Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[N:42])[C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].CCO.C1COCC1>[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[N:42])[C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1
Reactant: N#Cc1ccccc1Cn1c(C2CCCC(NC(=O)OCc3ccccc3)C2)nc2ccn(Cc3ccccc3)c(=O)c21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccccc1Cn1c(C2CCCC(N)C2)nc2ccn(Cc3ccccc3)c(=O)c21
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A solution of {3-[5-benzyl-3-(2-cyano-benzyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (78 mg, 0.14 mmol) in 1:3 EtOH/THF (8 mL) was hydrogenated over 10% Pd/C (73 mg, 0.068 mmol) at room temperature. After 2 h, the catalyst was removed by filtration, rinsing with MeOH, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 94:6:0.5 CH2Cl2/MeOH/NH4OH to give 2-[2-(3-amino-cyclohexyl)-5-benzyl-4-oxo-4,5-dihydro-imidazo[4,5-c]pyridin-3-ylmethyl]-benzonitrile (45 mg, 75% yield). The HCl salt was prepared by treating the amine in EtOAc with ethereal HCl (0.2 mL). 1H-NMR (500 MHz, 1 mL CDCl3+1 δ L d-Trifluoroacetic acid: 8 (dd, 1H, J=7.8, 1.4 Hz), 7.62 (dt, 1H, J=7.8, 1.4 Hz), 7.53 (dt, 1H, J=7.8, 1.4 Hz), 7.49 (d, 1H, J=7.5 Hz), 7.37 (br m, 5H), 7.26 (dd, 1H, J=7.8, 1.4 Hz), 6.60 (d, 1H, J=7.5 Hz), 6.35 (d, 1H, J=16.3 Hz), 6.17 (d, 1H, J=16.3 Hz), 5.28 (d, 1H, J=14.0 Hz), 5.25 (d, 1H, J=14.0 Hz), 3.45 (br s, 1H), 3.34 (br t, 1H, J=11.7 Hz), 2.38 (br d, 1H, J=11.7 Hz), 2.29 (q, 1H, J=11.7 Hz), 2.15 (br d, 1H, J=11.7 Hz), 2.0 (br d, 1H, J=13.3 Hz), 1.66 (m, 2H), 1.59 (q, 1H, J=11.7 Hz), 1.48 (br t, 1H, J=11.7 Hz). MS: calculated for C27H27N5O+H 438.2; found: 438.3.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])OC1)=O)(C)(C)C.Br[CH2:22][Cl:23].C([Li])CCC.Cl>CCCCCC.O1CCCC1>[ClH:23].[NH2:8][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11](=[O:20])[CH2:22][Cl:23]
Reactant: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Reactant: ClCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N[C@@H](Cc1ccccc1)C(=O)CCl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (1.00 g) and bromochloromethane (0.31 ml) were added to dehydrated tetrahydrofuran (36 ml). After cooling to −78° C., 1.53 M solution (3.07 ml) of n-butyllithium in hexane was added to the obtained mixture, and they were stirred for 40 minutes. 6 N Hydrochloric acid was added to the reaction mixture to terminate the reaction. The temperature of the reaction mixture was elevated to room temperature. The reaction mixture was concentrated to a half volume, stirred at 50° C. for 1 hour and cooled to room temperature. After the addition of isopropyl acetate followed by the extraction with water twice, the obtained aqueous solution was analyzed by HPLC to find that intended (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (0.65 g) was obtained in a yield of 77%. According to HPLC analysis with an optically active column, the optical purity of (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride thus obtained was confirmed to be >99% e.e.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=1)=C=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:36][C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)=[O:35])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: Cc1cccc(NC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-m-tolylurea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 1-isocyanato-3-methylbenzene (22.3 mg, 0.17 mmol) according to General Procedure G to give 20 mg (27.7%) of a white solid. Anal. Calcd. for C26H33N5O m/z 431.3, found: 432.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (s, 1H), 7.39 (d, J=8.9 Hz, 2H), 7.20 (s, 2H), 7.10 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 6.71 (d, J=7.4 Hz, 1H), 6.15 (d, J=7.6 Hz, 1H), 3.89 (d, J=11.1 Hz, 1H), 3.77 (d, J=13.2 Hz, 1H), 3.26 (d, J=8.9 Hz, 1H), 2.79 (m, 1H), 2.57 (m, 1H), 2.42 (m, 1H), 2.24 (s, 1H), 1.88 (m, 3H), 1.65 (m, 4H), 1.45 (m, 1H), 1.21 (m, 4H), 1.11 (m, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([C:10]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:11]=1[F:27])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.09 g, 54.76 mmol) in DMF (300 mL) was added NaN3 (4.27 g, 65.71 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 19.43 g, 83.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.98 (s, 1H), 7.75 (d, 1H), 7.27 (m, 5H), 7.02 (m, 4H), 4.07 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:7][CH:6]=1)=[O:4].[C:26](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:26])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(CNCC2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN(C)CC2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1,1-dimethylethyl 2-[[[[4-(methoxycarbonyl)phenyl]methyl]amino]methyl]-1-pyrrolidinecarboxylate in dichloroethane was stirred as acetic acid (400 mg, 6.65 mmol), formaldehyde (37% solution in water), and sodium triacetoxyborohydride (1100 mg, 5.18 mmol) were added sequentially. The reaction was stirred at ambient temperature for 17 hours, treated with a saturated aqueous solution of sodium bicarbonate and extracted with EtOAc. The combined organic layers were dried and concentrated. Purification by flash chromatography afforded 1,1-dimethylethyl 2-[[[[4-(methoxycarbonyl)phenyl]methyl]methylamino]methyl]-1-pyrrolidinecarboxylate (670 mg).
Reaction SMILES: O[C:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]1[CH2:8][CH2:7][N:6](C(OCC)=O)[CH2:5][CH2:4]1.Cl>C(O)C>[C:14]1([C:2](=[C:3]2[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(OC)cc2)CC1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reaction time: 18 h
Yield: 25 %

