Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Mg]Cl)(C)C.[CH3:16][C:17]1[C:18](=[O:22])[CH2:19][CH2:20][CH:21]=1>C1COCC1.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([CH:21]2[CH2:20][CH2:19][C:18](=[O:22])[CH:17]2[CH3:16])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1ccc(I)cc1Br
Reactant: CC1=CCCC1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCC(=O)C2C)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), tert-butyl bromoacetate (2.35 g, 12 mmol) and cesium carbonate (10.5 g, 30 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 2 g (63%) 5-tert-butoxycarbonylmethoxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[O:15])[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:3]1=2.[C:23]([Mg]Br)#[CH:24].[CH2:27]1COCC1>>[CH3:1][CH:2]1[CH:11]([CH3:27])[CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:15])[C:23]#[CH:24])[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:3]1=2
Reactant: C#C[Mg]Br
Reactant: CCOCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reactant: C1CCOC1
Product: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CC(C)C2C
Reaction time: 1 h
Yield: 97 %

Procedure:
40 g (131 mmol) of 5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of THF. 290 mL (145 mmol) of 0.5N ethynylmagnesium bromide solution are added and the reaction medium is then stirred for 1 hour. After treatment with 1N hydrochloric acid solution and extraction with ethyl acetate, followed by evaporation, the residue is purified by chromatography on a column of silica (eluent: 8/2 heptane/EtOAC). A yellow oil is obtained (m=42 g; yield=97%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([C:27](OCC)=[O:28])[CH2:12][N:13]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][C:15]([CH3:17])([CH3:16])[C:5]=3[C:4]=2[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:44]([NH2:47])([CH3:46])[CH3:45]>>[CH:44]([NH:47][C:27]([C:11]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[C:5]=2[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([C:18](=[O:26])[C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:12]=1)=[O:28])([CH3:46])[CH3:45]
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(F)cc21
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(F)cc21

Procedure:
In a similar manner, ethyl 9-fluoro-3-(4-fluorobenzoyl)-1,1-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate was saponified, converted to the corresponding carboxamide using CDI and isopropylamine, and then oxidized to give 9-fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino-[4,5-b]indole-5-carboxylic acid isopropylamide MS (ESI): 438 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12](=[O:14])[NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C(C(OCC)=O)=NC2C(=CC=CC=2)N=1.[Br:31][CH2:32][C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(COC)OC>[Br-:31].[C:34]([C:33]([CH2:32][N+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:11]([C:12](=[O:14])[NH2:13])[C:2]=1[NH2:1])=[O:39])([O:36][CH2:37][CH3:38])=[O:35]
Reactant: NC(=O)c1nc2ccccc2nc1N
Reactant: CCOC(=O)C(=O)CBr
Agent: CCOC(=O)c1nc2ccccc2nc1Cl
Solvent: COCCOC
Product: CCOC(=O)C(=O)C[n+]1c(N)c(C(N)=O)nc2ccccc21
Product: [Br-]

Procedure:
A solution of 1 g of 2-amino-3-carbamoyl-quinoxaline prepared from 2-chloro-3-carbethoxy-quinoxaline by the method of Gowenlock et al [J. Chem. Soc., 1945, p. 622-5] in 50 ml of dimethoxy ethane and ethyl bromopyruvate was stirred for 2 days and was filtered to obtain 1.44 g of 1-carbethoxycarbonylmethyl-2-amino-3-carbamoyl-quinoxalinium bromide as a yellow crystalline solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([NH2:31])[CH3:30]>O1CCOCC1.CC#N>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:31][CH:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[F:22])[CH3:30])=[C:3]([S:9]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([S:14][CH3:13])[CH:16]=2)(=[O:11])=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: CSc1cccc(N)c1
Reactant: CC(N)c1ccccc1F
Solvent: C1COCCO1
Solvent: CC#N
Product: CSc1cccc(NS(=O)(=O)c2cc(F)ccc2NC(C)c2ccccc2F)c1
Yield: 8.9 %

