Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:26]CC2C=CC(OC)=CC=2OC)=[N:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[F:25])=[O:16])=[CH:10][CH:9]=1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:26][C:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[F:25])=[O:16])=[CH:10][CH:9]=2)[S:6][N:5]=1
Reactant: COc1ccc(CNc2nsc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2C#N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(N)c3C#N)cc2)c1
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A suspension of 1-(4-{4-cyano-3-[(2,4-dimethoxybenzyl)amino]isothiazol-5-yl}phenyl)-3-(2-fluoro-5-methylphenyl)urea (593 mg, 1.15 mmol) in 50 mL of DCM was treated with 1.5 mL of TFA. Solid was dissolved and the reaction turned to yellow and then red in color. TLC indicated the completion of the reaction in <30 min. Saturated Na2CO3 solution was added and the mixture was stirred for 30 min. Layers were separated and the aqueous layer was extracted with DCM×3. The combined organics was washed with brine and dried with MgSO4, filtered, and concentrated. The crude product was redissolved in 100 mL of EtOAc. Insoluble impurity was filtered through celite and washed with EtOAc. Filtrate was concentrated in vacuo to afford the product as a cream solid (398 mg, 94%).
Reaction SMILES: O[C:2]1([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:15]=[CH:14]3)[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH:27]([Si:20]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:2]3[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH:3]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)([CH3:29])[CH3:28]
Reactant: CC(=O)N1CCC(O)(c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Reaction time: 72 h
Yield: 66.4 %

Procedure:
1-(4-Hydroxy-4-[1-triisopropylsilyl-1H-indol-5-yl]-piperidin-1-yl)ethanone (3.11 g, 7.4 mmol) in dichloromethane (100 ml) was treated with pyridinium p-toluenesulfonate (3.8 g, 15.1 mmol) and stirred for 72 hours. The solution was poured into water and extracted with dichloromethane (100 ml). The extractions were dried (MgSO4), concentrated and the crude product purified by flash chromatography using ethyl acetate as eluant, to give 1-(4-[1-triisopropylsilyl-1H-indol-5-yl]-1,2,3,6-tetrahydropyridin-1-yl)-ethanone (1.95 g, 66%) as a white solid; δH (CDCl3) 0.80 (18H, d, J 8.5 Hz, 6×CH3), 1.30 (3H, m, 3×CH), 1.75 (3H, d, J 6.7 Hz, COCH3), 2.30 (2H, m, tetrahydropyridinyl H), 3.25 (1H, t, J 5.6 Hz, tetrahydropyridinyl H), 3.40 (1H, t, J 5.6 Hz, tetrahydropyridinyl H), 3.75 (1H, m, tetrahydropyridyl H), 3.85 (1H, m, tetrahydropyridyl H), 5.60 (1H, m, CH=CR), 6.20 (1H, d, J 2.2 Hz, ArH), 6.80 (2H, m, ArH), 7.00 (1H, d, J 7.3 Hz, ArH), and 7.20 (1H, m, ArH).
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:12])[NH2:5].[CH3:23][N:24]=[C:25]=[S:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]2[NH:5][C:25](=[S:26])[N:24]([CH3:23])[C:3]2=[O:22])=[O:12])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccc(Cl)cc1
Reactant: CN=C=S
Product: CN1C(=O)C(CCCCNC(=O)OCc2ccc(Cl)cc2)NC1=S

Procedure:
Using an analogous procedure to Example 1 Nε-p-chlorobenzyloxycarbonyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([OH:17])[CH:14]([OH:16])[CH3:15]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:17][CH2:13][CH:14]([OH:16])[CH3:15])=[O:3]
Reactant: COc1ccccc1OC(=O)Cl
Reactant: CC(O)CO
Product: COc1ccccc1OC(=O)OCC(C)O

