Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11](I)=[CH:10]2)[CH2:6]1)[CH3:3].[C:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:32]=3)[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:30]3[CH:29]=[C:28]4[C:33]([CH:34]=[CH:35][C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:27]4)=[CH:32][CH:31]=3)=[CH:10]2)[CH2:6]1)[CH3:3]
Reactant: CN(C)CC1CC(n2cc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
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: O
Solvent: CN(C)C=O
Product: CN(C)C[C@H]1C[C@@H](n2cc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)ncnc32)C1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 7-(3-dimethylaminomethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (891.5 mg, 2.401 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-quinoline (795 mg, 2.40 mmol), Na2CO3 (634 mg, 5.98 mmol), and Pd(PPh3)4 (171 mg, 0.148 mmol; 6 mol %) in DMF (40 mL)/water (8 mL) for 5 min at ambient temperature, then the mixture was heated to 80° C. (bath temp.) for 4.5 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (4×30 mL), and the combined extracts were washed with brine and dried over MgSO4. The crude material (yellow oil) was chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-28)→5% MeOH in CH2Cl2 (29-56)→10% MeOH in CH2Cl2 (57-80)→10% MeOH in CH2Cl2 with 0.07M NH3 (81-130)]. Mixed fractions were chromatographed again [5 g/25 mL cartridge, eluting with CH2Cl2 (1-5)→5% MeOH in CH2Cl2 (6-24)→10% MeOH in CH2Cl2 with 0.07M NH3 (25-40)]. One obtained the target compound as beige solid. 1H NMR (CDCl3, 400 MHz): δ=2.10-2.23 (mc, 2H), 2.27 (s, 6H), 2.35-2.46 (mc, 1H), 2.49 (d, J=6.8 Hz, 2H), 2.77-2.86 (mc, 2H), 5.17 (brs, 2H), 5.20-5.30 (mc, 1H), 7.31 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.6, 8.4 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.30 (brs, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=27.13 (+), 36.50 (2C, −), 45.26 (+), 45.73 (2C, +), 66.10 (−), 101.20 (Cquart), 116.07 (Cquart), 119.00 (+), 120.74 (+), 125.98 (Cquart), 127.38 (+), 127.55 (2C, +), 128.28 (+), 128.47 (+), 128.86 (2C, +), 129.52 (+), 136.45 (Cquart), 136.55 (+), 139.41 (Cquart), 148.51 (Cquart), 150.92 (Cquart), 152.04 (+), 156.99 (Cquart), 158.13 (Cquart). MS (ES+): m/z 449.2 (23) [MH+], 404.1 (4) [MH+−HN(CH3)2], 338.2 (4) [MH+−C4H5CH2N(CH3)2]. HPLC: tR=2.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:20]1([O:26][CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([C:7]([C:23]2[CH:24]=[CH:25][C:20]([O:26][CH2:27][CH3:28])=[CH:21][CH:22]=2)=[O:9])[CH:10]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Reactant: CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acid 56 (4.9 g, 18.57 mmol) in CH2Cl2 (62 mL) were added oxalyl chloride (2.1 mL, 24.14 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (93 mL) and cooled to 0° C. To the mixture was added phenetole (2.4 mL, 18.57 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (2.7 g, 20.43 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 73 was dried under high vacuum and used without further purification (7.0 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:18]C.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[OH:18]
Reactant: COc1cc2c(C3CCN(C)CC3)c[nH]c2cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3cc(F)c(O)cc23)CC1
Yield: 92.8 %

Procedure:
By a method similar to Preparation 8, using 6-fluoro-5-methoxy-3-(1-methylpiperidin-4-yl)-1H-indole (0.410 g) and 25 g of pyridine hydrochloride gave 0.360 g (93%) the title compound: Mass spectrum (ion spray): m/z=248 (M).
