21
Temperature: -25 °C
Reaction time: 1 h

Procedure:
A 22 l. round bottom flask was charged with 568.9 g (5.07 mol) of potassium t-butoxide under a nitrogen atmosphere. To the flask was added 4.1 l of dry tetrahydrofuran and the resulting slurry was cooled to approximately -25° C. To the slurry was added 500.0 g (2.56 mol) of (8aR-trans)-(-)-octahydro-1-(n-propyl)-6(2H)-quinolinone over a period of 15 minutes. The addition funnel was rinsed twice with 30 ml portions of dry tetrahydrofuran and the mixture was allowed to warm to about 12° C. over a period of about 90 minutes. The mixture was warmed to about 25° C. and held at that temperature for about one hour. The mixture was cooled to about -26° C. and 386.8 g (422 ml, 5.22 mol) of ethyl formate was added to the mixture dropwise over a period of about 30 minutes. The mixture was held at about 0° C. overnight, cooled to about -8° C. and 150.0 g of glacial acetic acid was added to the stirred mixture. The pH of the mixture was about 11 following addition of the acid. The mixture was cooled to about -40° C. and a solution of 534.3 g (2.8 mol) of p-toluenesulfonyl chloride in 1610 ml of dry tetrahydrofuran was added rapidly while maintaining the temperature below about -35° C. The mixture was warmed to about 0° C. and held at this temperature for about one hour. The tetrahydrofuran was evaporated from the mixture under vacuum and 2.46 l. of dry DMF was added. The resulting solution containing trans-(-)-octahydro-7-[[[(4-methylphenyl)sulfonyl]oxy]methylene]-1-(n-propyl)-6(2H)-quinolinone was held for further processing.