Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]3=2)[C:3](=O)[C:2]1=[O:15].C(OC[C:21](=O)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)(=O)C.[C:32]([OH:35])(=[O:34])C.Cl>C(O)C.[OH-].[Na+].O.C(#N)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][C:21]1[C:2]([OH:15])=[C:3]([C:32]([OH:35])=[O:34])[C:4]2[C:9](=[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]3=[CH:6][CH:5]=2)[N:1]=1
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1Nc2c(ccc3c2CCCC3)C1=O
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)c(Cl)c2)nc2c3c(ccc12)CCCC3
Temperature: 25 °C
Yield: 20 %

Procedure:
The Pfitzinger reaction was used. In a 2-necked 25 mL round-bottomed flask, 6,7,8,9-tetrahydrobenzo[g]indoline-2,3-dione (0.119 g, 0.590 mmol) was taken up in 1 mL ethanol and 3 mL 10 M NaOH, and the mixture heated to reflux temperature. A solution of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate (0.200 g, 0.767 mmol) in 3 mL ethanol was added in small portions over the course of 1 hour, by syringe. Refluxing was continued for an additional hour after the addition was complete, and the reaction mixture was then cooled to room temperature and acidified with glacial acetic acid, and the yellow precipitate collected by filtration. This crude product was purified by preparative HPLC (acetonitrile/water/triethylamine), and the pure salt thus obtained was converted back to the free acid by acidification of a 5% acetonitrile in water solution with concentrated HCl. The bright yellow precipitate was collected by filtration and dried under vacuum (47.8 mg, 20% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.73-1.86 (m, 4H) 2.81 (t, J=6.1 Hz, 2H) 3.12 (t, J=5.9 Hz, 2H) 4.30 (s, 2H) 7.28 (t, J=8.7 Hz, 2H) 7.53 (d, J=8.1 Hz, 1H) 7.59 (d, J=2.0 Hz, 1H) 8.19 (d, J=8.6 Hz, 1H); HRMS (ESI+) calcd for C21H18Cl2NO3 (MH+) 402.0658, found 402.0661.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:42][C:43]([CH3:46])=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:38][CH2:39][C:34]([C:41]3[S:42][C:43]([CH3:46])=[CH:44][N:45]=3)([OH:33])[CH2:35][CH2:36]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: Cc1cnc(C2(O)CCC(=O)CC2)s1
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cnc(C2(O)CCC(N[C@@H]3CC[C@@](C(=O)N4CCc5ccc(C(F)(F)F)cc5C4)(C(C)C)C3)CC2)s1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (40 mg, 0.1 mmol) of Step C-2 from Example 1 and 4-hydroxy-4-(5-methyl-1,3-thiazol-2-yl)cyclohexanone (32.6 mg, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (31 μL, 0.22 mmol) followed by sodium triacetoxyborohydride (56 mg, 0.26 mmol) at room temperature. After being stirred overnight, the mixture was diluted with methylene chloride and neutralized with NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica eluting with 5% MeOH/CH2Cl2 to give two isomers (13 mg and 10 mg). LC-MS calculated for C29H38F3N3O2S: (M+H)+550; found 550.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SC)cc1
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)=O)cc1
Yield: 46.4 %