Procedure:
A mixture of 106 parts of ethyl 4-[hydroxy(4-methoxyphenyl)phenylmethyl]-1-piperidinecarboxylate, 1200 parts of concentrate hydrochloric acid and 200 parts of ethanol was stirred and refluxed for 18 hours. Gazeous hydrogen chloride was bubbled through the mixture and stirring was continued for 18 hours at reflux temperature. The whole was evaporated. The residue was dissolved in a mixture of 200 parts of ethanol and 1950 parts of a hydrobromic acid solution 48% in water. The mixture was stirred and refluxed overnight. After evaporating, the residue was suspended in 1000 parts of water and treated with ammonium hydroxide. The oil was dissolved in 2100 parts of trichloromethane. The solution was washed with 500 parts of water, dried, filtered and evaporated. The residue was suspended three times in 70 parts of 2,2'-oxybispropane and the latter was evaporated each time. The residue was solidified in 40 parts of acetonitrile. The product was filtered off and dried, yielding 20 parts (25%) of 4-[phenyl(4-piperidinylidene)methyl]phenol; mp.>260° C. (intermediate 32).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].CO>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.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[OH:10][C:8]1[CH:9]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(O)cc1-c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-4-hydroxybenzaldehyde (350 mg, 1.74 mmol), phenyl boronic acid (233.5 mg, 1.92 mmol), Pd(PPh3)4 (60 mg, 0.052 mmol), saturated sodium bicarbonate (6.0 mL), methanol (15 mL), and toluene (6.0 mL) was heated in a pressure tube at 120° C. overnight. Ethyl acetate and water were added and the layers separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (30%) to afford 5-hydroxy-[1,1′-biphenyl]-2-carbaldehyde (651).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Br[CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][NH:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(=O)OCc2ccccc2)cc(OC)c1C
Temperature: 80 °C
Yield: 47.5 %

Procedure:
A suspension of compound 1g (382 mg, 1.0 mmol), benzyl 2-bromoacetate (0.224 mL, 1.4 mmol), and potassium carbonate (276 mg, 2.0 mmol) in DMF (3 mL) was sealed in a pressure tube and heated at 80° C. for 5 h and at rt for two days. The reaction mixture was diluted with water, and the resulting solid precipitate was recovered by filtration and washed with MeOH and hexane to give compound 14a (252 mg, 48%) as a yellow solid. ESI-MS m/e 531.3 (M+1).
Reaction SMILES: [N:1]([C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[N:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.C(OP(OCC)OCC)C>C1(C)C=CC=CC=1>[S:7]1[C:6]2=[N:5][C:4]3[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:1][C:3]=3[N:10]2[CH:9]=[CH:8]1
Reactant: O=Nc1c(-c2ccccc2)nc2sccn12
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1c2nc2sccn21
Yield: 35.2 %