Procedure:
The title compound (139 mg, 0.32 mmol) was prepared in two steps from 2,5-difluorobenzenesulfonyl chloride (1.07 g, 5.0 mmol) and 3-(methylsulfanyl)aniline (769 mg, 5.5 mmol) in 1,4-dioxane at 70° C.; followed by 1-(2-fluorophenyl)ethanamine (500 mg, 3.6 mmol) in MeCN (0.5 mL) at 200° C. in a Biotage Initiator microwave reactor using the methods of (IntB1).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][OH:13]>>[S:1]([O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([Cl:6])[CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1cccc(Cl)c1
Product: NS(=O)(=O)OCCOc1cccc(Cl)c1
Yield: 44 %

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-(3-chlorophenoxy)ethanol. The oil obtained was further purified by chromatography and recrystallization as in Example 38 to give white solid, mp 66°-69° C., in 44% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[CH3:14].[OH-:15].[Na+]>CSC.C(OCC)(=O)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][OH:15])[CH:4]=2)[N:9]=1
Reactant: [OH-]
Reactant: Cc1cc(Cl)nc2ccc(CBr)cc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1cc(Cl)nc2ccc(CO)cc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-methylquinoline (0.39 g) in dimethyl sulfide (5 mL) was added 1 M aqueous sodium hydroxide (5 mL) at room temperature, and the mixture was stirred at 70° C. for 1 h. After cooled to room temperature, the reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated brine, the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=3:1−ethyl acetate/hexane/chloroform=1:3:1−ethyl acetate) to obtain (2-chloro-4-methylquinolin-6-yl)methanol (0.14 g).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:15]=[CH:16][C:17]([O:25]CC2C=CC=CC=2)=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])=[N+]=[N-].C(Cl)Cl>CO.[C].[Pd]>[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:15]=[CH:16][C:17]([OH:25])=[C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:19]=1)[O:6][Si:7]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:12][CH3:13]
Reactant: CC[Si](CC)(CC)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H](CN)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of N-[5-((R)-2-azido-1-triethylsilyloxyethyl)-2-benzyloxyphenyl]methanesulfonamide (1.84 g) and 10% palladium-carbon (0.18 g) in methanol (15 mL) /methylene chloride (15 mL) was stirred at room temperature for 5 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide as a crude product. The crude N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide was dissolved in tetrahydrofuran (40 mL), and 2,5-dioxopyrrolidin-1-yl (4-bromophenoxy)acetate (1.39 g) was added to the solution. After being stirred at room temperature for 3 hrs, the reaction mixture was concentrated in vacuo, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford the title compound (1.01 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO.ClCCl>[CH2:22]([NH:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 40 h
Yield: 50.9 %

Procedure:
To (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (2.36 g, 7.58 mmol) in a mixture of Methanol (15.00 ml) and Dichloromethane (15 ml) was added BENZALDEHYDE (0.845 ml, 8.34 mmol). To the resulting clear solution SODIUM CYANOBOROHYDRIDE (0.702 g, 10.61 mmol) was added in portions at 20-25° C. to avoid intensive foaming and the solution was stirred at 20-25° C. for 40 h. The solution was quenched at 20-25° C. with 1N HCl (12 ml), neutralised with 3N NaOH (12 ml), the mixture was extracted with DCM (100 ml). The organic phase was washed with brine, dried (MgSO4), evaporated to dryness. The residue was purified on a column with EA-MeOH 9:1 as eluent, fractions collected, concentrated to approx 20 ml, cooled in ice. The precipitate collected, washed with Ethyl Acetate-Petroleum Ether 1:1, dried on air to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (1.55 g, 3.86 mmol, 50.9% yield).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:13][C:14]([NH2:18])=[N:15][C:16]=2[CH3:17])=[C:8]([O:27][CH3:28])[CH:7]=1>CS(C)=O.CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:18][C:14]1[N:15]=[C:16]([CH3:17])[C:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([CH2:5][C:1]#[N:2])=[CH:7][C:8]=2[O:27][CH3:28])=[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:13]=1
Reactant: [C-]#N
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
Potassium cyanide (0.53 g) was added to a solution of the product from step (vi) (0.99 g) in DMSO (10 mL) and DMF (10 mL) under nitrogen. The resulting mixture was stirred at rt for 20 h and diluted with saturated aqueous NaHCO3 (50 mL). The mixture was extracted with EtOAc and the combined organic phase was washed with water and brine, dried, filtered and evaporated. The crude product was purified by chromatography, eluting with 5% MeOH in DCM to afford the subtitle compound as an orange solid 0.6 g.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1[nH]c(=O)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O
Product: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O