Procedure:
To a solution (6.7 ml) of 6-bromo-2-(4-methylsulfanylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (334 mg) in dichloromethane was added m-chloro perbenzoic acid (200 mg) at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was washed with 1N sodium hydroxide and water, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-1/4) to give the title compound (160 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:20][C:21]([NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[S:22])[C@H:13]([CH2:14]O)[C@@H:12]([C:16]([F:19])([F:18])[F:17])[O:11][CH2:10]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([C:16]([F:18])([F:17])[F:19])[C@H:13]1[CH2:14][S:22][C:21]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:20]2
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
N-(((3S,4R,5S)-3-(2,3-Difluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (2.99 g) was dissolved in pyridine (14 mL), and the mixture cooled to −20° C. Trifluoromethanesulfonic anhydride (1.55 mL) was added dropwise over 10 min and the reaction mixture was allowed to warm to −10° C. After stirring for 2 h, a further portion of trifluoromethanesulfonic anhydride (1.0 mL) was added dropwise over 10 min, the reaction was stirred for a further 2 h, and was then quenched by the addition of ammonium chloride (sat., aq., 50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (5% to 20% EtOAc/hex) to obtain the title compound (1.20 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.86 (d, J=10.6 Hz, 1H), 3.20 (br. s., 1H), 3.55 (br. s., 1H), 4.04 (br. s., 1H), 4.65 (d, J=8.8 Hz, 1H), 4.81 (br. s., 1H), 7.06-7.24 (m, 3H), 7.40-7.64 (m, 3H), 7.82-8.21 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([F:17])[C:10]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.CCCCCC.[C:30](=[O:32])=[O:31].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([F:17])[C:12]([C:30]([OH:32])=[O:31])=[C:13]([F:16])[C:14]=1[F:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1c(F)c(F)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
31.8 g of the compound (6) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 93 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 12.9 g (41 mmol) of 4-heptyloxy-2,3,5,6-tetrafluorobenzoic acid (7).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][C:10]=2[Cl:33])[CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[Cl:33][C:10]1[CH:11]=[C:12]([C:15]2[CH2:19][C:18]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=2)[CH:13]=[CH:14][C:9]=1[N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]1
Reactant: COC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
To a stirred suspension of 1-{2-Chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid methyl ester (Preparation 13, 0.55 g, 1.086 mmol) in THF:MeOH:H2O (1:1:1, 9 mL) was added lithium hydroxide (0.228 g, 5.43 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours. After consumption of starting material, reaction mixture was concentrated in vacuo; acidified with 1N HCl up to pH ˜5. Acidified aqueous layer was extracted with ethyl acetate (5×20 mL). Combined organic layer was dried over sodium sulphate and evaporated under reduced pressure and was triturated with n-pentane (25 mL) to afford off white solid (0.4 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ: 3.45-3.50 (m, 1H), 4.12-4.16 (m, 2H), 4.26-4.33 (m, 4H), 6.67 (d, 1H, J=9.04 Hz), 7.51-7.53 (m, 2H), 7.81 (s, 2H), 12.75 (bs, 1H); LC-MS (M+H): =528.80.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([O:9]C(=O)C)[CH2:6]1)=[O:4].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([OH:9])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](OC(C)=O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-3-acetoxycyclobutanecarboxylic acid methyl ester (trans/cis=5:1) (4.70 g, 27.3 mmol) in dry methanol (45 mL) was added sodium methoxide (25 wt % solution in MeOH, 0.62 mL, 2.7 mmol), and the solution was stirred at ambient temperature. More NaOMe solution (0.31 mL, 2.4 mmol) was added after 1 h and 2 h, and stirring was continued overnight. Most of the methanol was evaporated, water was added (≈100 mL), and the mixture was extracted with CH2Cl2 (6×60 mL). The combined organic layers were washed with NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated (vacuum down to ≈40 mbar) to give the title compound as brown oil, trans/cis=5:1 based on 1H NMR. The material thus obtained was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 2.17-2.27 (m, 2H), 2.54-2.64 (m, 2H), 3.00-3.09 (mc, 1H), 3.70 (s, 3H), 4.53-4.62 (mc, 1H).
Reaction SMILES: C1(C[N:8]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[NH:11][C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)C=CC=CC=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[H-].[Na+].C1(O)C=CC=CC=1>CN(C)C=O>[N:32]1([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[NH:8][C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]2=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1c2ccccc2Nc2ncccc2N1Cc1ccccc1
Reactant: BrCCCCCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: O=C1Nc2cccnc2N(CCCCCCCN2CCCCC2)c2ccccc21
Yield: 17 %

