Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH:10]([CH2:22][OH:23])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH:10]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)OC(CO)C2
Product: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)OC(COC(C)=O)C2
Reaction time: 3 h
Yield: 95 %

Procedure:
23.19 g (69.2 mmoles) of 1-(3-chlorophenyl)-3-hydroxymethyl-6,7-dimethoxyisochromane are dissolved in 100 ml of acetic anhydride. The reaction mixture is boiled for 3 hours under reflux, then it is evaporated in vacuo, and three times 50 ml each of 99.5% ethanol are distilled off the residual gum in vacuo. Thus 24.8 g of crude 1-(3-chlorophenyl)-3-acetoxymethyl-6,7-dimethoxyisochromane are obtained. Yield: 95%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:14][CH3:15])[CH3:13])[CH:2]1[O:4][CH2:3]1.[NH3:16]>O>[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:14][CH3:15])[CH3:13])[CH2:3][NH2:16]
Reactant: N
Reactant: CCC(C)c1ccccc1OCC1CO1
Solvent: O
Product: CCC(C)c1ccccc1OCC(O)CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A 2.5 liter autoclave is charged, at room temperature and under nitrogen blanketing, with 429 g (2.1 mol) of o-sec-butylphenyl glycidyl ether and 30.2 g of water. Then 698.5 g (41.08 mol) of ammonia gas is blown in under pressure over 5 minutes and the reaction mixture is thereafter heated to 80° C. over 2 hours. After 1 hour at 80° C., the reaction mixture is cooled to room temperature, the pressure in the system is removed and the reaction product is concentrated on a rotary evaporator at 80° C./13 mbar. Gas chromatographic analysis shows the resultant amine to be 92.5% pure. It has a viscosity of 1240 mPa·s.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]3[C:32]([NH:1][C:2]4[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=4[O:4][C:5]4[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=4)=[N:30][CH:29]=[N:28][C:20]=3[N:21]=2)[CH2:26][CH2:27]1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Reactant: Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Oc2ccc(O)cc2)c(Nc2ncnc3nc(C4CC4)ccc23)c1

Procedure:
The product from Example 122b was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 122b for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.03-1.18 (m, J=6.25 Hz, 4H), 2.20-2.35 (m, 1H), 2.30 (s, 3H), 6.57-6.85 (m, 5H), 7.03 (dd, J=8.27, 1.65 Hz, 1H), 7.36 (d, J=1.84 Hz, 1H), 7.52 (d, J=8.46 Hz, 1H), 8.50 (s, 1H), 8.65 (d, J=8.46 Hz, 1H), 9.18 (s, 1H), 9.70 (s, 1H); MS (ESI)+ m/z 385 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=2)[O:2]1.C(N(CC)CC)C.ClC(OCC)=O.[CH:33]([C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]([CH3:46])[CH3:45])[C:37]=1[CH2:38][NH2:39])([CH3:35])[CH3:34]>C1COCC1.C(OCC)(=O)C.O>[CH:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:36]([CH:33]([CH3:35])[CH3:34])[C:37]=1[CH2:38][NH:39][C:12](=[O:14])[CH2:11][C@H:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:46])[CH3:45]
Reactant: CC(C)c1cccc(C(C)C)c1CN
Reactant: CCCCC[C@H](CC(=O)O)c1cccc2c1OCO2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC[C@H](CC(=O)NCc1c(C(C)C)cccc1C(C)C)c1cccc2c1OCO2
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
To a solution of 407 mg (1.54 mmol) of (R)-3-(2, 3-methylenedioxyphenyl) octanoic acid in 8 ml of THF were added 0.24 ml of triethylamine and then 0.15 ml (1.6 mmol) of ethyl chloroformate. After stirring for 20 minutes, a solution of 264 mg (1.38 mmol) of 2, 6-diisopropylbenzylamine in tetrahydrofuran was added to the mixture, which was stirred at room temperature for 2 hours. The reaction mixture was mixed with 10 ml of water and shaken with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 348 mg of (R)-N-(2, 6-diisopropylbenzyl)-3-(2,3-methylenedioxyphenyl) octanamide as white crystals. Yield, 52%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:29]=[CH:28][C:13]2[CH2:14][O:15][C:16](=[O:27])[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[CH:11]=1.C(N(CC)C(C)C)(C)C.[O:39]=[C:40]1[CH2:45][O:44][C:43]2[CH:46]=[CH:47][C:48]([CH:50]=O)=[N:49][C:42]=2[NH:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH3:8][O:9][C:10]1[CH:29]=[CH:28][C:13]2[CH2:14][O:15][C:16](=[O:27])[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH2:50][C:48]4[CH:47]=[CH:46][C:43]5[O:44][CH2:45][C:40](=[O:39])[NH:41][C:42]=5[N:49]=4)[CH2:23][CH2:22]3)[C:12]=2[CH:11]=1
Reactant: COc1ccc2c(c1)N(CCCN1CCNCC1)C(=O)OC2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)N(CCCN1CCN(Cc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)OC2

