Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[F:69][C:70]1[CH:75]=[CH:74][C:73]([C:76](=[O:88])[CH2:77][CH2:78][CH2:79][C:80]([N:82]2[CH2:87][CH2:86][O:85][CH2:84][CH2:83]2)=[O:81])=[CH:72][CH:71]=1>CO.C(OCC)(=O)C>[F:69][C:70]1[CH:75]=[CH:74][C:73]([C@@H:76]([OH:88])[CH2:77][CH2:78][CH2:79][C:80]([N:82]2[CH2:83][CH2:84][O:85][CH2:86][CH2:87]2)=[O:81])=[CH:72][CH:71]=1
Reactant: O=C(CCCC(=O)N1CCOCC1)c1ccc(F)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1CCOCC1
Temperature: 31 °C
Reaction time: 24 h

Procedure:
ES-KRED-119 (3.5 gm, Chiral Vision) was dissolved in 450 ml buffer (containing 250 mM potassium phosphate, 2 gm NADP+, 330 mM D-glucose, 1 gm glucose dehydrogenase, pH 7.0). A solution of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1,5-dione in MeOH (50 gm in 50 ml) was added. The mixture was stirred at 31° C. for 24 hrs and monitored by HPLC. Ethyl acetate (250 ml) was added and the phases were separated. The organic layer was evaporated to get 49 gms of the (S)-5-(4-Fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one (ee: >99%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: O=[N+]([O-])c1ccccc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Oc1cccc(Cl)n1
Reactant: C1COCCN1
Product: Oc1cccc(N2CCOCC2)n1
Temperature: 90 °C

Procedure:
To a stirring solution of morpholine (10 ml) was added 6-chloro-2-pyridinol (1.5 g, 11.57 mmol) and the mixture was heated at 90° C. for 60 h. The reaction mixture was cooled to RT and concentrated under reduced pressure (while heating) to afford the title compound as a brown solid (85%. The crude material was used without further purification. MS (ESI) 181.2 (M+H+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(N(CC)CC)C>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 97 %

Procedure:
10 g (100 mmole) of succinic anhydride, 10 mL (97 mmole) of benzyl alcohol and 10 mL of triethylamine were combined, the mixture was heated to reflux, allowed to reflux for about 5 minutes, and then was allowed to stir unheated for 1 hour. After this time, the mixture was poured into 250 mL of 1M hydrochloric acid and was extracted with 2-75 mL portions of ethyl acetate. The organic phases were combined, washed with deionized water, washed with brine, and then were dried over anhydrous magnesium sulfate. The organic phase was concentrated to oil which upon sitting yielded crystalline 19.6 g (94% yield) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=O>CO>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=[N:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: NC1CCNC1
Solvent: CO
Product: Fc1cc(F)cc(C=NC2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
1.72 g (20 mmol) of 3-amino-pyrrolidine are initially introduced into 20 ml of methanol, and 2.84 g (20 mmol) of 3,5-difluorobenzaldehyde are added dropwise at 20° C., while cooling in a water bath. The mixture is subsequently stirred at room temperature for one hour and is concentrated in vacuo on a rotary evaporator, and the residue (4.5 g) is distilled. 0.9 g of an oil, boiling point: 80° C.-85° C./0.04 mbar, are obtained, which decomposes to give a highly viscous mass within 4 weeks when stored at room temperature.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].OC[C:11]1[C:16]([OH:17])=[C:15]([CH2:18][OH:19])[CH:14]=[C:13](C)[CH:12]=1.SCCC(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:1]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:16]([OH:17])[C:15]=2[CH:18]=[O:19])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1cccc(O)c1
Reactant: Cc1cc(CO)c(O)c(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CCS
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(O)c1-c1cccc(O)c1C=O
Reaction time: 8 h

