Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[C:9]([O:13][C:14]([N:16]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:17]1[C:18]2[C:25]([I:26])=[CH:24][N:23]([C@@H:27]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([CH:39]=O)[CH2:28]3)[C:19]=2[N:20]=[CH:21][N:22]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:44]([O:43][C:41]([N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[C:17]1[C:18]2[C:25]([I:26])=[CH:24][N:23]([C@@H:27]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C@H:29]([CH2:39][N:2]([CH3:3])[CH3:1])[CH2:28]3)[C:19]=2[N:20]=[CH:21][N:22]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1C[C@H](n2cc(I)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncnc32)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1M dimethylamine THF solution (0.3 ml) and acetic acid (0.2 ml) were added to a solution of (2S,4S)-tert-butyl 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-formylpyrrolidine-1-carboxylate (68 mg) obtained in Step 5 in methylene chloride (2 ml), and the resulting mixture was cooled to 0° C. Sodium triacetoxyborohydride (127 mg) was added to the reaction mixture, and stirred at 0° C. for 2 hours. The reaction mixture was neutralized using a sodium hydrogen carbonate aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, amorphous substance (31.9 mg). Physical properties: m/z [M+H]+ 687.2
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: CCCCCCC#Cc1ccc(C=O)cc1
Reactant: NCc1ccc(Br)cc1
Product: CCCCCCC#Cc1ccc(CNCc2ccc(Br)cc2)cc1
Yield: 86 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-oct-1-ynylbenzaldehyde and 4-bromobenzylamine gave the title compound as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.47 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.30-7.19 (m, 4H), 3.78 (s, 2H), 3.75 (s, 2H), 2.42 (t, J=6.8 Hz, 2H), 1.69-1.55 (m, 2H), 1.54-1.42 (m, 2H), 1.42-1.27 (m, 4H), 0.93 (t, J=6.8 Hz, 3H). M+(LC/MS(ESI)): 384.4 HPLC (Condition A), Rt: 4.18 min (HPLC purity: 97.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([O:17]CC)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.O>C1COCC1.CO>[CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(C)c1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)O)c1OCc1ccccc1
Yield: 90.3 %

Procedure:
Ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate (755 mg, 2.9 mmol) was likewise hydrolyzed using LiOH.H2O (243 mg, 5.8 mmol) in THF (20 mL), MeOH (4 mL), and water (10 mL), to afford 608 mg of 5-benzyloxy-1-methyl-4-carboxylic acid (25) as a white solid, m.p. 117-122° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:25]4=[N:26][C:27]([NH:30][C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)=[N:28][CH:29]=[C:24]4[CH:23]=[N:22]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:36][N:34]1[CH:35]=[C:31]([NH:30][C:27]2[N:26]=[C:25]3[N:21]([CH2:20][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:22]=[CH:23][C:24]3=[CH:29][N:28]=2)[CH:32]=[N:33]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCNCC5)c4)c3n2)cn1
Yield: 11.6 %

Procedure:
tert-Butyl-4-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1-carboxylate (1.10 g, 2.25 mmol) was treated with TFA/DCM (1:2, 12 mL) for 1 h at rt. After evaporation to dryness, the residue was purified by preparative HPLC to afford the title compound (103 mg, 0.26 mmol, 12% over two steps). 1H NMR (d6-DMSO) δ 9.83 (s, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.58 (s, 1H), 7.18-7.06 (m, 1H), 7.00 (s, 1H), 6.84-6.75 (m, 1H), 6.73-6.58 (m, 1H), 5.48 (s, 2H), 3.84 (s, 3H), 2.99-2.91 (m, 4H), 2.79-2.71 (m, 4H), 2.22 (br s, 1H); LC-MS method B, (ES+) 390.1, RT=4.93 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:15][CH3:16])=[N:4][N:5]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([NH2:9])=[O:8].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>CN(C)C=O>[CH2:13]([O:12][CH2:11][CH2:10][N:5]1[C:6]2[C:7](=[O:8])[NH:9][C:17](=[O:18])[NH:1][C:2]=2[C:3]([CH2:15][CH3:16])=[N:4]1)[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOCCn1nc(CC)c(N)c1C(N)=O
Solvent: CN(C)C=O
Product: CCOCCn1nc(CC)c2[nH]c(=O)[nH]c(=O)c21
Temperature: 80 °C
Yield: 38.2 %

