Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[O:19])=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH3:22])=[O:19])=[CH:16][C:11]=3[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(-c3ccc(F)cc3)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To the solution of (R)-1-(3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (61 mg, 0.10 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) and triethylsilane (0.05 mL, 0.313 mmol). The mixture was stirred at room temperature for 10 min, concentrated in vacuo and purified on reversed phase HPLC to afford (R)-1-(3-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (40 mg, 0.083 mmol, 83%) as a yellow solid. MS ESI calcd. for C21H19FN5O [M+H]+ 376, found 376. 1H NMR (600 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.12 (s, 1H), 9.06 (s, 1H), 8.04 (dd, J=8.8, 5.5 Hz, 2H), 7.75 (s, 1H), 7.65 (s, 1H), 7.39-7.27 (m, 6H), 7.22-7.18 (m, 1H), 4.86 (m, 1H), 1.39 (d, J=6.9 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N:1]1([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: OCCCCn1cnc2cnc3ccccc3c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCCn1cnc2cnc3ccccc3c21
Yield: 50.4 %

Procedure:
The general method described in Step 6 of Example 1 was used to oxidize 4-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (20.0 g, 82.9 mmol) with DMSO (48.6 g, 620 mmol), oxalyl chloride (58.0 g, 456 mmol), and triethylamine (126 g, 1.25 mol) to provide 4-(1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (10.0 g) as a light orange oil after chromatography on silica gel (elution with 10% methanol in dichloromethane) followed by brief treatment with trifluoroacetic acid (0.10 g, 1 mmol) in a mixture of THF (50 mL) and water (20 mL).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[K+].[K+].C(Cl)Cl>C(#N)C.O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH:10]=[O:12])=[N:3][C:2]=1[Br:1]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: COc1ccc(C)nc1Br
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(C=O)nc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A stirred mixture of 2-bromo-3-methoxy-6-methyl-pyridine (2.00 g, 9.9 mmol), Cu(II) sulfate pentahydrate (2.47 g, 9.9 mmol), and potassium peroxydisulfate (8.03 g, 29.7 mmol) in 80 mL of acetonitrile/H2O (1:1) was heated under reflux. After 1 hour, the dark green mixture was cooled to room temperature and CH2Cl2 was added. The layers were separated and the aqueous layer further extracted with CH2Cl2. The organics were combined, dried (MgSO4), filtered and evaporated. The resulting crude product was purified on silica gel [Biotage, hexane:ethyl acetate (4:1)] to give a white solid (0.51 g, 24% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]2C(OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O[C@@H]1CCN[C@H](c2ccc(F)cc2)C1

Procedure:
A mixture of benzyl 2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.07 mmol) (reagent preparation 20) and 5% Pd on carbon (0.1 g) in acetic acid:methanol 1:10 (20 mL) was hydrogenated at 45 psi using a Parr apparatus for 16 hours. The catalyst was removed by filtering through Celite, and the filtrate concentrated to give (±)-(2S,4R)-2-(4-fluorophenyl)piperidin-4-ol as an oil. The material was taken into chloroform (100 mL) and di-tert-butyl dicarbonate (0.74 g, 3.4 mmol) was added, followed by the dropwise addition of diisopropylethylamine (1.5 g, 12 mmol). The reaction was warmed to reflux for 10 minutes, then allowed to cool to 25° C. over 30 minutes. The organic solution was washed with 0.1M aqueous hydrochloric acid (45 mL), water (50 mL) and saturated sodium bicarbonate (50 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes, 1:1) to give (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (0.59 g, 65% yield). 1H NMR (400 MHz, d6-DMSO): 7.25 (m, 2H), 7.10 (m, 2H), 4.96 (t, 1H), 4.46 (d, 1H), 3.90 (m, 1H), 3.77 (m, 1H), 3.23 (dt, 1H), 2.06 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H), 1.45 (m, 1H), 1.29 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1>CS(C)=O.CC(OC)(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@H]1CCNC1
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), (S)-pyrrolidin-3-ol (46.1 mg, 0.529 mmol) and TEA (147 μL, 1.058 mmol) in DMSO (200 μL) was stirred at 90° C. for 16 h. The RM was diluted with 30 mL of TBME/EtOAc (1:1), sequentially washed 5 times with 0.5 M HCl and brine then evaporated to dryness under reduced pressure. The crude product was purified by flash column chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 10% to 50% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound as a white solid. UPLC-MS (condition 1) tR 2.83 min, m/z=444.9 [M+H]+, m/z=443.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.92 (m, 1H) 1.91-2.04 (m, 1H) 3.27 (d, J=10.76 Hz, 1H) 3.34-3.45 (m, 1H) 3.67 (dd, 1H) 3.81 (dd, J=10.39, 4.77 Hz, 1H) 4.30-4.42 (m, 1H) 4.97 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.81-7.90 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[C:22]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:21][C:20]([NH2:27])=[C:19]([OH:28])[CH:18]=1>>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10]3[O:28][C:19]4[CH:18]=[CH:17][C:22]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:21][C:20]=4[N:27]=3)=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cc(S(=O)(=O)O)ccc1O
Reactant: CCOC(=O)c1ccc(N2CCCC2)cc1
Product: O=S(=O)(O)c1ccc2oc(-c3ccc(N4CCCC4)cc3)nc2c1

