Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:50])([CH3:49])[O:6][C@H:7]([C@@H:22]([CH3:48])/[CH:23]=[C:24](/[CH3:47])\[CH2:25][C@H:26]([CH3:46])[C@@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:28]([CH3:37])[C@@H:29]([OH:36])[C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:8]([CH3:21])/[CH:9]=[CH:10]\[C:11]([N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([CH3:4])[CH3:3].ClC(Cl)(Cl)[C:53]([N:55]=C=O)=[O:54]>C(Cl)Cl>[NH2:55][C:53]([O:36][C@@H:29]([C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:28]([CH3:37])[C@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C@@H:26]([CH3:46])[CH2:25]/[C:24](/[CH3:47])=[CH:23]\[C@H:22]([CH3:48])[C@@H:7]([O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:49])[CH3:50])[C@@H:8]([CH3:21])/[CH:9]=[CH:10]\[C:11]([N:13]([CH3:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:12])=[O:54]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)N(C)c1ccccc1
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)N(C)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[(1,1-dimethylethyl) dimethylsilyl]oxy]-13-hydroxy-N,4,6,8,10,12,14-heptamethyl-N-phenyl-2,7,15,17-octadecatetraenamide (110 mg, 0.152 mmol, 1 eq) in CH2Cl2 (2 mL) is treated with trichloroacetyl isocyanate (43 mg, 0.228 mmol, 1.5 eq) at 23° C. (20 minutes). The solution is concentrated, and the residue dissolved in CH3OH (2 mL). To this solution is added K2CO3 (0.1 g) and the mixture is stirred at 23° C. (2 hours). The reaction mixture is concentrated and the residue dissolved in Et2O (5 mL). The organic solution is washed with H2O (1×20 mL) and brine (1×20 mL). The aqueous layer is extracted with Et2O (3×5 mL) and the combined extracts are dried (Na2SO4) and concentrated. Chromatography (SiO2, 30–50% EtOAc-hexanes gradient elution) provided the desired compound (70 mg, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[CH:14]=1.BrC1C=CC(C(NC2C=CC=C(C(C)(C)C)C=2)=O)=CC=1F>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Product: Cc1cc(Br)ccc1C(=O)Nc1cccc(C(C)(C)C)c1

Procedure:
4-Bromo-N-(3-tert-butyl-phenyl)-2-methyl-benzamide was synthesized from 3-tert-butyl-phenylamine and 4-bromo-2-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide above. LCMS calcd for C18H20BrNO (m/e) 345, obsd 346 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
{3-[1-(3-Benzyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (Example 47, 25 mg, 0.0569 mmol) in CHCl3 (10 mL) at 25° C. was treated with 4-chloro-benzoylchloride (31.5 μL, 0.248 mmol) and triethylamine (23.0 μL, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (17.2 mg, 52.3%) as a colorless film: LC/MS 86% at 3.74 min (ESI+) 578 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH:15]([NH:17][NH:18][CH:19]=O)=O>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:19]=[N:18][N:17]=[CH:15]2)=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: O=CNNC=O
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Product: O=[N+]([O-])c1ccc(-n2cnnc2)cc1C(F)(F)F