Procedure:
A mixture of 146.0 g m-cresol, 25.2 g 2,6-bis(hydroxymethyl)-p-cresol, 5.0 g 3-mercaptopropionic acid and 1.5 g p-toluenesulfonic acid monohydrate in 200 ml glacial acetic acid were charged into a 1-L reaction vessel equipped with a paddle stirrer, reflux condenser and a nitrogen inlet tube. The mixture was heated to reflux and maintained at reflux to allow formation of the alternating copolymer. After 8 hours, 146.5 g salicyaldehyde were added over time to the reaction mixture to form substantially m-cresol-salicylaldehyde block segments. Reflux was continued for 8 hours. The reaction mixture was slowly poured into 7-L deionized water to precipitate the resin. Once the solvent had exchanged with water, the product was collected on a filter, slurried once in warm deionized water for about 30 minutes, again collected, rinsed with water and dried in a vacuum oven under about 125 mm Hg and at about 100° to 105° C. About 281 g of a block copolymer resin having a number average molecular weight, M n, of 1472 Daltons and a Tg of 233° C. were obtained.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1.CCN(CC)CC>CN(C=O)C>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([S:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1ccc(S)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(Sc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.120 g, 0.40 mmol), methyl 2-(4-mercaptophenyl)acetate (0.100 g, 0.55 mmol), and Et3N (0.145 g, 1.3 mmol) in DMF was heated at 110° C. for 24 h. After this time, the mixture was concentrated, diluted with EtOAc (100 mL), washed with 10% aqueous LiCl (2×100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 100% hexanes to 1:1 ethyl acetate/hexanes to afford the title compound (0.164 g, 100%) as a white solid. MW=409.93. 1H NMR (CDCl3, 300 MHz) δ 7.78-7.77 (m, 1H), 7.61-7.46 (m, 3H), 7.37 (d, J=8.2 Hz, 2H), 7.30-7.28 (m, 3H), 6.89 (s, 1H), 3.73 (s, 3H), 3.70 (s, 2H), 3.09 (t, J=7.7 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.24-2.05 (m, 4H); APCI MS m/z 410 [M+H]+.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].O.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH3:19])[CH:18]=[CH:17][C:16]([C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:15][CH:14]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C1CCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)C2CCC2)cc1
Reaction time: 0.33 h

Procedure:
Cyclobutylcarbonyl chloride (23.8 g.) in dry toluene (25 ml) was added dropwise during 1 hour to a stirred suspension of anhydrous aluminium chloride (29.4 g) in dry toluene (150 ml). After stirring a further 20 minutes, the mixture was poured into iced water (1 l) and the organic layer was separated, washed with water, dried over magnesium sulphate, filtered and evaporated. The residue was distilled under reduced pressure and the fraction b.p. 79-80°/0.03 mm was collected. On standing the product solidified and the solid had m.p. 32°-34°.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:24][C:17]4[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:16]=4[N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:25])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:39]1[CH2:42][CH:41]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:40]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH:1]1([C:5]2[C:13]([C:14]3[NH:24][C:17]4[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:16]=4[N:15]=3)=[CH:12][C:8]([C:9]([N:39]3[CH2:42][CH:41]([C:43]4[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=4)[CH2:40]3)=[O:10])=[C:7]([CH3:25])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CCN(C)CC3)cc1C(=O)O
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CCN(C)CC3)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoic acid (compound 82.9, 40 mg, 0.12 mmol), EDC.HCl (45.4 mg, 0.24 mmol, 2.00 equiv), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 23 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL). The resulting solution was stirred for 4 h at room temperature then quenched by the addition of water/ice (10 mL). The resulting mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the crude product which was purified by Prep-HPLC using the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, WATER WITH 0.03% NH4OH and CH3CN (30% CH3CN up to 43% in 8 min, up to 100% in 4 min, down to 30% in 2 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing clean product were combined to yield 2.2 mg (4%) of the title compound as a white solid. m/z (ES+) 480 (M+H)+.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:27][C@@H:2]([CH3:1])[C@H:3]([C:4]([N:6]2[C@H:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][O:8][C:7]2=[O:18])=[O:5])[CH2:30]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C/C=C/C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 44.9 %

