Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH:18]=[CH:19]/[CH:20]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[BH4-].[Na+]>CO>[OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH:18]=[CH:19]/[CH:20]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCCCCCC(/C=C/C=C/c1ccccc1C(=O)CCCC(=O)OC)OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(/C=C/C=C/c1ccccc1C(O)CCCC(=O)OC)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107.6 %

Procedure:
To 3 ml of methanol was added 0.1g (0.21 mmol) of the titled product of Example 10. The reaction mixture was cooled to 0°C. and 3mg of NaBH4 was added. After 30 minutes, the reaction was complete. The reaction mixture was quenched with acetone and the volatile components were removed in vacuo. The residue was partitioned between diethyl ether (ether) and water. The organic layer was separated and the aqueous layer was extracted once more with ether and the combined extracts were washed with brine and dried (K2CO3). Removal of the solvent produced 0.11g of a pale yellow oil. The product of this reaction was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:23][N:24]=1.Cl[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:32]>N1C(C)=CC=CC=1C>[C:31](=[O:32])([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)[O:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCOC(=O)Cl
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: Cc1cccc(C)n1
Product: CCCCOC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 48 (200 mg, 0.44 mmol) in 2,6-lutidine (2.0 ml) was added butyl chloroformate (73 μl, 0.57 mmol) at 0° C. and stirred at room temperature for 2 h. The crude product was purified by prep HPLC (C18) to provide the titled compound (123 mg, 50%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCNCC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCN(CCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 95 mg (0.26 mmol) of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride and 52 mg (0.51 mmol) of 5-hydroxypentanal.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:22])[CH2:19][CH2:20][CH3:21]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CCCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and n-butanol there is obtained butyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 1.02 (t, CH2CH3), 1.4-2.0 (4H), 4.15 (t, OCH2), 4.27 (s, 4H), 4.57 (broad s, NH), 7.3-7.7 (8H);
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][O:13][CH3:14].Cl>[OH-].[K+].O>[CH3:14][O:13][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COCCOc1ccccc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1ccccc1C(=O)O
Reaction time: 6 h
Yield: 98 %

Procedure:
A mixture of the product of Example 25A (0.27 g, 1.3 mmol) in 40% aqueous potassium hydroxide was stirred for 6 hours. The mixture was then diluted with water, made slightly acidic by the addition of 2 N aqueous HCl, and then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 0.25 g of the title compound.
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([CH2:36][Cl:35])=[CH:38][CH:39]=2)=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 63%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([CH2:21][OH:22])[O:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48](O)[CH:47]=1)=[O:45].CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48]([O:22][CH2:21][CH:13]2[CH:14]3[CH:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[CH:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[Cl:1])[O:12]2)[CH:47]=1)=[O:45]
Reactant: COC(=O)c1cc(O)no1
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(Cl)ncnc43)C2O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2OC(n3cnc4c(Cl)ncnc43)C3OC(C)(C)OC23)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of [6-(6—Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (0.570 g, 1.74 mmol) in 16 mL of dry dichloromethane was added polymer-bound triphenylphosphine (PS-TPP; Argonaut Tech., 2.14 mmol/g, 0.91 g, 1.2 eq), followed by methyl-3-hydroxy-5-isoxazolecarboxylate (0.248 g, 1 eq). The mixture was sonicated for 15 minutes then stirred at room temperature for 1 h under argon. The reaction mixture was cooled to 0° C. and under argon flow diethylazodicarboxylate (0.33 g, 1.1 eq), dissolved in 1 ml of dichloromethane, was added dropwise via syringe. The mixture was protected from light and stirred at 0° C. for 30 min. then at room temperature for 20 h. The resin was washed liberally with dichloromethane and methanol. The organic solution obtained from the washes was concentrated to give, after flash chromatography purification, 0.740 g of the product as a white solid (95% yield). 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (s, 1H), 6.42 (s, 1H), 6.23 (d, J=2.1 Hz, 1H), 5.43 (dd, J=2.1 Hz, 1H), 5.14 (dd, J=3.6 Hz, 1H), 4.7 (m, 1H), 4.61 (dd, J=3.9 Hz, 1H), 4.49 (dd, J=5.7 Hz, 1H), 3.93 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H). MW calculated for C18H18ClN5O7 (MH+) 452, found 452 by LCMS.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc(Br)c2c1NCC2