Procedure:
Prepared in analogy to example 31f from 7-(benzo[1,3]dioxol-5-yloxy)-4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester and POCl3. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.89 (s, 1H), 8.35 (d, 1H, J=9.2 Hz), 7.57 (d, 1H, J=1.9 Hz), 7.50 (m, 1 H), 6.83 (d, 1H, J=7.8 Hz), 6.65-6.56 (m, 2H), 6.03 (s, 2H), 4.47 (t, 2H, J=7.1 Hz), 1.9-1.4 (m, 4H), 0.99 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:32][C:33]([C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][CH2:38][C@H:39]2[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[NH:34]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH2:13][C:14]1[O:16][N:34]=[C:33]([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][CH2:38][C@H:39]3[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[N:32]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C(=N)NO)cccc21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1OCC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared using General Procedure 2. A solution of 2-(3,4-diethoxyphenyl)acetic acid (150.0 mg, 0.67 mmol) in DMF (3 mL) was treated with HOBt (164.8 mg, 1.22 mmol) and EDC (172.7 mg, 0.9 mmol) at room temperature. The reaction was stirred for 2 h until the complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-54 (233.8 mg, 0.8 mmol) was added and stirred at room temperature for 2 h and then mixture was heated to 80° C. for 16 h. The reaction was diluted with NaHCO3 (10 mL) and extracted with EA (3×10 ml). The organic phase was dried over MgSO4 and the crude product was purified by a chromatography (EA/hexanes) to produce (R)-tert-butyl 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-56 (187 mg, 58%) as off-white solid and used directly in the next step. LCMS-ESI (m/z) calculated for C27H33N3O5: 479.2; found 502.2 [M+Na]+, tR=4.11 min. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 6.81 (ddd, J=20.2, 12.8, 5.1 Hz, 3H), 5.18 (d, J=8.4 Hz, 1H), 4.69 (d, J=8.3 Hz, 1H), 4.15 (d, J=6.1 Hz, 2H), 4.06-3.93 (m, 4H), 3.32 (ddd, J=17.4, 8.8, 3.4 Hz, 1H), 3.14-2.91 (m, 1H), 2.65-2.40 (m, 1H), 1.75 (dq, J=12.9, 8.4 Hz, 1H), 1.36 (ddd, J=40.2, 26.9, 22.6 Hz, 15H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21]C(=O)OC(C)(C)C)[CH2:11][C:10]1=[O:29].CO.C(Cl)Cl>C(Cl)Cl>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[CH:12]1[CH2:13][CH2:14][N:9]([CH3:8])[C:10](=[O:29])[CH2:11]1
Reactant: CN1CCC(c2ccncc2NC(=O)OC(C)(C)C)CC1=O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2ccncc2N)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
TFA (0.75 mL, 9.735 mmol) was added to a solution of tert-butyl N-[4-(1-methyl-2-oxo-4-piperidyl)-3-pyridyl]carbamate (74 mg, 0.2423 mmol) in DCM (2 mL) and was stirred at ambient temperature for 2 hours. The reaction mixture was adsorbed onto a pre-wetted (methanol/DCM (1:1), 2 mL) SCX-2 cartridge (2 g) and flushed with DCM/methanol (1:1, 20 mL) and then the basic components eluted with 2 M ammonia in methanol (20 mL). The basic eluent was evaporated to dryness to afford 4-(3-aminopyridin-4-yl)-1-methylpiperidin-2-one as a pale yellow oil (50 mg, 97%). MS (ES+) 206.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH3:54][N:55]([CH3:60])[C:56](=[O:59])[CH:57]=[CH2:58]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:23][CH3:24])[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[CH:4]=[CH:3][C:2](/[CH:58]=[CH:57]/[C:56]([N:55]([CH3:60])[CH3:54])=[O:59])=[CH:11][C:10]=2[N:9]=1
Reactant: C=CC(=O)N(C)C
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(/C=C/C(=O)N(C)C)ccc3c2n1CC1CCOCC1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.58 g, 1.5 mmol) in N,N-dimethylformamide (10 mL). To the solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and tri-ortho-tolylphosphine (91 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL), triethylamine (3.0 eq. 0.6 mL), and a solution of N,N-dimethylacrylamide (178 mg, 1.8 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system, (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 390 mg of (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylprop-2-enamide as an off-white crystalline solid, mp>260° C.
Reaction SMILES: [OH-:1].[Na+].C1(CO[C:11](=O)[CH2:12][C:13](=[O:32])[NH:14][C:15]2[CH:20]=[C:19]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[O:30][CH3:31])C=CC=CC=1>CO>[OH:1][CH:12]([C:11]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)[C:13]([NH:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[O:30][CH3:31])[C:21]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:29])=[O:32]
Reactant: [OH-]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=O)CC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=O)C(O)c1ccccc1

