Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:23])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:7]([O:13][CH3:14])=[C:8]([CH:10](Cl)[CH3:11])[CH:9]=1.[CH3:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[NH:27][N:26]=1.O>CN(C)C=O>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([CH:10]([C:8]3[C:7]([O:13][CH3:14])=[C:6]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=4)[C:5]([CH3:23])=[C:4]([Cl:3])[CH:9]=3)[CH3:11])[N:26]=[C:25]([CH3:24])[C:33]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred et 30° C. overnight. The mixture was cooled, treated with water and then filtered to provide the desired product. LCMS calculated for C22H21ClN7O (M+H)+: m/z=434.1; Found: 434.2
Reaction SMILES: [C:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:6]2=[N:5][CH:4]=1)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[CH:10][CH:9]=3)#[CH:2].C[Si]([N:29]=[N+:30]=[N-:31])(C)C>CO>[NH:29]1[C:1]([C:3]2[N:7]3[C:8]4[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:6]3=[N:5][CH:4]=2)=[CH:12][C:11]([C:21]([F:22])([F:23])[F:24])=[CH:10][CH:9]=4)=[CH:2][N:31]=[N:30]1
Reactant: C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CO
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3cnn[nH]3)cnc12
Temperature: 100 °C
Reaction time: 65 h
Yield: 13 %

Procedure:
A suspension of the 3-{[1-ethynyl-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 30 (20 mg, 0.06 mmol) in neat trimethylsilylazide (200 μL) was stirred at 100° C. for 65 h in a reaction vial. The reaction mixture was then stirred at 105° C. for 24 h to go to completion, and was then allowed to cool to room temperature, diluted in methanol (2 mL) and concentrated under vacuum. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 90/10) to afford a solid. Further purification by washing with dichloromethane afforded the title compound (3 mg, 13%) as a yellow solid.
Reaction SMILES: CO.C(O[C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[CH2:26]([CH2:28][NH2:29])[OH:27]>O>[OH:27][CH2:26][CH2:28][NH:29][C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Solvent: CO
Solvent: O
Product: CSc1ncc(C(=O)NCCO)c(Nc2ccc3[nH]ncc3c2)n1
Yield: 72 %

Procedure:
To the solution of methanol (20 ml) was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (1 g) prepared from preparation example 1, added ethanol amine (7 ml) at room temperature, and refluxed for 4 hr. The reaction mixture was cooled and slowly added H2O (40 ml) at 20° C. and stirred for 0.5 hr. The reaction mixture was filtered, washed with 25% aqueous methanol solution (10 ml), obtained the desired compound (0.75 g, 72%)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH:16]([CH3:31])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([S:18]([CH2:17][CH:16]([OH:15])[CH3:31])(=[O:20])=[O:19])=[CH:22][C:23]=2[CH3:30])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(S(=O)(=O)CC(C)O)ccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1cc(S(=O)(=O)CC(C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
2 g of 4-bromo-2-methylbenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 4-(2-hydroxypropylthio)-2-methylbenzonitrile. 950 mg of 4-(2-hydroxypropylthio)-2-methylbenzonitrile was reacted via Procedure T to give 4-(2-hydroxypropylthio)-2-methylbenzoic acid. 1.0 g of 4-(2-hydroxypropylthio)-2-methylbenzoic acid was reacted via Procedure R to give 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-2-methylbenzamide. MS (Q1) 445.3 (M)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[S:24][C:18]=2[CH2:17]1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[S:24][C:18]=2[CH2:17]1
Reactant: COc1ccc2[nH]cc(CCCCN3CCc4c(sc5ccccc45)C3)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2[nH]cc(CCCCN3CCc4c(sc5ccccc45)C3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 3.9 g of 2-[4-(5-methoxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine and 3.5 g of pyridine hydrochloride is stirred at 160° for 3 hours. After the usual working up, 2-[4-(5-hydroxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine is obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: Fc1cncc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2cncc(F)c12