Procedure:
7-Methoxy-1-(3-piperazin-1-ylpropyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one trifluoroacetate (Intermediate 118, crude, 886 mg, 1.66 mmol) was converted to the free base with N,N-diisopropylethylamine and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (220 mg, 1.23 mmol) and sodium triacetoxy borohydride (521 mg, 2.46 mmol) as described for Example 55 to give the free base of the product as a pink foam after chromatography on silica gel with dichloromethane/methanol (93:7), 86 mg (21%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.ClC(OC(C)C)=O>C1COCC1>[C:1]([N:8]1[CH2:9][CH:10]([CH2:12][OH:13])[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-Boc-azetidine-3-carboxylic acid (1.6 g) and Et3N (2 ml) in anhydrous THF (60 ml) was cooled to 0° C. Isopropyl chloroformate (1.3 g) was added via a syringe slowly; forming a white precipitate almost immediately. The reaction was stirred for 1 h at 0° C. and the precipitate was filtered out. The filtrate was cooled to 0° C. again and aqueous NaBH4 solution (900 mg, 5 ml) was added via pipette and stirred for 1 h. The reaction was quenched with NaHCO3 solution (50 mL) and the product was extracted with EtOAc (200 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in EtOAc and passed through a short silica gel pad. Concentrating the filtrate in vacuo provided the compound as a light yellow oil.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:27])=[O:28])=[CH:22][CH:21]=1)=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Product: NS(=O)(=O)c1ccc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)cc1

Procedure:
The reaction and recovery procedures of Example I are observed while reacting N-carbobenzyloxy-DL-proline with 4-aminobenzenesulfonamide to yield the desired product, 4-(N-carbobenzyloxy-DL-prolylamino)benzenesulfonamide, having a mp. of 144°-150° C.
Reaction SMILES: [I:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CC(O)=O.[CH:26]([C:28]1[N:29]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:30]=[CH:31][N:32]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][C:28]2[N:29]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:30]=[CH:31][N:32]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:12][CH:11]=2)=[CH:20][CH:21]=1
Reactant: NS(=O)(=O)c1ccc(CCNCc2ccc(I)cc2)cc1
Reactant: CC(C)(C)OC(=O)Cn1ccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a solution of 4-(2-((4-iodobenzyl)amino)ethyl)benzenesulfonamide (208 mg, 0.50 mmol), AcOH (0.05 mL) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (0.105 mg, 0.50 mmol) in DCE (10 mL) at 0° C. was added NaBH(OAc)3 (0.30 g, 1.5 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by biotage over silica gel eluting with DCM to 10% MeOH in DCM to afford tert-butyl 2-(2-(((4-iodobenzyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetate (27.9 mg, 91%). 1H NMR (400 MHz, CDCl3) 7.78 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 6.95 (d, J=1.2 Hz, 1H), 6.79 (d, J=0.8 Hz, 1H), 4.78 (s, 2H), 4.31 (s, 2H), 3.62 (s, 2H), 3.57 (s, 2H), 2.82-2.68 (m, 4H), 1.39 (s, 9H); MS (ESI), 611.1 (M+H)−.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]#[N:28])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N1C=CN=C1>O1CCCC1>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH2:27][NH2:28])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C

