Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:12]2[C:13](=O)[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[O:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:7]1[C:12]2[CH2:13][NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[O:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)CNc1ccccc1O2
Yield: 97.4 %

Procedure:
In a one liter three neck flask (argon atmosphere) was placed 50 ml of dry THF and 7.97 g (0.21 mole) of LAH. The suspension was stirred and a warm suspension of 29.57 g (0.14 mole) of 10,11-dihydro dibenz[b,f][1,4]oxazepine-11-one (Aldrich) in 500 ml of THF was added in a slow stream. The reaction mixture was stirred and heated to reflux for 3 hr. The reaction mixture was cooled and cautiously treated with 15 ml of water and 15 ml of saturated sodium sulfate solution. The mixture was stirred and heated to reflux for one hr. The solids were removed by filtration and washed with THF. The filtrate was concentrated to dryness to give 26.90 g of an oil that crystallized on standing. The nearly pure crystalline product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[C:20]([C:21]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCOCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:11]2[C:20]([C:21]3[N:29]=[C:28]([CH3:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cc3ccccc3nc2Cl)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc3ccccc3cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5-amino-2-methoxypyridine (50 mg, 0.41 mmol, Aldrich, St. Louis, Mo.) and 2-chloro-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)quinoline (77 mg, 0.20 mmol) in dioxane (4 mL) at 0° C. was treated with LiHMDS (1 M in THF, 0.51 mL, 0.51 mmol). The reaction mixture was stirred at 0° C. for 1 h and 18 h at room temperature. Then an additional amount of LiHMDS (1 M in THF, 0.51 mL, 0.51 mmol) was added and the reaction mixture stirred at room temperature for 2 h. The reaction was quenched by the addition of MeOH (2 mL) and the solvents were removed under vacuum. Purification of the crude reaction mixture by silica gel chromatography (2 to 3% MeOH/CH2Cl2) provided the title compound as a dark orange solid. m/z (ESI, +ve ion) 468 (M+H)+.
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:15])[C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[NH2:1][N:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:15])[C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1
Reactant: O=NN1CCN(C(=O)c2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: NN1CCN(C(=O)c2cccs2)CC1
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
To a solution of 1-nitroso-4-(2-thenoyl)piperazine (1.78 g) in a mixture of acetic acid (8 ml) and water (8 ml) was added Zn powder (1.55 g) in several portions at 6°-15° C. The suspension was stirred for 1.5 hours below 10° C. To the mixture was added acetic acid (4 ml) and Zn powder (780 mg) at 8°-12° C. The mixture was stirred for 2 hours at ambient temperature. To the suspension was added 17% aqueous sodium hydroxide solution (70 ml). The insoluble materials were filtered off. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by 5% methanol in dichloromethane) to yield 1-amino-4-(2-thenoyl)piperazine (1.17 g) as a pale yellow syrup.
Reaction SMILES: C([N:8]([CH2:22][C:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[N:24]O)[C@@H:9]([CH2:14][CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10](OC)=[O:11])C1C=CC=CC=1.[H][H]>[Pd].CO>[CH:15]1([CH2:14][C@@H:9]2[NH:8][CH2:22][CH:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[NH:24][C:10]2=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)[C@H](CC1CCCCCC1)N(CC(=NO)c1cc(F)cc(F)c1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NC(c2cc(F)cc(F)c2)CN[C@H]1CC1CCCCCC1

Procedure:
Under a hydrogen atmosphere 0.590 g (1.29 mmol) methyl (S)-2-(benzyl-{2-(3,5-difluoro-phenyl)-2-[hydroxyimino]-ethyl}-amino)-3-cycloheptyl-propionate and 0.10 g palladium on charcoal (10%) in 10 ml of methanol were hydrogenated for 3 days at 50° C. and 3.45 bar hydrogen pressure. After elimination of the catalyst the filtrate was concentrated by rotary evaporation. The residue was stirred with petroleum ether and diisopropylether and filtered off.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:11]=2[O:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:11]=2[O:10][CH2:9]1
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)[C@@H](N)COc2ccc(F)cc21
Yield: 90.3 %

