Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].Cl[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:31][N:30]=1>C(#N)C>[Cl:35][C:34]1[C:29]([O:7][C:8]2[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=2)[C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[N:30][CH:31]=[C:32]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])[CH:33]=1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCCC1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(OC(C)C)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCCC4)cc3Cl)cc(OC(C)C)c2)cn1
Temperature: 120 °C
Yield: 73.1 %

Procedure:
Cesium carbonate (782 mg, 2.4 mmol) was added to a solution of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (230 mg, 0.8 mmol) and 2,3-dichloro-5-(pyrrolidin-1-ylcarbonyl)pyridine (234 mg, 0.96 mmol) in acetonitrile (5 mL) and the stirred mixture heated in a microwave reactor at 120° C. for 2 hours. The mixture was cooled to RT and the acetonitrile evaporated in vacuo. The residue was partitioned between water (25 mL) and ethyl acetate (50 mL), the organic layer washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (290 mg).
Reaction SMILES: C(O[C:4]([C:6]1[O:15][C:9]2=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]=1[NH2:16])=[O:5])C.[NH2:17][C:18](N)=[O:19].N>O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]2[C:7]3[NH:16][C:18](=[O:19])[NH:17][C:4](=[O:5])[C:6]=3[O:15][C:13]=2[N:12]=1
Reactant: CCOC(=O)c1oc2cc(C)ncc2c1N
Reactant: NC(N)=O
Agent: N
Solvent: O
Product: Cc1ccc2c(n1)oc1c(=O)[nH]c(=O)[nH]c12
Reaction time: 0.5 h

Procedure:
A round-bottomed flask was loaded up with 3-amino-6-methyl-furo[2,3-d]pyridine-2-carboxylic acid ethyl ester, 16 (926 mg, 4.20 mmol, 1 eq) and urea (2.52 g, 42.0mmol, 10 eq). The mixture was heated up at 190° C. for 3 h until no more ammonia release was observed. H2O (10 mL) was added, and the reaction mixture was stirred for 30 min vigorously; it was then filtered, and the solid was washed with H2O (3×10 mL) before drying to furnish the product as a pale brown solid (1.60 g, quant.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([O:15][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g (0.0047 mol) of [bis(4-fluorophenyl)]hydroxy(1H-1,2,4-triazol-1-ylmethyl)silane in 20 ml of tetrahydrofuran was added 0.8 ml (0.0063 mol) of chlorotrimethylsilane. A solution of 0.8 ml (0.0057 mol) of triethylamine in 5 ml of tetrahydrofuran was added dropwise, giving a thick white precipitate. The mixture was stirred overnight at room temperature, then filtered and concentrated to an oil. The residue was taken up in ether, filtered, and the filtrate was evaporated to afford the title compound as a clear colorless oil: nmr (CDCl3) 0.1 (9H, s), 4.3 (2H, s), 7.2 (4H, t, J=9 Hz), 7.6 (4H, d of d, J=9,6 Hz), 8.0 (2H, s).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]>[Ru]>[CH:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:10][CH:11]=1)=[CH:2][CH3:3]
Reactant: C=CCOCc1ccc(C(C)(C)C)cc1
Agent: [Ru]
Product: CC=COCc1ccc(C(C)(C)C)cc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
204 g (1.0 mol) of p-tert-butylbenzyl allyl ether are treated with 2.04 g of ruthenium on aluminium oxide (5%) and stirred under a nitrogen atmosphere for 1 hour at a bath temperature of 180° C. After filtering off the catalyst the remainder is distilled in a high vacuum. There are obtained 163.4 g of p-tert-butylbenzyl propenyl ether as a mixture of the Z- and the E-isomers (80.1% of theory based on p-tert-butylbenzyl chloride).
Reaction SMILES: [NH2:1]N.C1COCC1.C[N:9](C)/[CH:10]=[C:11](\[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)/[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])=O>>[N:25]1[CH:26]=[CH:27][C:22]([C:11]2[C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])=[N:1][NH:9][CH:10]=2)=[CH:23][CH:24]=1
Reactant: NN
Reactant: CN(C)/C=C(/C(=O)c1cccc(C#N)c1)c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 M solution of hydrazine in THF (0.090 ml, 88.5 mmol) was added to 3-((E)-3-dimethylamino-2-pyridin-4-yl-acryloyl)benzonitrile (6.13 g, 22.1 mmol) and the mixture was stirred at 60° C. for 1 h. The product 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (4.89 g, 19.8 mmol, 90%) was isolated as a white solid by filtration from the reaction mixture.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[N:65]([CH3:66])[C:64](=[O:67])[CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[N:65]([CH3:66])[C:64](=[O:67])[CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: CN1C(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 83.1 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (240 mg, 0.40 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (149 mg, 0.41 mmol) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (236 mg, yield: 82.7%).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.[CH:18]1(B(O)O)[CH2:20][CH2:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:18]1([C:2]2[C:3](=[O:17])[N:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=23)[CH2:20][CH2:19]1
Reactant: OB(O)C1CC1
Reactant: O=c1c(Br)c2n(n1-c1ccccc1)CCCC2
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1c(C2CC2)c2n(n1-c1ccccc1)CCCC2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a sealable tube under argon was added 3-bromo-1-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-one (0.11 g), cyclopropylboronic acid (0.064 g), potassium phosphate (0.43 g), tricyclohexyl phosphine (0.016 g) and toluene (1 mL) and water (0.1 mL). To this was added palladium acetate (0.006 g) and the tube was sealed and stirred at 100° C. for 2 days. The reaction vessel was then cooled and the diluted with water/EtOAc. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo to afford a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 3-cyclopropyl-1-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-one as a light yellow solid. MS (ESI+): 255.4 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:28]>[C].[Pd]>[CH2:1]([O:8][C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][C:17](=[O:28])[N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
(S)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate (1.089 g, 3.00 mmol) described in Reference Example 5 was dissolved in methanol (15 mL), 10% palladium-carbon (50% water content, 200 mg) was added, followed by stirring at room temperature for 1 hour under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through Celite and the solvent was concentrated under reduced pressure to afford 595.5 mg of the title compound (yield 86.6%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1)N>CN(C)C=O>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Solvent: CN(C)C=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)ccn1
Yield: 34.1 %