Procedure:
In accordance with the procedure of Example 1, 10.0 g of ethyl 4-pyrrolidinobenzoate were reacted with 8.7 g of 2-aminophenol-4-sulfonic acid to yield 2-(p-pyrrolidinophenyl)-benzoxazole-5-sulfonic acid, melting point 310° (with decomposition).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6][CH:7]=[CH:8][C:9]([OH:11])=O.[C:12]1(SC=CC(O)=O)[CH:17]=[CH:16][CH:15]=[CH:14]C=1>>[N:1]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:12]1)[C@@H:4]([NH:3][C:9](=[O:11])/[CH:8]=[CH:7]/[S:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:5]2
Reactant: O=C(O)C=CSc1ncc[nH]1
Reactant: O=C(O)C=CSc1ccccc1
Product: O=C(/C=C/Sc1ncc[nH]1)N[C@H]1CN2CCC1CC2

Procedure:
Employing essentially the same procedure as that described in Example 1 above but substituting 3-(2-imidazolylthio)acrylic acid for the 3-(phenylthio)acrylic acid and purifying by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent resulted in formation of the title compound; MS (ES−) 279. (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10](=[O:20])[CH2:9]2)=[CH:4][C:3]=1[F:21].[Li+].[OH-:23].Cl>C1COCC1.O>[C:16]([O:15][C:13]([NH:11][CH2:12][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:21])[CH:4]=1)[CH2:9][C:10]([OH:23])=[O:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(Cl)c(F)c2)CC1=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](CC(=O)O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 92 (912 mg, 2.91 mmol) in THF/H2O (2:1; 15 mL) was added solid LiOH (209 mg, 8.72 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was acidified with 1M HCl to ca. pH 2-3 then twice extracted with EtOAc. The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to afford 902 mg (93.5%) of (S)-4-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)butanoic acid (100) which was used without further purification.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][N:15]1[CH2:14][CH2:13][C@@H:10]2[N:11]3[CH2:1][CH2:2][O:3][C:4]4[CH:5]=[CH:6][CH:7]=[C:8]([C:12]3=4)[C@@H:9]2[CH2:16]1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCO3

Procedure:
The title compound was prepared by the method of Example 361 as a red oil (11 mg, 24%) from (±)-cis-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino-[2,3,4-hi]pyrido[4,3-b]indole (30 mg, 0.12 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (51 mg, 0.24 mmol). 1H NMR (CDCl3, 300 MHz) δ1.87-2.15 (m, 5H), 2.25-2.45 (m, 3H), 2.65-2.79 (m, 2H), 2.86-2.95 (m, 3H), 3.15-3.30 (m, 3H), 4.44 (dd, J=6.9, 2.2 Hz, 2H), 6.26-6.38 (m, 2H), 6.41-6.50 (br-s, 2H), 6.60-6.72 (m, 3H), 7.78 (dd, J=9.1, 6.6 Hz, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O-:21].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:7]3[N:15]=[C:14]([O:21][CH3:20])[CH:13]=[CH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Temperature: 90 °C
Yield: 82 %

