Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][NH:4]1.CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:26])[O:24][CH3:25].[NH4+].[Cl-]>ClCCl>[F:13][CH:2]([F:1])[CH:3]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][N:4]1[C:23]([O:24][CH3:25])=[O:26]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(C(F)F)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(C(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
Methyl 2-(difluoromethyl)piperidine-4-carboxylate (1.85 g, 9.58 mmol) was dissolved in dichloromethane (50 mL), DIPEA (2.335 mL, 13.41 mmol) and methyl carbonochloridate (0.905 mL, 11.49 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M NH4Cl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. Crude dimethyl 2-(difluoromethyl)piperidine-1,4-dicarboxylate (2.35 g, 98%) was isolated.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:17][CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:17][CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:12][CH2:11]1
Reactant: COc1ccc(Cl)cc1OCC1CCNCC1
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1OCC1CCN(CCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5.85 g (0.020 mol) of 4-[(5-chloro-2-methoxyphenoxy)methyl]piperidine hydrochloride, 8.37 g (0.022 mol) of 3-bromo-N-(triphenylmethyl)propanamine and 6.91 g (0.050 mol) of K2CO3 in 50 ml of DMF are reacted. The reaction mixture is heated to 95°-100° C. It is cooled to room temperature, poured into 150 ml of water and extracted 3 times with ethyl acetate. The organic phases are combined, washed with water, dried over MgSO4, filtered and evaporated. The product is obtained after chromatography.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].NN>CCO>[NH2:25][C:23]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:16][CH2:15][CH:14]([OH:28])[CH2:13][CH2:12][NH2:3])[CH:24]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCC(O)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: N#Cc1ccc(N)cc1OCC(O)CCN
Temperature: 50 °C
Yield: 59.1 %

Procedure:
To a mixture of 2-(4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutoxy)-4-nitrobenzonitrile (2.96 g, 7.76 mmol) in EtOH (28.1 mL) was added hydrazine (12.18 mL, 388 mmol). The reaction mixture was heated at 50° C. for 1.5 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated and taken up in CH2Cl2. The solid was filtered off again, and the filtrate was concentrated and purified by Prep-HPLC to obtain 4-amino-2-(4-amino-2-hydroxybutoxy)benzonitrile (1.015 g, 59.1% yield). LC-MS (M+H)+=222.1. 1H NMR (500 MHz, methanol-d4) δ 7.24 (d, J=8.5 Hz, 1H), 6.35-6.26 (m, 2H), 4.17-4.09 (m, 1H), 4.05 (dd, J=9.5, 4.9 Hz, 1H), 3.97 (dd, J=9.5, 5.5 Hz, 1H), 3.20 (t, J=7.0 Hz, 2H), 2.08 (td, J=7.1, 3.5 Hz, 1H), 2.01-1.86 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]([CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nccn2CCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Add 4-(1H-imidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (40 g; 0.16 mol; 1.0 equiv), powdered KOH (35.6 g; 0.64 mol; 4.0 equiv), 2-(2-bromo-ethoxy)-tetrahydropyran (66.2 g; 0.32 mol; 2.0 equiv) to DMSO (250 mL) and stir at RT for 2 h. Quench the reaction with water and extract with EA. Evaporate the organic layer to give the title compound (58 g; 97%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:22][S:23][CH2:24][CH2:25][C:26](O)=[O:27])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:50]([O:54][C:55](=[O:76])[C@H:56]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1)([CH3:53])([CH3:52])[CH3:51]>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:50]([O:54][C:55](=[O:76])[C@H:56]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:26](=[O:27])[CH2:25][CH2:24][S:23][CH2:22][CH:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:61][CH:60]=1)([CH3:52])([CH3:53])[CH3:51]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CCSCC(COC(=O)CCCCCCCCCCCc1ccccc1)OC(=O)CCCCCCCCCCCc1ccccc1
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(COC(=O)CCCCCCCCCCCc2ccccc2)OC(=O)CCCCCCCCCCCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 6,7-bis(12-phenyldodecanoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 34 (200 mg) and 4-aminobenzoyl-glutamic acid di-t-butyl ester (108 mg) in pyridine (6 ml), phosphorus trichloride (4 drops) was added drop by drop, followed by stirring at room temperature for 1 hour. After the solvent was concentrated, the residue was purified by silica gel column (n-hexane:ethyl acetate=2:1) to yield the title compound (282 mg, yield 93%) as a colorless oily substance.