Procedure:
A solution of 0.85 g (2.74 mmol) ((S)-2-fluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 20 ml dichloromethane was treated with 21 ml trifluoroacetic acid for 3 hours. Extraction with aqueous sodium bicarbonate solution and dichloromethane and removal of the solvent gave 0.52 g (90%) (S)-7-amino-2-fluoro-9-methyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one as white solid, MS m/e (%): 211.3 (M+H+, 100).
Reaction SMILES: C(NCC)C.C([Li])CCC.[CH:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20]>CCCCCC>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:20]
Reactant: N#CC1CCCCC1
Reactant: CCOC(CBr)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCNCC
Product: CCOC(CC1(C#N)CCCCC1)OCC
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protective gas at -10° C., to 312.5 ml (0.5 mol) of a 15% strength solution of n-butyllithium in hexane. The mixture is stirred for 20 minutes and then cooled to -70° C. 54.6 g of cyclohexanecarbonitrile are added dropwise over the course of 30 minutes and, after a further 30 minutes, 98.5 g of bromoacetaldehyde diethyl acetal are added within 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room temperature, 100 g of ice are added, and the mixture is extracted twice with 500 ml of ethyl acetate, and the organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13](Br)[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][CH2:28][N:11]4[C:12]=3[C:13]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[C:36](=[O:41])[CH2:37]3)=[N:14]2)=[CH:25][CH:24]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(Br)c32)C1=O
Reactant: CN1CCNCC1=O
Product: CN1CCN(c2nn(Cc3ccc(F)cc3)c(=O)c3c(O)c4n(c23)CCN(C)C4=O)CC1=O
Temperature: 100 °C

Procedure:
A mixture of 10-(benzyloxy)-4-bromo-2-(4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.10 g, 0.19 mmol; Example 160, Step 1) and 1-methylpiperazin-2-one (2 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The benzyl protecting group was also cleaved in the process. The reaction mixture was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:26][C:24]2[N:25]=[C:21]([CH3:20])[S:22][CH:23]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(C=O)cs1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1csc(C)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-methylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 346.85 g/mol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:24]([O-])=[O:25].[Na+]>>[Cl:1][CH2:2][CH2:3][N:4]([N:24]=[O:25])[C:5]([N:7]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: COCC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Product: COCC(C)N(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 23.1 %

Procedure:
3.6 g of 1-(2-chloroethyl)-3-(1-methyl-2-methoxy-ethyl)-3-(D-galactopyranosyl)urea and 1.5 g of sodium nitrite are treated in the same manner as described in Example 24. 0.9 g of 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-(D-galactopyranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:22]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:31])[C:8]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc2c(c1)C(c1ncccc1C)CC(C)(C)O2
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(c1c(C)ccc[n+]1[O-])CC(C)(C)O2
Yield: 26.3 %

Procedure:
101 mg of 6-acetyl-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were dissolved in 5 ml of dichloromethane at room temperature and 91 mg of m-chloroperbenzoic acid were added. After 1 hour the mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water. The organic extract was dried over sodium sulphate and evaporated to give an oil. This oil was triturated with t-butyl methyl ether to give a solid which, after recrystallization from ethyl acetate/t-butyl methyl ether, gave 28 mg of 2-(6-acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-methylpyridine N-oxide of melting point 154-156° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[C:2]1([O:1][C:8]2[CH:13]=[CH:12][C:11]([Br:15])=[C:10]([CH3:14])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Oc2ccccc2)c1
Solvent: CC#N
Product: Cc1cc(Oc2ccccc2)ccc1Br
Yield: 97.8 %

