Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH3:14][CH2:15]N(C(C)C)C(C)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].CC(O)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:14]([O:12][C:11]([C:2]1([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([F:35])([F:34])[F:23])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1)=[O:13])[CH3:15]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccccc2C(F)(F)F)Cc2ccccc2C1
Reaction time: 912 h
Yield: 92 %

Procedure:
A 30 mL vial is charged with 2-aminoindan-2-carboxylic acid (450 mg, 2.19 mmol) and dry DCM (5 mL). A stirring bar is added and stirring is initiated. DIPEA (0.61 mL, 3.51 mmol) is added. 2-(trifluoromethyl)-benzoyl chloride (388 μL, 2.63 mmol) and DMAP (3 mg, cat.) are added. The reaction is capped. After 38 days, tlc analysis (silica, 10% iPrOH/DCM) indicates that the starting is completely consumed. The contents of the reaction flask are transferred to a reparatory funnel and diluted with EtOAc (60 mL). The organic phase is washed with dilute aqueous HCl (2×25 mL), saturated aqueous NaHCO3 (2×25 mL), and brine (25 mL), dried over MgSO4, filtered and evaporated by pumping to constant weight yields 0.84 g of light orange solid. This is diluted with DCM and applied to a silica column ((24 g) on an ISCO Companion. 14 mL fractions of UV positive eluent are collected. Fraction 4-10 are combined and evaporated by pumping to constant weight to give light yellow solid (0.76 g, 92%).
Reaction SMILES: NC(C)(C)C[O:4]C1C=CC(C#N)=CC=1F.[C:16]([C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25])=[C:20]([F:37])[CH:19]=1)#N>>[F:37][C:20]1[CH:19]=[C:18]([CH:16]=[O:4])[CH:36]=[CH:35][C:21]=1[O:22][CH2:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25]
Reactant: CC(C)(N)COc1ccc(C#N)cc1F
Reactant: CC(C)(COc1ccc(C#N)cc1F)NC(=O)OC(C)(C)C
Product: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C

Procedure:
Synthesized from 4-(2-amino-2-methylpropoxy)-3-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 19, tert-butyl [2-(4-cyano-2-fluorophenoxy)-1,1-dimethylethyl]carbamate (1.0 g) was used according to an analogous synthetic method to Preparation Example 20 to provide the title compound (715 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][N:54]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:59][C:56]1[CH:57]=[CH:58][C:53]([NH:52][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:23])([F:22])[F:24])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:54][CH:55]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 352.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 155A, 73 mg, 0.07 mmol) and triphenylphosphine (79 mg, 0.08 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (60.5 mg, 0.34 mmol). The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. At this time, reaction mixture was treated with 2-amino-5-bromopyridine (52 mg, 0.30 mmol) and a few drops of pyridine. The resulting reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was then diluted with methylene chloride (50 mL). The organic phase was washed with water (1×35 mL) and a saturated aqueous sodium chloride solution (3×35 mL), dried over magnesium sulfate and sodium sulfate, treated with charcoal, filtered through a pad of celite, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 70/30 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide (128.3 mg, quant) as a white solid: mp 81–85° C.; EI-HRMS m/e calcd for C21H22BrF3N2O3S (M+) 518.0486, found 518.0489.
Reaction SMILES: C([N:8]1[CH2:48][CH2:47][C:11]2[N:12]=[C:13]([C:26]3[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:46])=[N:29][N:30]4[S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.O.[OH-].[OH-].[Pd+2]>[CH3:46][C:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:34]([CH3:35])[C:26]=2[C:13]2[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]3[CH2:9][NH:8][CH2:48][CH2:47][C:11]=3[N:12]=2)[N:30]([S:36]([C:39]2[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=2)(=[O:37])=[O:38])[N:29]=1
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(Cc2ccccc2)CC3)CC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CNCC3)CC1(C)C
Temperature: 40 °C
Reaction time: 2.25 h

Procedure:
To a solution of (R)-6-benzyl-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.0 g, 4.51 mmol) in THF (24 mL) and water (6 mL) was added acetic acid (1.30 mL, 22.6 mmol). The solution was warmed to 40° C. and Pd(OH)2 20% on carbon (0.792 mg, 1.13 mmol) was added. The mixture was then stirred under a hydrogen atmosphere for 2.25 h. The mixture was then allowed to cool to rt and was filtered over Celite®, washing with EtOAc and MeOH. The filtrate was then basified with aqueous 1 N NaOH and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure. The residue was then purified via FCC (0-15% MeOH/DCM; with 10% NH4OH in DCM) to obtain the title compound. MS (ESI+) m/z 575.5 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1([C:16]2[N:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:24]([O-])(=O)C.[Na+].C=O>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:24][N:13]1[CH2:12][CH2:11][N:10]([C:16]2[N:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:15][CH2:14]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)[O-]
Reactant: N#Cc1cccnc1N1CCNCC1
Agent: C=O
Agent: [Na+]
Product: N#Cc1cccnc1N1CCN(Cc2cc3cccnc3[nH]2)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 2-(1-piperazinyl)nicotinonitrile (75 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (m, 1H) 7.32 (m, 1H) 7.52 (m, 1H) 7.77 (m, 1H) 7.90 (m, 1H). (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1OC(=O)c1ccccc1

