Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>>[F:24][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)[C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:12][CH2:13]2)=[O:9])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)(F)CCN3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D136) (30 mg) was prepared according to the general procedure described in Description 135 starting from (R)-methyl 4-(1-(4,4-difluoropiperidine-2-carboxamido)cyclopropyl)benzoate (D98) (47 mg) and 4-(trifluoromethyl)-benzylbromide (0.027 ml).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([CH:17]([OH:25])[CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:28](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:28][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][CH:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:16]=2)[OH:25])[CH2:20][CH2:21]1
Reactant: O=C([O-])[O-]
Reactant: OC(CC1CCNCC1)c1cc(-c2ccccc2)nc2ccccc12
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCC(CC(O)c2cc(-c3ccccc3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of 2.55 g of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanol (racemic), 1.1 g of methyl iodide and 0.6 g of potassium carbonate in 20 ml of dimethylformamide was stirred for 2 hours at the ambient temperature. 20 ml of water and 30 ml of toluene were then added. The organic phase was separated, wahsed with water, dried over magnesium sulfate and evaporated under reduced pressure. 1 g of crude product was obtained which was fixed on a column of silica gel. The elution was effected with a 9/1 chloroform-diethylamine mixture. 0.57 g of 2-(1-methyl-4-piperidyl)-1-(2-phenyl-4-quinolyl)-ethanol (racemic), which melted at 208° C. was thus isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:18])(=[N:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:18])(=[N:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])=[O:11])=[CH:6][CH:5]=1
Reactant: COCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COCC(=O)N=S(C)(=O)c1ccc(N)cc1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
107 mg (0.39 mmol) (RS)—S-(4-nitrophenyl)-N-(2-methoxy-acetyl)-S-methylsulfoximide is dissolved in 13.6 ml ethanol and treated with 40 mg palladium on activated charcoal (10% Pd). The mixture is stirred under hydrogen at normal pressure for 60 minutes at 24 C. The catalyst is filtered off and the solution concentrated. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 50 mg (53%) of the desired product is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH3:52][O:53][CH2:54][C@@H:55]1[O:57][CH2:56]1>CO>[CH3:52][O:53][CH2:54][C@H:55]([OH:57])[CH2:56][N:30]1[CH2:29][CH2:28][N:27]([C:25]([C:22]2[N:14]3[C:13]([CH2:12][N:11]([C:9]([C:7]4[CH:6]=[CH:5][C:4]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[C:39]([F:40])([F:42])[F:41])=[C:3]([CH3:2])[CH:8]=4)=[O:10])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15]3)=[CH:24][CH:23]=2)=[O:26])[CH2:32][CH2:31]1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: COC[C@H]1CO1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](O)CN1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C(F)(F)F)c(C)c2)C3)CC1
Temperature: 60 °C
Yield: 73.6 %

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (R)-(−)-glycidyl methyl ether (0.11 mL, 1.22 mmol). The reaction mixture was heated to 60° C. overnight then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 3% methanol in chloroform provided 0.40 g of title product as a white foam.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].I[C:32]1[C:33]2[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=2[N:35]=[CH:36][N:37]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)=[O:5])=[N:7][CH:8]=[CH:9][CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:28])([F:27])[F:29]
