Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[N:10]=[C:9]([C:11]2[N:15](C(OC(C)(C)C)=O)[C:14]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:13]=3[N:12]=2)[C:8]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:7][CH:6]=1.CCN(CC)CC.[S:50](Cl)([CH3:53])(=[O:52])=[O:51].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:8]1[N:7]=[CH:6][C:5]([C:4]#[C:3][CH2:2][NH:1][S:50]([CH3:53])(=[O:52])=[O:51])=[N:10][C:9]=1[C:11]1[NH:15][C:14]2[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:13]=2[N:12]=1
Reactant: Cc1ccc2nc(-c3nc(C#CCN)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3nc(C#CCNS(C)(=O)=O)cnc3N)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 3.6 %

Procedure:
tert-Butyl 2-[6-(3-aminoprop-1-ynyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl]-6-methyl-benzimidazole-1-carboxylate (90 mg, 0.1555 mmol) and Et3N (23.60 mg, 32.51 μL, 0.2332 mmol) were dissolved in DCM (10 mL) and cooled to 0° C. in and ice bath. Mesyl chloride (21.38 mg, 14.45 μL, 0.1866 mmol) as a solution in DCM (1 mL) was added dropwise and the reaction stirred at 0° C. for 20 minutes. The reaction mixture was washed with saturated aqueous NaHCO3 (×1) and brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was redissolved in DCM (10 mL) and TFA (177.3 mg, 119.8 μL, 1.555 mmol) added. The reaction mixture was stirred at ambient temperature for 1 hour then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (2 mg, 4% Yield). 1H NMR (400.0 MHz, D4-MeOH) δ 1.6 (3H, s), 2.25 (3H, s), 3.25 (2H, s), 6.25 (1H, d), 6.55 (1H, s), 6.7 (1H, d), 7.3 (1H, s); MS (ES+) 357.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(CC)=NC=2C2C=CC(Cl)=CC=2Cl)CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])[C:11]([CH2:30][CH3:31])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:32][CH2:16]1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.82-1.33, 1.58-1.71, 2.68-2.76, 3.06-3.19, 3.41-3.51, 3.65-3.75, 4.32-4.36, 5.52-5.54, 5.71-5.76, 7.23-7.52; MS (ESI+) for C26H27Cl2N3O m/z 469 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(Cl)cc1
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A round bottom flask was charged with chlorosulfonic acid (6.36 g, 96.0 mmol) at 0° C. and 4-chloro benzoic acid was added portion wise. The reaction mixture was heated at 130° C. for 5 h. The reaction mixture was then poured over ice and stirred for 10 minutes. The solids formed were filtered, washed with cold water and dried to afford 4-chloro-3-(chlorosulfonyl)benzoic acid as a white powder. This compound was then charged into a round bottom flask containing sodium sulfite (7.1 g, 56.4 mmol) and water (40 mL) portion wise. Aqueous sodium hydroxide (6 N) was then added drop wise till the pH of the reaction mixture reaches 10 and the reaction was stirred over night. The reaction was then made acidic (pH 2) by addition of 2N HCl. The solids formed were filtered and dried to get the title compound as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)(OC(C)(C)C)=O.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(O)=O>C1COCC1.O.CCOC(C)=O>[C:15]1([C:10]2[CH2:9][NH:8][CH2:13][CH2:12][CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C1=C(c2ccccc2)CNCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Add slowly (over 70 min) a solution of N-Boc-3-Piperidone (494.35 mmol; 98.50 mL; 98.50 g) in anhydrous THF (118.20 mL) to a suspension of 1M phenyl magnesium bromide in THF (593.22 mmol; 593.22 mL; 593.22 g) at 0° C. under nitrogen. Stir the mixture at 0° C. for 1.5 h. Then, add slowly trifluoroacetic acid (593.22 mmol; 44.86 mL). Concentrate partially the mixture removing about 450 mL of solvent to give brown oil and stir at 22° C. for 1 h. Then, add trifluoroacetic acid (9.81 moles; 741.53 mL) to this residue at 10° C. Stir the mixture at 22° C. for 15 min to give a red solution. Then, warm the red solution at 75° C. for 2 h and cool slowly to 22° C. for 18 h. Concentrate the mixture. Add an aqueous solution (50%) of NA OH (3.46 moles; 266.17 mL) to the resulting brown suspension at −20° C. Dilute the suspension with water (1 L) and EtOAc (3 L) and concentrate. Filter the brown suspension and concentrate the mother liquors to give a brown solution. Extract this solution with DCM (5×800 mL) and concentrate the organic layers. Filter the aqueous layer through CELITE® and separate the filtrates. Concentrate all the combined organics to give the title compound as brown oil (103.1 g, 98%). MS (m/z): 160 (M+1).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=1.CCCCCC.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=2[N+:32]([O-:34])=[O:33])(=[O:29])=[O:30])[C:3]1=[O:12]
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c([N+](=O)[O-])c1
Yield: 81.1 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 2 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.71 g of 4-methoxy-2-nitrobenzenesulfonyl chloride. Chromatography on silica using a DCM/hexane mixture (80/20; v/v) and then DCM as the eluent gives 2.8 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=192°-195° C.
