Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([N+]([O-])=O)[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10](CCl)[CH2:9]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.COC1C=C2C(=C(OC)C=1OC)NC(C(O)=O)=C2.CN(C=O)C>Cl.O>[CH2:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=[CH:15][C:16]=2[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c3c(ccc2c1)NCC3
Temperature: 20 °C
Reaction time: 2 h
Yield: 196.1 %

Procedure:
A solution of 13 (170 mg, 0.47 mmol) in HCl-saturated dioxane (10 mL) was stirred at 20° C. for 2 h, then evaporated under reduced pressure below 30° C. EDCI-HCl (270 mg, 1.41 mmol), 5,6,7-trimethoxyindole-2-carboxylic acid (118 mg, 0.47 mmol) and DMF (2.5 mL) were then added, and the mixture was stirred at 20° C. for 2 h. Addition of water precipitated a crude product, which was recrystallised twice from CH2Cl2 /iPr2O to give 1-chloromethyl-5-nitro-3-[5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole (14a) (156 mg, 67%), mp 243-245° C. 1H NMR (CDCl3) δ9.44 (s, 1 H, NH), 9.24 (s, 1 H, H-9), 8.43 (dd, J=7.9, 1.2 Hz, 1 H, H-7), 7.87 (dd, J=7.7, 1.5 Hz, 1 H, H-4), 7.70-7.60 (m, 2 H, H-5,6), 7.03 (d, J=2.5 Hz, 1 H, H-3'), 6.87 (s, 1 H, H-4'), 4.88 (dd, J=10.8, 2.1 Hz, 1 H, H-2), 4.74 (dd, J=10.4, 8.9 Hz, 1 H, H-2), 4.36-4.26 (m, 1 H, H-3), 4.10 (s, 3 H, OCH3), 3.99 (dd, J=11.4, 3.1 Hz, 1 H, CHHCl), 3.95 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 3.58 (dd, J=11.4, 9.9 Hz, 1 H, CHHCl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[N:8][C:7]([O:6][CH2:5][C:4]3[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=3)=[C:12]([CH:11]=2)[C:13]([Cl:43])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid (120 mg, 0.20 mmol) from Example 77 in methylene chloride (3 mL) was added a drop of DMF (cat.) and oxalyl chloride (0.100 mL, 1.1 mmol). The reaction was stirred at rt for 1 h and was then evaporated to dryness. The acid chloride was dissolved in methylene chloride and used directly in the subsequent amide formation.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]1.[F-].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[N:21]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of Example A1 (1.5 g, 5.96 mmol), N-methyl-4-(tributylstannyl)imidazole (3.32 g, 8.94 mmol) and Pd(PPh3)4 (0.344 g, 0.298 mmol) in toluene (30 mL) sparged with Ar and heated at 110° C. overnight. The mixture was cooled to RT, treated with 10% KF and EtOAc, stirred at RT for 2 h, the solids removed via filtration through diatomaceous earth and washed with 5% MeOH/DCM. The layers of the filtrate were separated and the organic layer was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was washed with a small amount of Et2O and dried to afford 2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61 g, 91%). 1H NMR (400 MHz, Acetone-d6): δ 8.54 (d, J=2.8 Hz, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.98 (dd, J=8.9, 2.8 Hz, 1H), 7.69 (d, J=1.4 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.55 (s, 1H), 6.97 (dd, J=5.6, 2.6 Hz, 1H), 3.81 (s, 3H); MS (ESI) m/z: 298.1 (M+H+).
Reaction SMILES: [CH:1](=[N:5]/[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])\[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[O:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].O.[OH-].[Na+]>CC1CCCO1>[CH2:23]([O:22][C:18]([O:19][CH2:20][CH3:21])([C@@H:1]([NH:5][C@H:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[CH2:2][CH2:3][CH3:4])[C:17]([O:25][CH2:26][CH3:27])=[O:16])[CH3:24]
Reactant: CCC/C=N/[C@@H](C)c1ccccc1
Reactant: CCOC(OCC)=C(OCC)O[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
With HBF4OEt2: (S,E)-N-butylidene-1-phenylethanamine (Example 1, 10.0 g, 57.0 mmol) was dissolved in 250 mL 2-methyltetrahydrofuran and cooled to 0° C. HBF4OEt2 (9.24 g, 57.0 mmol) was added to the mixture followed by a solution of trimethyl((1,2,2-triethoxyvinyl)oxy)silane (Example 10, 11.34 g, 45.6 mmol) in 80 mL 2-methyltetrahydrofuran, and the mixture was stirred at 0° C. for three hours and fifteen minutes. Water (400 mL) was added to quench the reaction, the mixture was neutralized (pH=7.6) with 10N NaOH, the phases were separated and the organic phase was extracted once more with further 400 mL water. Water (300 mL) and 2-methyltetrahydrofuran (50 mL) were added to the mixture, the pH was acidified (pH=5.6) with 2N HCl and the phases were separated. The organic phase was extracted with further 300 mL water and 50 mL 2-methyltetrahydrofuran and the solvent of the organic phase was removed in vacuo to yield 17.1 g crude (S)-ethyl 2,2-diethoxy-3-(((S)-1-phenylethyl)amino)hexanoate as a 86.14 (syn:anti) diastereomeric mixture.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(Br)s1
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)s1