Procedure:
Specifically, 4-fluoroisoquinoline (3) is nitrified with potassium nitrate in sulfuric acid, to thereby form 4-fluoro-5-nitroisoquinoline (4a) and a position isomer (4b) thereof [step A]. Subsequently, these two products are reduced by use of concentrated hydrochloric acid and stannous chloride dihydrate, to thereby form 4-fluoro-5-aminoisoquinoline (5a) and a position isomer (5b) thereof [step B]. 5-Amino-4-fluoroisoquinoline (5a) is separated through column chromatography for purification [step C]. The purified product is diazotized with sodium nitrite [step D]. The diazo compound is subjected to Sandmeyer reaction employing SO2 gas-saturated acetic acid and cupric chloride dihydrate [step E], to thereby yield 4-fluoroisoquinoline-5-sulfonyl chloride (2a).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([NH2:14])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](Cl)=[O:28]>C1C=CC=CC=1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27]([NH:14][C:12]1[O:11][N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH:13]=1)=[O:28]
Reactant: Nc1cc(-c2cccc(C(F)(F)F)c2)no1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(-c2cccc(C(F)(F)F)c2)no1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3-(Trifluoromethyl)phenyl)-5-aminoisoxazole (2.5 grams), triethylamine (1.5 grams) and 50 ml. benzene were placed in a 100 ml. flask. Next, 2,6-difluorobenzoylchloride (2.6 grams), dissolved in 5-10 ml. benzene, was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 2 hours and was then warmed to 60° C. for about 18 hours. Following this, the mixture was washed with dilute sodium bicarbonate, water, brine, and then dried over MgSO4. The final product was first filtered, recrystallized from benzene/pentane, and then dried, m.p. 123°-126° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:6][C:5]=1[Cl:16].B(Br)(Br)Br>ClCCl>[Cl:16][C:5]1[CH:6]=[C:7]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)[CH:8]=[C:9]([Cl:10])[C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1c(Cl)cc(-c2nnn[nH]2)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1c(Cl)cc(-c2nnn[nH]2)cc1Cl
Reaction time: 8 h

Procedure:
The mixture of 110 mg of 2,6-dichloro-4-tetrazolylbenzoic acid methylester, 0.5 ml of dichloromethane solution containing 1M BBr3 and 5 ml of dichloromethane was stirred overnight. The obtained substance was treated by an ordinary method using dichloromethane as an extractant and purified by reverse phase HPLC to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([C:14]#N)[CH:5]=1.[OH-:16].[Na+].[OH2:18].Cl>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([C:14]([OH:18])=[O:16])[CH:5]=1
Reactant: COCc1cc(C#N)nc(C(F)(F)F)c1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCc1cc(C(=O)O)nc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(methoxymethyl)-6-(trifluoromethyl)pyridine-2-carbonitrile (0.36 g, 1.7 mmol, from Step C) in ethanol (20 mL) was added 1.0M sodium hydroxide in water (6.5 mL, 6.5 mmol) and the reaction was heated in an oil bath held at 90° C. for 4 hours. Upon cooling to room temperature, 1N HCl was added to achieve pH 2, and the product was extracted with ethyl acetate (3×). The combined extracts were dried over sodium sulfate, decanted and concentrated to afford a crystalline solid which was used without further purification. 1H NMR (300 MHz, CD3OD) δ 8.29 (s, 1H), 7.95 (s, 1H), 4.66 (s, 2H), 3.49 (s, 3H); 19F NMR (282 MHz, CD3OD) δ−69.56 (s); LCMS (M+H)+: 236.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-3-nitrobenzoic acid (40.40 g, 0.20 mole) was suspended in DCM (100 mL) containing 3 drops of DMF. Oxalyl chloride (1.5 equivalents, 0.3 mole, 27 mL) was added in small portions and the mixture stirred overnight at room temperature. After refluxing for an additional hour to complete the reaction, volatiles were removed under reduced pressure and the residue was coevaporated twice with hexane to give the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[O:4][C:5]2[CH:18]=[C:17]([CH3:19])[C:16]([Cl:20])=[CH:15][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].CN(C)C1C=CC=CC=1.[F:31][C:32]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>ClCCl>[Cl:20][C:16]1[C:17]([CH3:19])=[CH:18][C:5]2[O:4][C:3](=[O:21])[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:32]=3[F:31])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[C:6]=2[CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cc1cc2oc(=O)c(N)c(-c3ccccc3C)c2cc1Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1cc2oc(=O)c(NC(=O)c3ccc(F)cc3F)c(-c3ccccc3C)c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-amino-6-chloro-7-methyl-4-(2-methylphenyl)-2H-1-benzopyran-2- one (300 mg), N,N-dimethylaniline (0.13 ml) and dichloromethane (4 ml) was dropwise added 2,4-difluorobenzoyl chloride (0.15 ml). The mixture was stirred for 20 hours at room temperature, washed with water and dried (MgSO4). By distilling off the solvent, 6-chloro-3-(2,4-difluorobenzoylamino)-7-methyl-4-(2-methylphenyl)-2H-1-benzopyran-2-one was obtained as crystals (406 mg, 92.5%). Recrystallization from ethanol gave colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.C=O.[CH3:34][NH2:35].[CH3:36]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:7]([C:8]1[CH2:34][N:35]([CH3:36])[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(Cl)c(Cl)c2)OCCCN2CCOCC2)O1
Reactant: CN
Reactant: CO
Agent: C=O
Product: CN1CC(C(=O)N(Cc2ccc(Cl)c(Cl)c2)OCCCN2CCOCC2)=C(O)C1=O
Yield: 47 %