Procedure:
The reaction of 2-methoxyphenyl chloroformate with propylene glycol is conducted on a 0.01 mole scale employing the same conditions as described in Example III. A 0.9 g yield of the pure product is obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:17])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[C:22]([F:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:17])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[C:22]([F:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: Cc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Solvent: CO
Product: Cc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 4h30) of 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (8.080 g; 18.903 mmol), and purification by FC (DCM/MeOH=50/1) afforded 1-chloro-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (4.730 g; 54%). LC-MS: tR=1.08 min.; [M+H]+=461.98 g/mol.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][CH:18]([CH3:33])[CH2:19][CH:20]([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:14]>ClCCl>[CH3:14][C:13](=[CH:15][CH2:16][CH2:17][CH:18]([CH3:33])[CH2:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:12]
Reactant: C=CCCCCCCCCCC(O)CC(C)CCC=C(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=CCCCCCCCCCC(=O)CC(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
Pyridinium chlorochromate (15 g, 0.07 mol) was added to a solution of 2,6-dimethyl-nonadeca-2,18-dien-8-ol (18 g, 0.058 mol, prepared as above in EXAMPLE III) in dichloromethane (100 mL) and stirred at room temperature for 6 hours. Silica gel (˜15 g) was added to the reaction mixture, and the resulting mixture was concentrated via rotary evaporation. The crude concentrated mixture was scrapped away from the flask with a spatula and filtered through a silica gel plug using ethyl acetate (100%). The filtrate was concentrated and chromatographed on silica gel with ethyl acetate in hexanes (2%) as the eluent providing 2,6-dimethyl-nonadeca-2,18-dien-8-one as a colorless oil (15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:21][CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])[C:9]2=[O:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:21][CH3:22])[C:14]([OH:16])=[O:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1ccc2ccc(Cl)cc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C(=O)O)n1ccc2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of (S)-2-(7-Chloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid, tert butyl ester (322 mg) in dichloromethane (14 ml) was cooled to 0° C. Trifluoroacetic acid (3.5 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 2 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the sub-title product as a white solid (236 mg, 89%); m.p. 159.6-160.1° C.; [α]24D−47.0° (c=1.01, CHCl3); ir (solid) 1731.4, 1639.3, 1577.8, 1209.1, 1168.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.82 (3H, t), 2.00-2.25 (2H, m), 5.20 (1H, m), 6.70 (1H, d), 7.49 (1H, d), 7.70-7.81 (2H, m), 8.18 (1H, s; 13C NMR (100 MHz, d6-DMSO) δ 10.8, 22.7, 60.8, 104.9, 126.5, 126.6, 128.8, 131.6, 132.5, 133.1, 135.8, 160.5, 171.7; MS ES (+) 266.27 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:27])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][OH:12])[NH:8]2)=[CH:4][CH:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc2ccc(Br)cc2[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
The product from Step 1 (1.87 g, 8.3 mmol) was combined with t-butyldimethylsilyl chloride (1.38 g, 9.1 mmol) and imidazole (734 mg, 10.8 mmol) in DMF (15 mL). The mixture was stirred 2 h at room temperature. The solvents were removed by rotary evaporation under reduced pressure. The resulting residue was partitioned in EtOAc and saturated aqueous ammonium chloride. The organic layer was washed with brine, dried over Na2SO4, concentrated and chromatographed on silica gel (0-15% EtOAC in hexanes) to give the product (2.7 g, 96%). LC-MS 340.2, 342.2 [M+H]+, RT 1.62 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][OH:11].O.[OH-].[Na+]>>[N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCCN1CCCCC1

