Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[C:38]2[C:37]3[CH2:39][NH:40][CH2:41][CH2:42][C:36]=3[CH:35]=[CH:34][C:33]=2[NH:32][C:31](=[O:43])[C:30]1=[O:44].C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[O:44]=[C:30]1[NH:29][C:38]2[C:37]3[CH2:39][N:40]([C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH2:12]4)=[O:16])[CH2:41][CH2:42][C:36]=3[CH:35]=[CH:34][C:33]=2[NH:32][C:31]1=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCc3ccc4[nH]c(=O)c(=O)[nH]c4c3C2)CC1
Temperature: 70 °C
Reaction time: 19 h
Yield: 72.6 %

Procedure:
A solution of N-Boc-4-piperidinecarboxylic acid (158 mg, 0.69 mmol) and carbonyldiimidazole (119 mg, 0.69 mmol) in tetrahydrofuran (3 mL) under a nitrogen atmosphere was reluxed for 15 min. This solution was then added to suspension of the quinoxalinedione from Example 30 (100 mg, 0.46 mmol) in anhydrous dimethylformamide (3 mL). After stirring for 15 min (nitrogen atmosphere), triethylamine (0.96 mL, 0.69 mmol) was added and the reaction was stirred at 70° C. for 19 h. The mixture was concentrated to dryness and the residue triturated with water and collected by filtration. A beige solid (143 mg, 73% yield) was obtained. mp=283-286° C.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1ccccn1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccccn3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-pyridinecarbonyl chloride: ESMS m/e: 484.6 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8].[C:16]1([CH2:22][CH2:23][SH:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([CH2:2][S:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:7]([CH3:8])[O:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1CBr
Reactant: SCCc1ccccc1
Product: Cc1onc(-c2ccc(Br)cc2)c1CSCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 4-bromomethyl-3-(4-bromo-phenyl)-5-methyl-isoxazole and 2-phenyl-ethanethiol.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[C:31]([CH3:34])(C)[CH3:32]>>[F:22][C:21]1[CH:32]=[C:31]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)[CH:34]=[CH:17][CH:18]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)(C)C(=O)CBr
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)cs2)C1

Procedure:
250 mg (about 0.211 mmol) of the compound from Example 53A and 154 mg (0.710 mmol) of 1-bromo-3,3-dimethylbutan-2-one were reacted according to the General Method 3. Yield: 88 mg (29% of theory).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:16])[NH:11][CH2:12][C:13](=O)[CH3:14])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][C@@H:8]1[NH:7][CH:13]([CH3:14])[CH2:12][NH:11][C:10]1=[O:16]
Reactant: CC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNC(=O)[C@H](C)N1
Reaction time: 24 h

Procedure:
(1S)-[1-(2-oxo-propylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester (5.93 g, 24.3 mmol) is stirred in a solution of 30% trifluoroacetic acid in methylene chloride (100 mL) for three hours. The solvents are removed in vacuo. The residue is dissolved in 50 mL of MeOH and transferred to a par bottle. Palladium on carbon (10%, 1.0 g) is added, and the mixture is hydrogenated under pressure for 24 hours. The catalyst is filtered off; the MeOH is removed in vacuo to afford (3S, 5RS)-3,5-dimethyl-piperazin-2-one which is directly protected with a benzyl carbamate without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22].CCN(C(C)C)C(C)C>CC#N>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1Cl
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
A mixture of 2-(2-chloro-6-fluoro-3-nitrophenyl)pyridine* (618 mg, 2.6 mmol), 2-methoxyethylamine (0.23 mL, 2.6 mmol) and DIPEA (0.48 mL, 2.7 mmol) in MeCN (5 mL) was stirred for 1.5 h at 0° C. After warming to RT, the volatiles were removed in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-70% EtOAc/cyclohexane) to afford the title compound as a yellow oil (414 mg, 54%). LCMS (Method C): RT 2.95 min [M+H]+ 292. 1H NMR (CDCl3, 400 MHz): δ 8.73 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 8.47 (1H, bs), 8.26 (1H, dd, J=9.5, 6.0 Hz), 7.79 (1H, ddd, 8.0, 8.0, 2.0 Hz), 7.45-7.43 (1H, m), 7.32 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 6.52 (1H, dd, 9.5, 8.0 Hz), 3.29-3.26 (2H, m), 3.28 (3H, s), 2.63-2.60 (2H, m)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=4)[N:32]=3)[CH2:23][CH2:22]2)[CH:16]=1)=[O:13].[I-].[Na+]>C1COCC1.CC(N(C)C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:37])[F:38])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)[CH:16]=2)=[O:13])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(CCCCl)Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCCC(=O)Nc2cccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)CC1
Temperature: 60 °C
Yield: 47.8 %

