Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12](=[O:35])[C@H:13]1[O:22][C@@H:17](OC(=O)C)[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:27][C:28](=[O:30])[CH3:29])[C@@H:14]1[O:31][C:32](=[O:34])[CH3:33].[Cl:36][C:37]([Cl:41])([Cl:40])[CH2:38][OH:39]>ClCCl>[CH3:10][O:11][C:12](=[O:35])[C@H:13]1[O:22][C@H:17]([O:39][CH2:38][C:37]([Cl:41])([Cl:40])[Cl:36])[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:27][C:28](=[O:30])[CH3:29])[C@@H:14]1[O:31][C:32](=[O:34])[CH3:33]
Reactant: OCC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H]1O[C@H](OCC(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BF3-Et2O (15 ml) was added dropwise to a cooled solution at 0° C. of 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronic acid methyl ester (11.23 g, 0.03 mol) and 2,2,2-trichloroethanol (20 ml) in anhydrous dichloromethane (250 ml) under inert atmosphere. The mixture was stirred at room temperature overnight and then washed with 1N HCl (100 ml), water (100 ml) and brine (100 ml). The organic phase was dried over sodium sulphate, filtered and concentrated to dryness. 1-O-trichloroethyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronic acid methyl ester 1 (8.95 g) was obtained after recrystallization of the crude product from ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH:17][C:18](=[O:28])[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][CH2:31][O:32][C:33](/[C:35](/Cl)=[N:36]\[OH:37])=[O:34].CCN(CC)CC.C(OCC)(=O)C>C(Cl)Cl>[CH2:31]([O:32][C:33]([C:35]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:29])[NH:17][C:18](=[O:28])[C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[O:37][N:36]=1)=[O:34])[CH3:30]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#Cc1ccc(CC(NC(=O)c2c(C)cc(C)cc2C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc(CC(NC(=O)c3c(C)cc(C)cc3C)C(=O)OC(C)(C)C)cc2)on1
Temperature: 0 °C
Yield: 65.4 %

Procedure:
195 mg (0.498 mmol) of (3) and 377 mg (2.49 mmol) of ethyl chlorooximido acetate were dissolved in 4 ml of DCM and cooled to 0° C. 417 μl (2.99 mmol) of Et3N dissolved in 4 ml of DCM were added slowly (1 drop/7 seconds). After 3 h additional 3 eq. of ethyl chlorooximidoacetate and Et3N were added. The reaction mixture was poured into ethyl acetate, washed with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was purified by column chromatography on silica gel using ethyl acetate/hexane to give 165 mg of (4).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]([CH2:15][CH2:16][N:17]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C[CH:37]([C:42]1[C:43]([CH2:45][C:46]([CH3:51])([CH3:50])[CH2:47][C:48]=1[CH3:49])=[O:44])[CH2:38][CH2:39][CH2:40][CH3:41].C(O)(=O)C.C(=O)(O)[O-].[Na+]>COCCOCCOC>[O:7]([CH2:15][CH2:16][N:17]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[CH:49][C:48]2[CH2:47][C:46]([CH3:50])([CH3:51])[CH2:45][C:43](=[O:44])[C:42]=2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:1])=[CH:30][CH:29]=1)[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1ccc(C=O)cc1
Reactant: CC(C)(C)[O-]
Reactant: CCCCC(C)C1=C(C)CC(C)(C)CC1=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CC(=O)O
Product: CCCCCCC1=C(C=Cc2ccc(N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc2)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 11 %

Procedure:
Potassium t-butoxide (30.32 g, 97%, 0.262 mol.) was added to a solution of p-N,N-Bis(2-t-butyldimethylsiloxyethyl)aminobenzaldehyde (, 53.4 g, 0.122 mol.) and 2-hexyl-isophorone (compound 10, 26.6 g, 0.118 mol.) in diglyme (200 mL, KOH dried) over 3 min. Ice bath was used to keep the temperature below 50° C. The reaction mixture was stirred at room temperature for 25 min. and then was poured to dilute acetic acid (0.28 mol HOAc in 200 mL of water). The extra acid was neutralized saturated aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried with magnesium sulfate and rotovapped to dryness. The residue was purified by a silica gel column using ethyl acetate/hexane (1/20, v/v) to afford 8.33 g red thick oil: yield 22% based on reacted starting material. Only about starting materials reacted. 1H NMR (CDCl3): δ7.36 (d, 8.81 Hz, 2H), 7.14 (d, 16.06 Hz, 1H), 6.88 (d, 16.09 Hz, 1H), 6.69 (d, 8.91 Hz, 2H), 3.78 (t, 6.06 Hz, 4H), 3.56 (t, 5.89 Hz, 4H), 2.53 (br, 2H), 2.48 (s, 2H), 2.29 (s, 2H), 1.33 (m, 8H), 1.05 (s, 6H), 0.90 (s, 18H), 0.04 (s, 12H) ppm. 13C NMR (CDCl3): δ198.87, 148.41, 147.67, 134.47, 134.19, 128.52, 124.38, 121.71, 111.54, 60.21, 53.42, 51.37, 39.82, 32.27, 31.65, 29.90, 29.37, 28.39, 25.79, 24.30, 22.54 ppm.
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=[O:21])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]([C:32]2[CH:42]=[C:41]([CH3:43])[C:35]3[N:36]([CH3:40])[C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)=[O:31])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][N:36]1[C:35]2[C:41]([CH3:43])=[CH:42][C:32]([C:30]([C:25]3[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([N:4]4[CH2:5][CH2:6][CH:7]([N:8]5[CH2:14][CH2:13][C:12]6[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=6[NH:10][C:9]5=[O:21])[CH:2]([F:1])[CH2:3]4)[CH:24]=3)=[O:31])=[CH:33][C:34]=2[O:38][C:37]1=[O:39]
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1F)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)nc(C)n3)CC1F)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
82 mg (0.28 mmol) 3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 85 mg (0.27 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.10 mL (0.56 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H][H]>C(O)C.[Pd]>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccccc12
Yield: 65.3 %