Procedure:
A mixture of 8.5 grams of analytically pure 5-nitroso-6-phenylimidazo[2,1-b]thiazole (0.04 mole) and 10 ml. of triethylphosphite (0.05 mole) in 50 ml. of anhydrous toluene is refluxed for three hours with constant stirring and under a constant flow of dry nitrogen. The temperature of the oil bath is kept between 110° and 120° C. After cooling, the toluene and excess triethyl phosphite are removed by vacuum distillation at 0.2 Torr. The temperature of the oil bath is kept under 120° C. also during the distillation. The residue which is a thick oily liquid is kept over night at 0° C., during which time it solidifies. The solid is washed on a glass filter with cold carbon tetrachloride and then recrystallized twice from 2-propanol to yield three grams of 5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.N[C:13]1NC=CN=1.C[O-].[Na+].C([O:24][CH:25]([CH3:36])[C:26](=O)[CH2:27][CH:28](OCC)OCC)(=O)C.Cl.C>CCOC(C)=O.CCO>[N:8]1[CH:9]=[CH:10][N:11]2[CH:28]=[CH:27][C:26]([C:25]([OH:24])([CH3:36])[CH3:13])=[N:6][C:7]=12
Reactant: CCOC(CC(=O)C(C)OC(C)=O)OCC
Reactant: Nc1ncc[nH]1
Agent: C
Agent: C[O-]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccn2ccnc2n1
Temperature: 24 °C
Yield: 73 %

Procedure:
A 3 l round-bottomed flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet adaptor was charged with 2-aminoimidazole hemisulfate (84.6 g, 641 mmol) and absolute EtOH (900 ml). The resulting slurry was stirred at 24° C. and solid NaOMe (69.2 g, 1.28 mol) was added in two portions over 15 min. After the addition was complete the reaction temperature was 46° C. The mixture was warmed to 60° C. and stirred for 45 min. The mixture was then cooled to 50° C. A solution of crude 4-acetoxy-1,1-diethoxy-4-methyl-3-butanone (253.5 g of 57 wt % material, 611 mmol) and absolute EtOH (150 ml) was added over 1 h maintaining a reaction temperature of about 45° C. After the addition, the reaction was maintained at 60° C. for 3 h and then cooled to 20° C. The pH was adjusted to 5.9 by addition of aqueous HCl (5N, 130 ml) in 10 ml portions. Darco G-60 (9.0 g) was added and the slurry was stirred for 30 min. The solids were removed by filtration through a pad of Solka-floc and the cake was rinsed with EtOH (200 ml). The filtrate was concentrated to about 200 ml by rotary evaporation, then 300 ml of EtOAc was added and the mixture was concentrated to about 300 ml. This was repeated three times with crystals forming during the process. The final slurry was diluted to 600 ml with EtOAc and then cooled to 5° C. with stirring. The solids were collected on a frit, rinsed with cold EtOAc (50 ml) and dried overnight under vacuum at 22° C. to provide 2-(imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (79 g) as a crystalline solid: 1H NMR (MeOH-d4, 400 MHz) δ 8.80 (1H, d, J 7.2), 7.77 (1H, d, J 1.6), 7.66 (1H, d, J 1.6), 7.39 (1H, d, J 7.2), 1.60 (6H, s); 13C NMR (MeOH-d4, 100.61 MHz) δ 169.7, 147.8, 134.7, 132.8, 111.1, 105.4, 72.8, 28.4.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:31][OH:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(CO)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Reaction time: 2 h
Yield: 84.6 %

