Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]([C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([O:24][CH3:25])[N:18]=[C:17]([O:26][CH3:27])[N:16]=1)[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]#[N:14])[CH:7]=[C:8]([CH3:10])[CH:9]=1)#N.[H-].[Na+].CN(C=[O:34])C>>[CH:21]([C:20]1[C:15]([C:3]([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][C:13]#[N:14])[CH:7]=[C:8]([CH3:10])[CH:9]=2)=[O:34])=[N:16][C:17]([O:26][CH3:27])=[N:18][C:19]=1[O:24][CH3:25])([CH3:23])[CH3:22]
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(C=CC#N)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=CC#N)c2)n1
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a stirred solution of 3-{3-[Cyano-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methyl]-5-methyl-phenyl}-acrylonitrile (96) (1.8 g, 4.97 mmol) in anhydrous DMF (20 ml) under nitrogen atmosphere, was added 60% sodium hydride (238 mg, 5.96 mmol). After 20 min., oxygen was bubbled into the reaction mixture for 3 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The organic layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 1.34 g (77%) of a white solid. m.p. 144-145° C.; 1H NMR (300 MHz, CDCl3) δ 1.19 (6H, d, J=6.9 Hz), 2.42 (3H, s), 2.83 (1H, m), 3.94 (3H, s), 4.08 (3H, s), 5.92 (1H, d, J=16.8 Hz), 3.39 (1H, d, J=16.8 Hz), 7.49 (1H, s), 7.69 (1H, s), 7.75 (1H, s).
Reaction SMILES: C([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:5]1)(O)=O.S(Cl)(Cl)=O.[O:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:41]([O:37][C:22]([NH:21][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[CH:17][CH:16]=2)[CH2:5]1)=[O:31])[C:40]1[CH:13]=[CH:4][CH:5]=[CH:38][CH:39]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1ccc(C(=O)N2CC(C(=O)O)Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Solvent: O=S(Cl)Cl
Product: O=C(NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To 3-carboxy-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (3.7 g) are added tetrahydrofuran (50 ml) and thionyl chloride (5 ml). The mixture is reacted at 60° C. for 1 hour. The reaction mixture is concentrated and to the residue is added acetone (20 ml). To the mixture is added dropwise a solution of sodium azide (1.0 g) in water (5 ml) under ice-cooling. The reaction mixture is stirred at the same temperature for 30 minutes and extracted with dichloromethane, dried over magnesium sulfate. The solvent is concentrated and to the resulting residue are added anhydrous toluene (30 ml) and benzyl alcohol (1.7 g). The mixture is refluxed for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1) to give 3-benzyloxycarbonylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl)-1,2,3,4-tetrahydroquinoline (3.7 g) as colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: OCCc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C)c(OCCc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 2-(4-bromophenyl)ethanol (20.0 mL, 143 mmol), 2,3,5-trimethylphenol (31.1 g, 229 mmol), azodicarboxylic dipiperidide (72.1 g, 286 mmol) and tributylphosphine (88 mL; 357 mmol) in toluene (2.00 L) was heated to reflux for 2 h. The mixture was allowed to cool to rt. The mixture was filtered, washed with toluene and the solvents were partially removed under reduced pressure. The residue was diluted with Et2O and washed with aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (petroleum ether→Et2O/petroleum ether 1:3) yielded the title compound (33.1 g, 73%). LC-MS: Rt=6.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3cc(-c4ccccc4)nn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-5-phenylpyrazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:23]=[C:22]([N:24]([CH3:26])[CH3:25])[C:21]4[CH2:20][CH2:19][CH2:18][CH:17]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:16]=4[N:15]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:23]=[C:22]([N:24]([CH3:26])[CH3:25])[C:21]4[CH2:20][CH2:19][CH2:18][C@H:17]([C:27]5[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=5)[C:16]=4[N:15]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N(C)C)n2)CCCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC[C@@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,N4-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (Example 127) was purified using chiral SFC to afford peak A (Example 127A) and peak B (Example 127B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 13 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.3 min, tR (peak B) 9.6 min. The absolute stereochemistry of individual enantiomers (Examples 7 and 8) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 127).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:18][N:19]=[C:20]4[CH2:25][CH2:24][NH:23][CH2:22][C:21]=34)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[C:26]([N:23]1[CH2:24][CH2:25][C:20]2=[N:19][NH:18][C:17]([CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)=[C:21]2[CH2:22]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CNCC4)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2n[nH]c(CCCN3CCN(c4ccc(F)cc4)CC3)c2C1