Procedure:
(R)-5-Bromo-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole (60 mg, 0.2 mmol) was dissolved in ethanol (1 mL) and hydrogenated over 10% palladium on carbon (45 mg) at 60 p.s.i. of hydrogen pressure at room temperature for 16 hours. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic phase was dried (Na2SO4), and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluting with 89:10:1 CH2Cl2 :MeOH:NH4OH) to give the title compound (28 mg). Anal. Calcd for C14H18N2 ·1/8 CH2Cl2C, 75.42; H, 8.18; N,12.46 Found: C,75.50; H,8.51; N,12.09⟦alpha⟧sup.25D =+60.2° (c=0.088, CHCl3).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].O>CN(C=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:8][O:9][CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C)(C)OC[C@H](CO)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COC[C@@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of compound 14b (562 mg, 2.0 mmol) in DMF (10 mL) at 0° C. was added NaH (200 mg, 5.0 mmol). The reaction was stirred for 30 min and to it was added methyl 2-(bromomethyl)benzoate (366 mg, 1.6 mmol). The reaction mixture was stirred for 3 h, poured into H2O and extracted with EA (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give compound 14c (275 mg, 40% yield) as an oil.
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][C:6]1[C:15]2[C:10](=[C:11]([O:16]C)[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1>ClCCl.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:5][C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cccc2c(Cl)ncnc12
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1cccc2c(Cl)ncnc12
Temperature: 25 °C

Procedure:
A solution of boron trichloride in dichloromethane (1.0 molar, 46.0 mL) is added via syringe to a solution of 4-chloro-8-methoxyquinazoline (2.24 g, 11.5 mmol) in chloroform, under a nitrogen atmosphere. The reaction mixture is heated at reflux for 1/2 hour, cooled to room temperature and diluted with a mixture of ice and saturated sodium bicarbonate solution. The phases are separated and the aqueous phase is extracted with chloroform. The organic phases are combined, washed with a 10% ethylenediaminetetraacetic acid (EDTA) solution, dried over MgSO4 and concentrated in vacuo to obtain the title product as a white solid, 1.93 g (93%), mp>252° C.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][N:15]([CH2:17][CH2:18][C@@H:19]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:20][N:21]([CH3:35])[C:22](=[O:34])[C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Br:33])[CH:24]=4)[CH2:14]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4]C[CH2:2]1.N1CC(N2CCC(C(N(C)C)=O)CC2)C1.[C:58]([OH:61])(=[O:60])C>CO>[CH:58]([OH:61])=[O:60].[CH:58]([OH:61])=[O:60].[Br:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=1)[C:22]([N:21]([CH3:35])[CH2:20][C@H:19]([C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[CH2:18][CH2:17][N:15]1[CH2:14][CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([N:1]([CH3:2])[CH3:4])=[O:6])[CH2:8][CH2:9]2)[CH2:16]1)=[O:34]
Reactant: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: CN(C)C(=O)C1CCN(C2CNC2)CC1
Solvent: CO
Product: CN(C)C(=O)C1CCN(C2CN(CC[C@H](CN(C)C(=O)c3cc(Br)cc(C(F)(F)F)c3)c3ccc(F)cc3)C2)CC1
Product: O=CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
A mixture of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 0.178 g, 0.40 mmol), 1-azetidin-3-yl-N,N-dimethylpiperidine-4-carboxamide (see method 3; 0.084 g, 0.40 mmol), acetic acid (0.3 mL), (polystyrylmethyl)trimethylammonium cyanoborohydride (0.098 g, 0.52 mmol) and methanol was stirred at RT for 6 h. The resin was filtered off and washed with methanol. The solvent of the filtrate was removed by evaporation and the product was purified by reversed phase chromatography (C8) using acetonitrile and aqueous ammonium formate/formic acid solution (0.1 M N4CO2H, 0.1 M HCO2H, pH 4) as eluent. There was obtained 0.23 g (77%) of the title compound. 1H NMR (500 MHz, CD3OD): δ 1.6-2.0 (cm, 6H), 2.6-4.2 (cm, 24H), 7.0-8.0 (cm, 6H), 8.4 (s, 1H); LCMS: m/z 642 (M+1)+.
Reaction SMILES: COCCC[N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1.BrN1C(=O)CC[C:22]1=[O:27].O.Cl[CH2:30]Cl>>[CH3:30][O:27][CH2:22][CH2:19][CH2:18][O:17][C:15]([C:12]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][NH:6][C:14]=2[CH:13]=1)=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: ClCCl
Reactant: CCOC(=O)c1cc2c(ccn2CCCOC)cn1
Solvent: O
Product: COCCCOC(=O)c1cc2[nH]ccc2cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2.00 g) in dichloromethane (40 mL) was added N-bromosuccinimide (1.49 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→4/1) to give ethyl 3-bromo-1-(3-methoxypropyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-3)] (2.12 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>O1CCCC1.[Ni].O>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(F)c(N2CCSCC2)c(F)c1
Reaction time: 24 h

