Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([C:30]([CH2:38][CH3:39])([CH2:34][C:35](O)=[O:36])[C:31]([OH:33])=[O:32])[CH3:29].[K+].[Br-]>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:22]=[C:23]([NH:24][C:35](=[O:36])[CH2:34][C:30]([CH2:38][CH3:39])([CH2:28][CH3:29])[C:31]([OH:33])=[O:32])[CH:25]=[CH:26][CH:27]=3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)(CC(=O)O)C(=O)O
Reactant: Nc1cccc(OCc2ccc3ccc(OCc4ccccc4)cc3n2)c1
Agent: [Br-]
Agent: [K+]
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(OCc4ccccc4)cc3n2)c1)C(=O)O

Procedure:
Analogously to Example 3, the title compound is prepared starting from 3-(7-benzyloxy-2-quinolinylmethoxy)aniline and 2,2-diethylsuccinic acid. Slightly yellowish crystals of m.p. 89°-95° are obtained; IR (KBr): 3325, 2966, 1689, 1599, 1545, 1512, 1492, 1436, 1380, 1208, 1157, 1024, 842, 775, 695 cm-1.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].CCN(CC)CC>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:17]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)CCCCl)CC1
Yield: 98914.6 %

Procedure:
Ethyl piperazine-1-carboxylate (800 mg, 5.06 mmol) was treated with 4-chlorobutanoyl chloride (856 mg, 6.07 mmol) in anhydrous CH2Cl2 (25 mL) containing Et3N (1.54 kg, 15.17 mmol) at 20° C. for 2 h, and then washed with 1 M HCl(aq). The organic phase was dried over MgSO4, and concentrated under reduced pressure to give ethyl 4-(4-chlorobutanoyl)piperazine-1-carboxylate (1.315 kg, 99% yield). C11H19ClN2O3; pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (2H, q, J=7.2 Hz), 3.62 (2H, t, J=5.6 Hz), 3.58 (2H, m), 3.46 (6H, m) 2.49 (2H, t, J=6.8 Hz), 2.11 (2H, m), 1.25 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 170.1, 155.1, 61.7, 45.2, 44.8, 43.7 (2×), 41.4, 29.8, 27.8, 14.7; ESI-HRMS calcd for C11H20ClN2O3: 263.1162. found: m/z 263.1175 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[CH:19][N:18]=[C:17]3[N:24](C(OC(C)(C)C)=O)[CH:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)[C:16]=23)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:50]>CCOCC>[ClH:50].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]3[CH2:22][CH2:23]3)=[CH:19][N:18]=[C:17]3[NH:24][CH:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)[C:16]=23)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(C3CC3)cnc3c2c(NC(=O)c2cccnc2)cn3C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(C3CC3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Yield: 48 %

Procedure:
(R)-tert-Butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (81 mg, 0.14 mmol) was treated with TFA followed by 2M HCl in ether as described in Example 1, Step K, to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (33 mg, 48% yield). 1H NMR (400 MHz, D2O) δ 9.16 (d, 1H), 8.82 (dd, 1H), 8.72 (dt, 1H), 7.95 (s, 1H), 7.92 (dd, 1H), 7.41 (s, 1H), 3.98-3.93 (m, 1H), 3.61-3.53 (m, 1H), 3.32-3.25 (m, 2H), 3.15-3.06 (m, 1H), 1.96-1.85 (m, 2H), 1.64-1.56 (m, 1H), 1.52-1.41 (m, 1H), 1.39-1.27 (m, 1H), 0.98-0.92 (m, 2H), 0.70-0.61 (m, 2H); LCMS (APCI+) m/z 377.2 (M+H)+, Retention time=2.12 minutes (Method 2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:30])[C:6]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[OH-].[Li+]>O1CCCC1.C(O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:30])[C:6]([CH:19]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([OH:22])=[O:21])=[C:7]2[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c(Br)cccc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 20.9 %