Procedure:
To a cooled solution of 2-hydroxy- 2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (8.0 parts) in dry pyridine (42 parts) was added benzoyl chloride (4.75 parts) at such a rate that the temperature did not exceed 10° C. After one hour the mixture was poured into a slight excess of dilute hydrochloric acid. The product was extracted with ether and the ethereal solution washed, dried with sodium sulphate and evaporated to give an oil which solidified on scratching. The solid was recrystallised from a mixture of benzene and light petroleum to give 2-benzoyloxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (5.1 parts), melting point 102°-104° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][CH:41]=1)CCC>CN1CCCC1=O.C(OCC)(=O)C.[F-].[K+]>[O:38]1[CH:39]=[CH:40][CH:41]=[C:37]1[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(Br)c1)O2)C(C)=CC(C)(C)N3
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(-c4ccco4)c1)O2)C(C)=CC(C)(C)N3
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A solution of Example 11 (0.253 g, 0.531 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was deoxygenated with nitrogen, treated with 2-(tributylstannyl)furan (0.33 mL, 1.06 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.045 g, 0.005 mmol), heated to 85° C. for 13 hours, cooled to room temperature, diluted with ethyl acetate and saturated KF, stirred for 3 hours, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C=O)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(CCCCC(=O)O)s2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3c(s2)CCCCC3=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-[5—(4-methylphenyl)thiophen-2-yl]valeric acid (2.60 g) in tetrahydrofuran (30 ml) was added oxalyl chloride,(1.24 ml) at room temperature and then a drop of DMF, and the mixture was stirred 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dichloromethane(30 ml). To the mixture was added tin tetra-chloride (1.5 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane:=1:9→1:5) to give 2—(4-methylphenyl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclo-hepta[b]thiophene (2.07 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12]C.[CH3:14][Li].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(OCC)C>[CH2:20]([O:19][C:17]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:7](=[O:12])[CH2:8][CH:9]1[CH3:14])=[O:18])[CH3:21]
Reactant: COc1ccnc2c(Cl)cccc12
Reactant: [Li]C
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Product: CCOC(=O)N1c2c(Cl)cccc2C(=O)CC1C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
8-Chloro-4-methoxyquinoline (1.0 g, 5.2 mmol, dissolved in 6 mL of anhydrous tetrahydrofuran) was added dropwise via cannula to a solution of methyllithium (18.4 mL of a 1.4M solution in diethyl ether) cooled with an ice/water bath. After 45 min, ethyl chloroformate (4.9 mL, 51.7 mmol) was added to the reaction mixture via syringe. After 1.5 hours, the reaction mixture was quenched with 60 mL of a 1N aqueous HCl solution, 100 mL of THF and 20 mL of methanol. After 3 days, the tetrahydrofuran was removed in vacuo , and the remaining aqueous phase was extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.5 g of crude product. Purification by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded 0.79 g of the title product (57%). 1H NMR (CDCl3) δ 1.2 (d, 3H), 1.3 (t, 3H), 2.6 (d, 1H), 3.1 (dd, 1H), 4.2-4.4 (m, 2H), 5.1-5.2 (m, 1H), 7.2 (d, 1H), 7.6 (d, 1H), 7.9 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:10][CH:11]=[C:6]2[CH2:5][NH:4][C:3]1=[O:26].FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[N:10][CH:11]=[C:6]2[CH:5]=[N:4][C:3]1=[O:26]
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C)C(=O)NC4)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3ncc4cnc(=O)n(C)c4n3)cc2)CC1
Reaction time: 48 h
Yield: 62.6 %

Procedure:
Prepared from 250 mg (0.50 mmol) of 1-methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 336 mg (2.99 mmol) of potassium tert-butoxide in 12 mL of tetrahydrofuran. The reaction mixture is stirred for 48 hours. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 110 mg (61%) of the title compound: mp 259-260° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22](=[O:26])[NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:10]([OH:12])([CH2:11][N:23]2[C:24]3[C:19](=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:25]=3)[CH:20]=[CH:21][C:22]2=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CO2)C1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(=O)n(CC3(O)CN(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 80 °C
Reaction time: 240 h
Yield: 9.7 %

Procedure:
A solution of oxa-5-azaspiro[2.3]hexane-5-carboxylic acid tert-butyl ester (69 mg; prepared according to WO 2007/044515) in DMF (1 mL) was added to a suspension of 7-methoxy-2(1H)-quinolinone (60 mg; commercial) and Cs2CO3 (223 mg, 2 eq.) in DMF (2 mL). The reaction mixture was stirred at 80° C. for 10 days. The solvent was removed under reduced pressure and the residue was partitioned between water and EA. The aq. layer was extracted with EA. The combined org. layers were dried over Na2SO4, filtered, evaporated and purified by CC (DCM-MeOH 19:1 to 9:1) to afford the title intermediate as a yellow oil (12 mg, 10% yield).
Reaction SMILES: [CH2:1]([O:6]N=O)[CH2:2]C(C)C.N[C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.O.C(=O)(O)[O-].[Na+]>C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:6][C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:2]
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: CC(C)CCON=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C

