Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O:23]CC=C)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:56]>C1COCC1.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>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O-:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Na+:56]
Reactant: C=CCOC(=O)C1=C(c2ccc(OC)c(F)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1F
Reaction time: 1 h
Yield: 59 %

Procedure:
Allyl (5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.807 g), tetrakis(triphenylphosphine)palladium(0) (50 mg) and triphenylphosphine (10 mg) were dissolved in THF (12 mL), and thereto was added at room temperature sodium 2-ethylhexanoate (0.5M ethyl acetate solution, 4.46 mL). The solvent was removed in vacuo, and to the residue was added dichloromethane (10 mL). The mixture was extracted with ion-exchange water (10 mL×3 times) and the aqueous layers were combined and stirred for 1 hour in vacuo. The dichloromethane was removed by distillation and the aqueous layer was purified with C18 reverse column chromatography (Wakosil 40C18, 38φ×60 mm, mobile phase; 0˜5% THF ice-cooled ion-exchange water). The fractions containing the object compound were combined and THF therein was removed in vacuo under stirring for 1 hour. The residue was lyophilized to give sodium (5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (450 mg, yield 59%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:17]([CH3:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: CC(=O)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c23)CC1
Yield: 36 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 36% yield; NMR Spectrum: 1.96 (s, 3H), 2.19 (s, 3H), 2.44 (s, 3H), 2.46 (t, 2H), 2.50 (hidden by DSMO, 2H), 2.86 (t, 2H), 3.36-3.42 (m, 4H), 4.46 (t, 2H), 6.95 (d, 1H), 7.17-7.25 (m, 2H), 7.60 (d, 1H), 7.65 (s, 1H), 8.16 (s, 1H), 8.30 (s, 1H), 8.34 (s, 1H); Mass Spectrum: 503 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)[CH2:6][C:5]2=[N:18]S(C(C)(C)C)=O.O=[C:26]([CH3:30])[C:27](=[S:29])[NH2:28]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([N:18]=[C:26]([CH3:30])[C:27](=[S:29])[NH:28]3)[CH2:6][CH:7]([CH:12]3[CH2:17][CH2:16][CH2:15][O:14][CH2:13]3)[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CC(C)(C)S(=O)N=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Reactant: CC(=O)C(N)=S
Solvent: CC#N
Product: CC1=NC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)NC1=S
Temperature: 130 °C

Procedure:
N-(6-Bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)-2-methylpropane-2-sulfinamide (Example 47 Step 1, 0.5 g, 1.21 mmol) and 2-oxopropanethioamide (Intermediate 2, 0.373 g, 3.62 mmol) were dissolved in dry acetonitrile (4.0 mL) in a dry microwave vial. The vial was sealed and heated with MW for 20 min. at 130° C. The solvent was evaporated to give the crude title compound that was used directly in the next reaction. MS (ES+) m/z 395 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9]2)=[C:4]([CH3:19])[CH:3]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.[Cu]I>[CH2:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:3][C:4]=2[CH3:19])[CH2:10][CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(Br)ccc1C1(OCc2ccccc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1C1(OCc2ccccc2)CC1
Yield: 89.7 %

Procedure:
Using General Procedure D; 4-bromo-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 74, 320.0 mg, 1.00 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (19.0 mg, 0.1 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(I) (70.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound (300.0 mg, 89%) was isolated by chromatography (0-2% EtOAc-hexanes).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31](O)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][C@H:36]1[OH:48]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][C@H:36]4[OH:48])=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c3) and tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:8].[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:30])[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[O:28]=[C:27]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:30]
Reactant: C[C@H](NC(=O)c1cccn1N)c1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)N[C@@H](C)c1ccccc1
Yield: 94.3 %