Procedure:
The compound from step 5a (245 mg, 1.00 mmol) was reacted with N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (254 mg, 1.2 mmol) according to the procedure of Example 1d, to afford the title compound (170 mg). MS m/z 379 (M+H)+. NMR (CDCl3) d 7.15-7.40 (10H, m), 4.69 (1H, m), 4.20 (1H, dd, J=16.5, 9.0 Hz), 4.18 (1H, dd, J=9.0, 6.0 Hz), 3.71 (1H, d, J=13.5 Hz), 3.65 (1H, m), 3.56 (1H, d, J+13.5 Hz), 3.24 (1H, dd, J=13.5, 3.3 Hz), 2.70-3.10 (4H, m), 2.17 (1H, dd, 8.4, 7.5 Hz), 1.08 (3H, d, J=6.9 Hz).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][CH:40]=5)=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][CH:40]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)nc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)nc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.96 g) was dissolved in methylene chloride (29 ml), and a solution of m-chloroperbenzoic acid (0.38 g) in methylene chloride (14 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 295) (0.23 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])#[CH:18]>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccc(F)cc1F
Product: O=c1[nH]c2nccc(C#Cc3ccc(F)cc3F)c2c2ccccc12
Yield: 63.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 1-ethynyl-2,4-difluorobenzene (90 mg, 0.65 mmol) to provide 252 (91 mg, 63% yield) as a tan solid. LC-MS (M+H=333 obsd.=333).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]1([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred mixture of naphthalen-1-ol (196 mg, 1.35 mmol) in MeCN (5 mL) was added ethyl bromoacetate (269 mg, 1.62 mmol) and K2CO3 (372 mg, 2.70 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was filtered and the filtrate concentrated. The residue was used directly for the next step without further purification (300 mg, Yield 95%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:1]1([NH:4][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:7]3[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=3)[CH2:12][CH2:13]2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C1CCC(c2cccnc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1cncc([C@H]2CC[C@H](NC3CC3)CC2)c1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
Cyclopropyl amine (11.4 mL, 165 mmol) was added to a solution of 4-(3-pyridyl)cyclohexanone (19.2 g, 110 mmol) in DCE (360 mL) and acetic acid (12.6 mL, 220 mmol). The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (46 g, 220 mmol) was added protionwise. After being stirred for 21 h at 23° C., the reaction was re-cooled to 0° C. and quenched with 1 M NaOH (200 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL) and the combined organic layers were washed with brine (300 mL), dried with MgSO4, filtered, and concentrated in vacuo. The crude mixture of cis and trans amines was purified by flash column chromatography (gradient elution, 40% EtOAc/hexanes (2.5% TEA)→70% EtOAc/hexanes (2.5% TEA)) to provide trans-N-cyclopropyl-4-(pyridine-3-yl)cyclohexylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:18](=O)[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].[BH4-].[Na+].[C:29]([OH:32])(=[O:31])[CH3:30]>C(O)C>[C:29]([OH:32])(=[O:31])[CH3:30].[C:29]([OH:32])(=[O:31])[CH3:30].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[OH:21])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CNc1ccnc2cc(Cl)ccc12)NCc1ccccc1O
Yield: 40 %