Procedure:
A mixture of 4-amino-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazole-5-carboxamide from step 2 (2.44 g, 10.8 mmol) in N,N-dimethylformamide (40 mL) was treated with carbonyldiimidazole (1.92 g, 11.9 mmol) and heated at 80° C. overnight. The mixture was concentrated in vacuuo and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as the eluent to provide 1.04 g of the title compound. MS (ESI) m/z 253.
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH:9][C:3]2([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: C#CC1(N)CCCCC1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Product: C#CC1(NS(=O)(=O)c2cccc(Cl)c2)CCCCC1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH2C2 was added triethylamine (68 mL, 0.48 mmol), followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 min, the mixture was partitioned between ethyl acetate and 3N aq. HCl. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated in vacuuo to give the title compound as a white solid (90 mg, 93% yield);
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[S:18][C:17]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=4)[CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:16]=3[C:6]=2[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:9]=1)[CH3:2].[NH:34]1[CH:38]=[CH:37][CH:36]=[N:35]1.CN[C@@H]1CCCC[C@H]1NC>CN(C)C=O.[Cu]I>[CH2:1]([O:3][C:4]1[C:5]2[S:18][C:17]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30]([N:34]5[CH:38]=[CH:37][CH:36]=[N:35]5)=[CH:29][CH:28]=4)[CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:16]=3[C:6]=2[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:9]=1)[CH3:2]
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(I)cc3)cc(C(F)(F)F)c12
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CN(C)C=O
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(-n4cccn4)cc3)cc(C(F)(F)F)c12

Procedure:
0.30 g (0.5 mmol) 4-ethoxy-9-trifluoromethyl-7-(4-iodo-phenyl)-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine, 0.14 g (2.1 mmol) pyrazole, 0.22 g (1.0 mmol) potassiumphosphate-tribasic, 0.06 g (0.3 mmol) copper(I)-iodide and 0.014 g (0.1 mmol) (1R,2R)—N,N′-dimethyl-1,2-cyclohexanediamine in 5 ml N,N-dimethylformamide (dry) are stirred at 110° C. under nitrogen atmosphere for 24 h. The solvent is removed in vacuo and the residue is suspended in 20 ml water, sucked off, washed with 100 ml water and suck dried. Following purification by means of flash chromatography (methanol/dichloromethane 1:10) 0.04 g (15%) 4-ethoxy-9-trifluoromethyl-2-piperazin-1-yl-7-(4-(1H-pyrazol-1-yl)-phenyl)-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Br:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Br)C[C@H]1N
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.11 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.082 g), DBU (0.054 g) and anhydrous acetonitrile (5 ml) was refluxed for 1.5 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml) and washed with 10% aqueous citric acid solution and water successively. The organic layer was concentrated under reduced pressure and to the oily residue was added methanol to crystallize. The resulting precipitate was collected by filtration, washed with chilled methanol and this was added to concentrated hydrochloric acid-methanol (1:1, 2 ml) and stirred for an hour at room temperature. The reacting mixture was neutralized with concentrated aqueous ammonia, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:concentrated aqueous ammonia=20:6:1) and then recrystallized from dichloromethanemethanol (1:1) to give the title compound (0.04 g) as pale yellow powder, mp 186°-190° C. (decompd.).
Reaction SMILES: NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1.[N+](C1C=CC(C2CCC(C(OC)=O)C2)=CC=1)([O-])=O.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C@H:42]2[CH2:46][CH2:45][C:44](=[CH:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]2)=[CH:38][CH:37]=1>>[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([C@H:42]2[CH2:46][CH2:45][CH:44]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]2)=[CH:40][CH:41]=1
Reactant: CCOC(=O)C=C1CC[C@H](c2ccc(N)cc2)C1
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Agent: COC(=O)C1CCC(c2ccc([N+](=O)[O-])cc2)C1
Product: CCOC(=O)CC1CC[C@H](c2ccc(N)cc2)C1

Procedure:
Following the procedure described for methyl 3-(4-aminophenyl)cyclopentanecarboxylate, replacing methyl 3-(4-nitrophenyl)cyclopentanecarboxylate (Intermediate 84(ii)) with ethyl [(3S)-3-(4-aminophenyl)cyclopentylidene]acetate the title compound was obtained; 1H NMR δ1.18 (t, 3H), 1.21-1.76 (m, 2H), 1.80-2.12 (m, 2H), 2.23-2.48 (m, 2H), 2.80-3.01 (m, 1H), 3.16-3.30 (m, 2H), 4.06 (q, 2H), 4.79 (s, 2H), 6.45-6.51 (m, 2H), 6.84-6.91 (m, 2H); MS m/e M+MeCN 289.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH:20]([CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:19]4)=[N:16][CH:15]=[N:14][C:10]=3[NH:11]2)=[CH:7][CH:6]=1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:25][CH2:24][CH:20]1[CH2:19][N:18]([C:17]2[C:9]3[C:8]4[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=4)[NH:11][C:10]=3[N:14]=[CH:15][N:16]=2)[CH2:23][CH2:22][O:21]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1ncnc(N3CCOC(CNC(=O)OC(C)(C)C)C3)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1ncnc(N3CCOC(CN)C3)c12
Yield: 75.6 %