Procedure:
A solution of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine (3.00 g, 11.5 mmol) in tetrahydrofuran (60 mL) is added to a Parr bottle containing a mixture of Raney nickel (1 g) in water (15 mL) under N2, and the reaction mixture is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 24 hrs. The catalyst is removed by filtration through Celite, rinsing with tetrahydrofuran and water, the filtrate is diluted with water (50 mL) and EtOAc (50 mL), and the layers are separated. The organic phase is washed with saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil is chromatographed on a Flash 40M 90 g silica gel cartridge eluting with EtOAc/heptane (15/85). Pooling and concentration of those fractions with an Rf=0.19 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 85-86° C.; MS (ESI+) for C10H12N2F2S m/z 231 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:18]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH:34]=O)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[C:36]([CH:41]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1>[CH2:4]([O:3][C:1]([N:11]1[CH2:15][CH2:14][CH:13]=[C:12]1[CH:16]=[CH:41][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH2:21]([O:20][C:18]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH:34]=[CH:41][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=CC1CCCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1=CCCN1C(=O)OCc1ccccc1
Product: CCOC(=O)C=CC1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-carbobenzyloxypyrrolidine-2-carboxaldehyde or N-carbobenzyloxypiperidine-2-carboxaldehyde (5.00 mmol) [S. Kiyooka, et al., J. Org, Chem., 5409 (1989) and Y. Hamada, et al., Chem. Pharm. Bull., 1921 (1982)] in anhydrous tetrahydrofuran at -78° C. was added (carbethoxymethylene) triphenylphosphorane (2.09 g, 6.00 mmol. 1.2 eq) as a solid portionwise. The resulting reaction mixture was stirred at room temperature under nitrogen for 2 hours, and then heated at reflux under nitrogen for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was column chromatograPhed using silica gel (approximately 100 g) and elution with 20% diethyl ether in hexanes afforded either ethyl 3-(N-benzyloxycarbonylpyrrolin-2-yl)-2-propenoate or ethyl 3-(N-benzyloxycarbonylpiperid-2-yl)-2-propenoate.
Reaction SMILES: [CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@@H:7]([CH2:18][OH:19])[NH:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:27](=[S:29])=[S:28].[CH3:30]I>CS(C)=O>[CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@@H:7]([CH2:18][OH:19])[N:6]1[C:27]([S:29][CH3:30])=[S:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Reactant: CI
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCC[C@H]1c2[nH]c3ccccc3c2C[C@@H](CO)N1C(=S)SC
Yield: 60 %

Procedure:
In the same manner as described in Example 13 by using (1RS, 3RS)-cis-1-butyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (1.05 g), triethylamine (0.53 g), CS2 (0.50 g), methyl iodide (0.95 g) and dimethylsulfoxide (8 ml), there is prepared the title compound (0.85 g, 61%) as white powder. NMR (CDCl3, δ): 0.96 (t, J=7.0 Hz, 3H, C1 --(CH2)3CH3), 2.72 (s, 3H, CSSCH3), Mass m/e: 348 (M+), 300 (M+ --CH3SH).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:9][C@:10]12[CH2:27][CH2:26][C@H:25]3[C@@H:15]([CH2:16][CH2:17][C@@H:18]4[C@:23]3([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]4)[C@@H:14]1[CH2:13][CH2:12][C:11]2=O.C([BH3-])#N.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C.CO>[CH3:9][C@:10]12[CH2:27][CH2:26][C@H:25]3[C@@H:15]([CH2:16][CH2:17][C@@H:18]4[C@:23]3([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]4)[C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:8]
Reactant: NCCCCCCN
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCCCCCCN)CC[C@@H]12
Yield: 124.9 %