Procedure:
Reaction of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.200 g, 0.42 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.090 g (47% yield) of the title compound as a white amorphous solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 1.66 (2H, m, CH2), 2.27 (2H, t, J=7.1 Hz, NCH2), 2.32 (4H, broad, 2×NCH2), 2.95 (3H, s, NCH3), 3.55 (4H, broad, 2×OCH2), 3.86 (2H, broad t, OCH2), 4.06 (2H, s, NCH2), 4.88 (2H, s, NCH2), 7.35 (1H, dd, J=2 Hz and J=8.1 Hz, aromatic), 7.61 (1H, d, J=8.1 Hz, aromatic), 7.65 (1H, d, J=2 Hz, aromatic). HRMS (FAB+) calculated for C20H26Cl2N3O5: [M+H]+: 458.124952. found: 458.123753.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl>[CH3:1][C:2]1([C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[O:7])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CC1(C(=O)O)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C2(C)CC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
1-Methyl cyclopropane carboxylic acid (2.96 g, 29.54 mmol) was added to a solution of tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (5 g, 26.85 mmol) in dichloromethane (135 ml) at room temperature. Triethylamine (9.4 ml, 67.13 mmol) was then added. The reaction was cooled down to 0° C. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate, 17.4 ml, 29.54 mmol) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was diluted in dichloromethane (100 ml) and a 20% aqueous potassium carbonate solution (80 ml) added. The mixture was stirred at room temperature for 18 hours and the layers separated. The organic layer was washed with 20% potassium carbonate solution (50 ml), brine (80 ml), dried over magnesium sulfate, concentrated in vacuo and azeotroped with diethyl ether to provide the title compound as a white solid (6.815 g, 95%).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([O:18][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.15 g, 0.52 mmol) is dissolved in dimethylformamide (2.5 mL). Benzyl bromide (0.062 mL, 0.52 mmol) and cesium carbonate (0.085 g, 0.26 mmol) are added, and the reaction is stirred at room temperature overnight. The reaction is diluted with water, and the aqueous layer is extracted several times with methylene chloride. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give trans benzyl 3-(acetylthiomethyl)-2-oxo-1-aza-cyclodecane-10-carboxylate m.p. 117°-118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CCOC(CNC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Yield: 5 %

Procedure:
The N-(1-tert-butyloxycarbonyl-4-piperidinyl)-N-(2,2-di-ethoxyethyl)amine [Rf : 0.48 (reversed phase silica gel; methanol/5% aqueous brine=6:4)] employed is prepared by reductive amination of 1-tert-butyloxycarbonyl-4-piperidone with aminoacetaldehyde diethyl acetal
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:10]([OH:14])[CH2:11][CH2:12][CH3:13]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:14][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2]
Reactant: CCCCO
Reactant: CC(=O)N1CCCCC1
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: CCCCOC1CCCCN1C(C)=O
Yield: 57.1 %