Procedure:
11-Acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (20 mg) was dissolved in ethyl acetate (5 ml) and the solution was subjected to catalytic reduction for 2 hours using 10% palladium on carbon under atmospheric pressure at room temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of methanol and chloroform (5:95, v/v) to yield 11-acetyl-8-carbamoyloxymethyl-4-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (17 mg).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Agent: OB(O)c1ccccc1
Product: COc1ccc(OC)c(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)c1
Yield: 65 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2,5-dimethoxyphenyl boronic acid. The title compound was obtained as a yellow solid, (yield=65%).
Reaction SMILES: [CH3:1][C:2]1([C:19]2[S:23][CH:22]=[C:21]([C:24](=[CH2:30])[C:25]([O:27]CC)=[O:26])[CH:20]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]3([CH3:18])[CH3:17].[OH-].[Li+].Cl>C1COCC1>[CH3:1][C:2]1([C:19]2[S:23][CH:22]=[C:21]([C:24](=[CH2:30])[C:25]([OH:27])=[O:26])[CH:20]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]3([CH3:17])[CH3:18]
Reactant: C=C(C(=O)OCC)c1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C(=O)O)c1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1

Procedure:
A mixture of ethyl [5-(3,5,5,8,8-pentamethyl-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-3-yl)thiophen-3-yl]acrylate (430 mg, 1 mmol) and lithium hydroxide (430 mg, [lacuna] mmol) in THF (10 ml) was heated under reflux for 12 h. The mixture was acidified to pH 1 with a concentrated hydrochloric acid solution, extracted with ethyl ether and washed with water. After drying, the organic phase was concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[C:3]=1[F:11].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16]([NH:15][CH:12]([CH3:14])[CH3:13])=[N:10][C:4]=2[C:3]=1[F:11]
Reactant: CC(C)N=C=S
Reactant: Nc1cc(Cl)c(Cl)c(F)c1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(F)c(Cl)c(Cl)cc2[nH]1
Yield: 30.9 %

Procedure:
4,5-Dichloro-3-fluoro-1,2-phenylenediamine (3.37 g, 17.28 mmol), isopropyl isothiocyanate (2.10 g, 20.76 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (9.52 g, 22.48 mmol) and pyridine (100 mL) were used according to general procedure I. The title compound was recrystallized from 1,4-dioxane to provide a tan solid (1.40 g, 31%); m.p. 212-215° C.; 1H NMR (DMSO-d6) δ: 11.15 (br s, 1H, NH), 7.21 (s, 1H, Ar—H), 6.99 (d, J=7.8 Hz, 1H, NH), 3.92 (m, 1H, CH), 1.21 (d, J=6.4 Hz, 6H, overlapping CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:19][CH3:20])[C:17]([NH2:18])=[C:13]2[CH:12]=[CH:11][CH:10]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](O[C:38](=O)[CH3:39])OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.CCC(=O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:19][CH3:20])[C:17]([NH:18][CH:2]([CH2:7][CH2:38][CH3:39])[CH2:3][CH3:4])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1N
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC(=O)CC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCC(CC)Nc1c(CC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
After dissolving [7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (30 mg) in acetic acid (1 mL), 3-hexanone (0.024 mL) and sodium sulfate (139 mg) were added and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (41.5 mg) was then added, and stirring was continued for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (21 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2].[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CCNCc1cc(C(=O)OCC)ccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CN(CC)C2CCOCC2)c1

Procedure:
Ethyl 2-[(ethylamino)methyl]biphenyl-4-carboxylate and tetrahydro-4H-pyran-4-one were treated with sodium triacetoxyborohydride in the presence of acetic acid to obtain ethyl 2-{[ethyl(tetrahydro-2H-pyran-4-yl)amino]methyl}biphenyl-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH:18](C3C=CC=CC=3)[CH3:19])[CH:10]=2)=[CH:5][CH:4]=1.CO[C:28]1[CH:33]=[CH:32][C:31](C2CCCC(=O)C=2)=[CH:30][CH:29]=1.C1(CCCCN)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CC(NCCC(C)c3ccccc3)CCC2)cc1
Reactant: COc1ccc(C2=CC(=O)CCC2)cc1
Agent: NCCCCc1ccccc1
Product: COc1ccc(C2=CC(NCCCCc3ccccc3)CCC2)cc1

Procedure:
Following the general procedure of example 28, (RS)-[3-(4-methoxy-phenyl)-cyclohex-2-enyl]-(3-phenyl-butyl)-amine (2.8 g; 56% light yellow oil, MS: m/e=336.2 (M+H+)) was prepared from 3-(4-methoxy-phenyl)-cyclohex-2-enone (3.0 g; 14.8 mmol) and 4-phenyl-butylamine (2.21 g; 14.8 mmol).