Procedure:
The title compound was prepared from (S)-1-amino-N-(1-phenylethyl)-1H-pyrrole-2-carboxamide (3.50 g, 15.3 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (2.89 g, 15.3 mmol) following the experimental procedure described in Preparation 73a. 5.78 g (92% yield) of the desired compound were obtained.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[O:7]=[C:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CBr
Reactant: O=C1C=CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC=CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-cyclohexen-1-one (20 g, 0.208 mmol) in tetrahydrofuran (250 ml) was added to a preformed lithium diisopropylamide solution (prepared from diisopropylamine (31 ml) and n-butyllithium (140 ml, 1.6M solution) at −70° C.) over 20 minutes and stirred for a further 20 minutes. Ethyl bromoacetate (25 ml, 0.228 mmol) was added dropwise and the reaction stirred for 1 hour warming to room temperature. The reaction was quenched with 6N HCl (200 ml) and the product extracted into ether (3×300 ml). Combined organic phase washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. The crude oil was purified by silica chromatography eluting with hexane-ethyl acetate mixtures (10-20%), to give ethyl (2-oxo-cyclohex-3-enyl)acetate as a colourless oil, 11.8 g. 1H NMR δ (ppm) (CDCl3): 6.98-6.94 (1H, m), 6.03-6.00 (1H, m), 4.19-4.11 (2H, m), 2.92-2.82 (2H, m), 2.49-2.41 (2H, m), 2.30-2.23 (1H, m), 2.16-2.11 (1H, m), 1.87-1.77 (1H, m) and 1.28-1.24 (3H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:29][CH3:30])[CH:26]([CH3:28])[CH3:27]>>[CH2:25]([N:29]([CH3:30])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CNCC(C)C
Product: CC(C)CN(C)CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and isobutyl(methyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:17])[N:3]=1.C(N(CC)CC)C.Br[CH2:26][C:27]1[CH:41]=[CH:40][C:30]([CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:29][CH:28]=1>C(#N)C>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:31][P:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:39])=[CH:40][CH:41]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:17])[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(CBr)cc1)OCC
Reactant: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 38 %

Procedure:
To a solution of ethyl (2,6-dibromo-3-nitropyridin-4-yl)carbamate (1 equiv.) (described in ref. 18, Preparation 67) in acetonitrile (0.40 M) was added triethyl amine (1.5 equiv.) and diethyl 4-(bromomethyl)benzylphosphonate (1.3 equiv.) (described in ref. 88, Ex 25 Step 1). The reaction mixture was then heated to 60° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (38%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1>CO.[Pt]=O>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1
Reactant: OCCc1cnccn1
Agent: O=[Pt]
Solvent: CO
Product: OCCC1CNCCN1
Yield: 98.5 %

Procedure:
A solution of 1.80 g (14.50 mmol) of 2-(2-hydroxyethyl)pyrazine in 40 ml of methanol was hydrogenated over 24 hours using 0.8 g of platinum oxide, The reaction was filtered through Celite and TLC (10% methanol/0.2% ammonium hydroxide/chloroform) revealed that the reaction was 50% complete. The material was redissolved in 50 ml of methanol and hydrogenated again under the same conditions. The mixture was filtered through Celite and rinsed with 45 ml of methanol. Concentration in vacuo yielded 1.86 g (98%) of a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C1COCC1>[NH2:17][C:18]1[CH:25]=[C:24]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: CN(C)CCO
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(N)ncc1C#N
Reaction time: 0.03 h

Procedure:
2-(dimethylamino)ethanol (0.293 ml, 2.92 mmol) was treated at room temperature with KHMDS (1 M in THF, 2.19 ml, 2.19 mmol). The reaction mixture was stirred for 2 min and then added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 100 mg, 0.729 mmol) in THF (2 ml). The resulting dark brown solution was stirred at room temperature for 60 min, quenched with sat. aq. NH4Cl, directly absorbed on isolate and dried under vacuum. The crude material was purified by reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 100:0 to 0:100). The product containing fractions were concentrated. The residue was treated with a small amount sat. aq. NaHCO3 and NaCl (s) and extracted with CH2Cl2 (5×). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 0.45 min; ESI-MS 207.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:14]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:38](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:38][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:35])[C:10]2[C:15]([C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][C:13]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c(=O)n1Cc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 90.6 %