Reactant: COCN(c1cccnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 248 mg (0.53 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 239 mg (0.58 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.32 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 4 mL methanol and 4 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:30](Cl)(=O)[CH:31]([CH3:33])[CH3:32].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH:31]([C:33]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][CH:8]([CH:11]3[O:29][C:14]4=[CH:15][N:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=5)[CH:18]=[C:13]4[CH2:12]3)[CH2:9][CH2:10]2)[N:4]=1)([CH3:32])[CH3:30]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)c1nc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-hydroxy-4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine (45 mg), isobutyryl chloride (12 μL), and triethylamine (50 μL) in tetrahydrofuran (5 mL) is stirred for 30 min at room temperature prior to heating to 80° C. for 5 h. The heating is continued over night at reflux. The reaction mixture is diluted with ethyl acetate after cooling to room temperature, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is triturated with a small amount of methanol and the precipitate is filtered off, washed with diethyl ether, and dried to give the title compound. LC (method 5): tR=1.30 min; Mass spectrum (ESI+): m/z=469 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:16]2[CH2:15][CH2:14][NH:13][CH:12]([CH3:11])[CH2:17]2)=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CC1CNCCN1
Solvent: ClCCl
Product: CC1CN(C(=S)Nc2ccc(Cl)cc2)CCN1
Temperature: 25 °C

Procedure:
A solution of 4-chlorophenyl isothiocyanate (8.0 g, 47.17 mmol) in dichloromethane (250 mL) was added dropwise over 30 minutes to an ice cooled solution of 2-methylpiperazine (9.45 g, 94.33 mmol) in dichloromethane (250 mL). Once the addition was complete, the reaction was stirred at room temperature for an hour. The reaction was then washed with water (3×), dried over MgSO4 and concentrated under reduced pressure, to give the title compound as a white solid, 11.8 g.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[C:9][Si](C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1cccnc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1F
Reaction time: 1 h
Yield: 86.2 %

Procedure:
2-Fluoro-3-[(trimethylsilyl)ethynyl]pyridine (8.8 g, 0.046 mol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (2 mL). A 1.0 M solution of tetra-n-butylammonium fluoride (12 g, 0.046 mol) in THF (46 ml) was then added dropwise at 0° C., and the reaction mixture was stirred for 1 hour. The reaction was extracted with ethyl acetate, and the combined organic extracts were washed with brine (3×), dried over MgSO4 and concentrated. The crude was purified via column chromatography on silica gel (10% ethyl acetate:90% hexanes) to provide 4.8 g of the desired product. 1H NMR (400 MHz, CDCl3): δ 8.20 (m, 1H), 7.88-7.92 (m, 1H), 7.17-7.21 (m, 1H), 3.40 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[N:30]([Si](C)(C)C)=[N+:31]=[N-:32].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]2[NH:32][N:31]=[N:30][N:29]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=1[Cl:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1
Yield: 88 %

Procedure:
To a solution of 1-(3-cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (0.60 g, 1.39 mmol) in toluene (30 mL) was added azidotrimethylsilane (0.55 mL, 4.17 mmol) and dibutyltin oxide (0.10 g, 0.42 mmol). The reaction mixture was heated and stirred under argon at reflux temperature for 40 h. The solution was cooled and the toluene removed under reduced pressure. Methanol was then added and removed under reduced pressure. Ethyl acetate was added and the reaction mixture was washed with water and brine. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 10% methanol/dichloromethane) yielded a white solid (0.58 g, 87%). MS(ES) m/e 474.2 [M +H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(I)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1cc(-c2ccccc2)ccn1
