Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[OH:2][C@@H:3]1[C:12]2[CH:11]=[CH:10][N:9]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:8]3[C:7]=2[NH:6][C@H:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:4]1[OH:23]>>[OH:2][C@H:3]1[C:12]2[CH:11]=[CH:10][N:9]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:8]3[C:7]=2[NH:6][C@H:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:4]1[OH:23]
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@@H]3O
Agent: Br
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@H]3O
Temperature: 0 °C

Procedure:
To a of 0° C. cooled and stirred solution of hydrobromic acid is added 1.00 g (3.39 mmol) (7R,8R,9R)-7,8-dihydroxy-2-methyl 9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine. After 0.5 h the reaction is quenched by adding ice and aqueous ammonia solution until the reaction mixture is transferred to pH 9.8. The precipitated solid is separated, washed with water and dried in vacuo at 60° C. to provide the title compound as a armorph solid. 1H-NMR (200 MHz,[D6] DMSO): δ=2.30 (s, 3H), 3.84 (m, 1H), 4.34 (t, 1H), 4.48 (dd, 1H), 6.72 (d, 1H), 7.25-7.45 (m, 5H), 7.56 (d, 1H), 7.73 (d, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:20]([N:6]2[C:7](=[O:15])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CCC1
Reactant: O=c1[nH]c2ccccc2c2ccccc12
Product: O=C(C1CCC1)n1c(=O)c2ccccc2c2ccccc21

Procedure:
5-Cyclobutanecarbonyl-5H-phenanthridin-6-one was prepared from 5H-phenanthridin-6-one and cyclobutanecarbonyl chloride according to GP 1. Yield, 2%. 1H-NMR (CD3OD): δ=1.95-2.09 (m, 1H), 2.11-2.26 (m, 1H), 2.36-2.55 (m, 4H), 3.64 (ψ-quint, J=8.5 Hz, 1H), 7.32 (“t”, J=7.5 Hz, 1H), 7.37 (“t”, J=7.7 Hz, 1H), 7.47 (“t”, J=7.5 Hz, 1H), 7.53 (“t”, J=7.5 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H); (+)-ESI-MS: m/z=278 [M+H]+, 196 [5H-phenanthridin-6-one+H]+.
Reaction SMILES: C1([Se][CH2:8][CH2:9][O:10][C:11](=[O:24])[C@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:13][C:14](=[O:16])[CH3:15])C=CC=CC=1.OO>C1COCC1.C(Cl)(Cl)Cl>[CH:9]([O:10][C:11](=[O:24])[C@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:13][C:14](=[O:16])[CH3:15])=[CH2:8]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC[Se]c1ccccc1
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.6 g (6.66 mmol) of N-acetylphenylalanine 2-(phenylseleno)ethyl ester in 20 ml of THF, 8 ml of a 30% H2O2 solution were added dropwise within 10 minutes at 0° C., and the solution was stirred at 0° C. for another 30 minutes. After stirring the mixture for 12 hours at room temperature, it was diluted with 80 ml of CHCl3 and extracted with 3×50 ml of water. The organic phases were then dried over sodium sulfate, and the solvent was removed. The residue was taken up in 70 ml of chloroform and was refluxed for 24 hours. After cooling, the solvent was removed. Flash column—chromatography (PE:EE=3:1) yielded 1.3 g (84% of th., 93% of lit.) of a light-yellow liquid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14](Cl)=[CH2:15])[C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[NH:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH:13]=[C:14]([CH3:15])[S:11]1
Reactant: C=C(Cl)CN(C(N)=S)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Temperature: 90 °C
Yield: 95.3 %

Procedure:
N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (1.00 g) was added to 98% sulfuric acid (9.96 g) at room temperature with stirring, and the mixture was heated to 90° C. and stirred at the same temperature for 1.0 hour. After cooling, ice-water was added to the reaction mixture, which was then neutralized by addition of sodium carbonate and extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 0.835 g of 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline as an oil (81% yield as a corrected value from the below-mentioned purity). From the results of analysis by liquid chromatography, the purity was determined to be 85%.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[F-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:19][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CF