Procedure:
1-Methylpiperazine (152 μl, 1.37 mmol) was added to 4-chloro-N-[3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]butanamide (160 mg, 0.343 mmol) and sodium iodide (10 mg, 0.069 mmol) in a mixture of THF (2 mL) and DMA (0.5 mL). The resulting solution was heated at 60° C. for 16 hours, then cooled and evaporated to give the crude product, which was purified by flash chromatography on silica, eluting with a gradient of 0-10% 2M ammonia in methanol in DCM. The solvents were evaporated, then the resulting gum triturated with ether and the precipitate filtered and dried to give 4-(4-methylpiperazin-1-yl)-N-[3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]butanamide (87 mg, 48%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]=[CH:19][N:20](S(C3C=CC=CC=3Br)(=O)=O)[CH:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].CS(C)=O.[Li+].[OH-]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[CH2:15][CH2:16]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(c2cn(S(=O)(=O)c3ccccc3Br)cn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1Br)N1CCC(c2c[nH]cn2)CC1
Yield: 94 %

Procedure:
To a 20 mL vial containing 1-[(2-bromophenyl)sulfonyl]-4-{1-[(2-bromophenyl)-sulfonyl]-1H-imidazol-4-yl}piperidine (884 mg, 1.50 mmol) were added a stirbar and DMSO (10 mL). Once the DMSO solution was homogeneous, LiOH (3 mL, 1.0 M) was added slowly. After 30 min the reaction mixture was diluted with EtOAc, washed with water (×4) and brine (×1), dried over MgSO4, filtered and concentrated to dryness to give the title compound (522 mg, 94%). MS (ESI): mass calcd. for C14H16BrN3O2S 369.01 m/z found 370.0 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.08 (dd, J=7.9, 1.7, 1H), 7.72 (dd, J=7.8, 1.3, 1H), 7.62 (s, 1H), 7.45-7.41 (m, 1H), 7.40-7.35 (m, 1H), 6.76 (s, 1H), 3.88 (d, J=12.8, 1H), 2.90 (m, 2H), 2.76-2.69 (m, 1H), 2.09-2.01 (m, 2H), 1.77-1.67 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#N)[CH:6]=[CH:5][N:4]=1.Cl.NNC(N)=[O:15].C([O-])(=O)C.[Na+].C(O)C>[Ni].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:15])[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(C#N)ccn1
Reactant: NNC(N)=O
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C=O)ccn1
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A mixture of 2-methoxy-4-cyanopyridine (57.2 g), semicarbazide hydrochloride (71.24 g), sodium acetate (69.86 g), ethanol (1200 ml) and water (370 ml) was hydrogenated at 344 kPa using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 450 ml, water (900 ml) was added and the mixture was allowed to stand at 0° overnight. The mixture was filtered and the solid was washed with water and was dissolved in 10% hydrochloric acid (950 ml). Formaldehyde solution (36% w/v, 420 ml) was added and the mixture was warmed for 30 minutes, allowed to cool and was added to a solution of sodium acetate (280 g) in water (840 ml). The mixture was extracted with ether (3×500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 2-methoxypyridine-4-carboxaldehyde (20.53 g, 35%) m.p. 33°-35°. A sample recrystallised from petroleum ether had m.p. 33°-36°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[N:10]([O-])=[O:11].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:10]=[O:11])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(N=O)cc(C)c1O