Procedure:
A mixture of 3-phenoxytoluene (2.5 g, 0.0136 mol) and N-bromosuccinimide (2.54 g, 0.0142 mol) was stirred in acetonitrile (20 mL) for 2.5 hours under an atmosphere of nitrogen. The solvent was removed under reduced pressure. Carbon tetrachloride was added to the residue and the resulting solid was removed by filtration. The filtrate was concentrated to yield 4-bromo-3-methylphenyl phenyl ether as yellow oil (3.5 g, 0.0133 mol):
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[C:33]2([C:52]4[C:43](=[CH:44][C:45]5[O:50][CH2:49][CH2:48][O:47][C:46]=5[CH:51]=4)[O:42][CH2:41]2)[C:34](=[O:40])[NH:35]3)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[C:33]2([C:52]4[C:43](=[CH:44][C:45]5[O:50][CH2:49][CH2:48][O:47][C:46]=5[CH:51]=4)[O:42][CH2:41]2)[C:34](=[O:40])[N:35]3[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1Nc2cccc(-c3ccc(Oc4ccccc4)cc3)c2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3ccc(Oc4ccccc4)cc3)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 196-199° C. (dichloromethane/ether); 1H NMR (300 MHz, CDCl3) δ 8.61-8.57 (m, 1H), 7.69-7.65 (m, 1H), 7.40-7.18 (m, 5H), 7.12-7.05 (m, 1H), 7.02-6.97 (m, 2H), 6.93-6.86 (m, 2H), 6.84-6.71 (m, 4H), 6.39 (s, 1H), 6.21 (s, 1H), 5.26 (d, J=15.8 Hz, 1H), 4.95 (d, J=15.8 Hz, 1H), 4.73 (d, J=9.0 Hz, 1H), 4.43 (d, J=9.0 Hz, 1H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.2, 157.4, 156.3, 155.6, 149.6, 144.7, 142.4, 139.8, 137.9, 137.1, 133.5, 130.4, 130.1, 129.7, 128.7, 125.4, 123.1, 122.8, 122.3, 121.7, 118.6, 118.4, 111.2, 108.7, 99.3, 77.9, 64.5, 64.0, 58.5, 46.2; MS (ES+) m/z 555.0 (M+1).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]([C:14]2[NH:18][N:17]=[CH:16][CH:15]=2)=[C:8]2[C:13]=1[CH:12]=[N:11][CH:10]=[CH:9]2)([O-])=O.CN(C=O)C.CS(O[CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)(=O)=O.Cl.CCO>C(OCC)C.O>[CH:12]1[C:13]2[C:8](=[C:7]([C:14]3[CH:15]=[CH:16][N:17]([CH2:29][CH2:30][NH2:31])[N:18]=3)[CH:6]=[CH:5][CH:4]=2)[CH:9]=[CH:10][N:11]=1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(-c2ccn[nH]2)c2ccncc12
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: NCCn1ccc(-c2cccc3cnccc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To 0.50 g of 8-nitro-5-(1H-pyrazol-5-yl)isoquinoline was added 5 ml of dry DMF and the mixture was stirred at RT for 30 min. To this was added 0.65 g of 2-(tert-butoxycarbonylamino)ethyl methanesulfonate diluted to 1.5 ml of dry DMF and the mixture was microwaved for 30 min at 160° C. After pouring the mixture to water, it was extracted with EtOAc. Combined organic phases were washed with water and brine, dried with Na2SO4 and evaporated. Crude product was purified by CombiFlash (5% MeOH in DCM). Product fractions were combined and evaporated to give 0.59 g of Boc-protected product. For Boc deprotection 8 ml of 10% HCl/EtOH solution was added to the evaporation residue, stirred at RT until disappearance of starting material by TLC. 3 ml of diethylether was added to the mixture and the precipitate was filtered, washed with diethylether and dried to give 0.30 g of the product as HCl-salt. 1H-NMR (400 MHz; d6-DMSO): δ 1.57 (br s, 2H), 3.04 (t, 2H), 4.25 (t, 2H), 6.90 (d, 1H), 8.00 (d, 1H), 8.17 (d, 1H), 8.47 (d, 1H), 8.75 (d, 1H), 8.91 (d, 1H), 9.83 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1(N)CCCCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C:13](=[O:15])[NH:18][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)OCc1ccccc1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.4 %