Procedure:
The following compound m.p. 100°, was prepared similarly to the previous Preparation using 4-nitro-3-trifluoromethylaniline and 1,2-diformylhydrazine as the starting materials: ##STR126##
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:45])[CH2:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:45])[CH2:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C1C=CC=CC=1.[OH:7][CH:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CC(C)=O>[O:7]=[C:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1
Reactant: C=CCC1C(=O)C=CC1O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: C=CCC1C(=O)C=CC1=O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Into a mixture of 150 ml of dried benzene and 100 ml of acetone, was dissolved 1.5 g of 4-hydroxy-5-allyl-2-cyclopentenone. After adding 3 g of freshly distilled aluminum isopropoxide, the mixture was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature, washed twice with 30% sulfuric acid, then with water until the washings had become neutral. After drying over anhydrous sodium sulfate, the mixture was stripped of the solvent by distillation and the residue was distilled in vacuo to obtain 1.2 g (81% yield) of 4-keto-5-allyl-2-cyclopentenone boiling at 53° C./4 mmHg.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C([O:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]Br)=[CH:26][C:25]=1[F:34])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)=[CH:26][C:25]=1[F:34]
Reactant: Fc1cc(OCCBr)ccc1OCc1ccccc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)c(F)c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (347 mg, 1.54 mmol), 2-(4-benzoxy-3-fluorophenoxy)ethyl bromide (499 mg, 1.54 mmol) and potassium carbonate (531 mg, 3.85 mmol) in two steps as white-off solid (272 mg): mp 148-150° C. 1H NMR (CD3OD) 1.38 (m, 2 H), 1.699 (m, 3 H), 2.100 (s, 3 H), 2.375(d, J=6.3 Hz, 2 H), 2.834 (m, 2 H), 3.307 (m, 2 H), 3.427 (d, J=11.7 Hz, 2 H), 4.078 (t, J=4.8 Hz, 2 H), 6.48 (m, 1 H), 6.638 (m, 2 H), 6.844 (m, 4 H). Anal. Calcd for C21H27ClFNO2.0.3H2O: C, 65.45; H, 7.22; N, 3.64. Found: C, 65.54; H, 7.15; N, 3.60.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+].C(OCC)(=O)C>CN(C)C=O>[C:25]([S:27][CH:18]1[CH2:17][N:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)[CH2:19]1)(=[O:28])[CH3:26]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
To a solution of 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (739 mg, 2.01 mmol) (obtained as described in Reference Example 64(3)) in dimethylformamide (20 ml) was added potassium thioacetate (1.38 g, 12.1 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 3.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate=(1:1)→ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]azetidine (698 mg, yield 100%) as a pale brown solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:17][CH2:18][O:19][C:20]([CH:22]1[CH2:28][CH2:27][C:25](=O)[CH2:24][CH2:23]1)=[O:21]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:18]([O:19][C:20]([CH:22]1[CH2:28][CH2:27][C:25]2([O:4][CH2:1][CH2:2][O:3]2)[CH2:24][CH2:23]1)=[O:21])[CH3:17]
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 73.1 %

Procedure:
Ethylene glycol (18.2 g) and p-toluenesulfonic acid monohydrate (2.37 g) were added to a solution of 4-cyclohexanonecarboxylic acid ethyl ester (25 g) in toluene (500 ml) and stirred under reflux for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (23 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH2:28][NH2:29]>CO>[CH3:1][O:2][C:3]([C:5]1[N:29]([CH2:28][C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: COc1cc(CN)cc(OC)c1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (539 mg) in methanol (10 ml) was added 3,5-dimethoxybenzylamine (1.25 g), and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and 4N hydrogen chloride ethyl acetate solution (5 ml) was added to the obtained residue. The mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→4/1) to give the title compound (555 mg, 73%).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[CH2:11]1[N:17]([C:18]2[N:28]=[C:27]3[C:21]([C:22]([C:24]([C:37]([OH:39])=[O:38])=[CH:25][N:26]3[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])=[O:23])=[CH:20][C:19]=2[F:40])[CH2:16][C@@H:13]2[CH:14]([NH2:15])[C@H:12]12>>[CH:33]1[C:32]([F:35])=[CH:31][C:30]([F:36])=[C:29]([N:26]2[C:27]3=[N:28][C:18]([N:17]4[CH2:11][C@@H:12]5[C@@H:14]([NH2:15])[C@@H:13]5[CH2:16]4)=[C:19]([F:40])[CH:20]=[C:21]3[C:22](=[O:23])[C:24]([C:37]([OH:39])=[O:38])=[CH:25]2)[CH:34]=1
Reactant: NC1[C@H]2CN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)C[C@@H]12
Agent: CS(=O)(=O)O
Product: N[C@@H]1[C@H]2CN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)C[C@@H]12
Temperature: 45 °C