Procedure:
Prepared analogously to Example 18 by reacting 5,11-dihydro-5-(phenylmethyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one with 1-bromo-7-(1-piperidinyl)-heptane in the presence of sodium hydride and dimethylformamide and subsequent acidolytic cleaving of the phenylmethyl group by heating with 80% polyphosphoric acid in the presence of phenol. Yield: 17% of theory. Colourless crystals m.p. 118°-120° C. (after recrystallisation from diisopropyl ether and cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[CH2:16][CH2:15][N:14](C#N)[CH2:13][CH2:12]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: N#CN1CCN(c2n[nH]c3ccc(Cl)cc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc2[nH]nc(N3CCNCC3)c2c1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(5-chloro-1H-indazol-3-yl)-1-piperazinecarbonitrile of Example 36a in THF (175 ml) under N2 was added, dropwise, lithium aluminum hydride (20 ml, 0.02 mol of a 1M lithium aluminum hydride solution in THF). After total addition, the reaction was heated to reflux and stirred for 3 hours. The reaction was cooled in an ice bath and the excess lithium aluminum hydride was destroyed by the dropwise addition of H2O (15 ml). This was filtered through a coarse sintered glass funnel and the filter cake was washed well with THF. The filtrate was concentrated to afford a biphasic H2O-oil (7.5 g). This was partitioned between CH2Cl2 and H2O and the H2O was extracted again with CH2Cl2 adding a small amount of saturated NaCl solution. The combined CH2Cl2 extract was washed with H2O, dried with MgSO4 and concentrated to afford 3.2 g of a solid, m.p. 60°-62° C. The solid was purified by preparative HPLC (Water's Associates Prep. LC/System 500, 2 silica gel columns eluting with 20% methanol-CH2Cl2) to afford 1.9 g of product. A small amount was recrystallized from toluene and collected, then washed with hexane affording solid 5-chloro-3-(1-piperazinyl)-1H-indazole, m.p. 178°-180° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)=[C:27]([F:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([F:38])[C:28]([O:32][CH2:33][CH:34]5[CH2:37][CH2:36][CH2:35]5)=[C:29]([F:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC3CCC3)c(F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC4CCC4)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[4-(cyclobutylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (139 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 44 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 1.82-1.90 (m, 4H), 2.00-2.06 (m, 2H), 2.65-2.70 (m, 1H), 3.17 (s, 3H), 3.39 (s, 3H), 4.07-4.13 (m, 2H), 5.32 (s, 2H), 6.20-6.26 (m, 1H), 7.34 (s, 1H), 7.63 (d, J=8.7 Hz, 2H), 7.77 (s, 1H), 12.67 (br s, 1H); APCI-MS (m/z) 516.11 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH2:15](Br)[CH:16]=[CH2:17].[C:19]1([C:30]2CCCCCCCCCC=2)[CH2:29]CCCCCCCNN=1>C(O)C>[CH2:15]([N:1]([CH2:30][CH:19]=[CH2:29])[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1)[CH:16]=[CH2:17]
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Reactant: Nc1ccc2[nH]c3cnccc3c2c1
Reactant: C=CCBr
Solvent: CCO
Product: C=CCN(CC=C)c1ccc2[nH]c3cnccc3c2c1

Procedure:
360 mg of 6-amino-β-carboline are heated in 20 ml of ethanol with 0.54 ml of allylbromide and 0.74 ml diazabicycloundecene for 3 hours at 70° C. After concentration to dryness and dispersing in ethyl acetate/saturated sodium chloride solution, the organic phase is separated, dried, filtered and concentrated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate=1:1 as eluant and 50 mg of 6-diallylamino-β-carboline as oil are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][C:9]2[C:4](=[C:5]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1>C(C(C)=O)C>[O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][C:9]2[C:4](=[C:5]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1
Reactant: BrCc1ccsc1
Reactant: CC(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 79 °C
Reaction time: 20.5 h