Reaction SMILES: C([C:4]1([CH:8]([O:10][CH:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:27][CH:26]=4)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]4[N:42]=[CH:43][N:44]=[C:18]34)[CH2:13][CH2:12]2)[CH3:9])[CH2:7][CH2:6][CH2:5]1)(=O)C.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:50].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:50][C:4]1([CH:8]([O:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]5[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][CH:30]=4)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]4[N:42]=[CH:43][N:44]=[C:18]34)[CH2:15][CH2:16]2)[CH3:9])[CH2:5][CH2:6][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC(C)C3(C(C)=O)CCC3)CC2)c2ncnn12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C3(O)CCC3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a mixture of 4′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (9.20 g), 30% aqueous hydrogen peroxide solution (77.5 mL) and chloroform (80 mL) was added trifluoroacetic acid anhydride (42.8 mL), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and 1 M sodium thiosulfate were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (15 mL)-methanol (15 mL) was added 2 N aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (1.45 g, 17%).
Reaction SMILES: [CH:1]1[C:15](=[NH:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.Cl.C(N)(C)(C)C.[OH2:23]>>[CH:1]1[C:15]([NH2:16])=[N:14][C:13](=[O:12])[N:3]([C@@H:4]2[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]2[OH:23])[CH:2]=1
Reactant: N=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: O
Agent: Cl
Solvent: CC(C)(C)N
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
2,2'-O-cyclocytidine hydrochloride (6.5 g) was dissolved in 35 mL water at 80° C. The solution was cooled to room temperature and t-butylarnine (2.8 g) was added and the mixture stirred for 2 hours. Thereafter, the solvent was evaporated under vacuum and ethanol (16 g) was added. The mixture was stirred at room temperature for 12 hours. Filtration of the resulting precipitation yielded 5 g of pure cytarabine after drying, which corresponds to a yield of 83%. The product was characterized by comparison of its melting point, and NMR and IR spectra with those previously reported for cytarabine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([OH:25])=O)[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1.Cl.CN.[CH2:34]([N:36](CC)CC)C.C(Cl)CCl>C(#N)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:36][CH3:34])=[O:25])[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Agent: CN
Agent: Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CNC(=O)c1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 24.7 %

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (100 mg, 0.24 mmol) (example 10-8), methylamine hydrochloride (67 mg, 1 mmol), triethylamine (155 mg, 1.5 mmol), and EDC (57 mg, 0.3 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in MeOH (3 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient) to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)-N-methylbenzamide (25 mg, 25%) as white solid. MS M+H calculated 423.17; found 423.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [H-].[Na+].C(N1CCCCC(=O)C1)C1C=CC=CC=1.C(OP(CC(OCC)=O)(OCC)=O)C.[CH2:32]([O:34][C:35](=[O:51])[CH:36]=[C:37]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39](CC2C=CC=CC=2)[CH2:38]1)[CH3:33].[ClH:52].CCOC(C)=O.[H][H]>[C].[Pd].CCO.C1COCC1>[ClH:52].[NH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH:37]([CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:51])[CH2:38]1
Reactant: CCOC(=O)C=C1CCCCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1CCCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride and 1-benzylazepane-3-one were added to a THF solution of ethyl diethoxyphosphorylacetate under ice cooling and stirred for two hours at room temperature to give a stereoisomeric mixture of ethyl(1-benzylazepane-3-ylidene)acetate. After the obtained stereoisomeric mixture of ethyl(1-benzylazepane-3-ylidene)acetate was processed with 4M HCl-EtOAc solution, EtOH and 10% palladium carbon were added and stirred for 15 hours at room temperature under the hydrogen atmosphere to give ethyl azepane-3-ylacetate hydrochloride.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1([CH3:16])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])O1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC>[CH3:8][C:9]1([CH3:16])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:5]2[CH:6]=[C:1]([OH:7])[CH:2]=[CH:3][C:4]1=2
Reactant: Oc1ccccc1
Reactant: CC1(C)CCC(C)(C)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 13.2 g (0.1403 mol) of phenol and 12.8 g (0.0998 mol) of 2,2,5,5-tetramethyltetrahydrofuran in 50 ml of heptane was added 13.1 g (0.0982 mol) of aluminum chloride in small portions. After the addition was complete the mixture was stirred at room temperature for 2.5 hours, at reflux for 2 hours and then at room temperature for a further 16 hours. The reaction mixture was then treated with 100 ml of 3N HCl and stirred for 0.5 hours. The mixture was filtered and the residue washed with water and dried in-vacuo to give crude product. The organic layer was separated from the filtrate and the aqueous layer extracted with 3×75 ml of ether. The organic layers were combined and washed with saturated NaCl solution, dried (MgSO4) and then concentrated in-vacuo to give further crude product. The crude product was recrystallized from hexanes to give the title compound as pale brown crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:14][CH2:15][O:16][CH3:17]>>[CH3:17][O:16][CH2:15][CH2:14][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: COCCBr
Product: COCCn1ncc2cc(CO)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-1 and step 2 of Example 13 from 1H-indazole-5-carboxylic acid and 1-bromo-2-methoxyethane.