Procedure:
Tetrahydrofuran (250 cm3), ethyl (1α,5α,6α)-7-(6-benzylidenylamino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (25.05 g, 47 mmol) obtained above, and water (250 cm3) were treated with 97% methanesulfonic acid (13.3 g, 138 mmol) and heated to reflux for 24 h. The resulting solution, which contained trovafloxacin methanesulfonate salt, was cooled to 45° C., treated with activated carbon (2.5 g) for 1 hr and filtered. Treatment of the filtrate with saturated aqueous sodium bicarbonate to pH 8 (see PCT Publication No. WO 97/07800, example 1A) yields the above-titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:18][C:19]1[CH:26]=[C:25](F)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1>CC(N(C)C)=O.CCOC(C)=O.O>[NH2:18][C:19]1[CH:26]=[C:25]([O:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN1CCC(O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCC(Oc2cc(N)ncc2C#N)C1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
1-methylpyrrolidin-3-ol (89 mg, 0.875 mmol) was treated at room temperature with KHMDS (1 M in THF, 0.788 ml, 0.788 mmol). The reaction mixture was stirred for 10 min, then added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 60 mg, 0.438 mmol) in DMA (1 ml). The mixture was then heated at 100° C. for 40 min, cooled to room temperature, diluted with EtOAc and water. The layers were separated and aq. layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified twice by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(1 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a light brown wax. (UPLC-MS 3) tR 0.27 min; ESI-MS 219.1 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][NH2:6].[S:7]([O-:11])([O-:10])(=[O:9])=[S:8].[Na+].[Na+]>O>[NH2:6][CH2:5][CH2:4][CH2:3][SH:8]=[S:7](=[O:9])([OH:11])[OH:10]
Reactant: O=S([O-])([O-])=S
Reactant: NCCCCl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NCCC[SH]=S(=O)(O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In the reaction vessel purged with nitrogen, 580 g (4.47 moles) of hydrochloride of 3-chloropropylamine was added, and 1048 mL of water was further added thereto to dissolve hydrochloride of 3-chloropropylamine. The obtained solution was kept at from 60° C. to 70° C., and 1164 g (4.69 moles) of pentahydrate of sodium thiosulfate was added thereto. The total used amount of water was 1470 g (the total of 1048 g of water and 422 g of water contained in pentahydrate of sodium thiosulfate). The solution was stirred for 4 hours while the reaction vessel was heated at a bath temperature of 80° C. After 2 hours, a little amount of solid was precipitated. The obtained reaction mixture was cooled, and then stirred overnight at room temperature. The obtained mixture was filtrated to afford the solid mainly containing S-(3-aminopropyl)thiosulfuric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]1[C:16]([C:17]2[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=2[O:24][CH2:25][C:26]([CH3:31])([N+:28]([O-])=O)[CH3:27])[NH2:20])=[CH:15][CH:14]=[N:13]1.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>ClCCl.CO.[Zn]>[NH2:28][C:26]([CH3:31])([CH3:27])[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:19]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][C:17]=1[C:16]1[N:12]([CH3:11])[N:13]=[CH:14][CH:15]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(Cl)cc2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobenzoyl chloride (280-, 0.22 mmol) was added to a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (58 mg, 0.20 mmol) and N,N-diisopropylethylamine 0.22 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the mixture was diluted with dichloromethane, washed with 0.5M citric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL) and acetyl chloride (71 μl, 1.0 mmol) was added slowly while stirring. Zinc dust (65 mg, 1.0 mmol) was added in small portions, and the mixture was stirred at 55° C. After 2 h, the mixture was allowed to cool to room temperature, and diluted with methanol. The white precipitate was removed by filtration and washed with methanol. The combined washings were evaporated to dryness. The residue was suspended in 1M HCl, the solution was cooled on an ice bath, and made alkaline with ammonium hydroxide. The solution was extracted with ethyl acetate, and the extract was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by RP-HPLC. The trifluoroacetate salt was dissolved in a mixture of ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate, and evaporated to dryness to afford the free base. The free base was dissolved in mixture of methanol and acetyl chloride (350-, 0.5 mmol) and the solution was evaporated to dryness to give the title compound as a hydrochloride salt (44 mg, 45%). LCMS m/z (%)=401.3 (M+H 37Cl 13.1%), 399.2 (M+H 35Cl 31.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 6H), 3.70 (s, 3H), 3.92 (s, 2H), 6.37 (d, J=1.77 Hz, 1H), 7.25 (d, J=9.09 Hz, 1H), 7.50 (d, J=1.77 Hz, 1H), 7.59-7.65 (m, 2H), 7.73 (d, J=2.53 Hz, 1H), 7.87 (dd, J=8.97, 2.65 Hz, 1H), 7.95-8.01 (m, 2H), 8.03 (s, 3H), 10.39 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:2][C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[C:5]#[N:6])=[C:16]([CH:20]=1)[C:17]([O:19][CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[O:18]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1COC(=O)c1cc(Br)ccc1OCc1ccccc1C#N
Temperature: 55 °C
Reaction time: 16 h