Procedure:
25 Grams of 2,6-dimethylphenol was dissolved in 246 ml of 50% aqueous glacial acetic acid solution. To this solution being kept at 15° C. or lower was added dropwise 91 g of 30% aqueous sodium nitrite solution, whereby 2,6-dimethyl-p-nitrosophenol was obtained. The compound was reduced to be converted to an amino compound. The amino compound was subjected to diazotization at 0° to 2° C. Into the resulting reaction mixture was poured a 50% aqueous zinc chloride solution. By thorough mixing, a double salt of a diazonium salt with zinc chloride was deposited. Infrared absorption spectra (KBr tablet method): around 3300 cm-1, 2200 cm-1, 1570 cm-1, 1080 cm-1, 930 cm-1 ; ultraviolet absorption spectra (solvent: water), wavelength at maximum absorption: 364 nm. SYNTHESIS EXAMPLES 5 AND 6
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:21][OH:22].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:5][O:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH:21]=[O:22]
Reactant: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1CO
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
7-((R)-2-Hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic Acid Methyl ester 95% Ethanol (0.5 mL) was added to a mixture of nickel (II) chloride (105 mg, 0.81 mmol) and sodium borohydride (15 mg, 0.40 mmol). The mixture immediately turned black. After 15 min at rt, ethylene diamine (86 μL, 1.29 mmol) was added. After 15 min at rt, a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (from Example 1, step 3, 43.3 mg, 0.16 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 16.7 mg (38%) of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester. Step 2. 7-((R)-2-Formyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester EDCI (36 mg, 0.19 mmol) and DMSO (18 μL, 0.25 mmol) were added sequentially to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester (16.7 mg, 0.062 mmol) in benzene (1.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (13.2 mg, 0.068 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 2.5 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×1 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[N-:33]=[N+:34]=[N-:35].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]1[NH:35][N:34]=[N:33][N:5]=1
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C#N)c3)nc2-c2ccc3ncccc3c2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(-c4nnn[nH]4)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A mixture of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile (Example 76) (100 mg, 0.238 mmol) and sodium azide (20.9 mg, 0.321 mmol) in toluene (1 mL) was stirred at 120° C. for overnight. The reaction mixture was cooled to room temperature and basified to pH 9-10 with 5N NaOH solution in the ice bath. The mixture was extracted with CH2Cl2 (5 mL, 3 times), and then the aqueous layer was acidified to pH 4 with 2N HCl solution. The precipitate was filtered, washed with H2O, and dried under vacuum for overnight to afford the solid, which was recrystallized from MeOH/CH2Cl2/Et2O to give the title compound (56 mg, 51%). (300 MHz, CDCl3+CD3OD) δ 2.49 (3H, s), 4.17 (2H, s), 6.98 (1H, d), 7.08 (1H, dd), 7.13 (1H, d), 7.35-7.41 (2H, m), 7.45-7.50 (1H, m), 7.81 (1H, dd), 7.97-8.01 (2H, m), 8.05 (1H, d), 8.13 (1H, dd), 8.80 (1H, dd). MS (ESI) m/z 463 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[N:25]([CH3:34])[C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([F:33])=[CH:28][CH:27]=4)(=[O:23])=[O:22])=[C:16]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39].C(OCC)(=O)C>CCOCC>[ClH:39].[CH3:38][S:35]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][C:17]=1[NH:20][S:21]([C:24]1[N:25]([CH3:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([F:33])=[CH:28][CH:27]=2)(=[O:22])=[O:23])(=[O:37])=[O:36]
Reactant: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2cc(F)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCNCC3)cc2S(C)(=O)=O)cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[4-(5-fluoro-1-methyl-1H-indole-2-sulfonylamino)-3-methanesulfonyl-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.019 g) was treated with 2.5 N HCl/ethyl acetate (2.5 ml). The reaction mixture was stirred at rt for 3 h, then ether (20 ml) was added. The precipitate was collected, washed with ether and dried under high vacuum over P2O5 to produce the title compound (0.014 g) as an off-white amorphous powder. MS (ISN): 464.0 (M−H)−
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=C[CH:29]=[C:28]2[C:24]=1[C:25]1([C:36]3=CC4OCOC=4C=C3O[CH2:33]1)[C:26](=[O:32])[NH:27]2.ClCC1N=C(C(C)C)OC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH:25]([C:26]1[O:32][CH:24]=[C:28]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[N:27]=1)([CH3:36])[CH3:33]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC(C)c1nc(CCl)co1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)co1