Reaction SMILES: C1(C)C(S([O-])(=O)=[O:8])=CC=CC=1.C1(C)C(S([O-])(=O)=O)=CC=CC=1.[CH2:23]([Sn+2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>CN(C)C=O.O>[CH2:23]([Sn:27](=[O:8])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Reactant: CCCC[Sn+2]CCCC
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[Sn](=O)CCCC

Procedure:
Employing the same formulation as in Example 1, dibutyltin bis-toluenesulfonate (DBTTS) was evaluated, using a solution of this catalyst in dimethylformamide. A portion of this catalyst solution was diluted with 10% water and aged at room temperature for three weeks. From the results reported in Table 2, it is seen that no apparent change in activity occurred in the aged sample. Addition of water to a stannous octoate solution, on the other hand, produces an immediate precipitate of dibutyltin oxide which is relatively inactive as a co-catalyst for urethane production.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[CH2:10]([NH:17][C:7](=[O:9])[C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[NH:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CC[C@H](C(=O)NCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Oxo-D-proline (5.0 g), benzylamine (4.65 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.5 g) and 1-hydroxybenzotriazole (6.3 g) were mixed in acetonitrile (100 mL) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 3 hr. The mixture was diluted with ethyl acetate (200 mL), and washed successively with 1M hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (4.02 g) as a white powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9]>O1CCOCC1.O.O1CCOCC1>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[O:9])[CH2:2]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCNC1
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)C1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A solution of 3-pyrrolidinol (4.0 g) in dioxane-water (10:1, 50 ml) mixed solvent was cooled to 5° C., and into which a solution of 4-nitrobenzyl chloroformate (10.9 g) in dioxane (20 ml) was added dropwise, while maintaining the pH at 8-9, followed by 10 minutes' stirring at 5° C. Distilling the solvent off under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure. Washing the residue with ethyl acetate, 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (6.6 g) was obtained as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:6]2[NH:7][C:8]3[CH2:9][C:10]([CH3:38])([CH3:37])[CH2:11][C:12](=[O:36])[C:13]=3[CH:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([C:6]2[C:15]([C:16](=[O:27])[C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[C:12](=[O:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC(C1CCCC1)=C(C(=O)c1ccc(C(F)(F)F)cc1)C2c1ccc(F)c(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)c(F)c2)C1

Procedure:
0.9 g (1.7 mmol) of 2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)4,6,7,8-tetrahydro-1H-quinolin-5-one were oxidized at room temperature within one hour to give the pyridine, using 4.5 g of manganese dioxide (activated) in 25 ml of methylene chloride. The manganese dioxide was separated off and the methylene chloride was distilled off, and the mixture was then filtered off with suction using petroleum ether. This gave 0.8 g of crystals of melting point: 210-212° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.Cl>CN(C)C=O.[Cl-].[Ca+2].[Cl-].[Ag]=O>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:3][C@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: C1=COCCC1
Reactant: CC(C)COC(=O)[C@@H](C)O
Agent: O=[Ag]
Agent: Cl
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)[C@@H](C)OC1CCCCO1
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of isobutyl (R)-lactate (73 g, 0.5 mol, Merck) and 3,4-dihydro-2H-pyran (70 g, 0.83 mol, Merck) was treated with 5M hydrogen chloride in dimethylformamide (4 ml) and set aside at ambient temperature overnight in calcium chloride protected 250 ml round-bottom flask. Silver oxide (15 g) was added, the mixture stirred magnetically for 2 hours and then filtered. The product was isolated by distillation (13 Pa, b.p. 94∝96° C.) to provide isobutyl 2-O-tetrahydropyranyl-(R)-lactate (102.5 g, 89%) as a colorless oil.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C1COCC1.[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52](=[O:57])(=[O:56])[N:53]([CH3:55])[CH3:54])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][NH:41][CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C=O>CO>[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52](=[O:56])(=[O:57])[N:53]([CH3:54])[CH3:55])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][N:41]([CH3:1])[CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)C=C(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A 1M solution of sodium cyanoborohydride in THF (0.15 mL, 0.15 mmol) was added to a solution of 13-cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 20) (10 mg, 0.015 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield product 13-cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (8.5 mg, 10 μmol, 68% yield) as a bright yellow solid. LCMS: m/e 688 (M+H)+. LCMS retention time: 1.91 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.) 1H NMR (400 MHz, MeOD) δ ppm 8.07 (br s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.54 (br d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.14 (dd, J=8.5, 2.5 Hz, 1H), 7.09 (d, J-2.5 Hz, 1H), 7.06 (s, 1H), 5.23 (br d, J=14.8 Hz, 1H), 4.37-3.06 (in, 10H), 4.25 (br d, J=14.8 Hz, 1H), 3.89 (s, 3H), 2.98 (s, 6H), 2.94-2.76 (m, 4H), 2.15-1.69 (m, 6H), 1.52-1.10 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([O:35][CH2:36][C:37](Cl)=O)[CH3:34].C(N(CC)CC)C>ClCCl.C(O)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:31]=[C:34]1[CH2:33][O:35][CH2:36][CH3:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOCC(=O)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