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4c(Br)ccc(C)c43)c2cc1OC
Yield: 70 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 70% yield from 4-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 223°-225° C.; LC-MS: 400, 402 (MH+); anal. RP18-HPLC RT: 5.23 min.).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24](N)[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(NC1SC=C(CC(O)=O)N=1)=O)(C)(C)C.CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[CH2:24][C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SC(Sc2c[nH]nn2)C(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2CC(=O)N12
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 103.7 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethyl-thio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and 2-(2-t-butoxycarbonylaminothiazol-4-yl) acetic acid (287 mg : 1.11 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N- methylmorpholine (0.27 ml: 2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 40 minutes. The reaction mixture is quenched with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=3:1) to give 7β-2-(2-t-butoxycarbonylaminothiazol- 4-yl) acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4- carboxylic acid diphenylmethyl ester (812 mg) as pale yellow foam Yield : 77%.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH3:26]>C(O)(C(F)(F)F)=O>[C:16]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:22]=[C:23]2[CH2:24][CH2:25][CH3:26])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(O)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(benzyloxy)-N2-phenylpyridine-2,3-diamine (90 mg, 0.31 mmol), trimethyl orthobutyrate (5 mL), and TFA (20 μL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue dissolved in MeOH (5 mL). Palladium on carbon (20% wt./wt., 15 mg,) was added and the mixture was stirred vigorously under H2 (1 atm) for 1 h. The mixture was filtered through Celite® and concentrated to give the title compound as a white solid (26 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.6 Hz, 3H), 1.65 (s, J=7.3 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 6.51 (d, J=8.6 Hz, 1H), 7.45-7.56 (m, 3H), 7.60 (t, J=7.6 Hz, 2H), 7.87 (d, J=8.3 Hz, 1H), 10.75 (br s, 1H).
Reaction SMILES: C([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][S:12][C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=2)[C:7]([C:20]([F:23])([F:22])[F:21])=[N:6]1)(C)(C)C.Br.C(O)(=O)C>O>[Cl:10][C:9]1[NH:5][N:6]=[C:7]([C:20]([F:21])([F:23])[F:22])[C:8]=1[CH2:11][S:12][C:13]1[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=1
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(C(C)(C)C)c2Cl)=NO1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(SCc2c(C(F)(F)F)n[nH]c2Cl)=NO1
Temperature: 45 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
19.8 g (53.4 mmoles) of 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline was added to 170 ml of a 25% hydrogen bromide-acetic acid solution. The mixture was stirred at 40 to 50° C. for 2 hours to give rise to a reaction. After the completion of the reaction was confirmed, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 12.0 g (yield: 60.6%) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light yellow crystals (melting point: 120.0 to 122.0° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a three-neck flask flushed with argon and fitted with a magnetic stir bar was added 30 ml of dry THF, 1,379 gm (6.9 mmol) of p-benzyloxyphenol (the compound of Formula IV), 0.8 gm (6.0 mmol) of (2S,3S)-3-prophloxiranethanol (the compound of Formula V), and 1.98 gm (7.59 mmol) of triphenyl-phosophine. The resulting solution was heated to reflux and 1.2 ml (2.32 gm, 7.59 mmol) of diethyl azodicarboxylate was added over a period of 7 hr. After the addition was complete the reaction mixture was allowed to cool to room temperature and stir for an additional two days under argon. The solvent was then removed, and the residue purified by flash chromatography on silica gel using 85.15 hexanes/ethyl acetate as eluent. In this manner 1.6 gm (78%) of 4-benzyloxy-1-[2S,3S)-epoxyl]-hexyloxybenzene (the compound of Formula VI) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: BrCCc1ccccc1CCBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCc1ccccc1CC2

Procedure:
A mixture of 6-bromo-indan-1-one (300 mg, 1.43 mmol), 1,2-bis(2-bromoethyl)-benzene (414.3 mg, 1.43 mmol) in THF (10 mL) was added NaH (114 mg, 2.86 mmol) at room temperature, the mixture was refluxed for 2 hours. The mixture was quenched with water, concentrated, then extracted with DCM, washed with brine, dried over Na2SO4, concentrated to 6′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-1′(3′H)-one (20 mg, 5%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[O:20]1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]5[O:20][CH2:19][O:27][C:26]=5[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)OCO5)cc3CC[C@@H]12
Yield: 57.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,4-methylenedioxyphenyl boronic acid (131 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 130 mg (57%) of the title compound as an amorphous solid. mp 146°-152°. FDMS: m/e=349. α[D]589 =+67.92 (c=1.06, chloroform).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].O.CC(=O)OCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:12]([CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCNCC
Reactant: Clc1cc(Cl)c(Cl)nn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)c1cc(Cl)nnc1Cl
Reaction time: 72 h

Procedure:
3,4,6-Trichloropyridazine (2 g) and diethylamine (2.4 ml) were initially charged in toluene (10 ml) and left to stand at RT for 3 days. Then the mixture was admixed with water and EA, and the EA phase was removed. The EA phase was washed three times with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (70 g cartridge, n-heptane/EA gradient 0-50% within 60 min). 1.1 g of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31](B2OC(C)(C)C(C)(C)O2)=[C:32]2[C:36]=1[NH:35][CH:34]=[CH:33]2>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[CH2:7][CH:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)=[C:32]2[C:36]=1[NH:35][CH:34]=[CH:33]2
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Reactant: CC1(C)OB(c2ccc(F)c3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4ccc(F)c5[nH]ccc45)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 2 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 90 mg, 0.228 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (119 mg, 0.456 mmol) and PdCl2(dppf) (8.34 mg, 0.011 mmol) in dioxane (2.5 mL) and aqueous saturated NaHCO3 (0.5 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.22 (m, 3H), 3.24-3.36 (m, 2H), 3.39-3.75 (m, 3H), 3.88-4.06 (m, 2H), 4.06-4.16 (m, 1H), 4.62-4.77 (m, 2H), 7.05-7.21 (m, 2H), 7.45-7.53 (m, 1H), 7.55-7.62 (m, 1H), 7.62-7.72 (m, 3H), 7.90-7.97 (m, 2H), 11.85-12.09 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H24FN5O3S, 494.16. found 494.5.
Reaction SMILES: [Si]([O:18][CH2:19][CH:20]1[CH2:26][CH:25]2[CH:23]([CH2:24]2)[CH2:22][N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[OH:18][CH2:19][CH:20]1[CH2:26][CH:25]2[CH:23]([CH2:24]2)[CH2:22][N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CC2CC2CC1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC2CC1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (D14) (2.10 g, 4.5 mmol) in THF (80 ml), TBAF 1M sol. in THF (9.01 ml) was added and the reaction mixture was stirred at RT for 18 hrs. Solvents were evaporated in vacuo and the resulting residue was purified on SPE-Si (5 g) cartridge eluting with a mixture cHex/EtOAc from 90/10 to 40/60. Collected fractions after solvent evaporation afforded the title compound (D15) (0.93 g).
Reaction SMILES: C([O:5][C:6]([C:8]12[CH2:15][CH2:14][CH:11]([CH:12]=[CH:13]1)[N:10]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[O:9]2)=[O:7])CCC.[OH-].[Na+]>O1CCOCC1>[CH2:19]([O:18][C:16]([N:10]1[CH:11]2[CH2:14][CH2:15][C:8]([C:6]([OH:7])=[O:5])([CH:13]=[CH:12]2)[O:9]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCOC(=O)C12C=CC(CC1)N(C(=O)OCc1ccccc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1OC2(C(=O)O)C=CC1CC2
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of di-ester (c) (42.13 g, 0.122 mol) in 1,4-dioxane (250 ml) was added aqueous sodium hydroxide solution (0.5 M, 250 ml, 0.125 mol). The mixture was stirred for 1 hour then washed with diethyl ether (×3). The aqueous phase was adjusted to pH2 with 5 M hydrochloric acid, and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried and evaporated to give a cream solid (29.53 g, 84%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(O)(=O)C>C(O)C>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol), p-anisaldehyde (69 μL, 0.56 mmol) and glacial acetic acid (31 μl) in ethanol (5 mL) was stirred at room temperature for 1 h. The resultant precipitate was collected by filtration and isolated as a white solid (100 mg, 59%). 1H NMR (CDCl3): 9.05 (s, 1H), 7.72 (s, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.44 (d, J=6.9 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 6.23-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.85 (s, 3H), 3.06 (s, 1H), 2.96 (s, 1H), 1.94-1.86 (m, 1H), 1.67 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.45-1.40 (m, 1H).