Procedure:
2-Benzyl-6-benzyloxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) was dissolved in DMF (3 ml) and methyl iodide (0.04 ml) and potassium carbonate (90 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and evaporated under reduced pressure, and the obtained residue was crystallized from hexane to give the title compound (140 mg).
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:22]([CH3:24])([CH3:23])[CH2:21][NH:20][CH:19]=[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]=3[NH:15][C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35](Cl)=[O:36]>>[CH2:28]([O:27][C:25]([C:18]1[C:14]2[NH:15][C:16]3[CH:17]=[C:9]([N:8]([CH2:30][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=[CH:11][C:12]=3[C:13]=2[C:22]([CH3:24])([CH3:23])[CH2:21][N:20]([C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:41])=[CH:32][CH:33]=2)[CH:19]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C1=CNCC(C)(C)c2c1[nH]c1cc(N(C)Cc3ccccc3)ccc21
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(N(Cc3ccccc3)Cc3ccccc3)ccc21

Procedure:
In a manner similar to Example 2A, but using ethyl 8-(benzyl(methyl)amino)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 3,4-difluorobenzoyl chloride, the following compound was prepared:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15]([NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: NCc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(NCc1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of (±)-N-[2,6-bis(1-Methylethyl)phenyl]-α-bromobenzeneacetamide (4.3 g, 12 mmol), benzylamine (1.8 g, 18 mmol), and triethylamine (8.0 mL, 57 mmol) in toluene was refluxed (96 hours) then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), washed with water (2×100 mL), with saturated aqueous sodium bicarbonate (1×100 mL), with brine (1×100 mL), then dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate/hexane to yield 3.35 g (72.8%) of the title compound as a white solid, mp 134°-137° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[CH3:15][O:16][C:17]1([O:28][CH3:29])[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.Cl[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[CH3:15][O:16][C:17]1([O:28][CH3:29])[CH2:22][CH2:21][C:20]([C:31]([O:33][CH3:34])=[O:32])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CCOC(=O)C1CCC(OC)(OC)CC1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OC)CCC(OC)(OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a −78° C. solution of iPr2NEt (3.95 mL, 27.7 mmol) in THF (50 mL) was added n-BuLi (17.3 mL of a 1.6 M solution in hexanes; 27.7 mmol) was added. After 15 min, ethyl 4,4-dimethoxycyclohexane-carboxylate (4.0 g, 18.50 mmol) was added and the reaction mixture was stirred at −78° C. for 1 h. Methyl chloroformate (2.87 mL, 37.0 mmol) was added and the reaction mixture was warmed to rt. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude oil was chromatographed (SiO2; continuous gradient from 0 to 20% EtOAc:hexanes) to afford the title compound (4.7 g, 93% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.21 (q, J=7.1 Hz, 2H), 3.75 (s, 3H), 3.19 (s, 6H), 2.16-2.05 (m, 4H), 1.79-1.69 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:7]([Cl:16])[CH:6]=1)C.C([BH-](CC)CC)C.[Li+].O>O1CCCC1>[Cl:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([Cl:16])[C:8]=1[S:12]([CH3:15])(=[O:14])=[O:13])[CH2:4][OH:3]
Reactant: CCOC(=O)c1cc(Cl)c(S(C)(=O)=O)c(Cl)c1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1c(Cl)cc(CO)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dichloro-4-(methylsulfonyl)benzoic acid ethyl ester (2.6 g) in tetrahydrofuran (50 mL) was added lithium triethylborohydride (1 M in tetrahydrofuran, 24 mL) at 0-5° C. under nitrogen. The mixture was stirred for 30 min and then water (2 mL) was added and the tetrahydrofuran was evaporated under vacuum. Toluene (100 mL) and water (30 mL) w ere added and then hydrogen peroxide (30% in water, 20 mL) was added at 10-20° C. After 30 min, the separated solid was dissolved by adding ethyl acetate (100 mL). The organic phase was separated and washed with saturated sodium pyrosulfite solution (25 mL) and then with potassium bicarbonate solution (1 M, 25 mL) and then dried with sodium sulphate and evaporated to dryness (yield 1.8 g). 1H-NMR (400 MHz, DMSO-d6) d=3.43 (s, 3H), 4.57 (s, 2H), 5.6 (b, 1H), 7.59 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:14]([NH:17][S:18]([CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:19])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([CH:26]([OH:28])[CH3:27])=[N:4]1)[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:28][CH:26]([C:5]2[CH:6]=[C:7]([C:8]3[CH:9]=[C:10]([C:14]([NH:17][S:18]([CH2:21][C:22]([F:23])([F:24])[F:25])(=[O:20])=[O:19])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=3)[N:3]([CH2:1][CH3:2])[N:4]=2)[CH3:27])=[CH:32][CH:31]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCn1nc(C(C)O)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCn1nc(C(C)Oc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1