Reaction SMILES: [Si]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:33]=[C:32]3[C:28]([NH:29][C:30](=[O:41])[N:31]3[CH2:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:27]([C:42](OC)=[O:43])[N:26]=2)[CH:22]=[CH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:46]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)C=2)=NC=1NCC1CCOCC1>ClCCl>[OH:18][C:19]1[CH:20]=[C:21]([C:25]2[N:33]=[C:32]3[C:28]([NH:29][C:30](=[O:41])[N:31]3[CH2:34][CH:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:27]([C:42]([NH2:46])=[O:43])[N:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc(NCC2CCOCC2)c1N
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Yield: 70 %

Procedure:
Methyl 2-(3-(tert-butyldiphenylsilyloxy)phenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-2-(3-(tert-butyldiphenyl-silyloxy)phenyl)-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyrimidine-4-carboxylate (0.276 g, 0.536 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.522 g, 3.22 mmol) in dichloromethane (15 mL) were reacted according to General Procedure F and purified via biotage chromatography (0-75% EtOAc in hexanes) to afford the title compound (0.202 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.40 (t, J=8.39, 1H), 7.00 (d, J=7.99, 1H), 3.94 (s, 3H), 3.8 (m, 4H), 3.24 (t, J=10.79, 3H), 2.15 (m, 1H), 1.57 (d, J=12.39, 2H), 1.31 (m, 5H), 1.11 (d, J=7.59, 18H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH2:6]([O:13][C@H:14]([C@@H:17]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:19]=[CH2:20])[CH:15]=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH2:6]([O:13][C@H:14]([C@@H:17]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@@H:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:19]=[CH2:20])[CH:15]([OH:16])[CH2:3][CH:2]=[CH2:1])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=C[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](C=O)OCc1ccccc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](C=C)OCc1ccccc1
Reaction time: 4 h

Procedure:
Allyl magnesium bromide (1.0 M in Et2O, 1.44 mL, 1.44 mmol) was added dropwise over 5 min to a solution of aldehyde 47 (200 mg, 0.48 mmol) in THF (10 mL) at −78° C. The reaction mixture was left stirring at this temperature for 4 h before being quenched with NH4Cl solution (30 mL). The resulting layers were separated and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (0-4% EtOAc in hexanes, gradient) to give product 53 as a mixture of two diasteroisomers.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:38]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1)(=[O:40])[CH3:39]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCN)cc(OC)c1C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCNC(C)=O)cc(OC)c1C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
To a solution of compound 44a (21 mg, 0.05 mmol) and pyridine (0.008 mL, 0.1 mmol) in dichloromethane (1 mL) was added acetyl chloride (0.004 mL, 0.055 mmol). The reaction mixture was stirred for 1.5 h, and additional acetyl chloride (0.004 mL) was added. After an additional 5 min, the reaction was quenched by addition of water and concentrated. The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to afford compound 45a (8 mg).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:49][CH2:48][CH:47]=[CH:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:49][CH2:48][CH:47]=[CH:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCC=CCN(c2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC/C=C\CN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21
Agent: N[C@H]1CC/C=C\CN(c2ccccc2)C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC=CCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S,Z)-2-oxo-1-phenyl-1,2,3,4,5,8-hexahydroazocin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 63 (5.6 mg, 0.022 mmol) to give a white solid (3.5 mg, 25% yield). Anal. Calcd. for C44H52N4O6S m/z 764.4. found: 765.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.09 (16H, m), 7.00 (1H, d, J=7.1 Hz), 5.98-5.87 (1H, m), 5.60 (1H, d, J=11.5 Hz), 5.34 (1H, t, J=4.7 Hz), 5.11-5.05 (1H, m), 5.04-4.84 (3H, m), 4.06-3.97 (1H, m), 3.66 (3H, s), 3.08-2.99 (1H, m), 2.87-2.70 (5H, m), 2.49-2.33 (4H, m), 2.13-1.96 (3H, m), 1.88-1.73 (3H, m), 1.71-1.51 (7H, m), 1.38-1.28 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:28])[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.O>CN(C)C=O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[CH:18]([F:17])[F:28])[CH:7]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (5.3 g) and 2-(difluoromethyl)-1H-benzimidazole (3.9 g), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (5.49 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.C([O-])([O-])OCC.[CH2:20]([OH:22])[CH3:21]>S(=O)(=O)(O)O>[CH2:20]([O:22][C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[CH3:21]