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 4-chloromethyl-2-isopropyloxazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (22%) as a colorless solid: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.24 (t, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 6.98 (t, 1H), 6.65 (s, 1H), 6.26 (s, 1H), 5.88 (d, 2H), 4.85 (d, 1H), 4.77 (d, 1H), 4.71-4.66 (m, 2H), 3.04-2.95 (m, 1H), 1.18 (dd, 6H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 169.1, 155.6, 148.7, 142.4, 142.2, 136.8, 135.2, 132.4, 129.2, 123.9, 123.4, 120.5, 109.9, 103.6, 101.9, 93.7, 79.9, 57.9, 36.2, 28.1, 20.7, 20.6; MS (ES+) m/z 405.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17](C)=[CH:18]C=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([Li])CCC.CC1[O:42]C(C=O)=C(C)N=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[O:42][C:17]([CH3:18])=[N:16][C:15]=3[CH3:21])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(C)c(C=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.5 g, 3.48 mmol, Intermediate 12: step d) was added THF (65 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-butyllithium (2.5 M in hexanes, 1.62 mL, 4.04 mmol) was added drop wise. The color of the solution became a dark opaque reddish-brown color. After 2 minutes, 2,4-dimethyloxazole-5-carbaldehyde (520 mg, 4.16 mmol, in 3 mL THF) was introduced and the color of the mixture went from an opaque dark brown to a light yellow homogeneous color within about 1 minute. After 25 minutes the mixture was quenched with aqueous NH4Cl. The reaction was diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light yellowish foam. The crude material was chromatographed on silica gel (10% CH3CN-DCM grading to 30% CH3CN containing 1% MeOH) to provide the title compound as a white amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17](C(OC)=O)([F:19])[F:18]>CN(C=O)C.O>[F:18][CH:17]([F:19])[O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution of 4-hydroxybenzonitrile (4.76 g, 40 mmol) in 150 mL of DMF was added 5.52 g (40 mmol) of K2CO3. The mixture was heated at 95° C. and 5.27 mL (50 mmol) of CICF2CO2Me was added slowly over 10 minutes. The reaction was stirred at 95 ° C. for 15 minutes and a 1.5 mL portions of ClCF2CO2Me were added until no changes were observed by TLC. The reaction was stirred overnight at room temperature diluted with water (300 mL) and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford the corresponding nitrile as a white solid (3.0 g, 44%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([C:19]1[C:20]([Cl:29])=[N:21][C:22]3[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:6]2.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl.[C:51]([N:58]1[CH2:63][CH2:62][CH:61]([C:64](O)=[O:65])[CH2:60][CH2:59]1)([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>CN(C=O)C>[C:54]([O:53][C:51]([N:58]1[CH2:63][CH2:62][CH:61]([C:64]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:7]([C:19]2[C:20]([Cl:29])=[N:21][C:22]4[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6]3)=[O:65])[CH2:60][CH2:59]1)=[O:52])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CN)ccc21
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc3c(c2)cc(-c2cc4ccccc4nc2Cl)n3C(=O)OC(C)(C)C)CC1

Procedure:
A solution of tert-butyl 5-(aminomethyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-4, 204 mg, 0.5 mmol, 1 equiv), HOAT (68 mg, 0.5 mmol, 1 equiv), triethylamine (101 mg, 1.0 mmol, 2 equiv), EDC (144 mg, 0.75 mmol, 1.5 equiv) and 1-BOC-piperidine-4-carboxylic acid (126 mg, 0.55 mmol, 1.1 equiv) in DMF (5 mL) was stirred under ambient conditions for 18 hr. The reaction was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to provide tert-butyl 5-[({[1-(tert-butoxycarbonyl)-4-piperidinyl]carbonyl}amino)methyl]-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-5) as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, 1H, J=8 Hz), 8.16 (s, 1H), 8.05 (d, 1H, J=8 Hz), 7.85 (d, 1H, J=8 Hz), 7.76 (t, 1H, J=8 Hz), 7.59 (t, 1H, J=8 Hz), 7.49 (s, 1H), 7.28 (dd, 1H, J=8, 2 Hz), 6.61 (s, 1H), 4.48 (d, 2H, J=5 Hz), 4.12 (m, 2H), 2.72 (m, 2H), 2.26 (m, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.42 (s, 9H), 1.25 (s, 9H).