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) ) of α-ethynyl- 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 371 mg (19%) of the expected methyl ester, with a melting point of 84°-85° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:22]=[CH:21][C:20](OC)=[N:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:27][C:20]1[CH:21]=[CH:22][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:14][CH2:13][C:12]3[O:15][N:16]=[C:17]([CH3:18])[C:11]=3[C:10]=2[N:19]=1
Reactant: COc1ccc2c(n1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Temperature: 140 °C

Procedure:
To 5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine (0.050 g, 0.147 mmol) were added phosphoryl chloride (1 mL, 11 mmol) and DMF (0.1 mL) at room temperature. The reaction was heated to 140° C. for 4 h using microwave irradiation before 2M aq. NaOH and 2M aq. Na2CO3 were added to quench the excess of reagent. The desired product was extracted using EtOAc (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. A fraction of the residue was purified by reverse phase chromatography to give the title product as a white solid. LC/MS m/z 344 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=8.52 Hz, 1H), 7.49 (d, J=8.31 Hz, 1H), 7.46 (td, J=2.10, 8.70 Hz, 2H), 7.41 (td, J=2.10, 8.70 Hz, 2H), 4.80 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.[CH:25](N(CC)C(C)C)([CH3:27])[CH3:26].BrCCC>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][N:23]([CH2:26][CH2:25][CH3:27])[CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)c1Cl
Solvent: CCCBr
Solvent: C1COCCO1
Product: CCCN1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3
Temperature: 100 °C
Yield: 81 %

Procedure:
To a solution of (±)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) in 1,4-dioxane (0.5 mL) and N,N-diisopropylethylamine (108 mg, 0.83 mmol) were added 1-bromopropane (21 mg, 0.17 mmol) and KI (catalytic amount). The reaction mixture was heated at 100° C. for 15 h. The reaction mixture was cooled to 20° C. then concentrated in vacuo and chromatographed on a silica gel column by elution with CHCl3/MeOH (99/1) to give the title compound (27 mg, 82%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 0.92(t, J=7.3 Hz, 3H), 1.58-1.75 (br, 2H), 2.03-2.23 (m, 5H), 2.42-2.55 (br, 2H), 2.58-2.67 (m, 1H), 2.75 (t, J=7.4 Hz, 2H), 2.85-2.95 (br, 1H), 2.98-3.12 (br, 1H), 3.31 (dt, J=10.3, 3.6 Hz, 1H), 3.37-3.45 (br, 2H), 6.94 (s, 1H), 6.97 (s, 1H), 7.15-7.20 (m, 2H), 7.36-7.42 (m, 1H) ppm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]([F:73])([F:72])[C:34]1[CH:35]=[C:36]([C:44]([CH3:71])([CH3:70])[C:45]([N:47]([C:49]2[C:50]([C:62]3[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=3[CH3:69])=[CH:51][C:52]([N:55]3[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]3)=[N:53][CH:54]=2)[CH3:48])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.[C:74](O)(=[S:76])[CH3:75]>C1COCC1>[F:73][C:33]([F:32])([F:72])[C:34]1[CH:35]=[C:36]([C:44]([CH3:70])([CH3:71])[C:45]([N:47]([CH3:48])[C:49]2[C:50]([C:62]3[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=3[CH3:69])=[CH:51][C:52]([N:55]3[CH2:60][CH2:59][CH:58]([O:61][C:74](=[S:76])[CH3:75])[CH2:57][CH2:56]3)=[N:53][CH:54]=2)=[O:46])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: CC(O)=S
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Yield: 58.1 %