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: CCO
Agent: CCOC([O-])[O-]
Agent: O=S(=O)(O)O
Product: CCOC1=Cc2ccc(OC)cc2CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
33.5 g of 6-methoxy-2-tetralone was dissolved in 27.6 ml of ethanol, followed by subsequently adding 37.8 ml of ethyl orthoformate and one drop of concentrated sulfuric acid. The mixture thus prepared was stirred at 100° C. for 4 hours. After distilling off the solvent under a reduced pressure, the resulting residue was subjected to silica gel column chromatography using chloroform as an eluant. Fractions of interest were pooled and concentrated to collect precipitated crystals, thereby obtaining 5.82 g of 3,4-dihydro-2-ethoxy-6-methoxynaphthalene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[N:42]1[CH2:47][CH2:46][C:45]2[C:48]3[CH2:54][CH2:53][CH2:52][CH2:51][C:49]=3[S:50][C:44]=2[C:43]1=[O:55])(=[O:24])[CH3:23]>>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[C:43](=[O:55])[C:44]3[S:50][C:49]4[CH2:51][CH2:52][CH2:53][CH2:54][C:48]=4[C:45]=3[CH2:46][CH2:47]2)=[CH:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 55 %

Procedure:
Following Example 176d, 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one 172a and (2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 111a were reacted to give 179a in 55% yield. LCMS: (M+H)+ 624
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:69]1[CH:74]=[CH:73][C:72]([N:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)=[CH:71][CH:70]=1>CN(C=O)C>[CH3:25][C:24]([CH3:27])([O:23][C:21]([NH:1][C@H:2]([C:18]([N:78]1[CH2:79][CH2:80][N:75]([C:72]2[CH:73]=[CH:74][N:69]=[CH:70][CH:71]=2)[CH2:76][CH2:77]1)=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:22])[CH3:26]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 18.8 g (0.0494 mol) of Boc-Lys(Z)-OH, 6.5 g (0.05 mol) of DIEA, 16 g (0.05 mol) of TBTU, 6.6 g (0.049 mol) of HOBt and 100 ml of dimethylformamide were added dropwise, with stirring, 8.1 g (0.0494 mol) of 1-(4-pyridinyl)piperazine, dissolved in 40 ml of DMF, and the mixture was stirred over-night at room temperature. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was then washed three times successively with 70 ml of saturated aqueous sodium hydrogen carbonate solution and once with 70 ml of saturated aqueous saline solution, dried over sodium sulphate and evaporated down in vacuo. 24.2 g (93.2% of theory) of a yellowish oil were obtained, which was used for the following reactions without further purification.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]2[O:10][C:11]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH2:12][C:13](=[O:14])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C(Cl)(=O)C>CO>[C:1]([N:5]1[CH:9]=[C:8]2[O:10][C:11]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH2:12][C:13](=[O:14])[C:7]2=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1nn(C(C)(C)C)cc1O2
Solvent: CO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCNCC1)O2
Temperature: 0 °C
Yield: 96.5 %

Procedure:
To a 200 L reactor was charged: tert-butyl 2′-tert-butyl-7′-oxo-6′,7′-dihydro-2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazole]-1-carboxylate (8.3 kg, 22.8 moles), ethyl acetate (89 L), and methanol (24 L). Solution was cooled to 0° C., and acetyl chloride (11.0 L, 155 moles) was added over 30 minutes. After addition, reaction was allowed to warm to ambient temperature and react for 4 hours. Heated solution in order to distill to a 41 L reaction volume, slowly refilling with ethyl acetate (˜0.22 L) until an internal temperature of 72° C. was reached. Cooled to ambient temperature over 3 hours, filtered the solids through a Nutsche Filter, washed with ethyl acetate (5.3 L), and dried under vacuum at 50° C. for 12 hours. Isolated 6.6 kg (22.0 moles, 96%) of 2′-tert-butyl-2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a white crystalline solid.