Procedure:
Combine piperidine (18.01 g, 0.212 mol), 3-chloro-1-propanol (10 g, 0.106 mol) and water (3.2 g, 0.18 mol) and heat on a steam-bath for ˜5 hours. Add sodium hydroxide (6.35 g, 0.16 mol) to the cooled solution and heat the resulting mixture on a steam-bath for ˜30 minutes. Add water, separate the organic layer, and extract the aqueous layer with dichloromethane, twice. Combine the organic layers and wash with water, dry with sodium sulfate and evaporate the solvent to give the final, desired compound. The final compound may be purified by chromatography.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C=O)C>[Br:1][C:25]1[C:17]([O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(COc2ccc3c(c2)OCO3)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc2c(cc1OCc1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-bromosuccinimide (10.7 g, 0.06 mol) in dry DMF (70 ml) was added dropwise and with stirring a solution of 5-phenylmethoxy-1,3-benzodioxole (13.68, 0.06 mol) in dry DMF (80 ml). The resulting solution was stirred for 24 h at room temperature, poured into 300 ml of H2O and extracted with chloroform (3×70 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from absolute EtOH affording 17.4 g (94.5%) of 6-bromo-5-phenylmethoxy)-1,3-benzodioxole as white crystals mp 61.5°-62° C.; NMR (CDCl3, 90 MHz) δ 5.04 (S, 2H, CH2Ph), 5.91 (S, 2H, OCH2O), 6.56 (S, 1H, ArH), 6.99 (S, 1H, ArH), 7.14-7.63 (m, 5H, CH2Ph). Anal. calcd. for C14H11BrO3 : C, 54.75; H, 3.61; Br, 26.01. Found: C, 54.81; H, 3.64; Br, 25.68.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:8][C:7]1[C:2]([F:1])=[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=[CH:5][C:6]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)ccc(-c2ccccc2)c1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2ccccc2)c(F)c1CBr
Yield: 112.4 %

Procedure:
A stirred solution of 2,4-difluoro-3-methyl[1,1'-biphenyl] (2.2 g, 0.011 mole) and N-bromosuccinimide (1.9 g, 0.011 mole) in 100 ml of carbon tetrachloride was irradiated with a 250 watt infrared lamp for 4 hours. The reaction mixture was allowed to reflux from the heat of the lamp. The reaction mixture was then filtered, and the filter cake was washed with three portions of carbon tetrachloride. The washes and filtrate were combined and evaporated under reduced pressure to give 3-bromomethyl-2,4-difluoro[1,1'-biphenyl] (3.5 g) as an oil whose nmr spectrum was consistent with that expected for the named compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[C:16]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16](=[O:18])[CH3:17])=[CH:26][CH:25]=2)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(=O)CC1C
Reactant: CC(=O)Oc1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(N=C2CC(C)N(C(C)=O)c3ccccc32)cc1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
[Step 1] 100 mg of 1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline and 227 mg of 4-acetoxyaniline were dissolved in 3 mL of toluene, and 250 μL of titanium tetrachloride (1.0 M dichloromethane solution) was added to the solution under ice cooling. The mixture was stirred for one hour under ice cooling, and then was stirred for another one hour at room temperature. After completion of the reaction, the reaction liquid was filtered through Celite and was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform), and thus 50 mg (30%) of 1-acetyl-2-methyl-4-[(4-acetoxyphenyl)imino]-1,2,3,4-tetrahydroquinoline was obtained as a yellow soup-like substance.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][NH:16][CH2:15][CH2:14]4)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[CH3:21][C@@:22]1([CH2:29][S:30](Cl)(=[O:32])=[O:31])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23]1>CCOC(C)=O.CCOC(C)=O.CO>[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][N:16]([S:30]([CH2:29][C@@:22]3([CH3:21])[NH:23][C:24](=[O:28])[NH:25][C:26]3=[O:27])(=[O:31])=[O:32])[CH2:15][CH2:14]4)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: c1cc(C2CC2)ncc1-c1cc2c(cn1)CNCC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4ccc(C5CC5)nc4)ncc3C2)NC(=O)NC1=O
Yield: 6.8 %