Procedure:
3-(3-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (0.3 g) obtained in Example 141 was dissolved in a mixed solution of chloroform (5 ml) and saturated aqueous sodium hydrogencarbonate solution (5 ml), and acetyl chloride (0.3 ml) was added dropwise under ice-cooling. After the dropwise addition, the chloroform layer was partitioned and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give 5-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([Br:11])[CH:6]=[C:5]([F:12])[C:3]=1[NH2:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([Br:11])[CH:6]=[C:5]([F:12])[C:3]=1[NH:4][C:13](=[O:15])[CH3:14]
Reactant: COc1c(Br)cc(F)c(N)c1Br
Reactant: CC(=O)OC(C)=O
Product: COc1c(Br)cc(F)c(NC(C)=O)c1Br
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Compound 8-5 (212.7 g, 0.711 mol) was added to acetic anhydride (200 mL) in one portion at 20° C. The reaction mixture was stirred for 30 minutes and then was filtered to get 8-6 (192 g, 79.2%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[SH-:16].[Na+]>O>[CH2:14]([O:13][C:11]([C:4]1[CH:3]=[C:2]([SH:16])[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[N:5]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(Cl)n2cnnc2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(S)n2cnnc2n1
Yield: 75.8 %

Procedure:
The product obtained in Step 1 (6 g) was added all at once under ice cooling to a solution of sodium hydrosulfide (5.5 g) in 100 ml of water, with stirring in nitrogen, and the mixture was stirred at room temperature for two hours. After filtering off the insoluble matters, the yellow filtrate was acidified to pH 2.0 with 6N hydrochloric acid, and the formed crystals were collected by filtration, washed with 20 ml of water and air-dried, affording 4.5 g of the objective compound as faint yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]2[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=2[CH:73]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:26])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:60][CH2:61][C:62]4[CH:63]=[CH:64][C:65]5[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=5[CH:73]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(C)C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.65 g, 3.95 mmol) and Et3N (1.6 g, 15.8 mmol) in MeCN (35 ml) was stirred at rt for 5 min and then HATU (3 g, 7.9 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (906 mg, 4.74 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by column chromatography and preparative HPLC to provide the product (500 mg, yield 21%). 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.92 (s, 1H), 7.82 (s, 1H), 7.61 (m, 5H), 7.40 (m, 3H), 4.49 (d, 2H), 4.37 (d, 2H), 2.39 (s, 3H), 1.44 (s, 6H) ppm; HPLC purity: 97.4% at 220 nm and 98.1% at 254 nm; MS: m/z=591.3 (M+H, ESI+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30](=[CH2:32])[CH3:31].S(=O)(=O)(O)O>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([O:24][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)C
Reactant: O=C(Nc1ccccc1CCc1ccccc1C(=O)O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1CCc1ccccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of 2-[2-(2-(phenylmethoxycarbonylamino)phenyl)ethyl]benzoic acid (5.2 g, 0.014 mol) in methylene chloride (100 mL) was treated with isobutylene (15 mL) and sulfuric acid (0.14 mL) and stirred at room temperature. Isobutylene was added over the period of several days until the reaction was complete. The reaction mixture was washed with 5% aqueous sodium carbonate and with water. The organic phase was dried with magnesium sulfate and concentrated in vacuo to give an oil which was purified by chromatography (silica gel, hexane:ethyl acetate 95:5) to give t-butyl 2-[2-(2-(phenylmethoxycarbonylamino)phenyl)-ethyl]-benzoate (1.8 g, 31%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH3:19])=[CH:15][C:16](O)=[O:17])[CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH3:19])=[CH:15][C:16]([Cl:23])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CC(=CC(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CC(=CC(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to that of Example 1(c), by reaction of 2.7 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-butenoic acid with 800 μl of thionyl chloride, 2.9 g (100%) of the expected acid chloride are obtained, which product will be used subsequently in the synthesis without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=2[O:12]C)[N:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=2[OH:12])[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC
Agent: Cl
Solvent: CCO
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Yield: 92.4 %

Procedure:
4-Methyl-5,6-dimethoxy-8-nitroquinoline (6.21 g, 25 mmol) was dissolved in ethanol (100 mL) containing concentrated hydrochloric acid (4.7 mL). The mixture was heated under reflux for 21 hours, then cooled to 10° and filtered. The solid was washed with cold (10°) ethanol (18 mL) followed by petroleum ether (15 mL) and air-dried to yield 5.41 g (92%) of the title compound, mp 253°-257° (dec).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:36])[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:36])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCNCC1
Yield: 128.4 %

Procedure:
tert-Butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate (0.0039 g, 0.0080 mmol) was treated with a mixture of trifluoroacetic acid and DCM (1:1) for 1 hour. The reaction was concentrated to provide 4 mgs of the desired material as a solid. MS ESI (+) m/z 390 (M+1) detected.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[I-].[Na+]>CCOC(C)=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:11][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)[C@H](C)O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)OCc1ccc(OC)cc1
Temperature: 150 °C
Yield: 61.9 %