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 8.5 g of N-acetylpiperidine and 49.7 g of n-butanol in the presence of 0.3 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of N-acetylpiperidine the current is switched off. The calculated mean cell voltage is 91 volts. Work-up of the electrolysis solution gives 7.6 g of 1-acetyl-2-n-butoxypiperidine (boiling point 70° C./0.1 mbar; nD25 =1.4656), which corresponds to a product yield of 56.8% and a current efficiency of 45.5%.
Reaction SMILES: FC(F)(F)C(O)=O.S([N:18]1[C:26]2[CH:25]=[C:24]([N:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)=[CH:29][C:28]3=[O:43])[CH:23]=[CH:22][C:21]=2[C:20]2[CH2:44][NH:45][CH2:46][CH2:47][C:19]1=2)(C1C=CC(C)=CC=1)(=O)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:60].Cl>>[ClH:60].[ClH:60].[CH2:44]1[C:20]2[C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][N:34]=5)=[CH:29][C:28]4=[O:43])=[CH:25][C:26]=3[NH:18][C:19]=2[CH2:47][CH2:46][NH:45]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CNCC3)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2ccc(C(F)(F)F)cn2)ccn1-c1ccc2c3c([nH]c2c1)CCNC3
Yield: 25 %

Procedure:
1-(5-Tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one trifluoroacetic acid salt (163 mg, 0.248 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 106 (step b) to provide the title compound (30 mg, 25%) as an orange solid: mp 308-313° C.; 1H NMR (500 MHz, CD3OD) δ 9.04 (s, 1H), 8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 7.81 (d, J=7.0 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.24 (dd, J=7.1, 2.0 Hz, 1H), 7.11 (dd, J=8.3, 2.0 Hz, 1H), 4.49 (s, 2H), 3.65 (t, J=6.2 Hz, 2H), 3.21 (t, J=6.2 Hz, 2H); ESI MS m/z 411 [M+H]+; HPLC (Method B) 97.6% (AUC), tR=12.4 min.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC1(C)OC(=O)[C:37](=[C:41]([OH:49])[CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:36](=O)[O:35]1>C(Cl)Cl.CO>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36](=[O:35])[CH2:37][C:41](=[O:49])[CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CCOC(=O)CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCC(=O)CC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Yield: 37.1 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol), 7 mL of toluene and 70 mg of ethyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-4-hydroxybutanoate (1.1 molar equivalent) were refluxed for 6 hours. After cooling, the solvent was evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 48 mg yield=29% of the desired product (formula below) as a red powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]1[N:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: COc1ccccc1C=O
Reactant: NCc1ccc2ccccc2c1
Product: COc1ccccc1C1CCCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available naphthalen-2-ylmethanamine and commercially available 2-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions H): tR=1.35 min.; [M+H]+: 346.35 g/mol.
Reaction SMILES: CON(C)[C:4]([CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:28]([O:27][CH2:26][C:4](=[O:5])[CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:24]1[CH:25]=[CH:8][CH:7]=[CH:6][CH:4]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C(CCc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NC(CCc1ccccc1)C(=O)COCc1ccccc1
Temperature: -60 °C

Procedure:
The mixture was cooled to −60° C. and stirred under nitrogen while a solution comprised of tert-butyl 1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (17 g, 52.73 mmol) in anhydrous THF was added via syringe and the mixture was stirred until the reaction was complete. The reaction was quenched slowly with ammonium chloride solution and the mixture was stirred for 15-30 minutes. The mixture was extracted with ethyl acetate (3×7 mL) and the combined extract was dried (Mg2SO4), filtered and concentrated. Product was purified from the residue by flash column chromatography using silica gel 60 to provide tert-butyl 3-benzyloxy-2-oxo-1-phenethylpropylcarbamate (17.15 g, 44.72 mmol). 1H NMR (CDCl3): δ 1.43 (s, 9H), δ 1.74-1.82 (m. 1H), δ 2.14-2.16 (m, 1H), δ 2.60-2.67 (m, 2H), δ 4.13-4.14 (d, 2H), δ 4.49-4.61 (m, 3H), δ 5.14-5.17 (d, 1H), δ 7.1-7.4(m, 10H).