Procedure:
20 mg (0.045 mmol) of 4-[2-(tert-butoxycarbonylamino-methyl)-morpholin-4-yl]-9H-pyrimido[4,5-b]indole-7-carboxylic acid methyl ester (from Synthesis 3-1-F) was dissolved in methanol and deprotected on a MP-TsOH cartridge. The product was eluted with 2 N ammonia in methanol and concentrated in vacuo to give 11.6 mg (0.034 mmol, 75%) of the title compound as a beige solid. LC-MS (1) Rt 1.68 min; m/z (ES+) 342. 1H NMR (ppm, MeOD) δ 8.41 (1H, d, J=0.8 Hz), 8.08 (1H, s), 7.88 (1H, dd, J=8.5, 1.5 Hz), 7.80 (1H, d, J=8.3 Hz), 4.21 (1H, d, J=12.6 Hz), 4.13 (1H, d, J=13.1 Hz), 4.06 (1H, dd, J=11.6, 2.5 Hz), 3.93 (3H, s), 3.81 (1H, td, J=11.9, 2.0 Hz), 3.71-3.69 (1H, m), 3.34 (2H, d, J=0.8 Hz), 3.00 (1H, dd, J=12.6, 10.8 Hz), 2.77 (1H, s), 2.76 (1H, d, J=2.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.[Cl-].ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:27]([NH2:29])=[O:28])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ncc(-c3ccc(C(C)NC(N)=O)cc3)s2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) in methylenie chloride (1 mL) cooled to 0° C. was added trichloroacetyl isocyanate (50 μL, 0.42 mmol, 1.2 eq.). The mixture was stirred at 0° C. for 10 minutes and then methanol (10 mL) and a catalytic amount of Na2CO3 were added. The mixture was stirred at room temperature for 5 hours. The reaction was then concentrated. The reaction mixture was purified on silica gel eluting with ethyl acetate:hexane gradient (0-80%) to give the title compound (42 mg, 34%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.66 (s, 1 H), 7.45-7.53 (m, 2 H), 7.32-7.40 (m, 2 H), 7.28-7.31 (m, 2 H), 7.02-7.06 (m, 2 H), 6.44 (d, J=8.09 Hz, 1 H), 5.42 (s, 2 H), 4.59-4.77 (m, 1 H), 3.79 (s, 3 H), 1.29 (d, J=6.99 Hz, 3 H); MS (DCI) m/z 370 (M+H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-p-tolyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O.O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH:24]=[CH2:23])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)Oc1ccc(O)c2c1CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC(C)=O)c2c1NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 Grams of 5-acetoxy-3,4-dihydro-8-hydroxy-2(1H)-quinolinone was dissolved in 500 ml of dimethylformamide (DMF), to this solution were added 52 g of potassium carbonate powder and 50 ml of allyl bromide, the mixture thus obtained was stirred at room temperature for 8 hours. To this reaction mixture was diluted with 500 ml of water, extracted with 2 liter of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol, there was obtained 70 g of 5-acetoxy-8-allyloxy-3,4-dihydro-2(1H)-quinolinone as brown needle-like crystals.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH:18]([C:23]3[CH:24]=[C:25]([CH:28]=[C:29]([F:31])[CH:30]=3)[C:26]#[N:27])[C:19]([F:22])([CH3:21])[CH3:20])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:15][CH:16]([CH:18]([C:23]3[CH:24]=[C:25]([C:26]4[NH:34][N:33]=[N:32][N:27]=4)[CH:28]=[C:29]([F:31])[CH:30]=3)[C:19]([F:22])([CH3:21])[CH3:20])[CH2:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(F)C(c1cc(F)cc(C#N)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(F)C(c1cc(F)cc(-c2nnn[nH]2)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 16 h