Yield: 15.5 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (20.0 g, 82 mmol), phenylboronic acid (10.2 g, 82 mmol), Pd(Ph3P)4 (2.84 g 2.46 mmol), sodium carbonate (26.0 g, 246 mmol), DME (600 mL) and water (150 mL) was degassed with nitrogen and then refluxed overnight. The reaction was concentrated and the extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then vacuum distilled to give 2-chloro-4-phenylpyridine (2.79 g. 12.7 mmol. 82% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:43][NH2:44]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[C:29]3[C:28]([C:31]([NH2:32])=[N:43][NH:44]3)=[CH:27][CH:26]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(F)c(F)c4)C3)nc(N)n2)cc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccc(F)c(F)c3)C2)n1
Temperature: 150 °C
Yield: 70.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3,4-difluorophenyl)-3-piperidinecarboxamide (90 mg, 0.199 mmol), 3 mL of EtOH, hunig's base (0.104 ml, 0.597 mmol), and hydrazine anhydrous (0.025 ml, 0.796 mmol) weres added, and the yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford the title compound (65 mg) as a light yellow solid. LC-MS (ES) m/z=465 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 1H), 1.69-1.96 (m, 2H), 2.06 (m, 1H), 3.19 (m, 1H), 3.40-3.55 (m, 1H), 4.36-4.56 (m, 2H), 4.73-4.97 (m, 1H), 6.91-7.09 (m, 1H), 7.25-7.52 (m, 4H), 7.66-8.03 (m, 4H), 10.25-10.42 (m, 1H), 10.33 (d, J=8.8 Hz, 1H), 12.09 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (0.36 g, 1.43 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath and treated with triethyl amine (0.40 mL, 0.28 mmol) then dropwise with benzoyl chloride (0.18 mL, 1.55 mmol). The resulting solution was stirred 30 min, and the cooling bath was removed. After 30 min, the solution was concentrated, and the residue was partitioned between EtOAc (50 mL) and 1N HCl (10 mL). The organic layer was washed with brine (10 mL), dried (Na2SO4), and concentrated to a solid. The crude mixture was purified by radial chromatography (hexanes:EtOAc 3:1 to 2:1) to give the title compound as a white solid (325 mg, 64%): 1H NMR (400 MHz, CDCl3) 1.26 (s, 9H), 2.54 (t, J=7.1 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 4.55 (d, J=2H), 6.68 (dd, J=8.3, 2.4 Hz, 1H), 6.86 (d, J=2.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 7.25-7.29 (m, 2H), 7.34-7.37 (m, 1H), 7.49 (br s, 1H), 7.16-7.79 (m, 2H); MS (ES) m/z 356.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH:20][C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:26]3[CH2:27][CH2:28][CH:23]([C:21]([NH:20][CH3:19])=[O:22])[CH2:24][CH2:25]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CNC(=O)C1CCNCC1
Product: CNC(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and piperidine-4-carboxylic acid methylamide (Example 25) using General Procedure B-3 yielded 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-methylpiperidine-4-carboxamide.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[CH:17]1([CH:22]([CH3:28])[CH2:23][CH2:24][CH2:25][C:26]#N)[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH:29]S(O)(=O)=O>CC(OC)(C)C.CO>[CH:17]1([CH:22]([CH3:28])[CH2:23][CH2:24][CH2:25][CH:26]=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=S(=O)(O)O
Reactant: CC(CCCC#N)C1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CC(CCCC=O)C1CCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Diisobutylaluminum hydride (60 ml of 1.0 M solution in hexane) was added at −65° C. to a hexane (50 ml) solution of 5-cyclopentylhexanenitrile (5.0 g; 30 mmol; from example 11). After stirring at −70° C. for 0.5 hour, and at room temperature for 3 hours, methanol (1.8 ml) was added, and the stirring continued for 20 minutes. 10% H2SO4 (48 ml) was added, and the reaction mixture was diluted with MTBE (150 ml). The organic layer was separated, washed with saturated sodium bicarbonate solution (300 ml) and brine (3×300 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (100° C./0.2 torr) to give 2.6 g (51.5% yield) of 5-cyclopentylhexanal.