Procedure:
2-(1-Trityl-1H-imidazol-4-yl)-benzonitrile (17.6 g, 42.7 mmol) was dissolved in dry tetrahydrofuran (320 ml) and stirred under nitrogen in an ice bath. To this solution was added lithium aluminum hydride (1.0 M in THF, 45 ml, 45 mmol) dropwise over 15 min. After the addition was complete the ice bath was removed and the reaction was stirred at room temperature. The reaction was closely monitored by HPLC and was typically complete within 45 min to 1.5 h. This close monitoring was essential because with longer reaction times, the amount of deprotected imidazole increased. Once complete, the reaction was diluted with tetrahydrofuran (200 ml) and quenched with water (1.7 ml), 15% sodium hydroxide solution (1.7 ml) and water (5.1 ml). This mixture was stirred at room temperature for 3 h. The solid was filtered over a layer of celite and rinsed with tetrahydrofuran (200 ml). Rotary evaporation of the filtrate afforded 2-(1-trityl-1H-imidazol-4-yl)-benzylamine as a thick amber oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][O:7][SiH:6]([CH3:10])[O:5][CH2:4][CH2:3]1.[CH3:11][Si:12]([CH3:22])([CH3:21])[N:13]([CH2:18][CH:19]=[CH2:20])[Si:14]([CH3:17])([CH3:16])[CH3:15]>[Pt]>[CH3:1][N:2]1[CH2:9][CH2:8][O:7][Si:6]([CH3:10])([CH2:20][CH2:19][CH2:18][N:13]([Si:12]([CH3:21])([CH3:22])[CH3:11])[Si:14]([CH3:17])([CH3:16])[CH3:15])[O:5][CH2:4][CH2:3]1
Reactant: CN1CCO[SiH](C)OCC1
Reactant: C=CCN([Si](C)(C)C)[Si](C)(C)C
Agent: [Pt]
Product: CN1CCO[Si](C)(CCCN([Si](C)(C)C)[Si](C)(C)C)OCC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 11.9 %

Procedure:
To a sealed 300 mL nitrogen purged glass bottle was added 16.2 g (100 mmol) 1,5-dimethyl-1-aza-4,6-dioxa-5-silacyclooctane and 20.1 g (100 mmol) N,N-bistrimethylsilylallylamine and the bottle was heated to 75° C. with stirring. Then, 0.8 mL of a 2 wt % platinum solution of Karsted's catalyst in xylenes was added to the reaction. After 24 hrs, the product was isolated by vacuum distillation at 110° C. and 0.04 mm Hg (4.33 g, 11.9% yield). 1H NMR (300 MHz, C6D6) δ (ppm) 3.72 (4H, t), 2.71 (2H, t), 2.59 (4H, t), 2.41 (3H, s), 1.44-1.42 (2H, m), 0.44 (2H, t), 0.09 (3H, s), 0.06 (18H, s).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](I)=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38](B(O)O)=[C:37]([O:47][CH3:48])[CH:36]=1.O>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:38]4[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:35]([F:34])=[CH:36][C:37]=4[O:47][CH3:48])=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ncc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 85 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-iodo-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (9.7 mg, 0.0162 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (5.2 mg, 0.0243 mmol), and 1,1′-bis(di-t-butylphosphinoferrocene)palladium dichloride (1.0 mg, 0.00162 mmol) in 1N aqueous potassium carbonate (0.7 mL) and THF (0.7 mL) was heated at 85° C. in a sealed tube for 2 h. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.40 (20% EtOAc/hexanes). LCMS calc. 639.2; found 639.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.55 (s, 1H); 7.87 (s, 1H); 7.74-7.68 (m, 3H); 7.02 (dd, J=4.5, 8.1 Hz, 1H); 6.72 (d, J=11.7 Hz, 1H); 5.64 (d, J=8.0 Hz, 0.5H); 5.48 (d, J=7.9 Hz, 0.5H); 4.84 (d, J=16.4 Hz, 0.5H); 4.77 (d, J=16.5 Hz, 0.5H); 4.21 (d, J=16.5 Hz, 0.5H); 3.96 (d, J=16.3 Hz, 0.5H); 3.92-3.85 (m, 0.5H); 3.8-3.73 (m, 3.5H); 3.25-3.17 (m, 1H); 1.30-1.18 (m, 6H); 0.56 (d, J=6.4 Hz, 1.5H); 0.42 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[NH2:22][C:13]1[C:12]2[N:11]=[C:10]([CH2:23][CH2:24][CH2:25][CH3:26])[N:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNS(C)(=O)=O
Temperature: 25 °C
Yield: 28.7 %