Reaction SMILES: [CH:1]([N:4]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[CH2:5][C:6]#[C:7][CH2:8][NH:9][C:10]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:11])([CH3:3])[CH3:2].C(N)CN.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH:1]([N:4]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[CH2:5][CH:6]=[CH:7][CH2:8][NH:9][C:10]([C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:11])([CH3:3])[CH3:2]
Reactant: COc1ccccc1CCN(CC#CCNC(=O)C12CC3CC(CC(C3)C1)C2)C(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Solvent: O
Product: COc1ccccc1CCN(CC=CCNC(=O)C12CC3CC(CC(C3)C1)C2)C(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 79.6 %

Procedure:
A mixture of adamantane-1-carboxylic acid (4-{isopropyl-[2-(2-methoxyphenyl)ethyl]amino}but-2-ynyl)amide, (90 mg, 0.21 mmol), nickel chloride hexahydrate (60 mg, 0.25 mmol), ethylenediamine (0.15 ml, 0.25 mmol) and sodium borohydride (0.25 ml 1N solution in EtOH, 0.25 mmol) in 5 ml ethanol was stirred at ambient temperature for 10 h. The mixture was filtered, the solvent removed and the residue taken up in methylene chloride and washed with water. Evaporation of the solvent gave 71 mg of an oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:17]2[CH:28]=[C:27]3[C:29]4[CH:23]([CH2:24][CH2:25][CH2:26]3)[CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=2)[C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH2:4][N:5]([C:17]2[CH:18]=[C:19]3[C:29]4[CH:23]([CH2:22][CH2:21][CH2:20]3)[CH2:24][CH2:25][CH2:26][C:27]=4[CH:28]=2)[C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:15][CH:16]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N(CC2CC2)c2cc3c4c(c2)CCCC4CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N(CC2CC2)c2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A suspension of ethyl 4-[N-cyclopropylmethyl-(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.037 g) in ethanol (5 ml) was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred overnight at 50° C. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.028 g, yield: 82%) as colorless needles (melting point: 214-216° C.).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
12.8 g (29.2 mmol) 2-[3-(1-diphenylmethylpiperidine-4-yl)-propyl]-isoindol-1,3-dione are suspended in 110 ml ethanol and added to 2.2 ml (58.4 mmol) hydrazine hydrate and heated to boiling for three hours. After cooling, the mixture is concentrated under vacuum. The residue is dispersed between 300 ml dichloromethane and 50 ml 10% sodium hydroxide solution. The aqueous phase is extracted twice, each with 200 ml dichloromethane. The combined organic phases are washed twice, each with 20 ml water, and dried over sodium sulfate. The solvent is removed under vacuum and the residue is processed fruther without additional purification. Yield 7.3 g (81%)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[C:29]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:29](=[O:36])[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: O=C1CCCC(=O)O1
Product: O=C(O)CCCC(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide and glutaric anhydride following a procedure analogous to that described in Example 90. LC-MS Method 5 tR=2.034 min, m/z=494.3; 1H NMR (CD3OD) δ=1.52-1.69 (m, 4H), 1.79-2.04 (m, 16H), 2.41 (m, 2H), 2.62 (m, 2H), 3.16-3.27 (m, 2H), 3.86 (m, 2H), 3.98 (m, 3H), 7.15-7.39 (m, 3H), 7.41 (d, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[ClH:1].[CH3:24][NH:25][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[S:6]1(=[O:23])=[O:22]
Reactant: Cc1ccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)cc1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(C)cc2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(4-methylphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (81 mg) was reacted with methylamine and then treated with HCl to provide N-methyl-3-[1-(4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propan-1-amine hydrochloride (61 mg):
Reaction SMILES: OCCO[C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.OC1C=CC(C2C=CN=C(NC3C=[C:48]([O:50]C)[C:47]([O:52]C)=C(OC)C=3)N=2)=CC=1.C1(=O)OCCO1.[H-].[Na+]>>[OH:50][CH2:48][CH2:47][O:52][C:10]1[CH:5]=[CH:6][C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)[N:12]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(Nc2nccc(-c3cccc(OCCO)c3)n2)cc(OC)c1OC
Reactant: COc1cc(Nc2nccc(-c3ccc(O)cc3)n2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: O=C1OCCO1
Product: COc1cc(Nc2nccc(-c3ccc(OCCO)cc3)n2)cc(OC)c1OC

Procedure:
The compound was prepared in a manner analogous to the preparation of the compound of Example 47 from the compound of Example 49 (250 mg, 0.71 mmol), ethylene carbonate (70 mg, 6.78 mmol) and 60% sodium hydride (dispersion in oil) (30 mg, 0.78 mmol) to give the title compound (140 mg) as a yellow solid m.p 145-146°. MS m/z 398 (M+H)+.