Procedure:
To a solution of N-(benzyloxycarbonyl)glycine (13.21 g), 1-hydroxybenzotriazole hydrate (9.39 g) in dimethylformamide (92 ml) were added cyclohexylamine (7.95 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.32 g), and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed successively with water, aqueous sodium hydrogencarbonate solution, 10% hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (16.799 g).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[F:23][C:24]1([F:31])[CH2:26][CH:25]1[CH2:27][C:28](Cl)=[O:29]>O1CCCC1.CN(C)C1C=CN=CC=1>[F:23][C:24]1([F:31])[CH2:26][CH:25]1[CH2:27][C:28]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:29]
Reactant: O=C(Cl)CC1CC1(F)F
Reactant: CCCCCCCCCCCCCCO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOC(=O)CC1CC1(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2.08 g (9.7 mmol) 1-tetradecanol in 20 ml tetrahydrofuran (THF) was treated with 200 mg 4-dimethylaminopyridine (DMAP) and 1.35 ml (9.7 mmol) triethylamine and cooled to 0° C. A solution of 1.5 g (9.7 mmol) 2-(2,2-difluorocyclopropyl)acetyl chloride in 10 ml tetrahydrofuran at 0°-5° C. was added dropwise. The mixture was then stirred for 2 hours at room temperature. The precipitated triethylamine hydrochloride was separated, the solution concentrated under reduced pressure, and the residue dissolved in 50 ml diethyl ether. After washing with in turn 10 ml water, 10% caustic soda and water until neutral, the ether solution was dried over magnesium sulphate and evaporated in vacuo (200 mbar). The residue was distilled under an oil pump vacuum.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C@H:29]3[CH2:34][CH2:33][C@H:32]([CH2:35][OH:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[N:21][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C@H:29]3[CH2:30][CH2:31][C@H:32]([CH:35]=[O:36])[CH2:33][CH2:34]3)=[CH:25][CH:24]=2)=[N:21][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](CO)CC3)cc2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C=O)CC3)cc2)nc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.94 ml of oxalyl chloride in 25 ml of dry methylene chloride is treated dropwise at -60° C. within 10 minutes with a solution of 1.56 ml of dimethyl sulphoxide in 5 ml of methylene chloride. 2 minutes later the reaction mixture is treated dropwise at -60° C. within 10 minutes with a solution of 3.51 g of 5-hexyl-2-[p-(trans-4-(hydroxymethyl)cyclohexyl)phenyl]pyridine in 10 ml of methylene chloride and stirred at -60° C. for a further 15 minutes. Thereafter, the reaction mixture is treated with 7 ml of triethylamine, left to warm to room temperature and then poured into water and extracted with methylene chloride. The organic phase is washed twice with water, dried over magnesium sulphate and evaporated. The 5-hexyl-2-[p-(trans- -4-formylcyclohexyl)phenyl]pyridine obtained is purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][CH:24]=2)[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc(CCCCCCCCc2ccc(NC(C)=O)cc2)c2ccccc2c1OC
Agent: Cl
Solvent: CO
Product: COc1cc(CCCCCCCCc2ccc(N)cc2)c2ccccc2c1OC
Yield: 74.7 %

Procedure:
A solution of 554.6 mg (1.28 mmol) of 1-(3,4-dimethoxy-1-naphthyl)-8-(4-acetamidophenyl)-octane in 20 mL of MeOH was mixed with 21 mL of 2N HCl. The reaction mixture was refluxed for 23 hr. Then the reaction mixture was partitioned between 75 mL of CH2Cl2 and 21 mL of 2N NaOH. The aqueous phase was extracted with CH2Cl2 (5×40 mL). The CH2Cl2 extracts were combined, dried with MgSO4, and evaporated to dryness. Column chromatography on silica gel with 1% MeOH in CH2Cl2 gave 374.6 mg (75%) of aniline 537: 1H NMR (250 MHz, CDCl3, TMS) δ 8.14 (d, J=8 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 7.47 (t, J=8 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=8 Hz, 2H), 6.62 (d, J=8 Hz, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 3.1-3.0 (m, 2H), 2.5-2.4 (m, 2H), 1.8-1.3 (m 12H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.O=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.[BH3-]C#N.[Na+]>CO>[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:14][CH2:15][N:16]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:17][CH2:18]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (500 mg, 1.45 mmol, 1.00 equiv) in methanol (50 mL) at room temperature. To the resulting mixture was then added tert-butyl 4-oxopiperidine-1-carboxylate (865 mg, 4.35 mmol, 3.00 equiv), in portions at room temperature, followed by NaBH3CN (460 mg, 7.30 mmol, 5.00 equiv), in portions at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic layers combined and concentrated under vacuum to yield tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-1-yl)piperidine-1-carboxylate as a white solid.