Procedure:
The product from Example 164A (7 g) in 100 mL of THF and tetrabutylammonium fluoride (42 mL of a 1M solution in THF) was heated at reflux for 17 hours, cooled, concentrated to dryness, diluted with 125 mL of ethyl acetate, washed with 5% aqueous NaHCO3, brine, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide an oil. The oil was distilled in vacuo (50° C., 1.2 torr) to give 4.9 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (1.0 g), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.67 g, 1.1 eq), triphenylphosphine (2.35 g, 1.1 eq) in THF (15 mL) at 0° C. was added dropwise DEAD (6.74 g, 4.75 eq). The mixture was warmed to room temperature and stirred for 2 days. To the reaction mixture was added saturated NaHCO3 (aq), and the aqueous layer was extracted with ethyl acetate (15 mL×3), the organic layers were combined, dried (Na2SO4), and purified on silica gel column chromatography (10% ethyl acetate in pentane) to obtain the desired product as a light yellow oil (900 mg, 38% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10]2)[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(=O)(O)[O-].[Na+].O>[C:19]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:12][CH2:11][CH2:10]3)[CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccnc(NC2(c3ccccc3)CCC2)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccnc(NC3(c4ccccc4)CCC3)c2)cc1
Temperature: 140 °C
Yield: 18.2 %

Procedure:
To a 3 mL microwave reaction vessel was added 4-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine (50 mg, 165 μmol, 1.0 equiv), phenylboronic acid (30 mg, 248 μmol, 1.5 equiv), Cl2Pd(dppf) (12 mg, 16 μmol, 0.1 equiv), potassium carbonate (57 mg, 413 μmol, 2.5 equiv), dioxane (750 μL), and water (250 μL). The reaction was heated in a microwave reactor at 140° C. for 20 min and then diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 9 mg of 4-phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine (m/z [M+H]=301.2).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH2:41][CH2:42][CH2:43][O:44][Si](CC)(CC)CC)[CH2:3][CH2:4][C:5]1[C:17]2[CH2:16][N:15]3[C:10](=[CH:11][C:12]4[C:22]([O:25][C:26](=[O:35])[O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH2:23][CH3:24])[C:21](=[O:36])[O:20][CH2:19][C:13]=4[C:14]3=[O:18])[C:9]=2[N:8]=[C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=12.F.N1C=CC=CC=1>C(#N)C>[CH2:23]([C:22]1([O:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:12]2[CH:11]=[C:10]3[N:15]([C:14](=[O:18])[C:13]=2[CH2:19][O:20][C:21]1=[O:36])[CH2:16][C:17]1[C:5]([CH2:4][CH2:3][Si:2]([CH2:41][CH2:42][CH2:43][OH:44])([CH3:52])[CH3:1])=[C:6]2[CH:40]=[CH:39][CH:38]=[CH:37][C:7]2=[N:8][C:9]3=1)[CH3:24]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO[Si](CC)(CC)CC
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Temperature: 21 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
A mixture of Compound 52 (1.70 g, 2.3 mmol), hydrofluoric acid (48% in water, 1.8 mL, 46 mmol), and pyridine (4.5 mL, 55 mmol) in 20 mL of acetonitrile was stirred at 21° C. for 14 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford yellow oil, which was chromatographed to give the desired product (Yield: 48%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4]>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Cl-]>[N:1]([C:2]([CH3:6])([CH3:5])[C:3]#[N:4])=[N:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4]
Reactant: CC(C)(N)C#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Product: CC(C)(C#N)N=NC(C)(C)C#N