Procedure:
A mixture of (S)-methyl 2-hydroxypropanoate (1.5 g, 14.41 mmol), 1-(chloromethyl)-4-methoxybenzene (3.38 g, 21.61 mmol), DIPEA (4.03 ml, 23.05 mmol) and sodium iodide (0.150 g, 1.001 mmol) was heated to 150° C. for 2 h. Reaction mixture then was cooled to room temperature diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (2×50 mL) and brine. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The crude mixture was purified by flash chromatography on silica gel using an ISCO system (eluted with 9:1 Hexanes and EtOAc) to give (S)-methyl 2-((4-methoxybenzyl)oxy)propanoate (2 g) as a gummy liquid.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[O:17]=[C:18]1[N:22]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[NH:19]1>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[N:22]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]3([CH3:16])[CH2:7][C:6]4[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=4[O:4]3)[CH2:27][CH2:28]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[NH:19]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Solvent: Cc1ccccc1C
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(n3c(=O)[nH]c4ccccc43)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
In an autoclave, a suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g) and 4-(2-keto-1-benzimidazolinyl)piperidine (2.3 g) in xylene (20 mL) was stirred under nitrogen gas at 180° C. for 15 hours. The reaction mixture was then cooled, filtered, and washed with diethyl ether. The filtrate was washed with water and extracted with 1N-hydrochloric acid. The aqueous layer was neutralized with saturated aqueous NaHCO3 and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate (Na2SO4) and silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was crystallized from ethanol to give 1.2 g of 2-[[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine. Yield 55%. This product was dissolved in tetrahydrofuran with heating and after the solution was diluted with methanol, a stoichiometric excess of 10% HCl/methanol was added. The resulting solution was concentrated under reduced pressure and cyrstallized from methanol/diethyl ether to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11](=[O:28])[C@H:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:13]C(OCC1C=CC=CC=1)=O.CO>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11](=[O:28])[C@H:12]([C:24]([CH3:26])([CH3:25])[CH3:27])[NH2:13]
Reactant: COCCOCOCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: COCCOCOCCNC(=O)[C@@H](N)C(C)(C)C
Reaction time: 3 h

Procedure:
N-Benzyloxycarbonyl-L-tert-leucine-N-2-(2-methoxy-ethoxymethoxy)ethylamide was deprotected by hydrogenolysis, as described in Step G. Reaction was complete after 3 hours, leaving a single ninhydrin positive spot on TLC (5% methanol in dichloromethane). The solvent wwas removed to give the title compound as a white foam. Yield: 1.17 9(92%). 1H--NMR; δCD3OD), 4.66 (2H, s), 3.68-3.48 (7H, br m), 3.40 (1H, m), 3.35 (3H, s) and 0.95 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([F:15])[C:7]=1[C:8]([CH3:14])([CH3:13])[C:9]([F:12])([F:11])[F:10].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:8]([CH3:13])([CH3:14])[C:9]([F:11])([F:12])[F:10])=[C:6]([F:15])[CH:5]=1)[CH3:23]
Reactant: CC(C)(c1c(F)cc(O)cc1F)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(C(C)(C)C(F)(F)F)c(F)c1
Yield: 86.1 %

Procedure:
An acetone (5 ml) suspension of 3,5-difluoro-4-(2,2,2-trifluoro-1,1-dimethylethyl)phenol (227 mg, 0.95 mmol), ethyl bromoacetate (174 mg, 1.0 mmol) and potassium carbonate (261 mg, 1.9 mmol) was stirred at reflux for 1 hour. Then, the reaction was quenched with water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated and evaporated to furnish 267 mg (87% yield) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[CH:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH:27]([CH3:28])[CH2:26][NH2:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(N)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(C)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (dd, J=7.83, 1.01 Hz, 1 H), 7.82 (d, J=7.33 Hz, 1 H), 7.69-7.56 (m, 2 H), 7.46-7.38 (m, 2 H), 7.28 (dd, J=8.46, 1.64 Hz, 1 H), 6.11-5.96 (m, 1 H), 5.13 (s, 2 H), 3.66-3.49 (m, 2 H), 3.30-3.20 (m, 3 H), 2.47-2.39 (m, 3 H), 2.24-2.19 (m, 2 H), 1.32-1.22 (m, 3 H).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[OH-].[K+].[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([CH3:29])([CH3:28])[CH3:27]>CS(C)=O.O>[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][C:2]2[CH:20]=[CH:19][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product from Example 172b (215 mg, 0.655 mmol) was dissolved in DMSO (30 ml) to which KOH (75 mg, 1.31 mmol) and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester (137 mg, 0.655 mmol) were added. The reaction mixture was then heated to 80° C. for 2 h reaction mixture was then cooled to room temperature and diluted with water and the title compound collected by filtration (240 mg, 78%).
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([N:9]([CH3:15])[CH3:10])(=[O:7])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CNS(=O)(=O)CC(=O)C=C(C)N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(N)=CC(=O)CS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide and 1.9 ml of methyl iodide in 50 ml of dimethylformamide was treated with 6 g of finely ground dry potassium carbonate and the mixture was thereupon stirred intensively at room temperature under argon for 6 hours. The organic salts were then filtered off, rinsed with methylene chloride and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between water and methylene chloride, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The solid product was recrystallized from isopropanol, whereby there were obtained 2.5 g of 4-amino-N,N-dimethyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 137°-140°.