Procedure:
A mixture of 1.17 g (2.81 mmol) of 3-{1-[(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzonitrile, 914 mg (14.06 mmol) of sodium azide, and 715 mg (14.05 mmol) of ammonium chloride in 15 mL of DMF was stirred for 16 h. Then it was concentrated to remove solvents. The residue was purified by silica gel chromatography with CH2Cl2/MeOH/NH3 (2M) in MeOH to afford the title compound as a white solid;
Reaction SMILES: [Cl-].C[C:3](C)([O-:5])C.[K+].[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]>C1COCC1>[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH:3]=[O:5])[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC(C2CCC(=O)CC2)O1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(C=O)CC2)O1
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Methoxymethyltriphenylphophnium chloride (55.23 g) and THF (300 ml) were placed in a reaction vessel, and the solution was cooled to −20° C. Potassium t-butoxide (16.0 g) was added, and the stirring was continued for another 1 hour. Then, 4-(5-propyltetrahydro-2-furanyl)cyclohexanone (15 g) in a THF (100 ml) solution was added dropwise, and the stirring was continued for another 1 hour. The reaction mixture was warmed to room temperature, and the mixture was separated after the addition of water (200 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (toluene:ethyl acetate=18:1), and the resultant product was dissolved in acetone (200 ml) and hydrochrolic acid (6 M) (200 ml) was added, and then the stirring was continued at room temperature for another 1 hour. The mixture was extracted with toluene (100 ml) after the addition of water (200 ml). The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4-(5-propyltetrahydro-2-furanyl)cyclohexanecarboaldehyde (12.2 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:23][C:24]1[S:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:27]4[S:28][C:24]([CH3:23])=[CH:25][CH:26]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)s1
Temperature: 150 °C
Yield: 54.6 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (100 mg, 0.274 mmol), (5-methylthiophen-2-yl)boronic acid (70.0 mg, 0.493 mmol), 1,2-dimethoxyethane (1.1 mL), 1 N Na2CO3 aqueous solution (0.55 mL, 0.55 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (31.6 mg, 0.027 mmol) was added. The tube was sealed and heated in a microwave at 150° C. for 20 minutes. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 57.2 mg (yield 54.6%). 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.63 (s, 1H), 7.56 (broad s, 1H), 7.48 (d, J=3.6 Hz, 1H), 6.78 (dm, J=3.6 Hz, 1H), 5.50-5.36 (m, 1H), 3.71-3.61 (m, 1H), 3.46-3.36 (m, 1H), 3.24-3.15 (m, 1H), 2.91-2.76 (m, 1H), 2.45 (s, 3H), 2.36-2.28 (m, 2H), 1.41 (d, J=6.2 Hz, 3H), 1.15-1.09 (m, 2H), 1.08-1.01 (m, 2H) ppm; MS (ESI+) m/z 383 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1C[CH2:26][CH2:25][CH2:24]1.C([Li])CCC.C(Br)C=C>C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]([CH2:9][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:26][CH:25]=[CH2:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C=CCBr
Solvent: CCOC(C)=O
Product: C=CCN(CC(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine N-t-butoxycarbonyl-2,2-bis-phenyl-ethylamine (2.0 g, 7.73 mmol) and tetrahydrofuran (20 mL) and cool in a dry-ice/acetone bath to -78° C. Slowly, add n-butyllithium (4.4 mL, 1.6M in hexane, 7.04 mmol) and allow to stand for 30 minutes. Add allyl bromide (0.7 mL, 8.09 mmol) maintaining the temperature at -78° C. Warm to ambient temperature and allow to stand for 1.5 hour and then heat to reflux for 5 hours. Cool to ambient temperature and allow to stand for 18 hours. Extract the reaction mixture with a saturated ammonium chloride solution and separate the layers. Extract the aqueous layer with diethyl ether and combine the organic layers. Extract the combine organic layer with water and saturated sodium chloride solution. Separate the organic layer and dry over MgSO4, filter and evaporate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:30]=2)=[O:28])=[CH:22][C:18]=1[C:19](O)=[O:20]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:12][C:19](=[O:20])[C:18]3[CH:22]=[C:23]([NH:26][C:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[CH:30]=4)=[O:28])[CH:24]=[CH:25][C:17]=3[Cl:16])[CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccnc(N2CCOCC2)c1
Product: CN1CCN(Cc2cccc(NC(=O)c3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)c2)CC1
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 4, 3-(4-methylpiperazin-1-ylmethyl)aniline was reacted with 2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid to give the title compound in 32% yield; NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.31-2.35 (m, 8H), 3.42 (s, 2H), 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H), 7.02 (d, 1H), 7.1 (d, 1H), 7.22-7.3 (m, 2H), 7.57-7.65 (m, 3H), 7.84-7.94 (m, 2H), 8.28 (d, 1H), 10.47 (s, 1H), 10.52 (s, 1H); Mass Spectrum: M+H+ 549 and 551.