Procedure:
2-(Bromomethyl)benzonitrile (397 mg, 2.027 mmol) was added in one charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 1.84 mmol) in acetone (40 ml) under nitrogen at 20° C. The reaction mixture was stirred at 55° C. for 16 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (100 ml) and evaporated in vacuo to yield the title compound as an off-white solid. 350 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH2:12][NH:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[CH:16][C:15]=3[NH2:24])[CH:8]=2)[CH:2]=1.[C:25](OC)(OC)(OC)[CH2:26][CH2:27][CH3:28].Cl.N1C=CC=CC=1>>[CH2:26]([C:25]1[N:13]([CH2:12][C:9]2[CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[O:11][N:10]=2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:27][CH3:28]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCc1cc(-c2cccnc2)on1
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1Cc1cc(-c2cccnc2)on1
Yield: 84.5 %

Procedure:
The methods of Part H of Example 35 were used to treat N4-[(5-pyridin-3-ylisoxazol-3-yl)methyl]quinoline-3,4-diamine (0.95 g, 2.98 mmol) with trimethy orthobutyrate (0.57 mL, 3.6 mmol) and pyridine hydrochloride (0.069 g, 0.60 mmol) and purify the product to provide 0.930 g of 2-propyl-1-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10](=[O:12])[CH:11]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[O:12]=[C:10]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[CH:7][C:6]([C:4]([NH:22][NH2:23])=[O:3])=[CH:11]1
Reactant: NN
Reactant: CCOC(=O)c1cnn(COCC[Si](C)(C)C)c(=O)c1
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc(C(=O)NN)cc1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The title compound from Example 19.2 (0.85 g, 2.8 mmol) was stirred in ethanol. Hydrazine hydrate (0.720 g, 14.2 mmol) was added to the solution and the reaction was stirred at 50° C. for 1 hour. The reaction was concentrated and triturated with methanol and diethyl ether to produce a precipitate which was collected by vacuum filtration as the title compound (0.56 g, 57%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:22])([C:14]([NH:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:6][CH2:5]2.[O:24]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:24][C:7]([CH3:22])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:23])[C:14]([NH:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCC(C)C)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCC(C)C)=C(C)C1=O
Yield: 95.5 %

Procedure:
Oxidation as described in protocol B, using 101 mg (0.316 mmol) of 6-hydroxy-N-isopentyl-2,5,7,8-tetramethylchroman-2-carboxamide and 380 mg CAN (0.694 mmol) yielded 101.2 mg of 2-hydroxy-N-isopentyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][Zn+]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[F:21])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: Fc1ccccc1C[Zn+]
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cc3ccccc3F)cc21

Procedure:
Starting with 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester, the title compound was prepared by using similar methods to those described in Preparation 117 using 2-fluorobenzylzinc chloride instead of benzylzinc chloride. 1H NMR (Me-d3-OD): 8.15 (1H, s), 7.64-7.20 (3H, m), 7.20-7.03 (2H, m), 4.12 (2H, s), 3.74 (2H, s), 1.50 (9H, s), 1.37 (6H, s). MS: [M+H]+=357.