Procedure:
Using the method and quantities of Example 2, but replacing the `Arquad 16-29` by the surfactants listed below (in the proportions of 1.6% wt/wt based on total 2-amino-2-methylpropanenitrile used) gave 2,2'-azobis(2-methylpropanenitrile) in the yields indicated.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:22][C:23]1[S:27][C:26]([CH2:28]Cl)=[CH:25][CH:24]=1.CCOC(C)=O.C(Cl)(Cl)Cl>CCCCCC.O>[Cl:22][C:23]1[S:27][C:26]([CH2:28][N:15]2[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]2=[O:17])=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1ccc(Cl)s1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccc(Cl)s1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 5-chloro-2-(chloromethyl)thiophene and was isolated in 83% overall yield as a light yellow viscous oil after flash chromatography using 30-50% EtOAc in hexane; IR (CHCl3) 3418, 2943, 1677, 1500, 1400, 1278, 1062, 750 cm-1 ; 1H NMR (CDCl3) δ2.11-2.32 (m, 3H), 3.89 (q, J=5.4 Hz, 2H), 4.78 (dd, J=7.6, 5.5 Hz, 1H), 5.15 (ABq, JAB =16.0 Hz, 2H), 6.74 (d, J=3.7 Hz, 1H), 6.84 (d, J=3.7 Hz, 1H), 7.01-7.08 (m, 4H); MH+ at m/z=324; Anal. Calc'd for C15H14ClNO3S.0.25 H2O: C, 54.88; H, 4.45; N, 4.27; S, 9.77. Found: C, 54.86; H, 4.41; N, 4.04; S, 9.87.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1.NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(NC)=O>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][CH3:17])[CH:18]=2)[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: CNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NC)n2)cc1)OCC
Yield: 68 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1E with Compound 2C and replacing Compound 1C with 2-amino-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylbenzamide (Compound 8C, 517 mg, 1.22 mmol) to afford 550 mg of the title compound (68%). 1H NMR (400 MHz, CD3OD) δ 8.36 (br. s., 1H), 8.32 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.69 (dd, J=2.0, 8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.35 (dd, J=2.4, 8.5 Hz, 2H), 4.31 (t, J=6.9 Hz, 2H), 3.98-4.10 (m, 4H), 3.57 (t, J=6.1 Hz, 2H), 3.26 (s, 2H), 2.92 (s, 3H), 2.10 (t, J=6.4 Hz, 2H), 1.23 (t, J=7.1 Hz, 6H). MS (ESI): m/z: 662.74 [M+H]+. UPLC: tR=1.11 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17](OCC)=[O:18])=[C:4]2[CH2:3]1.[BH4-].[Li+].Cl.N>O1CCCC1.O>[OH:18][CH2:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
14.14 g (49.5 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 100 ml of tetrahydrofuran were treated portionwise at the boiling temperature with 1.35 g (62 mmol) of lithium borohydride, whereupon the mixture was boiled at reflux for 6 hours. The reaction mixture was then cooled, a mixture of 20 ml of water and 20 ml of concentrated hydrochloric acid was cautiously added thereto, the mixture was heated, stirred at the boiling temperature for 30 minutes, again cooled and treated with concentrated ammonia until the reaction was alkaline. The organic solvent was distilled off on a rotary evaporator and the aqueous suspension obtained was cooled and filtered. The filter residue was washed with water and dried. There was obtained 4,5-dihydro-3-hydroxymethyl-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 219°-221°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[C:11]([CH2:15][OH:16])[NH:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[C:11]([CH:15]=[O:16])[NH:12]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: OCc1cc2ccc(OCC3CC3)cc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2ccc(OCC3CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
To a dichloromethane (5 mL) solution of (6-cyclopropylmethoxy-1H-indol-2-yl)-methanol (197 mg, 907 μmol) described in Production Example 73-1-3 was added manganese dioxide (789 mg, 9.07 mmol) at room temperature, which was stirred at room temperature for 17 hours. The reaction solution was filtered followed by concentrating the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (144 mg, 74%) as a pale brown solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:9]=1[C:10]#[N:11]>>[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH3:6])[C:9]=1[C:10]#[N:11]
Reactant: CC[C@H](N)CO
Reactant: N#Cc1c(N)cccc1F
Product: CC[C@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (S)-2-aminobutan-1-ol and 2-amino-6-fluorobenzonitrile as brown solid (73%). MS 206 (MH+).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].ON1C(=O)CCC1=O.[CH2:59]([O:66][C:67]([NH:69][C@H:70]([C:83]([OH:85])=O)[CH2:71][CH2:72][CH2:73][CH2:74][NH:75][C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])=[O:68])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CO.[Pd]>[NH:69]([C:67]([O:66][CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:68])[C@H:70]([C:83]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])=[O:85])[CH2:71][CH2:72][CH2:73][CH2:74][NH:75][C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Agent: O=C1CCC(=O)N1O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 4 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
Compound XV (1.06 g, 1.5 mmoles) is hydrogenolyzed over palladium in methanol for 3 hours. After the solvent have been removed by evaporation in vacuo the residue is dissolved in ethyl acetate and chilled in an ice bath. To this is added Nα -benzyloxycarbonyl-Nε -t-butyloxycarbonyl-L-lysine N-hydroxy-succinimide (0.72 g, 1.5 mmoles) and the mixture is stirred at 4° C overnight. The precipitates which has separated are filtered off, washed with ice-cold ethyl acetate and dried in vacuo (1.31 g). An additional quantity of the product is obtained upon concentration of the filtrate (0.08 g). The combined precipitates are dissolved in methanol and most of the solvent is removed by evaporation in vacuo. The resulting sirupy residue is precipitated from ethyl acetate (20 ml)-ether (20 ml); yield 1.35 g (96%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[CH2:12][O:13][CH:14]1[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>CO>[ClH:37].[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[O:13][CH2:12][C:11]2[CH:10]=[C:9]([C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:8])[CH:36]=[CH:35][CH:34]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cccc(C(=O)c3ccccc3)c2)C1
Agent: Cl
Solvent: CO
Product: O=C(c1ccccc1)c1cccc(COC2CNCCC2c2ccc(F)cc2)c1

