Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[N:16]=[C:15]([C:36]([OH:38])=[O:37])[CH:14]=1)[CH2:10][CH2:11][CH3:12].[F:39][C:40]([F:44])([F:43])[CH2:41]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>ClCCl.C(N(CC)CC)C>[CH2:9]([C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:21][CH:20]=2)[N:16]=[C:15]([C:36]([O:38][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:37])[CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1cc(C(=O)OCC(F)(F)F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
N-Chlorosuccinimide (400 mg) was added to a stirred solution of 5-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrazole-3-carboxylic acid (682 mg), triethylamine (1.2 g), 2,2,2-trifluoroethanol (248 mg) and triphenylphosphine (891 mg) in dichloromethane (30 ml) by cooling with an ice-bath. After stirring for 15 minutes, triphenylphosphine (262 mg) and N-chlorosuccinimide (133 mg) were added and the mixture was stirred for 30 minutes. After addition of 2N-hydrochloric acid (15 ml) and stirring at room temperature for 30 minutes, the mixture was allowed to separate into layers. The organic layer was washed with water, dried, and concentrated to dryness to give a syrup, which was then purified by column chromatography on silica gel, to give a yellow syrup (460 mg, 58%).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Cl.[OH-].[Na+].[CH3:14][CH2:15]O>O>[CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([C:8]([O:10][CH2:14][CH3:15])=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCC(C(=O)O)CN1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1CCC(C)NC1
Temperature: 25 °C

Procedure:
To 194.1 (1044 mg, 7.29 mmol) in EtOH (5207 μL) was added concentrated hydrochloric acid (405 μL, 7.29 mmol). The resulting solution was heated at reflux for 18 hours. The reaction mixture was then cooled to room temperature and poured onto water. The reaction was brought to pH 10 with 1N sodium hydroxide in water and was then extracted with EtOAc. The organic phase was then dried over anhydrous Na2SO4 and filtered to provide ethyl 6-methylpiperidine-3-carboxylate. ESI-MS M+H 172.2.
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][S:3]1.[ClH:24]>C(Cl)Cl>[CH3:1][C@@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][S:3]1.[ClH:24]
Reactant: C[C@H]1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1SCc2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (prepared according to Example 1, Steps 1-5) (1.05 g, 3.12 mmol) in CH2Cl2 (20 mL) was added HCl (4M, in dioxane, 4 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford (R)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine as HCl salt (0.74 g, 99%). MS (APCI+) [M+H]+ 237.
Reaction SMILES: [NH3:1].[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[O:10]>[Pd].[H][H]>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[O:10].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: N
Agent: [Pd]
Agent: CC1CCCC(C)C1=O
Product: Cc1cccc(C)c1N
Temperature: 220 °C

Procedure:
A catalyst which is in the form of extrudate of 3 mm diameter and 10 mm length and which contains 1.8% by weight of palladium on a zinc-aluminum spinel as the carrier is introduced into a reactor consisting of a pressure-resistant cylindrical tube of 1.2 liters volume, and is heated to 220° C. Per hour, a gaseous mixture of 200 liters (S.T.P.) of ammonia and 200 liters (S.T.P.) of hydrogen and 100 g of vaporized 2,6-dimethylcyclohexan-1-one are passed over this catalyst bed under atmospheric pressure. The reaction product is cooled as soon as it leaves the reactor, and is distilled. 100 g of 2,6-dimethylcyclohexan-1-one give 93 g of 2,6-dimethylaniline of boiling point 216° C. at atmospheric pressure, corresponding to a yield of 97% of theory.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:15][CH2:16][CH2:17][C:18](OC)=[O:19].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:15][CH2:16][CH2:17][C:18]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:19]
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CCCC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.50 g (2.8 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (14 mL). After addition of 1.0 g (2.8 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC[C@H](O)c1ccccc1
Solvent: C1CCOC1
Product: NCC[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a THF solution of (S)-3-phenyl-3-hydroxypropanenitrile was slowly added THF solution of borane dimethyl sulfide complex at room temperature. Methyl sulfide was then distilled from the reaction vessel and the resulting THF solution refluxed for 2.5 h. After cooling to room temperature methanolic HCl was added to the reaction mixture. Methanol and methyl borate were removed by distillation and the reaction mixture neutralized with sodium hydroxide (5N). Extraction of the mixture with dichloromethane,followed by concentration provided the crystalline (S)-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][C:8]1[O:13]C(C)(C)O[C:10](=[O:16])[CH:9]=1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[O:23].CS(O)(=O)=O>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[N:18]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=2)[C:10](=[O:16])[CH:9]=[C:8]([OH:13])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)CC1=CC(=O)OC(C)(C)O1
Reactant: NC(=O)c1cccc(N)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: CC(=O)OCc1cc(O)cc(=O)n1-c1cccc(C(N)=O)c1
Temperature: 70 °C