Procedure:
Methanesulfonyl chloride (1.27 g, 11.1 mmol) was slowly added to a solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 10.6 mmol) in pyridine (60 mL). The reaction was maintained at ambient temperature overnight and then it was concentrated to dryness. The residue was combined with warm dichloroethane and water and then filtered to provide an off white solid. The dichloroethane layer was concentrated to provide an off white solid. The two solids were combined and then recrystallized from N,N-dimethylformamide to provide 1.1 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as a white solid, m.p. 210.0-211.0° C. Analysis: Calculated for C17H23N5O2S: % C, 56.49; % H, 6.41; % N, 19.37; Found: % C, 56.45; % H, 6.49; % N, 19.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[BrH:15]>CC(O)=O>[Br:15][CH2:12][CH2:13][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:11])=[O:14]
Reactant: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)C(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Treat the product of Step 1 (21.25 g, 91.96 mmoles) at room temperature with 130 ml. of HOAc saturated with HBr gas. Stir at room temperature for 2 days, then pour into 800 ml. of ice-water with stirring. Store the resultant gum in a freezer for two days, then decant the liquid from the solidified gum. Triturate the solid, filter, wash with water and air dry. Yield: 26.2 g (m.p.=80°-81° C.).
Reaction SMILES: C[O:2][CH2:3][PH:4]([O:6][C@@H:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:9])=[O:5].C(O)(C)C.N.O>CC(C)=O>[OH:2][CH2:3][PH:4]([O:6][C@@H:7]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:9])=[O:5]
Reactant: COC[PH](=O)O[C@@H](Cc1ccccc1)C(=O)Nc1ccc(C(=O)OC)cc1
Agent: N
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)O[PH](=O)CO)cc1
Reaction time: 8 h

Procedure:
The methyl ester product from part (b) (2.3 g., 5.88 mmole) is suspended in acetone (7 ml.) at room temperature. Trimethylamine is bubbled in for about 20 minutes to saturate the mixture. The reaction vessel is sealed, and the mixture is heated to about 95° and is stirred overnight. The volatiles are evaporated, and the residue is partitioned between ethyl acetate and 5% potassium bisulfate. The organic layer is washed once with brine, dried (Na2SO4), filtered, and the volatiles are evaporated to give 1.86 g. of 4-[[(S)-2=[(hydroxymethylphosphinyl)oxy]-1-oxo-3-phenylpropyl]amino]benzoic acid, methyl ester. TLC (silica gel; isopropanol:ammonia:water, 7:2:1) Rf =0.62.
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[CH3:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]=[N:23][C:17]=2[CH:16]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]([CH:10]3[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]3)[NH:23][C:17]=2[CH:16]=1
Reactant: CN1CCC(Cl)CC1
Reactant: Cc1ccc2c(c1)N=Cc1cccc3c1N2CC3
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)NC(C1CCN(C)CC1)c1cccc3c1N2CC3
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 1 L three-necked flask, 1,2-dibromoethane (0.3 ml) was added to a refluxing slurry of magnesium chips (4.1 gm) in tetrahydrofuran (80 ml) to initiate a Grignard reaction. A solution of N-methyl-4-chloropiperidine (28 ml) in tetrahydrofuran (30 ml) was added in portions to maintain a fast reflux. The resultant slurry was refluxed for 1 hour and cooled to about 0° C. A solution of 9-methyl-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (10.0 gm) in tetrahydrofuran (50 ml) was added dropwise. After 1.5 hours of stirring, the mixture was diluted with ethyl acetate (400 ml) and with saturated ammonium chloride solution (600 ml). The organic phase was separated. The aqueous phase was basified with 50% sodium hydroxide solution and then it was extracted twice with ethyl acetate (400 ml). The combined ethyl acetate solution was washed with water (2×300 ml) and brine (2×300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)C(OC)=O)(=[O:10])=[O:9])=[C:4](/[CH:33]=[CH:34]\[CH2:35]O)[CH:3]=1.C([N:40]([CH:43]([CH3:45])C)[CH2:41]C)(C)C.CS(Cl)(=O)=O.N1CCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[N:40]1([CH2:35]/[CH:34]=[CH:33]\[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:9])=[O:10])[CH2:41][CH2:45][CH2:43]1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCC2)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a suspension of methyl 7-{N-[4-fluoro-2-((Z)-3-hydroxy-prop-1-enyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 92, 0.150 g) in DCM (10 mL) was added N,N-di-isopropyl-N-ethylamine (0.112 g) and methanesulfonyl chloride (0.040 g). The mixture was stirred at room temperature for 15 minutes. A solution of azetidine (0.083 g) in toluene (2 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%. The resultant product was triturated with diethyl ether to give methyl 7-{2-[(Z)-3-azetidin-1-yl-prop-1-enyl]-4-fluorobenzene-sulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (0.030 g) as a white powder.