Procedure:
1N Sodium hydroxide (3 mL) was added to (2-methoxy-5-phenylcarbamoyl-phenylcarbamoyl)-acetic acid phenylmethyl ester from Example 252 (1.29 g, 3.1 mmol) in methanol (80 mL) and the reaction mixture boiled until most of the solvent was gone. Additional 1N sodium hydroxide (4 mL) and methanol (80 mL) were added and the mixture again concentrated to near dryness. Ethyl acetate (100 mL), water (100 mL), and 1N HCl (10 mL) were added, the layers separated, the organic layer washed with brine (50 μL), dried over magnesium sulfate, and concentrated to an oil. Trituration in hexanes/ethyl acetate (4:1) afforded the product (0.826 g); m.p. 173-175° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:14]2[S:15][C:16](I)=[CH:17][C:18]=2[P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[S:12][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:33]1[S:37][C:36]([C:38]2[S:39][CH:40]=[CH:41][C:42]=2[P:43]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44])=[CH:35][C:34]=1[P:51]([O:56][CH2:57][CH3:58])([O:53][CH2:54][CH3:55])=[O:52])CCC.[Cu]C#N.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:19]([C:18]1[CH:17]=[CH:16][S:15][C:14]=1[C:11]1[S:12][C:13]([C:40]2[S:39][C:38]([C:36]3[S:37][CH:33]=[C:34]([P:51]([O:56][CH2:57][CH3:58])([O:53][CH2:54][CH3:55])=[O:52])[CH:35]=3)=[C:42]([P:43]([O:45][CH2:46][CH3:47])([O:48][CH2:49][CH3:50])=[O:44])[CH:41]=2)=[C:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=1)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(-c2sccc2P(=O)(OCC)OCC)cc1P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)c1csc(-c2sc(I)cc2P(=O)(OCC)OCC)c1
Agent: N#C[Cu]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1csc(-c2sc(-c3sc(-c4sccc4P(=O)(OCC)OCC)cc3P(=O)(OCC)OCC)cc2P(=O)(OCC)OCC)c1
Yield: 82 %

Procedure:
At room temperature, 0.0564 g (0.1 mmol) of 4,3′-bis(diethoxyphosphoryl)-5′-iodo-[2,2′]-bithiophene and 0.0092 g (0.008 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in 2 ml of toluene, to which 0.0709 g (0.1 mmol) of 5-(tributylstannyl)-4,3′-bis(diethoxyphosphoryl)-[2,2′]-bithiophene and 0.0018 g (0.02 mmols) of commercially available copper(I) cyanide were added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 2.5 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution added, followed by stirring for 1 hour. The resulting solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate and ethyl acetate:hexane=15:1) to obtain the specified substance in the form of an orange oil at a yield of 0.0717 g (yield: 82%).