Procedure:
3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) (0.05 g; 0.144 mmol) and 4-hydrazino-2-methylpyridine (0.03 g; 0.187 mmol) are dissolved in a sealed tube in dimethylformamide (0.6 ml) and irradiated at 180° C. for 10 min. The solvent of the reaction mixture is removed and the crude product is purified by preparative HPLC yielding 0.02 g (34.1%) of the final product. MS: M=408.4 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1ccc(C=CCO)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
3-(4-Methylphenyl)acrylic acid (5.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained white solid was dissolved in tetrahydrofuran (120 ml), 1M diisobutylaluminum hydride/toluene solution (67 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature. Aluminum salt was collected by filtration through celite, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (3.84 g) as a white powder.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:16][O:17][CH3:18])[C:13](Cl)=[O:14])[N:8]=1.Cl.[NH2:20][CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:25]([CH2:28][Cl:29])[CH2:26][S:27][C@H:22]12.C(=O)([O-])O.[Na+]>O>[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:16][O:17][CH3:18])[C:13]([NH:20][CH:21]2[C:46](=[O:47])[N:23]3[C:24]([C:30]([O:32][CH:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:31])=[C:25]([CH2:28][Cl:29])[CH2:26][S:27][C@H:22]23)=[O:14])[N:8]=1
Reactant: CON=C(C(=O)Cl)c1nsc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a mixed solution of dichlorometahne (1000 ml) and tetrahydrofuran (200 ml) were added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl chloride (syn isomer) (64 g) and benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (100 g) at -15° C. The mixture was stirred at -15° C. for one hour. The reaction mixture was poured into ice-cooled water, and neutralized with sodium hydrogencarbonate. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (130.5 g)
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].O>CO>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)[CH2:16][CH2:15]3)[OH:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(c1ccc(-n2ccnc2)cc1)C1CCN(Cc2ccncc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccc(-n2ccnc2)cc1)C1CCN(Cc2ccncc2)CC1
Yield: 43.5 %

Procedure:
To a stirred solution of [4-(1H-imidazol-1-yl)phenyl][1-(4-pyridylmethyl)-4-piperidinyl]methanone (5.70 g, 16.5 mmol) in methanol (100 ml) at 0° C. was added sodium borohydride (2.1 g, 56 mmol) in three equal portions over a 24 hour period. Water was added and the solution was concentrated to a white suspension. This aqueous suspension was extracted three times with dichloromethane. The combined organic layers were dried (MgSO4), and filtered through a pad of silica gel (eluting with acetone). The eluent was concentrated and the resulting solid was recrystallized from tetrahydrofuran to afford the desired product, α-[4-(1H-imidazol-1-yl)phenyl]-1-(4-pyridylmethyl)-4-piperidine methanol (2.5 g, 43%): m.p. 174°-175° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCc4ccccc4)cc3)cc21