Procedure:
4-(3-Bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (described in a previous experimental) (0.11 g, 0.34 mmol) is added to a solution of NaOMe (prepared by the addition of Na metal (31 mg, 1.38 mmol) to dry MeOH (15 mL). After heating in a pressure vessel at 90° C. for 3 h, the solution is concentrated to dryness and the residue is partitioned between EtOAc and water. Workup of the organic portion gives 4-(3-bromophenyl)amino-6-methoxypyrido[3,2-d]pyrimidine (92 mg, 82%). 1H NMR (CDCl3) δ 8.73 (1H, s), 8.66 (1H, brs), 8.18 (1H, m), 8.05 (1H, d, J=8.9 Hz), 7.83-7.80 (1H, m), 7.30-7.24 (2H, m), 7.23 (1H, d, J=8.9 Hz), 4.12 (3H, s).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=3[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:30](=[O:35])(OCC)[NH2:31].C(O)C>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[C:1]12([CH2:11][N:12]3[C:13]4[C:14](=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:31][C:30]3=[O:35])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A mixture of 3.9 g of 2-(1-adamantylmethyl-amino)-5-nitrobenzophenone, 6.4 g of ethyl carbamate and 0.45 g of anhydrous zinc chloride was heated at 170°- 180°C for 1 hour, and then, distillating off the produced ethanol, heating was continued at that temperature for additional 1 hour. After cooling, chloroform was added thereto and insoluble material was filtered off. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residual oil was chromatographed on silica gel using chloroform as eluting solvent to give 1-(1-adamantylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 230°- 233°C, following recrystallization from a mixture of ethanol and chloroform.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[C:41](Cl)(=[O:65])[O:42][CH2:43][O:44][C:45](=[O:64])[C:46]1[CH:51]=[C:50]([S:52]([NH2:55])(=[O:54])=[O:53])[C:49]([Cl:56])=[CH:48][C:47]=1[NH:57][CH2:58][C:59]1[O:60][CH:61]=[CH:62][CH:63]=1>C(#N)C>[NH2:55][S:52]([C:50]1[C:49]([Cl:56])=[CH:48][C:47]([NH:57][CH2:58][C:59]2[O:60][CH:61]=[CH:62][CH:63]=2)=[C:46]([CH:51]=1)[C:45]([O:44][CH2:43][O:42][C:41]([N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:65])=[O:64])(=[O:53])=[O:54]
Reactant: NS(=O)(=O)c1cc(C(=O)OCOC(=O)Cl)c(NCc2ccco2)cc1Cl
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N(C(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. Nos. 3,819,706 and 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl carbonochloridate (1010) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (1020). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[F:11][C:8]1[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=[C:2]([F:1])[C:9]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: N#Cc1cccc(O)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: N#Cc1cccc(Oc2c(F)cc(C=O)cc2F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-hydroxybenzonitrile.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.ClCCl>[N:8]1([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][O:11][CH:10]([C:14]([O:16][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
4-{[(1,1-Dimethylethyl)oxy]carbonyl}-2-morpholinecarboxylic acid [Supplied by NeoMPS] (1 g, 4.32 mmol) was dissolved in N,N-dimethylformamide (20 ml) and potassium carbonate (0.598 g, 4.32 mmol) added. The mixture was stirred under nitrogen for 15 minutes at 20° C. Bromomethylbenzene (0.514 ml, 4.32 mmol) was added and the mixture stirred under nitrogen at room temperature for 18 hr. Water (25 ml) and dichloromethane (20 ml) were added and separated by hydrophobic fit. The aqueous phase was extracted with dichloromethane (2×20 ml). The organic phases were combined and the solvent was removed in vacuo. To the residue 1% lithium chloride solution (20 ml) and diethyl ether (20 ml) were added. The phases were separated and the aqueous phase was extracted with diethyl ether (2×15 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed in vacuo to give the title compound (1.19 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26]
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(Cl)cc21
Yield: 20 %

Procedure:
A mixture of 6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (200 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg, 0.78 mmol), 4-dimethylaminopyridine (95 mg, 0.78 mmol), methane sulfonamide (150 mg, 1.56 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (48 mg, 20%) as a light yellow solid: MS (ESI) M+1=462.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[CH3:10])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To a stirred solution of 5-Bromo-pyridine-2-carbaldehyde (10 g, 53.76 mmol) in tetrahydrofuran (200 mL) at 0° C. is added drop wise methyl magnesium bromide (45 mL, 64.51 mmol). Reaction mixture is stirred 0° C. for 6 hours and diluted using saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combiflash using 25% ethyl acetate in hexane as an eluent to give the title compound (8 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.34 (d, J=6.52 Hz, 3H), 4.66-4.72 (m, 1H), 5.47 (d, J=4.76 Hz, 1H), 7.48 (d, 8.36 Hz, 1H), 8.021 (dd, J1=2.44 Hz, J2=8.44 Hz 1H), 8.58 (d, J=2.36 Hz, 1H). LC-Ms (m/z): 203.9 [M+H].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a precooled (0° C.) solution of 5-methoxy-2-methyl-1H-indole (5.0 g, 31.0 mmol) in 100 mL DCM is added BBr3 (1 M solution, 46.5 mL) under a dry nitrogen atmosphere. The solution is then allowed to slowly warm to room temperature over a 2 h period. The solution is then poured into water, neutralized to pH 7 with sat aq sodium bicarbonate solution and extracted with EtOAc. The extract is washed by brine, dried over sodium sulfate, and concentrated to give 2-methyl-1H-indol-5-ol. MS (ESI) m/z 148.2 (M+1).
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:41]1([CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:54]1([CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:48]2[CH2:49][CH2:50][N:51]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:52][CH2:53]2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a methylene chloride solution (100 ml) containing tert-butoxycarbonyl-L-leucine monohydrate (9.96 g) and N-hydroxy succinimide (4.6 g) was added dropwise a methylene chloride solution (50 ml) of N,N'-dicyclohexylcarbodiimide (8.24 g) with a length of time for 1 hour under cooling with ice. After being stirred at room temperature for 4 hours, the reaction mixture was again cooled with ice, and a methylene chloride solution (50 ml) of 1-(diphenylmethyl)piperazine (10.08 g) was added dropwise in 20 minutes. The mixture was stirred overnight at room temperature. Following the removal of the precipitate by filtration, the solvent was removed by distillation under reduced pressure, and ethyl acetate was added. After any insoluble matters were again removed by filtration, the filtrate was washed first with an aqueous sodium bicarbonate solution and then with a saturated sodium chloride solution, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent, whereupon a crude reaction mixture was obtained. This reaction mixture was purified by silica gel column chromatography (developing solvent: chloroform followed by chloroform:methanol=50:1) to yield 16.5 g of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless amorphous substance (yield: 89%).