Procedure:
1.25 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.54 g of salicylaldehyde were stirred under reflux overnight in the presence of 1.25 g of molecular sieve (E. Merck, 3 Å). Thereafter, the mixture was filtered and the solvent was evaporated. From a small amount of diethyl ether and ethyl acetate there was obtained a crystalline product which was again taken up in 20 ml of ethanol. After the addition of 0.19 g of sodium borohydride the mixture was left to react overnight, thereafter 5 ml of glacial acetic acid were added thereto and the mixture was evaporated to dryness. After the addition of 10 ml of methanol the mixture was again evaporated. Addition of methanol and evaporation were repeated twice. The residue was then crystallized from 10 ml of ethanol. 0.9 g (40%) of colourless crystalline product of m.p. 150° C. was obtained.
Reaction SMILES: [CH:1]1([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]([N:25]=[C:26]=[O:27])=O)=[C:21]([F:28])[C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([F:28])[C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(C3CCCCC3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(cyclohexyl)hydrazinecarboxylate (Intermediate-64, 0.050 g, 0.23 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.225 g, 0.70 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.015 g of pure product. NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 1.22-1.23 (m, 2H), 1.30-1.37 (m, 2H), 1.62-1.64 (m, 2H), 1.78-1.81 (m, 4H), 3.90-3.92 (m, 1H), 4.27-4.28 (d, J=4.8 Hz, 2H), 7.37-7.41 (t, 1H), 7.46-7.48 (d, 1H), 8.17 (br s, 1H); MS (m/z): 409.36 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2([O:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH:12]([CH3:14])[CH:11]([O:15][CH3:20])[CH2:10]2)[CH2:16][CH2:17]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)C(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)CC(OC)C(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 93 mg 8-ethoxycarbonyl-3-hydroxy-2-methyl-1-oxa-8-azaspiro[4,5]decane in 1 ml N,N-dimethylforamide was cooled in ice, 16.7 mg oily sodium hydride (60%) was added, and the resulting mixture was stirred for 30 minutes under ice cooling. Methyl iodide (26.2 μl) was then added, and the mixture was stirred at room temperature for about 24 hours and poured into 5 ml ice water. After extraction with chloroform, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure from the dried solution, and the residue was purified by silica gel column chromatography using, as eluent, a mixed solvent of ethyl acetate/n-hexane (1:1 by volume), giving 47 mg 8-ethoxycarbonyl-3-methoxy-2-methyl-1-oxa-8-azaspiro[4,5]decane as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1Cl.[F-].[K+].Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>[N+](C)(C)(C)C.[Cl-].CS(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Reactant: Fc1cncc(Br)c1Cl
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2Br)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A thoroughly stirred mixture of 3-bromo-4-chloro-5-fluoropyridine free base (55 g, 0.26 mol), potassium fluoride (31 g, 0.53 mol) and Me4NCl (5.8 g, 53 mmol) in DMSO (400 mL) was heated to 130° C. for 2 hours. The reaction mixture was cooled to room temperature and tert-butyl piperidine-4-carboxylate hydrochloride 22 (66 g, 0.30 mol) and DIPEA (65 g, 0.50 mol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was portioned between DCM/water. The organic layer was washed with water (3×), dried over Na2SO4, and filtered over silica gel using DCM as eluent. The filtrated was evaporated to give tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26 (61 g, 65%) as a light yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.41 (d, 1H), 3.39-3.36 (m, 2H), 3.12 (tt, 2H), 2.49-2.43 (m, 1H), 1.91-1.87 (m, 2H), 1.71-1.64 (m, 2H) and 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −135.2; MS (ES+) 361.0.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.C[C:11]([N:13](C)C)=O>C([O-])(O)=O.[Na+].[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:11]#[N:13])=[CH:6][N:5]=1
Reactant: Nc1cc(F)c(I)cn1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cnc(N)cc1F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
4-fluoro-5-iodopyridin-2-amine (intermediate 22, 240 g, 1 mol), zinc cyanide (125 g, 1.05 mol), zinc (13 g, 0.2 mol), Pd2(dba)3 (25 g, 25 mmol) and dppf (55 g, 0.1 mol) in DMA (800 ml) were degassed and charged into the round bottom flask under nitrogen. The mixture was stirred at 100° C. for 3 h. The reaction mixture was diluted with 5% NaHCO3 (2 l), extracted with EtOAc (4×600 ml). The combined organic layers were washed with 5% NaOH (1 l), dried over Na2SO4, concentrated to 700 ml. The resulting organic phase was eluted through silica gel column with EtOAc (1.7 l). The combined organic filtrate was washed with 2 M HCl (3×800 ml). The pH of the aqueous phase was adjusted to 10 with saturated NaHCO3. The aqueous phase was extracted whit DCM (3×500 ml). The combined DCM was dried over Na2SO4 and concentrated. The residue was further purified by column chromatography (eluted with pentane: EtOAc 10:1 to 3:2) followed by recrystallization from pentane/EtOAc 3/1 to give the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 7.40 (s, 2H), 6.34 (d, 1H).