Procedure:
3-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2 oxopropyl acetate (4.00 g, 16.52 mmol) was dissolved in 1,4-dioxane (160 mL) and 3-aminobenzamide (1.73 g, 12.71 mmol) was added. The reaction was heated to reflux for 1 hour then cooled to 70° C. Methanesulfonic acid (1.22 g, 12.71 mmol) was added and the reaction brought back to reflux for 1 hour. The reaction was cooled to room temperature, concentrated and used as crude product for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[N:16][O:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:23](=[O:24])[O:12][N:11]=[C:10]2[C:13]2[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[N:16][O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Product: COCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A mixture of N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (76.5 g, 0.204 mol), 1,1′-carbonyldiimidazole (49.7 g, 0.307 mol), and ethyl acetate (720 mL) was heated to 60° C. and stirred for 20 min. LCMS indicated reaction completed. The reaction was cooled to room temperature, washed with 1 N HCl (2×750 mL), dried over sodium sulfate, and concentrated to give the desired product (80.4 g, 98%) as a crude brown solid. LCMS for C13H12BrFN5O4 (M+H)+: m/z=400.0, 402.0. 1H NMR (400 MHz, DMSO-d6): δ 7.94 (t, J=8.2 Hz, 1H), 7.72 (dd, J=9.1, 2.3 Hz, 1H), 7.42 (m, 1H), 6.42 (t, J=5.7 Hz, 1H), 3.46 (t, J=5.4 Hz, 2H), 3.36 (t, J=5.8 Hz, 2H), 3.26 (s, 3H).
Reaction SMILES: OC1C(OC)=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)C[C@@H]4CCCC(O)=O)CCC=2C=1.[OH:29][C:30]1[C:47]([O:48][CH2:49][CH2:50]OC)=[CH:46][C:45]2[C@@H:44]3[C@H:35]([C@H:36]4[C@@:40]([CH2:42][CH2:43]3)([CH3:41])[C:39](=[O:53])[CH2:38][C@@H:37]4[CH2:54][CH2:55][CH2:56][C:57]([OH:59])=[O:58])[CH2:34][CH2:33][C:32]=2[CH:31]=1>>[CH2:49]([O:48][C:47]1[C:30]([OH:29])=[CH:31][C:32]2[CH2:33][CH2:34][C@@H:35]3[C@@H:44]([C:45]=2[CH:46]=1)[CH2:43][CH2:42][C@@:40]1([CH3:41])[C@H:36]3[C@@H:37]([CH2:54][CH2:55][CH2:56][C:57]([OH:59])=[O:58])[CH2:38][C:39]1=[O:53])[CH3:50]
Reactant: COCCOc1cc2c(cc1O)CC[C@H]1[C@@H]3[C@@H](CCCC(=O)O)CC(=O)[C@@]3(C)CC[C@H]21
Agent: COc1cc2c(cc1O)CC[C@H]1[C@@H]3[C@@H](CCCC(=O)O)CC(=O)[C@@]3(C)CC[C@H]21
Product: CCOc1cc2c(cc1O)CC[C@H]1[C@@H]3[C@@H](CCCC(=O)O)CC(=O)[C@@]3(C)CC[C@H]21

Procedure:
4-(3-Hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15α-yl)-butyric acid (IVα-(C2-B)-3a) and 4-(3-Hydroxy-2-(2-methoxy-ethoxy)-17-oxo-estra-1,3,5(10)-trien-15α-yl)-butyric acid (IVα-(C2-E)-3a)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16][CH:17]=[C:18]([CH3:26])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:25])[CH2:23]O.P(Br)(Br)[Br:28]>C1COCC1>[Br:28][CH2:23][C:22]([CH3:25])=[CH:21][CH2:20][CH2:19][C:18]([CH3:26])=[CH:17][CH2:16][C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1]
Reactant: BrP(Br)Br
Reactant: COc1c(C)c(CC=C(C)CCC=C(C)CO)c(OC)c2ccccc12
Solvent: C1CCOC1
Product: COc1c(C)c(CC=C(C)CCC=C(C)CBr)c(OC)c2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 157.4 %