Procedure:
prepared following the procedure of Example 1 step 6 using the alcohol from Step 2 (121 mg, 0.29 mmol), 4-fluorophenol (49 mg, 0.44 mmol), PPh3 (113 mg, 0.44 mmol), and DIAD (85 mg, 0.44 mmol). The crude mixture was purified by column chromatography on silica eluting with 70% Et2O/iso-hexane and then by normal phase preparative HPLC to yield the ether (2.0 mg, 1%). 1H NMR (CDCl3, 500 MHz) δ 7.60-7.45 (3H, m), 7.36-7.30 (1H, m), 7.00-6.90 (4H, m), 6.28 (1H, s), 5.40 (1H, q, J=6.6 Hz), 4.90 (1H, s), 3.53-3.42 (4H, m), 1.82 (6H, s), 1.69 (3H, d, J=6.5 Hz), 1.40 (3H, t, J=7.2 Hz). MS (ES+) C24H27F4N3O3S requires: 513, found: 514 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([N:15]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])[CH3:3]>CCO.[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([NH2:15])[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)C(N)C1
Yield: 100.3 %

Procedure:
A solution of 3-azido-4-hydroxy-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.25 g, 1.06 mmol) in EtOH (20 mL) was hydrogenated in an H-Cube reactor (1 mL/min flow, 30 mm Pd/C 10% cartridge, full H2 mode, 50° C.). The solvent was evaporated in vacuo to yield 3-amino-4-hydroxy-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.23 g, 100% yield) that was used in the next step without further purification. C10H20N2O3 LCMS: Rt 0.58, m/z 217 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]([CH:15]=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[CH:1]([NH:4][C:5]1[C:14]([CH2:15][OH:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2nc(NC(C)C)c(C=O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2nc(NC(C)C)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a stirred solution of 2-(isopropylamino)-6-methoxyquinoline-3-carbaldehyde SLA 28186 (1.55 g, 6.35 mmol) in THF (100 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.24 g, 6.35 mmol) and the mixture was stirred for overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (40 mL). After stirring for 15 min at that temperature, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (2-(isopropylamino)-6-methoxyquinolin-3-yl)methanol SLA 28188 as an orange solid (1.45 g, 93% yield).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18]>CCCCCC>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1cccc(CCl)c1N
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CCCCCC
Product: COc1ccc2[nH]c(SCc3cccc(C)c3N)nc2c1
Yield: 48.5 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.75 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 4.00 g of 2-(chloromethyl)-6-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Trituration with hexane gave 3.02 g of the title compound: m.p. 132-134° C. Anal. Calc'd. for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04; S, 10.71. Found: C, 64.21; H, 5.77; N, 14.00; S, 10.38.