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[C:12]=2[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1>C(O)C>[NH2:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:12]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([NH2:3])[C:13]=2[N:14]=[CH:15]1
Reactant: Nc1nc2c(c3c1ncn3CCCCON1C(=O)c3ccccc3C1=O)CCCC2
Agent: NN
Solvent: CCO
Product: NOCCCCn1cnc2c(N)nc3c(c21)CCCC3
Reaction time: 8 h
Yield: 135 %

Procedure:
Anhydrous hydrazine (94 mg, 2.96 mmol) was added to 2-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione (600 mg, 1.48 mmol) in ethanol (25 mL) at ambient temperature. The reaction was stirred overnight, and additional hydrazine (2 equivalents) was added. After stirring for 2 hours at ambient temperature, the reaction was concentrated under reduced pressure. The residue was diluted with dichloromethane and concentrated under reduced pressure three times to remove the hydrazine and then dried under vacuum to provide 550 mg of impure 1-[4-(aminooxy)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as an orange solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[NH:7][C:6]2[CH:8]=[C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:11][C:5]=2[O:4][CH2:3]1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:25]([O:24][C:23](=[O:29])[NH:22][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[C:9]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:8][C:6]4[N:7]([C:39]5[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=5)[S:2](=[O:1])(=[O:36])[CH2:3][O:4][C:5]=4[N:11]=3)=[CH:13][CH:14]=2)[CH2:21][CH2:20][CH2:19]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)S(=O)(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
In a 15 mL reaction tube was added tert-butyl (1-(4-(2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.099 mmol), pyridin-3-ylboronic acid (24 mg, 0.197 mmol), copper(II)acetate (27 mg, 0.148 mmol) and 5 Å molecular sieves (30 mg) in anhydrous dichloromethane (1 ml). To this was added anhydrous pyridine (16 μl, 0.197 mmol) and the resulting black suspension stirred at room temperature under air for 24 hours. Further pyridine (1 mL) was added and the resulting black solution stirred at room temperature for 24 hours. Further pyridin-3-ylboronic acid (24 mg, 0.197 mmol) and copper (II)acetate (27 mg, 0.148 mmol) were added and the mixture stirred at room temperature for 72 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as an off-white solid (40 mg 70% yield). 1H-NMR (500 MHz, CDCl3) δ 8.67-8.76 (2H, m), 7.89 (1H, d), 7.54 (1H, dd), 7.20-7.35 (7H, m), 7.06 (2H, d), 7.03 (1H, s), 5.38 (2H, s), 5.07 (1H, br s), 2.20-2.60 (4H, m), 2.00-2.15 (1H, m), 1.78-1.90 (1H, m), 1.10-1.50 (9H, br s). LCMS (Method A) RT=6.98 min, M+H+=584.99.
Reaction SMILES: CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:49][C:50]1[CH:51]=[C:52]([C:57]2([C:62]([F:65])([F:64])[F:63])[CH2:61][CH2:60][NH:59][CH2:58]2)[CH:53]=[C:54]([Cl:56])[CH:55]=1.[Cl:66][C:67]1[CH:84]=[C:83](I)[CH:82]=[CH:81][C:68]=1[CH2:69][N:70]1C(=O)C2C(=CC=CC=2)C1=O.NN>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CO>[Cl:66][C:67]1[CH:84]=[C:83]([N:59]2[CH2:60][CH2:61][C:57]([C:52]3[CH:51]=[C:50]([Cl:49])[CH:55]=[C:54]([Cl:56])[CH:53]=3)([C:62]([F:65])([F:64])[F:63])[CH2:58]2)[CH:82]=[CH:81][C:68]=1[CH2:69][NH2:70]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1Cl
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: NN
Solvent: CO
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.1 %

Procedure:
Sodium tert-butoxide (0.2 g), Tris(dibenzylidene acetone)dipalladium(0) (chloroform adduct)(0.03 g) and xantphos (0.05 g) was added to the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.4 g) and 2-(2-chloro-4-iodobenzyl)-1H-isoindole-1,3-(2H)-dione (0.69 g) in toluene under argon atmosphere, and the mixture was heated with stirring at 80° C. for 3 hours. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure to yield the crude product. The product was dissolved in methanol, to which was then added aqueous hydrazine (0.03 g), followed by the mixture heated to reflux for 12 hours. The reaction solution was diluted with t-butylmethylether and then washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]phenyl}methanamine (0.12 g). 1H-NMR (CDCl3) δ: 2.47-2.54 (1H, m), 2.78-2.85 (1H, m), 3.46-3.49 (2H, m), 3.69-4.01 (4H, m), 6.47-6.50 (1H, m), 6.73-6.76 (1H, m), 7.25-7.35 (4H, m).