Procedure:
In an analogous manner to that described in Example 22(l), from tert-butyl (3RS,4RS)-3-(3-benzoyl-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate by cleavage of the BOC group with hydrogen chloride in methanol there was obtained [3-[(3RS,4RS)-4-(4-fluoro-phenyl)-piperidin-3-yloxymethyl]-phenyl]-phenyl-methanone hydrochloride (1:1) in the form of colourless crystals; MS: 390 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:6][CH2:7][CH2:8][CH:9]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]1=O)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[C:1]([Si:5]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:6][CH2:7][CH2:8][C:9]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCn1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn(Cc2ccc(C)cc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
A solution of 5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione (14.71 g, 27.8 mmol) in EtOH (500 mL) was treated with sodium borohydride (15.78 g, 0.417 mol) in three portions over 6 h and stirred at room temperature under N2 for an additional 16 h. The thick reaction mixture was cooled in an ice bath and slowly quenched with aqueous 1 N HCl (˜1 L) over a 1 h period. The reaction mixture was then worked up extractively with EtOAc, water and brine and the organic layer dried (MgSO4) and the solvent removed in vacuo to give 16.79 g crude 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-one that was de-silylated immediately.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:9])[CH3:8].[F:10][C:11]1([F:27])[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=[O:23])[CH2:13][CH2:12]1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:10][C:11]1([F:27])[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:22]([OH:23])[CH2:8][C:7]#[N:9])[CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12]1
Reactant: CC#N
Reactant: O=Cc1cccc(OCC2CCC(F)(F)CC2)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(OCC2CCC(F)(F)CC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium t-butoxide (2.59 mmole, 2.6 ml of a 1.0M solution in THF) was cooled to −50° C. Acetonitrile (0.106 g, 2.59 mmole) was slowly added and stirred for 15 min. Benzaldehyde 143 (0.55 g, 2.16 mmole) in THF (1.0 ml) was added and the reaction was allowed to warm to 0° C. over 30 min. Sat. NH4Cl (20 ml) and EtOAc (30 ml) was added and stirred for 10 min. The organic layer was dried over Na2SO4 and evaporated giving 3-(3-((4,4-difluorocyclohexyl)methoxy)phenyl)-3-hydroxypropanenitrile (144) as an oil. Yield (0.622 g, 97%): 1H NMR (400 MHz, DMSO-d6) δ 7.22 (t, J=7.8 Hz, 1H), 6.96-6.93 (m, 2H), 6.82 (ddd, J=8.2, 2.6, 0.8 Hz, 1H), 5.89 (d, J=4.8 Hz, 2H), 4.85-4.81 (m, 1H), 2.86 (ABd, J=16.4, 5.0 Hz, 1H), 2.77 (ABd, J=16.8, 6.8 Hz, 1H), 2.04-1.96 (m, 2H), 1.88-1.73 (m, 5H), 1.35-1.25 (m, 2H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:22]1[C:26]2=[N:27][CH:28]=[C:29]([NH2:31])[CH:30]=[C:25]2[CH:24]=[CH:23]1.[CH2:32]([N:34]([C:40]1[C:41]([F:50])=[C:42]([C:46]([F:49])=[CH:47][CH:48]=1)[C:43](O)=[O:44])[S:35](=[O:39])(=[O:38])[NH:36][CH3:37])[CH3:33]>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:34]([C:40]1[C:41]([F:50])=[C:42]([C:46]([F:49])=[CH:47][CH:48]=1)[C:43]([NH:31][C:29]1[CH:30]=[C:25]2[CH:24]=[CH:23][NH:22][C:26]2=[N:27][CH:28]=1)=[O:44])[S:35](=[O:38])(=[O:39])[NH:36][CH3:37])[CH3:33]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: CCN(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)NC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(c1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F)S(=O)(=O)NC
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.1 %

Procedure:
HOBt (0.011 g, 0.085 mmol), EDCI (0.036 g, 0.19 mmol), and 1H-pyrrolo[2,3-b]pyridin-5-amine (0.025 g, 0.19 mmol) was added to 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoic acid (0.050 g, 0.17 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (6 mL) and washed with brine (3×5 mL). The organic layers were dried over sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 5% MeOH-DCM to afford 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluoro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.005 g, 0.012 mmol, 7.2% yield). m/z (APCI-neg) M−1=408.0.