Procedure:
The title compound was prepared from 6-(6-cyclopropylpyridin-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride (0.63 mmol) and [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.70 mmol) following the general procedure of Example 1. Column chromatography with neat EtOAc and EtOAc-MeOH (9:1) as eluents gave 0.060 g of almost pure product. Recrystallisation from 99% EtOH gave 0.019 g (7.0%) of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([C:12]([CH2:14][CH3:15])=O)[CH3:11].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:10]([CH:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1)[CH2:14][CH3:15])[CH3:11]
Reactant: Cc1ccc(N)cc1C
Reactant: CCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(CC)Nc1ccc(C)c(C)c1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A solution of 3,4-xylidine (1.2 g., 0.01 mole) and diethyl ketone (5 ml.) in methanol (20 ml.) is stirred at room temperature in the presence of sodium cyanoborohydride (1.1 g.) and 3A molecular sieves (3.0 g.). The pH is monitored each half hour and maintained at 6 by adding acetic acid in 5 drop portions as required. After 7 hours, the sieves are removed by filtration and the filtrate is diluted with water (100 ml.) and then acidified with hydrochloric acid. The solution is then basified with solid potassium carbonate and extracted with ethyl ether. The ether solution is dried and then evaporated leaving the desired product as a residual oil in 97.5% yield and in 93% purity as determined by gas-liquid chromatography. The compound had a boiling point of 80° C. at a pressure of 0.1 mm. Its elemental analysis is as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C@@H:14]([CH2:17][OH:18])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C@@H:14]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of crude ((S)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol (1.65 g, 6.06 mmol) in dry DCM (10 ml), was added triethylamine (0.88 ml). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.49 ml) was added slowly dropwise to reaction mixture. The mixture was stirred at RT for 1 h and then 10 ml of aq 1 M HCl was added. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried with Na2SO4 The solvents were removed under reduced pressure and the crude product (2.22 g) was crystallized from IPA (15 ml), which gave a white solid (1.50 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]3([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: BrCC1(c2ccccc2)OCCO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccccc3)OCCO2)CCN(C)C1
Temperature: 100 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) was dissolved in 20 mL of DMF. The resulting solution was cooled in an ice-water bath and sodium hydride (840 mg, 4.2 mmol) was added under nitrogen atmosphere. 2-Bromomethyl-2-phenyl[1,3]dioxolane (2.43 g, 10 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH:DCM.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl>[OH-].[Na+]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Reaction time: 2 h

Procedure:
The ester from Example 1d (23.7 g, 58 mmol) was dissolved in 1M NaOH (190 ml) and refluxed for 6 h. The cooled solution was acidified with an excess of 6M HCl. The precipitated formed was allowed to stand for 2 h, filtered off and washed with water (3×200 ml). The white product was dried at 60° C. in vacuo. Yield 21.7 g (95%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH2:9][CH:10]([NH:13][C:14]([C:16]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:17]=1)=[O:15])[CH2:11][CH3:12]>ClCCl>[CH3:12][CH2:11][CH:10]([NH:13][C:14]([C:16]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH:17]=1)=[O:15])[CH2:9][CH3:8]
Reactant: CCC(CC)NC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)NC(=O)C1=CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 138.5 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a stirred solution of compound (F1) (0.60 g, 1.50 mmol) in dichloromethane (10 mL) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under high vacuum for 18 h to provide N-(pentan-3-yl)spiro[indene-1,4′-piperidine]-3-carboxamide (F2) as an oil (0.62 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 299 (M+1) Rt 1.9 minutes.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](O)=[O:15])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:6]1.C(OCC1C2C(=CN=C([C:44]([NH:46][OH:47])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:46]([OH:47])[CH3:44])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:6]1
Reactant: CN(C)Cc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Product: CN(C)Cc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)N(C)O)cc12

Procedure:
1-(2,4-Difluorobenzyl)-3-dimethylaminomethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(2,4-difluorobenzyl)-3-dimethylaminomethyl-1H-pyrrolo[2,3]-ccarboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6) δ: 8.91 (s, 1H), 8.43 (s, 1H), 7.74 (s, 1H), 7.29-7.37 (m, 2H), 7.04-7.10 (m, 1H), 5.62 (s, 2H), 3.70 (s, 2H), 2.22 (s, 6H). LCMS (API-ES, M+H+): 346.3. (b) 1-(2,4-Difluorobenzyl)-3-dimethylaminomethyl-N-hydroxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-3- dimethylaminomethyl-1H-pyrrol (DMSO-d6)δ: 9.44 (broad s, 1H), 8.96 (s, 1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.44 (m, 1H), 7.28-7.35 (m, 1H), 7.10 (m, 1H), 5.66 (s, 2H), 4.47 (s, 2H), 3.32 (s, 3H), 2.72 (s, 6H). LCMS (APCI, M+H+): 375.0. HRMS calcd for C19H21F2N4O2. (M+H) 375.1633, found 375.1632. HPLC: 97.62% purity.