Procedure:
6.45 g (18.22 mmol) of 8-(1,4-dimethoxy-3-methyl-naphtalen-2-yl)-2,6-dimethyl-octa-2,6-dien-1-ol was dissolved in 45 ml of dry THF. At 0° C., 0.9 ml (2.59 g, 9.58 mmol) PBr3 was added drop wise via septum and syringe and the clear, colourless solution was stirred at 0° C. for 3 h. The reaction was quenched by addition of ice cold water. The layers were separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-(8-bromo-3,7-dimethyl-octa-2,6-dienyl)-1,4-dimethoxy-3-methyl-naphtalene as a colorless oil (6.29 g, 15.08 mmol, 83%). The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)C=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:7][C:8]1[CH:15]=[C:14]([CH:4]=[CH:3][C:1]#[N:2])[CH:13]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: N#CCC(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CC=Cc1cccc(F)c1
Yield: 80.2 %

Procedure:
A mixture of 35.0 g (411 mmol) of cyanoacetic acid (CAS 372-09-8) and 56.2 g (453 mmol) of 3-fluorobenzaldehyde (CAS 456-48-4) in a mixture of 400 ml of toluene and 220 ml of pyridine is refluxed for 22 hours using Dean-Stark apparatus to remove the water formed during the reaction. The solvent is then removed under reduced pressure and the residue is co-evaporated 3 times with toluene. The residue is then taken up in ethyl acetate and the organic phase is washed successively with aqueous 1N sodium hydroxide solution, aqueous 1N hydrochloric acid solution and then with saturated sodium chloride solution. The organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of silica gel, eluting with toluene, to give 48.5 g a mixture of (E) and (Z) 3-(3-fluorophenyl)-2-propenenitrile in a ratio of (7/3)
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28]CC[Si](C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:35][CH:36]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)OCC[Si](C)(C)C)cc4)cc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 110.0 mg (0.213 mmol) 2-trimethylsilylethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]oxy]-benzoate (Compound 38) and 167.3 mg of tetrabutylammonium flouride (0.640 mmol, 0.64 ml of a 1M solution in THF) in 2.0 ml THF was stirred at room temperature for 22 hours. Ethyl acetate was added and the resulting solution washed with H2O and saturated aqueous NaCl then dried over MgSO4. Removal of the solvents under reduced pressure and washing of the residual solid with EtOAc and CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.10 (2H, d, J=8.8 Hz), 8.06 (1H, dd, J=2.0, 8.1 Hz), 7.82 (1H, d, J=1.9 Hz), 7.64 (1H, d, J=8.1 Hz), 7.35 (2H, d, J=8.6 Hz), 7.25 (4H, m), 6.08 (1H, t, J=4.7 Hz), 2.42 (2H, d, J=4.7 Hz), 2.35 (3H, s), 1.39 (6H, s).
Reaction SMILES: [Br-:1].[NH4+].CC1C=CC(S(O[C:14]2[CH2:18][CH:17]([C:19](=[O:36])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[C:28](=[O:35])[NH:29][CH:30]([CH:32]3[CH2:34][CH2:33]3)[CH3:31])[N:16]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:15]=2)(=O)=O)=CC=1.CN(C)C=O>O>[Br:1][C:14]1[CH2:18][CH:17]([C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28](=[O:35])[NH:29][CH:30]([CH:32]2[CH2:34][CH2:33]2)[CH3:31])=[O:36])[N:16]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:15]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 93 °C
Yield: 12.9 %

Procedure:
0.54 g of ammonium bromide was added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 25 ml of N,N-dimethylformamide, followed by heating to 93° C. One hour later, the reaction liquid was poured to 50 ml of water, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.11 g of the desired product in the form of a paste.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Main Culture: After inoculating the seed culture fluid with 50 ml of the fermentation medium contained in the 250 ml flask, it was cultured in a shaking culture medium at 220 rpm and 30° C. until fructose was completely exhausted. The pH of the medium was not controlled after it was adjusted to 5.0 at the initial stage of the fermentation. Wherein, the components of the medium were 50 g/L of glucose, 100 g/L of fructose, 5 g/L of a yeast extract, 2.5 g/L of ammonium sulfate and 2.5 g/L of dibasic potassium phosphate. The results of observing production of mannitol with the passage of time are shown in table 5. The maximum specific proliferation rate of the isolated strain was 0.26 h−1, the maximum quantity of biomass thereof was 3.9 g/L, and 42 g/L of mannitol was produced.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:20]=[CH2:21])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:34].[Na+].OO>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:20]([OH:34])[CH3:21])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (477 mg, 0.95 mmol) in THF (9.5 mL). Cool to 0° C. Add BH3 (1.9 mL, 1.89 mmol, 1M in THF). Stir 4 h at room temperature. Cool to 0° C. Add NaOH (3.8 mL, 3 M in water) and H2O2 (0.58 mL, 30% wt/wt % in water). Stir overnight at room temperature. Add ethyl acetate, wash with saturated NaHCO3 solution and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (mixture of diastereomers) as a white foam (92 mg, 0.19 mmol). MS (m/z): 522 (M+1); and 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one as a white foam (254 mg, 0.49 mmol). MS (m/z): 522 (M+1).
Reaction SMILES: CO.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1.[BH4-].[Na+].Cl>O1CCCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2ccccn2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCc1csc(-c2ccccn2)n1
Yield: 76 %