Procedure:
A solution of 0.22 g (0.84 mmol) triphenylphosphine and 0.15 g (0.84 mmol) diethyl azodicarboxylate in 3.33 ml THF was stirred for 15 min at 0° C. This solution was added to a solution of 0.25 g (0.42 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide and 64 mg (0.84 mmol) thioacetic acid in 10 ml THF at 0° C. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material a 2 N aqueous solution of sodium carbonate was added. The mixture was extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.16 g (59%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:41]>O1CCCC1>[Cl:41][C:11]1[N:10]2[N:13]=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[N:17]=3)=[C:9]2[CH:8]=[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:12]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-amine (120 mg, 0.26 mmol) in tetrahydrofuran (5 mL) at −78 ° C. was added n-butyllithium (0.8 mL, 1.3 mmol of 1.6 M solution in hexanes). The resulting reaction was stirred at −78° C. for 10 minutes, then carbon tetrachloride (1 mL) was added. The reaction mixture was allowed to warm to room temperature and then quenched by the addition of water. The phase were separated and the organic phase dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (1:1 hexanes-ethyl acetate) to give 7-chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-amine (12 mg) as a foam. 1H-NMR (CDCl3): δ 7.97 (d, 1H), 7.62 (q, 2H), 7.44 (d, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 6.22 (d, 1H), 5.30 (broad s, 1H), 4.44 (m, 1H), 4.18 (m, 1H), 3.94 (m, 1H), 1.4–2.1 (16H);19F-NMR (CDCl3): δ −113.24; MS m/z 492 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=2[N:10]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:29][CH:28]=1>>[CH:13]1([C:11]2[N:12]=[C:7]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:31][CH:32]=3)[C:8]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: NC(=O)Cc1ccc(Nc2nc(C3CCCC3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 54.9 %

Procedure:
Following general procedure H, 2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.200 g, crude) was reacted with 2-(4-aminophenyl)acetamide (0.038 g, 0.25 mmol) to afford the title compound (0.055 g, 27%) as a white solid. MW=400.49. 1H NMR (DMSO-d6, 500 MHz) δ 8.60 (s, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 3.71-3.64 (m, 2H), 3.36 (s, 2H), 3.10 (quin, J=8.0 Hz, 1H), 2.94 (t, J=6.5 Hz, 2H), 2.38-2.29 (m, 2H), 1.99-1.91 (m, 2H), 1.84-1.55 (m, 6H); APCI MS m/z 401 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][CH:9]([F:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=1>C(N(CC)CC)C.C(#N)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.[Cu](I)I>[F:8][CH:9]([F:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: Ic1cccnc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)Oc1ccc(C#Cc2cccnc2)cc1