Procedure:
Analogously to Example 308a, 0.103 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.0533 g of benzyl bromide are reacted. The title compound is obtained as a colourless oil. Rf=0.23 (1:1 EtOAc-heptane); Rt=5.95.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:31][C:32]3([OH:45])[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@@H:20]4[CH2:22][C@H:21]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:19])=[C:13]([O:29][CH3:30])[CH:12]=3)[C:3]=12.[ClH:46]>CC(C)=O>[ClH:46].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:31][C:32]3([OH:45])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@@H:20]4[CH2:22][C@H:21]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:19])=[C:13]([O:29][CH3:30])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc(-c2nn(CC3(O)CCNCC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of trans tert-butyl 4-{[4-amino-3-(3-methoxy-4-{[(2-phenylcyclopropyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00013 mol) in acetone (12 mL) and 6 N aqueous hydrochloride solution (3 mL) was stirred at 40° C. for 2 hours. Acetone was removed under reduced pressure, and the residue was lyophilized to give trans N1-(4-{4-amino-1-[(4-hydroxy-4-piperidyl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-phenyl-1-cyclopropanecarboxamide hydrochloride salt (0.07 g, 0.00012 mol).
Reaction SMILES: [BH4-].[Li+].[C:3]1([C@@H:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18](OCC)=[O:19])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[OH-].[Na+]>O1CCCC1.O>[C:3]1([C@@H:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:18][OH:19])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](N[C@H]1CCCC[C@@H]1CO)c1ccccc1
Temperature: 15 °C

Procedure:
Tetrahydrofuran (1.9 L) was charged to a reactor and cooled to 15° C. and lithium borohydride (52.8 g) was added under nitrogen. A solution of (1S,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (10, 237.9 g) in tetrahydrofuran (0.35 L) was added and the reaction mixture was heated to reflux for NLT 12 hours, under nitrogen. The mixture was cooled to below 10° C. and acetic acid (NLT 278 mL) was added, while maintaining the temperature between 5-15° C. in NLT 30 minutes. 25% aqueous sodium hydroxide solution (1.78 L) and water (˜2 L) were added to adjust pH to ˜8.7. The aqueous layer was separated and extracted with 2×0.75 L of heptanes, which was kept aside. The organic layer was concentrated to about 0.8 L volume and combined with the heptane extracts and additional water (0.75 L). The aqueous layer was separated and extracted with heptanes (0.75 L) and the combined organic extracts were washed with water (2×0.75 L), 3.5 M aqueous sodium chloride solution (0.75 L) and dried using anhydrous magnesium sulfate. The filtered solution was concentrated under vacuum and provided 184.1 g) of (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) as the major isomer.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.I.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](SC)=[NH:20].O>CN(C=O)C>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:19]([C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)=[NH:20])=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CNCCO2
Agent: I
Solvent: CN(C)C=O
Solvent: O
Product: N=C(Nc1ccc2c(c1)CNCCO2)c1cccs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylamine (3.67 g, 18 mmol) in DMF (60 ml) was added 2-thiophenecarboximidothioic acid, methyl ester, hydroiodide (5.52 g, 19 mmol). The mixture was heated to 50° C. for 24 h. The mixture was poured into water (50 ml), then basic water (150 ml) and was allowed to stir for 1 h. The solids were collected by filtration. The solid was dissolved in hot ethyl acetate, filtered, and diluted with hexane. The solids were collected by filtration (3.13 g, 64%), MS m/Z 274 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:25]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN1C(=O)CCC1.CO.[Cu]Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:25]=1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(Cl)cc2C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
A solution of 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.1 g, 0.27 mmol), 4-chloro-2-cyclohexyl-phenol (63 mg, 0.3 mmol), copper(I) chloride (13 mg, 0.13 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.01 mL, 0.07 mmol), and cesium carbonate (105 mg, 0.32 mmol) in NMP (3 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is quenched with 1N aqueous HCl and extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to obtain pH=4. The aqueous layer is extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by HPLC to afford 49 mg (38%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H31ClO4 478, found 479 and 481 (M+1 and M+3, 100%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1
Reactant: CCOC(=O)CCN1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCN1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 3-(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)propanoate (500 mg, 1.6 mmol, step 1 of Example 10) in CH2Cl2 (5 mL), trifluoroacetic acid (1.2 mL, 16 mmol) was added and stirred overnight at room temperature. The mixture was concentrated, and the residual oil was dissolved in CH2Cl2 (60 mL) and solid K2CO3 (5 g) was added, and stirred for 10 min. The mixture was filtered, and the filtrate was concentrated to give ethyl 3-[4-(aminomethyl)piperidin-1-yl]propanoate as a pale yellow oil. Following coupling reaction was carried out according to the procedure described in step 6 of Example 1 from 3,3-dimethyl-1,3-dihydro-2H-indol-2-one (Robertson, David W et al., J. Med. Chem., 1986, 29, 1832) and ethyl 3-[4-(aminomethyl)piperidin-1-yl]propanoate.