Procedure:
40 ml of methanol were added slowly to a mixture of 9.3 g of the ester of Stage C and 4.1 g of sodium borohydride in 100 ml of tetrahydrofuran and the mixture was refluxed for 2 hours. The reaction medium was allowed to return to ambient temperature and was poured into water and neutralized using N hydrochloric acid. Extraction was carried out with dichloromethane and the organic phase was dried. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica (eluant: AcOEt--CH2Cl2 1-1) to obtain 5.8 g of the expected product melting at 100° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[CH3:36][N:37]([CH3:61])[CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]=1NS(C)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:45]=[CH:46][C:41]([O:40][CH2:39][CH2:38][N:37]([CH3:61])[CH3:36])=[CH:42][CH:43]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCN(C)C)cc4)cnc32)cc1
Yield: 45.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step 1 of Example 14) (100 mg, 0.18 mmol) was coupled with N-(2-(2-(dimethylamino)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (Intermediate 27) (229 mg, 0.596 mmol) in sodium carbonate (57 mg, 0.54 mmol) Pd(PPh3)2Cl2 (6 mg, 0.009 mmol), Toluene/ethanol/water (5/2.5/1 ml) to afford 52 mg (39.39% yield) of the titled compound after purification by preparative TLC (SiO2-eluted by 5% methanolic ammonia in DCM). MS: m/z=731.4 (M+1).
Reaction SMILES: Cl[O-].[Na+].[NH2:4][C:5]([CH3:12])([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]#[N:7]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[N:4]([C:5]([CH3:12])([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]#[N:7])=[N:4][C:5]([CH3:12])([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]#[N:7]
Reactant: CC(C)CC(C)(N)C#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C

Procedure:
Next, 213 g of a 10% aqueous sodium hypochlorite solution was cooled to 5° C. and 0.5 g of benzyltriethylammonium chloride was added thereto. To the resulting aqueous solution was added 200 ml of an ethyl acetate solution containing 33 g of the resulting 90%-pure 2-amino-2,4-dimethylpentanonitrile over 30 minutes with stirring. This reaction mixture was stirred at 5° to 10° C. for 3 hours, and the organic and water phases were separated from each other. Ethyl acetate was removed from the organic phase under reduced pressure. The resulting white crystals were washed with water and dried to obtain 24.8 g of 2,2'-azobis(2,4-dimethylpentanonitrile). Yield was 85 mole %.
Reaction SMILES: CC(=O)CC(=O)CCCC.[CH2:11]([N:18]1[CH:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20][CH:19]1[C:33](OCC)=[O:34])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:25]([N:24]1[C:33](=[O:34])[CH:19]2[N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:22]([CH2:21][CH2:20]2)[C:23]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(C(=O)NCc2ccccc2)N1Cc1ccccc1
Agent: CCCCC(=O)CC(C)=O
Product: O=C1C2CCC(C(=O)N1Cc1ccccc1)N2Cc1ccccc1
Temperature: 215 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
2.1]octane-2,4-dione (LXVI). Ethyl 1-benzyl-5-(benzylcarbamoyl)pyrrolidine-2-carboxylate (LXV, 0.00122 mol, 450 mg) was heated under stirring at 210-220° C. for 3 h under atmospheric pressure and the formed ethyl alcohol was collected. After completion of the reaction (checked by TLC), the reaction mixture was cooled at room temperature and the residue was purified by column chromatography (silica gel, 60-120 mesh; EA-Hexane, 2:8) to afford the 3,8-dibenzyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione in 40-45% yield.