tert-Butyl{4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (28.1 g, 64.3 mmol) was dissolved in dichloromethane (319 mL). Ethoxyacetyl chloride (7.87 g, 64.5 mmol) was added dropwise via an addition funnel and the mixture was stirred for 1 hour. The dichloromethane was removed under reduced pressure and the resulting residue was dissolved in a solution of triethylamine (35.84 mL, 0.26 mol) and ethanol (319 mL). The reaction was heated at reflux for 4 hours, and then allowed to cool overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic fraction was washed sequentially with water and saturated aqueous sodium chloride; dried over anhydrous sodium sulfate; filtered; and concentrated under reduced pressure. The oily residue was dissolved in acetonitrile. The acetonitrile was subsequently removed under reduced pressure to provide 30 g of tert-butyl[4-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a brown solid.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Li])CCC.CI.[Cl-].[NH4+]>CN(C=O)C.CCOCC.C(OCC)(=O)C>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([CH3:17])=[N:13][CH:12]=[N:11]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OCCCn1cncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ncnn1CCCO[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 3-(tertbutyldimethylsilyloxy)-1-(1,2,4-triazol-1-yl)propane (7 g, 29 mmol) in DMF (100 ml) cooled at −70° C. was added 2.5M n-butyllithium (17.4 ml) over 45 minutes. After stirring for 90 minutes at −70° C., methyl iodide (3.6 ml, 58 mmol) was added. After stirring for 2 hours at ambient temperature, the mixture was poured onto saturated ammonium chloride. The mixture was then diluted with ether and ethyl acetate. The organic layer was separated, washed with aqueous sodium thiosulphate followed by brine, dried (MgSO4) and evaporated to give 3-(tertbutyldimethylsilyloxy)-1-(5-methyl-[1,2,4]-triazol-1-yl)propane (7.3 g, 98%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)O1.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccc(Cl)nn2)cc1
Temperature: 110 °C
Yield: 84.2 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.500 g, 2.28 mmol), 3,6-dichloropyridazine (0.340 g, 2.28 mmol), sodium carbonate (0.726 g, 6.85 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.068 g, 0.059 mmol) were mixed in 1,2-dimethoxyethane (11 mL) and water (3.8 mL) under nitrogen. The reaction mixture was heated (110° C.) for 12 h, cooled to RT, diluted with brine, and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum to a crude solid which was dissolved in DCM and extracted into 1N HCl (aq). The DCM layer was discarded, and the aqueous layer was basified with 1N NaOH (aq) and re-extracted with EtOAc. The EtOAc layer was dried (Na2SO4), filtered, and concentrated under vacuum to give the title compound (0.395 g). MS (ESI+) for m/z 206 (M+H)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:21](=[O:23])[CH3:22])[CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:21]([C:11]1[CH:10]=[C:9]([NH:8][C:3](=[O:5])[CH3:2])[CH:14]=[C:13]([S:15]([F:16])([F:20])([F:17])([F:18])[F:19])[CH:12]=1)(=[O:23])[CH3:22]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reaction time: 8 h
Yield: 99 %

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone trifluoroacetic acid salt (100 mg, example 4d) was dissolved in methylene chloride (10 ml), and triethylamine (120 μl) was added. Acetic anhydride (30 μl) was then added dropwise while stirring. After stirring for 4 h, the mixture was left to stand overnight and then further acetic anhydride (30 μl) was added. After stirring for a further 6 h, the reaction mixture was again left to stand overnight and then concentrated. The residue was taken up with ethyl acetate and water, and adjusted to pH 9 with saturated sodium hydrogencarbonate solution, and the aqueous phase was extracted twice more with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 80 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][O:22][CH3:23].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O>[CH3:23][O:22][N:21]([CH3:20])[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A solution of 20.3 grams (0.098 mole) of 3,4-dichlorophenylacetic acid in 200 mL of methylene chloride was stirred, and 10.7 mL (0.124 mole) of oxalyl chloride was added in one portion, followed by 6 drops of N,N-dimethylformamide. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time, 12.0 grams (0.123 mole) of N,O-dimethylhydroxylamine hydrochloride was added in one portion. The reaction mixture was then cooled to 0° C., and 35.9 mL (0.450 mole) of pyridine was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for about 18 hours. The reaction mixture was then diluted with 200 mL of water, and the organic layer was separated. The organic layer was washed with 200 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 5% ethyl acetate in methylene chloride, then gradually increasing to 15% ethyl acetate in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 19.4 grams of N-methoxy-N-methyl-3,4-dichlorophenylacetamide. The NMR spectrum was consistent with the proposed structure.