Procedure:
A solution of 3-iodopyridine (205 mg, 1.0 mg) in triethylamine was treated with tetrakis(triphenylphosphine)palladium (80 mg, 0.069 mmol), copper iodide (18 mg, 0.097 mmol) and a solution of 1-(difluoromethoxy)-4-ethynylbenzene (168 mg, 1.0 mmol) in acetonitrile at room temperature, heated at 60° C. for 1 h, cooled and concentrated to dryness to afford 3-{[4-(difluoromethoxy)phenyl]ethynyl}pyridine as a residue. The residue (240 mg) was dissolved in acetone, treated sequentially with a solution of NaHCO3 (50 mg) and MgSO4 (180 mg) in H2O and KMnO4 (327 mg), stirred for 10 minutes at room temperature and extracted with 1/1 Et2O/hexane. The combined extracts were concentrated to dryness to give 1-[4-(difluoromethoxy)phenyl]-2-pyridin-3-ylethane-1,2-dione. A mixture of 1-[4-(difluoromethoxy)phenyl]-2-pyridin-3-ylethane-1,2-dione (230 mg), N-methylguanidine hydrochloride (155 mg) and Na2CO3 (240 mg) in ethanol was heated at reflux temperature for 1.5 h. and concentrated in vacuo. The resultant residue was purified by chromatography (silica gel, EtOAc/2.0 M NH3 in EtOH: 97/3) to give the title compound (130 mg) as a solid, mp: 173-175° C., identified by NMR and mass spectral analyses. MS (+) APPI: 333 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12]N1C(=O)CCC1=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][CH2:29][CH2:30][N:31]([CH2:40][CH2:41][Cl:42])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([NH2:39])[CH:33]=1.C(N(CC)CC)C>C(#N)C>[Cl:28][CH2:29][CH2:30][N:31]([CH2:40][CH2:41][Cl:42])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([NH:39][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:33]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: Cc1ccc(N(CCCl)CCCl)cc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(N(CCCl)CCCl)cc1NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (Levi and Weed, U.S. Pat. No. 3,235,594 (1966)), to a solution of O1-(2,5-Dioxopyrrolidin-1-yl)O4-tert-butyl(2S)-2-(tert-butoxycarbonylamino)-butanedioate (Boc-L-Asp(Osu)-OtBu) (6a) (386 mg, 1.0 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added N,N-bis(2-chloroethyl)-4-methyl-benzene-1,3-diamine (16b) as a bis hydrochloride salt (320 mg, 1.0 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 h at room temperature. The reaction is followed by TLC and/or LC/MS to completion. The volatile solvents are removed under reduced pressure using a rotary evaporator. Aqueous work-up and purification by silica gel column chromatography furnish the target compound (16c).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)[CH3:2].[O:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[O:12])[CH2:11][C:14]([OH:13])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1nccc(C(C)=O)n1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Product: CCNc1nccc(C(=O)CC(O)(C(=O)OCC)C(=O)OCC)n1
Temperature: 110 °C

Procedure:
A mixture consisting of 1.9 g of 1-(2-ethylaminopyrimidin-4-yl)ethanone and 1.86 ml of diethyl ketomalonate is heated at 110° C. for 18 hours. The mixture is purified by column chromatography (silica gel, mobile phase: methylene chloride:methanol=98:2).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>O.CCOC(C)=O>[NH:11]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:12]1
Reactant: O=Cc1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Product: c1cnc2[nH]ncc2c1
Temperature: 25 °C

Procedure:
A solution of 2-chloropyridine-3-carbaldehyde (20 g, 141 mmol) and hydrazine monohydrate (60% in water, 113 g, 2.1 mol) in 140 mL water was heated at 100° C. for 72 hours. The reaction mixture was cooled to room temperature and diluted with 200 mL of EtOAc. The aqueous layer was separated and extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a light orange solid which was crystallized from hexanes to give the title compound as an off-white solid. 1H NMR (400 MHz, CH3CN-d3): δ 11.56 (s, 1H); 8.51 (dd, J=4.52, 1.56 Hz, 1H); 8.17 (dd, J=8.05, 1.58 Hz, 1H); 8.05 (s, 1H); 7.17 (dd, J=8.05, 4.51 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1
Reactant: Cc1cccc(C=O)c1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3cccc(C)c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
370 μL of a methanol solution containing 14 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide and 10 μL of acetic acid were added to 3.6 mg of 3-methylbenzaldehyde, and stirred at room temperature for 1 min. To the reaction mixture, 120 μL of a methanol solution containing 3.8 mg of sodium cyanoborohydride was added, and stirred at the same temperature overnight. After the solvent was removed under reduced pressure, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:methanol=20:1], to give 7.6 mg of (1-(2-(4-(3-methylbenzylamino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide as a pale yellow foam.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:50])([CH2:48][CH3:49])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:47])[CH3:46])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>O1CCOCC1.CO>[CH3:2][C:3]([CH3:50])([CH2:48][CH3:49])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:47])[CH3:46])[C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:35][CH:36]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(C)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(NC(C)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (4N, 2 mL) in dioxane was added to a solution of N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]-ethyl}acetamide in methanol (4 mL) at ambient temperature. The solution was stirred at 50° C. for 2 hr. Concentration of the solution afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.95-8.92 (m, 1H), 8.45-8.39 (m, 1H), 8.33 (dd, J=4.5, 9.0 Hz, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.18 (s, 1H), 5.49 (t, J=8.0 Hz, 1H), 3.56-3.48 (m, 3H), 2.52 (s, 2H), 1.96 (s, 3H), 1.25 (q, J=7.5, 15.0 Hz, 2H), 0.87 (t, J=7.5 Hz, 3H), 0.84 (s, 3H), 0.83 (s, 3H).