Procedure:
To a solution of ethyl 2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 0.061 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 3 mL) was added lithium hydroxide (7 mg, 0.31 mmol) and the reaction was heated to 50° C. overnight. Crude reaction purified by reverse phase HPLC (Gemini, 40-100% ACN/H2O+0.1% TFA). Product lyophilized to give a white powder (5.9 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, 1H), 7.77 (d, J=6.0 Hz, 1H), 7.58 (s, 2H), 7.55 (as, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.18 (m, 1H), 5.17 (s, 1H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C23H21BrClO3: 460.8. found; 460.2.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(F)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.78 (m, 3 H), 1.13-1.37 (m, 14 H), 1.93 (m, 2 H), 3.41 (m, 2 H), 4.40 (s, 2 H), 5.28-5.45 (m, 1 H), 6.0 (m, 1 H), 6.87-7.07 (m, 3 H), 7.34 (m, 1 H). Rf=0.36 (10% ethyl acetate/n-hexane). mp 117-118° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([N:25]([CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)C(=O)C(F)(F)F)[CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:55]=[C:56]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[NH:63][N:62]=[C:61]2[NH2:67].CCOC(C)=O.CO.N>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:53][C:54]1[CH:55]=[C:56]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[NH:63][N:62]=[C:61]2[NH:67][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH3:8])=[CH:17][C:18]=1[NH:25][CH:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: CN1CCC[C@H]1COc1ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC[C@H]1COc1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid trifluoroacetate (1 mmol, 531 mg) was dissolved in DCM and two drops of anhydrous DMF under nitrogen atmosphere. Oxalyl chloride (0.17 ml, 2 mmol) was added and the mixture was stirred at room temperature for 2 hours. Solvents were evaporated to obtain a yellow powder. The solid was redissolved in THF under an argon atmosphere and cooled at −20° C. DIPEA (0.56 ml, 3.2 mmol) was added. 5-(3,5-Difluorobenzyl)-1H-indazol-3-amine, dissolved in 10 mL of dry THF was then added dropwise in 15′. The reaction mixture was kept at −20° C. for 6 hours then the temperature was allowed to raise at room temperature overnight. The reaction was quenched with 15 mL of NaHCO3 5% and extracted twice with AcOEt (15 ml). Solvents were then evaporated and the residue was redissolved in 20 ml of MeOH. TEA (10 mmol, 1.5 ml) was added and the mixture was heated to 65° C. for 3 hr. Then the reaction was cooled to room temperature and the solvents removed to yield the crude product which was purificated by means of silica gel flash chromatography (AcOEt/MeOH/NH3 Aq. 85:15:05) to yield the title compound as a white powder (258 mg, 0.45 mmol, 45%).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][C:24]([CH3:28])=[CH:23]2>>[CH3:28][C:24]1[N:25]=[CH:26][C:27]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=[C:4]1[N:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@H:7]2[CH2:6][S:5]1
Reactant: Cc1cc2cccc(N)c2cn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: Cc1cc2cccc(N=C3SC[C@@H]4Cc5ccccc5CN34)c2cn1
Yield: 53.9 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (8 g) and 8-amino-3-methylisoquinoline (3.5 g) as the starting materials, (S)-3-[(3-methylisoquinol-8-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (4.1 g) is obtained in the form of pale yellow crystals, m.p.=156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@@H:6]1[F:18].[NH4+].[Cl-]>CCO.O.CCOC(C)=O.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C@H:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][C@@H:6]2[F:18])=[C:2]([Cl:1])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2Cl)[C@@H](F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2Cl)[C@@H](F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of tert-butyl (3S,4S)-4-(2-chloro-4-nitrophenoxy)-3-fluoropiperidine-1-carboxylate (0.8 g, 1.0 eq, 2.2 mmol), Fe (0.6 g, 5.0 eq, 10.8 mmol) and NH4Cl (0.6 g, 5.0 eq, 10.8 mmol) in EtOH/H2O (1:1, 50 mL) was stirred at 90° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure to leave a crude solid. The crude mixture was dissolved in EtOAc (50 mL) and partitioned with H2O (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the desired product in 45% yield. This product was taken to next step with out further purification.
Reaction SMILES: CC1(C)[O:31][C@@H:5]2[CH2:6][N:7]([C:10]3[CH:19]=[C:18]4[C:13]([CH:14]=[C:15]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:27]([F:30])([F:29])[F:28])[NH:16][C:17]4=[O:20])=[CH:12][CH:11]=3)[C:8](=[O:9])[C@@H:4]2[O:3]1.Cl.[OH-].[Na+]>C1COCC1>[OH:3][C@@H:4]1[C@H:5]([OH:31])[CH2:6][N:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:29])([F:28])[F:30])[NH:16][C:17]3=[O:20])=[CH:12][CH:11]=2)[C:8]1=[O:9]
Reactant: CC1(C)O[C@@H]2CN(c3ccc4cc(-c5ccccc5C(F)(F)F)[nH]c(=O)c4c3)C(=O)[C@@H]2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1[C@H](O)[C@H](O)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 6.4 %

Procedure:
The 7-((3aR,6aR)-2,2-dimethyl-4-oxotetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (630 mg, 1.42 mmol) obtained in step C was dissolved in THF (15 ml). Thereafter, 1 N hydrochloric acid (8.1 ml, 8.1 mmol) was added to the solution. The obtained mixture was stirred for 4 hours, while gently heating. Thereafter, the reaction solution was cooled to 0° C., and a 1 N sodium hydroxide aqueous solution was added thereto until liquid property became pH 8. An organic layer was separated, and a water layer was extracted with ethyl acetate. The organic layer was mixed with the extract. The mixture was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol), so as to obtain 36.7 mg of 7-((3R,4R)-3,4-dihydroxy-2-oxopyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (7%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[I-].[C:34]1([Zn+])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: [Zn+]c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and phenylzinc iodide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column and eluted with hexanes:ethyl acetate (3:1) to yield Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetate (15 mg, 63% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[SH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][S:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Sc1ccncc1
Product: CCN1c2ncc(CSc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 79 %