Procedure:
1 ml of isoamylnitrite is added to a suspension of 1 g of 3-amino-β-carboline in 100 ml of ethanol and 2 ml of concentrated sulfuric acid. The mixture is stirred at room temperature for an hour and then refluxed for an hour. As a result, a clear solution is obtained. After cooling, it is poured into a mixture of 100 ml of water and 100 ml of saturated sodium bicarbonate solution. It is extracted three times with 100 ml of ether each time and the evaporation residue of the combined ether extracts is chromatographed (silica gel, methanol/chloroform=95:5) and recrystallized from hexane. Yield: 0.3 g of 3-ethoxy-β-carboline with a melting point of 130°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH3:10].[CH2:12](O)[CH:13](C)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH3:10])[CH:13]([CH3:14])[CH3:12]
Reactant: CCCSCCCC(=O)OC
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCSCCCC(=O)OCC(C)C
Reaction time: 14.5 h

Procedure:
Into a 25 mm micro flask equipped with spin bar, hot plate (having built in magnetic stirrer), reflux condenser and thermometer are placed 5 grams (0.0284 moles) of methyl-4-(propylthio)butyrate; 8.4 grams (0.1136 moles) of isobutanol and 0.05 grams of para-toluene sulfonic acid. The reaction mass is heated to reflux and maintained at reflux with stirring for a period of 14.5 hours. At the end of the refluxing, the reaction mass is cooled and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:15].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:15]
Reactant: Cc1nccn1-c1ccc(I)cc1
Reactant: N#CC1(c2cccc(O)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1nccn1-c1ccc(Oc2cccc(C3(C#N)CCOCC3)c2)cc1
Temperature: 130 °C
Yield: 38.3 %

Procedure:
A mixture of 4-(2-methylimidazol-1-yl)phenyl iodide (1.28 g, 4.5 mmol), 4-cyano-4-(3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran (1.20 g, 5.9 mmol) and K2CO3 (4.15 g, 30 mmol) in pyridine (50 ml) was heated at 130° C., cupric oxide (636 mg, 8.0 mmol) added and the reaction mixture was heated under reflux for 2 days. The reaction mixture was cooled and filtered through a celite pad and the solids were washed with ethyl acetate (100 ml). The filtrate was concentrated in vacuo, and the resulting residue was diluted with water (100 ml) and extracted with ethyl acetate (50 ml×3). The combined organic extracts were washed with 1N aqueous NaOH (100 ml), water (100 ml) and brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography {LiChroprep NH2 (Merck), 100 g; eluted with hexane/ethyl acetate (1/1)} to afford 620 mg (38%) of the titled compound as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:19][CH3:20])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2ncccc2c1
Yield: 81 %

Procedure:
To a solution of quinoline-6-carboxylic acid (2.8 g, 16 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (2 mL). The reaction was heated to reflux overnight. The solvent was evaporated to give a brown residue that was taken up in ethyl acetate (150 mL). The mixture was washed with water (2×30 mL), saturated aqueous sodium bicarbonate (2×30 mL), and brine (2×30 mL). The organic layer was dried over sodium sulphate, filtered, and concentrated to an oil. Purification by flash column chromatography gave the title compound (2.0 g, 81%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:51])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)=[C:41](Br)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:51])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[C:42]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1ccc(OCC2CC2)c(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-bromo-4-cyclopropylmethoxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C([O:26][N:27]1N=N[C:29]2[CH:30]=[CH:31]C=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.CC1ON=C(N)C=1>ClC(Cl)C.CO>[CH3:31][C:30]1[O:26][N:27]=[C:28]([NH:33][C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:11]=3[CH:12]=2)=[O:18])[CH:29]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Cc1cc(N)no1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cc1cc(NC(=O)c2ccc3nc4n(c3c2)CCCNC4=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
A mixture of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate B, 51 mg, 0.21 mmol) and HATU (89 mg, 0.23 mmol) in dichloroethane (3 mL) is stirred at room temperature for 1 h. 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (64 mg, 0.64 mmol) is added and the mixture is stirred at room temperature for 10 min. 5-Methyl-3-aminoisoxazole (62 mg, 0.64 mmol) is added and the reaction is stirred at 60° C. for 16 h and is cooled to room temperature. The mixture is diluted with methanol, filtered and evaporated. The residue is purified via flash column chromatography using a gradient elution of 0-10% CH2Cl2/methanol and is triturated with CH2Cl2 (3 mL), filtered and dried to afford the title compound (25 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]([CH3:43])[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]([CH3:43])[CH2:35]1)=[O:31]
Reactant: CC1CC(N)c2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CC(C)c3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-3-methyl-indane