Procedure:
Methyl ethyl ketone (5 mL) was added to a mixture of N-(2-oxo-8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (500 mg) and potassium carbonate powder (265 mg), and 3-(bromomethyl)thiophene was added thereto. The mixture was stirred at an internal temperature of 79° C. for 20.5 hours, and then left to stand at room temperature. The mixture was partitioned between saturated aqueous sodium chloride solution (2 mL) and ethyl acetate (1 mL), and the aqueous layer was extracted with ethyl acetate (2 mL+1 mL). The organic layers were combined, and the solvent was evaporated under reduced pressure. Ethyl acetate (1.5 mL) and toluene (2.5 mL) were added to the thus-recovered residue, and the precipitated crystals were recovered through filtration. The container of the reaction mixture was washed with a mixture of ethyl acetate and toluene (3:5) (0.5 mL×2). The thus-recovered crystals were washed with a mixture of ethyl acetate and toluene (3:5) (1.0 mL×2), and then dried under reduced pressure at 60° C., whereby ethyl acetate solvates of the title compound (510 mg) were yielded.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.C1(P(=[CH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[C:36]([O:35][C:33](=[O:34])/[CH:32]=[CH:1]/[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)nc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Methyl 6-formylnicotinate (1.0 g, 6.06 mmol) and tert-butyl (triphenylphosphoranylidene)acetate (2.73 g, 7.27 mmol) were put in suspension in water (50 mL) and stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated under pressure. The residue was triturated in ethyl acetate and filtered. The filtrate was concentrated and purified by flash chromatography using hexanes-ethyl acetate 10% to give (E)-methyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)nicotinate. MS (APCI) 264 (M+). (E)-methyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)nicotinate was dissolved in ethanol in the presence of 50 mg Pd/C, 10% and stirred under hydrogen balloon overnight to give 6-2(tert-butoxycarbonyl-ethyl)nicotinic methyl ester. LCMS: 266 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[O-])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:12](=[O:14])[NH:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCNC(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 130 °C
Yield: 36.5 %

Procedure:
A mixture of {2-[3-(methyloxy)phenyl]ethyl}carbamate (30 g crude) and polyphosphoric acid (116 g) was maintained at 120-140° C. for 1 hr. After cooling to room temperature, water was added. The solution was adjusted to pH=9 with 6N sodium hydroxide and the organic products extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography to afford 6-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone (10 g, 40%). 1H NMR(CDCl3) δ 8.0 (1H), 6.85 (1H), 6.7 (1H), 6.35 (1H), 3.85 (3H), 3.55 (2H), 2.95 (2H).
Reaction SMILES: I[C:2]1[S:10][C:9]2[CH2:8][CH2:7][O:6][CH:5](N(C)C(=O)OC(C)(C)C)[C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:26][N:27](C)CCO>O>[N:20]1([C:2]2[S:10][C:9]3[CH2:8][CH2:7][O:6][CH:5]([CH2:26][NH2:27])[C:4]=3[CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN(C)CCO
Reactant: CN(C(=O)OC(C)(C)C)C1OCCc2sc(I)cc21
Reactant: C1CCNCC1
Solvent: O
Product: NCC1OCCc2sc(N3CCCCC3)cc21
Temperature: 85 °C
Reaction time: 28 h

Procedure:
A mixture of tert-butyl (2-iodo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylcarbamate (400 mg, 1.0 mmol, 1 eq), piperidine (2 mL), Cu metal (6.4 mg, 1 mmol, 0.1 eq), and K3PO4.3H2O (539.3 mg, 2.34 mmol, 2.3 eq) in 2-dimethylamino-ethanol (deanol) (5 mL) was stirred at 85° C. in a sealed tube for 28 hr. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified by Al2O3 column chromatography. The Boc protecting group was removed with HCl under standard conditions to give the product (2-(piperidin-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine.
Reaction SMILES: [C:1]([C:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:15].[Na+].[Na+].S(=O)(=O)(O)O>CCOCC.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)C1(O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C1CCCCC1=O
Temperature: 25 °C

Procedure:
A solution of 31.25 g. (0.20 mole) t-butylcyclohexanol in 80 ml. of ethyl ether was cooled to 10° C. To this was added dropwise, with stirring, a solution of 21.0 g. (0.07 mole) sodium dichromate dihydrate and 15.75 ml. (0.30 mole) concentrated sulfuric acid in 100 ml. water while maintaining the reaction mixture below 25° C. The mixture was then warmed to room temperature, stirred for two hours, poured onto ice-water, ether layer separated, the aqueous phase extracted again with ether and the combined extracts washed with water, sodium bicarbonate and dried (MgSO4). Evaporation of the ether afforded 30.6 g. (99%) of the desired ketone.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[CH:53][N:54]([CH2:56][CH:57]4[CH2:60][CH2:59][CH2:58]4)[CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[CH:53][N:54]([CH2:56][CH:57]4[CH2:58][CH2:59][CH2:60]4)[CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC4CCC4)cn3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn(CC4CCC4)cn3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 103 from 4'-[(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium azide in dimethylformamide.