Reaction SMILES: [CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:20])([F:19])[C@@H:16]1[CH2:18][O:17]1>>[CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:18][C@H:16]([OH:17])[C:15]([F:20])([F:19])[F:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: c1ccc(CC2CNCCO2)cc1
Product: O[C@@H](CN1CCOC(Cc2ccccc2)C1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottom flask was placed 2-benzylmorpholine (354 mg, 2 mmol), followed by (S)-2-(trifluoromethyl)oxirane (224 mg, 2 mmol). The mixture was stirred for 30 min. Another 100 uL of (S)-2-(trifluoromethyl)oxirane was added. Reaction mixture was continued at room temperature overnight, then concentrated in vacuo to afford (S)-3-(2-benzyl-morpholin-4-yl)-1,1,1-trifluoro-propan-2-ol a colorless oil (600 mg).
Reaction SMILES: C1([CH2:7][CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH2:9]([NH:10][C:35]([CH:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)=[O:36])[CH2:8][CH3:7]
Reactant: O=C(O)C1CCN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Reactant: NCCCc1ccccc1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: CCCNC(=O)C1CCN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 1C, substituting propan-1-amine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)piperidine-4-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.60 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 7.77 (t, J=5.6 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 7.39-7.33 (m, 2H), 6.89-6.83 (m, 2H), 4.77 (d, J=6.2 Hz, 4H), 3.64-3.56 (m, 2H), 3.05-2.94 (m, 2H), 2.63-2.52 (m, 2H), 2.28-2.14 (m, 1H), 1.79-1.59 (m, 4H), 1.47-1.33 (m, 2H), 0.84 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 408 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH2:21]O)[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C.CS([Cl:43])(=O)=O.O>C(Cl)Cl>[Cl:43][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:20]=[CH:19][N:18]=1
Reactant: COCc1cc(-c2nc(-c3ccnc(CO)c3)no2)ccc1-c1ccccc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3ccnc(CCl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methanol (0.282 g; 0.73 mmol) and DIEA (0.25 mL; 1.46 mmol) in DCM (6 mL) was added methanesulfonyl chloride (0.062 mL; 0.80 mmol). The mixture was stirred at ambient temperature for 1 hour and water added. The mixture was passed through a hydrophobic frit and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 100% EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.78 (1 H, d, J=5.1 Hz), 8.44 (1 H, d, J=1.8 Hz), 8.26 (1 H, s), 8.18 (1 H, dd, J=7.9, 1.9 Hz), 8.02 (1 H, dd, J=5.1, 1.5 Hz), 7.37-7.22 (4 H, m), 7.13 (1 H, d, J=7.5 Hz), 4.79 (2 H, s), 4.28-4.18 (2 H, m), 3.34 (3 H, s), 2.08 (3 H, s).
Reaction SMILES: [ClH:1].Cl.Cl.N[C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][N:12]2[CH2:13][CH2:14]3)[CH:8]=[N:9][CH:10]=1.N([O:21][CH2:22][CH2:23]C(C)C)=O.C(OCC)C>C(O)C.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH2:22]([O:21][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][N:12]2[CH2:13][CH2:14]3)[CH:8]=[N:9][CH:10]=1)[CH3:23]
Reactant: CC(C)CCON=O
Reactant: Nc1cncc(C2CC3CCN2CC3)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOc1cncc(C2CC3CCN2CC3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred solution of 2-(5-amino-3-pyridyl)-1-azabicyclo[2.2.2]octane trihydrochloride (25 mg, 0.08 mmol) in dry ethanol (3 mL) was added isoamyl nitrite (0.10 mL, 0.74 mmol) and the mixture was refluxed for 2 h. When TLC analysis of the reaction mixture showed absence of starting material, the mixture was allowed to cool to ambient temperature. The solvent was removed by rotary evaporation to yield a thick brown oil, which solidified upon addition of dry diethyl ether. The product thus obtained was dissolved in chloroform and kept overnight at 4° C. to induce crystallization. The resulting solids were filtered, washed with diethyl ether and finally dried under vacuum for 24 h, to yield 2-(5-ethoxy-3-pyridyl)-1-azabicyclo[2.2.2]octane dihydrochloride (10 mg, 51%) as colorless needles.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH3:21])([CH3:18])[CH2:13]1.[CH2:22](I)C>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH2:21][CH3:22])([CH3:18])[CH2:13]1
Reactant: CCI
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Product: CCOCC1(C)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared according to the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine except that ethyl iodide was used instead of methyl iodide.