Procedure:
Using a procedure analogous to that described in Example 117, the title compound, m.p. 140°-142° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-mercaptopyridine. The yield was 79% of theory.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C([Li])CCC.CCCCCCC.CN([CH:28]=[O:29])C>CC(O)=O.C1COCC1>[CH:28]([C:3]1[CH:2]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:12])[NH:8]2)=[O:29]
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=Cc1cccc2c1CCC(=O)N2
Temperature: -78 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
Following the procedure reported above for 2-ethyl-5-formyl-2H-1,2,3,4-tetrahydroisoquinolone described above, 6-bromo-1,2,3,4-tetrahydroquinol-2-one (1.07 g, 4.73 mmol), a solution oft-butyllithium in heptane (1.7M, 9.7 mL, 16.6 mmol), DMF (0.37 mL, 4.73 mmol) and THF 35 mL) were combined. The reaction mixture was stirred at −78° C. for 4 h and HOAc (1 mL) was added. The previously described workup provided crude product. Column chromatography (EtOAc:hexane::1:1, then DCM:MeOH::97:3) and removal of solvent in vacuo provided a white solid (116 mg, 14% yield): 1H NMR: 9.90 (s, 1H), 8.0 (s, 1H), 7.77–7.74 (m, 2H), 6.89 (d, 1H, J=8), 3.07 (t, 2H, J=7), 2.71 (t, 2H, J=7).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH:37]1([C:41](O)=[O:42])[CH2:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][C:41]([CH:37]4[CH2:40][CH2:39][CH2:38]4)=[O:42])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C(O)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNC(=O)C2CCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 8 h
Yield: 16.5 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.189 mmol) prepared in Example 32e, cyclobutanecarboxylic acid (98 mg, 0.948 mmol), EDC.HCl (181 mg, 0.948 mmol), HOBt (128 mg, 0.948 mmol) and DIPEA (245 mg, 1.897 mmol) in anhydrous DMF (4 mL) was stirred overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (19 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.C(OCC)(=O)[CH2:27][C:28]([O:30]CC)=[O:29].C(O)(=O)C.[OH-].[Li+].S([O-])(O)(=O)=O.[K+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CO>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([CH2:27][C:28]([OH:30])=[O:29])=[CH:7][CH:6]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C(=O)C[C@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)ccn1
Temperature: 135 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
A mixture of (R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 142, step 2; 3.5 g, 8.88 mmol), diethyl malonate (67.5 g, 421 mmol) sodium hydride (724 mg, 18.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (475 mg, 518 μmol) and 2-(di-tert-butylphosphino)biphenyl (155 mg, 518 μmol) in was heated at 135° C. for 90 min. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in water (13 mL) and acetic acid (19 mL, 19.8 mmol) then under cooling conc. sulfuric acid (11.9 g, 116 mmol) was added dropwise at a temperature below 30° C. The reaction mixture was heated at 120° C. for 16 h, then partitioned between 2 M aq. sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (110 mL), then after addition of 1 M aq. lithium hydroxide solution (350 mL, 350 mmol) and methanol (110 mL) the reaction mixture was stirred for 3 h at room temperature. After addition of 1 M aq. potassium hydrogensulfate solution (60 mL) and sat. aq. ammonium chloride solution (100 mL) the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Chromatography (SiO2) produced the title compound (1.96 g, 59%). White foam, MS (ESI+): m/z=374.3 ([M+H]+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][N:15]=1.[CH3:17][O:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C)C=O>[CH3:17][O:18][CH2:19][CH2:20][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][N:15]=1
Reactant: COCCBr
Reactant: Nc1nccnc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCn1c(-c2nccnc2N)nc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
3-(1H-benzimidazol-2-yl)pyrazin-2-amine (0.302 g, 0.14 mmol) was dissolved in N,N-dimethyl formamide (10 mL) and treated with 2-bromoethyl methyl ether (0.15 mL, 0.16 mmol) and cesium carbonate (0.475 g, 1.4 mmol). The mixture was stirred at ambient temperature for 20 hours and then filtered through celite. The filtrate was concentrated and partitioned between ethyl acetate and water. The mixture was extracted into ethyl acetate (×3) and the combined organic layers were washed with water, and then with saturated sodium chloride. The organics were dried over magnesium sulfate, filtered and concentrated. Trituration with diethyl ether afforded the title compound as tan solids (0.275 g, 0.10 mmol).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].CC1C=CC(S(O[CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:13][C:11]([C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:3]([CH2:1][CH3:2])[N:4]([CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:5]=1)=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 96 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (8.20 g, 44.6 mmol, prepared using procedure in WO9849166), tert-butyl (2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (17.4 g, 49.0 mmol, prepared using procedure in WO9926944) and cesium carbonate (16.0 g, 49.2 mmol) in N,N-dimethylformamide (100 ml) was stirred at 20° C. for 4 days and then at 50° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (300 ml) and water (300 ml). The phases were separated, and the aqueous layer extracted with further EtOAc (2×200 ml). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was partially purified by column chromatography (DCM/MeOH, 100:0-91:9) and then the regioisomers were separated by further column chromatography (Et2O/EtOAc, 100:0-50:50) to afford the title compound of preparation 34 (1.23 g, 3.35 mmol, 7.5%); mp 68-75° C.