Procedure:
A 100ml round-bottomed flask, equipped with a magnetic stir bar, condenser, and nitrogen inlet tube, was charged with 1,6-hexanediamine (0.904 g) and 15 ml of methanol. The solution was treated with glacial acetic acid until the pH was 6.7. To this mixture was added 15 ml of tetrahydrofuran, 5α-androstan-17-one (0.704 g) and sodium cyanoborohydride (0.228 g). The mixture was heated to reflux for 18 h. After cooling, the solution was made basic with aqueous 2M sodium hydroxide to a pH of 13-14. The solution was extracted with chloroform (3×) and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 1.2 g of an oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CN(C=[O:21])C>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:21])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C(N)=O)cc2)CC1
Temperature: 90 °C
Yield: 80 %

Procedure:
4-Fluorobenzonitrile (12 g, 99 mmol, 1 eq.) and 100 mL of DMF are placed in a 250 mL round-bottomed flask. N-Methylpiperazine (16 mL, 1.6 eq., 123 mmol) is added to this solution. The orange solution is heated at a temperature in the region of 90° C. for 15 hours. The solvent is then evaporated to dryness and the residue is diluted with 500 mL of diethyl ether. The solution is washed with sodium hydrogen carbonate solution (2×100 mL) and then with saturated sodium chloride solution (100 mL). After evaporation, the 4-(4-methylpiperazin-1-yl)benzonitrile (orange solid, 10 g, 77%) is used without further purification in the following hydrolysis step. It is added at a temperature in the region of 0° C. to a solution of 98% sulfuric acid (25 mL) and 5 mL of water. The purple solution is then heated at a temperature in the region of 100° C. for 8 hours. The solution is cooled and then hydrolyzed by pouring onto ice. The pH is adjusted to 9-10 with sodium hydroxide pellets. The precipitate obtained is filtered off and washed thoroughly with water and then with tetrahydrofuran, which partially dissolves the product. The water is separated out by settling. After evaporating the organic phase to dryness, a solid is obtained, which is purified by chromatography on silica gel, eluting with a methanol/dichloromethane mixture (15/85 by volume). 4-(4-Methylpiperazin-1-yl)benzamide (8.7 g, 80%) is thus obtained in the form of a white solid, which is used directly in the following step.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=3)[CH2:1]2)=[CH:15][CH:14]=1
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: ClC/C=C/c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)CCN(C/C=C/c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 36 h
Yield: 62.4 %

Procedure:
A mixture of 2 g of 1,2,3,4-tetrahydro-6-isoquinolinol and 2.5 g of (E)-1-chloro-4-[3-chloro-1-propenyl]-benzene, 2 g of potassium carbonate and 50 ml of DMF was stirred for 36 hours at 25° C. and then the DMF was evaporated off under reduced pressure. The residue was taken up in a mixture of methylene chloride and water and filtration was carried out to obtain 2.5 g of the desired product melting at 233-234° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH:13]([OH:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[OH:16][CH:13]1[C:12]2[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=2[C:6]2[CH:7]=[C:2]([C:22]#[C:21][C@:23]3([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:3]=[CH:4][C:5]=2[O:15][CH2:14]1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: COC(=O)c1nc2c(s1)C(O)COc1ccc(Br)cc1-2
Product: COC(=O)c1nc2c(s1)C(O)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (0.37 g) was subjected to General Procedure 0 to afford 280 mg (75%) of methyl 9-bromo-4-hydroxy-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Methyl 9-bromo-4-hydroxy-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (128 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford methyl 4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 25 mg and 7.9 mg (26% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1ccc(C)cc1C=O)OC
Yield: 94.1 %

Procedure:
To a solution of 100 mg (0.73 mmol) of 2-hydroxy-5-methyl-benzaldehyde in DMF (1 ml) were added 109 μl (0.92 mmol) of 2-bromo-1,1-dimethoxy-ethane and 112 mg (0.81 mmol) of potassium carbonate. The reaction mixture was heated to reflux for 90 min. Then water was added at RT and the mixture was extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to yield 2-(2,2-dimethoxy-ethoxy)-5-methyl-benzaldehyde as a yellow oil (154 mg, 93%). 1HNMR (CDCl3, 300 MHz): δ 2.32 (s, 3H), 3.48 (s, 6H), 4.09 (d, J=5.3 Hz, 2H), 4.75 (t, J=5.3 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4 and 2.3 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 10.48 (s, 1H).