Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCCC(C(=O)c2ccc(F)cc2)C1
Product: CC(=O)N1CCCC(C(=O)c2ccc(N3CCCCC3)cc2)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 3.73 g of 1-acetyl-3-(4-fluorobenzoyl)piperidine and 5 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixtures was then worked up in the same manner as Example 1. The residue was recrystallized from ethyl ether-n-hexane to give 3.2 g of colorless crystals melting at 116°-120° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.C(Cl)(=O)C(Cl)=O.O[NH:29][C:30](=[NH:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl>[CH3:21][C:2]1([CH3:1])[CH:11]([N:12]2[C:16]([C:17]3[O:18][N:32]=[C:30]([CH3:31])[N:29]=3)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Reactant: CC(=N)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1noc(-c2cncn2C2c3ccccc3C(=O)OC2(C)C)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.538 g, 1.88 mmol) (Example 23) is dissolved in dichloromethane (4 mL) and cooled to 0° C. Oxalyl chloride (0.41 mL, 4.702 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo. The residue obtained is redissolved in chloroform and N-hydroxyacetamidine (0.181 g, 2.44 mmol) is added. The reaction mixture is stirred at reflux for 72 h. The mixture is cooled to room temperature, washed with saturated solution of sodium bicarbonate and is extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethyl acetate, 3:7) to give dimethyl-4-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-imidazol-1-yl]-isochroman-1-one as a white solid; MS (ESI) m/z 325.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.61 (s, 3 H), 2.55 (s, 3 H), 6.94 (s, 1 H), 7.56 (d, J=7.1 Hz, 1 H), 7.63 (s, 1 H), 7.72 (td, J=7.6, 1.3 Hz, 1 H), 7.80 (td, J=7.6, 1.3 Hz, 1 H), 8.01 (s, 1 H), 8.30 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[Cl:17][C:18]1[N:23]=[N:22][C:21]([NH2:24])=[CH:20][CH:19]=1.O>C(O)CCC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:24]=2)[N:23]=1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: Nc1ccc(Cl)nn1
Solvent: O
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (1.5 g, 5.5 mmol) and 6-chloropyridazin-3-amine (1.4 g, 11 mmol) in 1-butanol (60 mL) was heated at reflux overnight. Then the mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a yellow solid (1.6 g, 84%). 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=9.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (dd, J=0.6, 1.2 Hz, 1H), 7.53 (s, 1H), 7.37 (dd, J=1.8, 8.4 Hz, 1H), 7.03 (d, J=9.3 Hz, 1H), 4.40 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:15]3=[N:14][C:13]=2/[CH:27]=[CH:28]/[C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].O.Cl>C1COCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:15]3=[N:14][C:13]=2/[CH:27]=[CH:28]/[C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Compound 6a (80 mg, 0.16 mmol) was suspended in THF/MeOH (1:1 v/v, 8 mL) and treated with 1 N LiOH solution (0.8 mL, 0.8 mmol). The mixture was stirred at 90° C. for 30 min, allowed to cool to rt, and treated with water (20 mL). The pH of the mixture was adjusted to ca. pH 3 using 1 N HCl solution. The reaction mixture was then extracted with 20% MeOH in DCM (4×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound 63 as an orange solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.60 (br. s., 1H), 8.55-8.67 (m, 1H), 8.20 (d, J=5.6 Hz, 1H), 8.12-8.18 (m, 1H), 8.04-8.12 (m, 2H), 8.00 (d, J=8.1 Hz, 1H), 7.88 (m, 3H), 7.69 (br. s., 1H), 7.37 (d, J=1.2 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 6.49 (d, J=5.9 Hz, 1H), 4.10 (m 4H), 3.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H23N5O4: 494.2 (M+H). Found 494.4.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:17][CH:16]=2)[CH2:6][CH:5]1[CH3:40])(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=2)[CH2:6][CH:5]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(Nc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)CC1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N1c2ccccc2C(Nc2ccc(CO)cc2)CC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
[Step 3] 615 mg of 1-acetyl-4-[(4-tert-butyldiphenylsilyloxymethylphenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 2 mL of tetrahydrofuran, and 2.8 mL of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) was added to the solution. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate solution and saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (developing solvent: ether only), and thus 264 mg (79%) of 1-acetyl-4-[(4-hydroxymethylphenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a yellow oily substance (cis:trans=3:1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@@H:12]4[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@@H:12]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CCN(C(=O)OC(C)(C)C)CC[C@@H]12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1CCN2c3c(cccc31)[C@@H]1CCNCC[C@@H]12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.7 %

Procedure:
Tert-butyl (6bS,11aS)-3-methyl-2,3,6b,7,8,10,11,11a-octahydro-1H,9H-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline-9-carboxylate (115 mg, 0.33 mmol) was dissolved in 20% TFA (3 mL) in CH2Cl2 at rt. The reaction was stirred at rt for 2.5 hrs. Ice chips were added to the reaction, an then it was basified with 50% NaOH until pH=14. Brine (5 mL) was added and then the reaction was extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with brine, dried, and concentrated to afford the title compound (84.1 mg, 103%) as a viscous oil. 1H NMR (CDCl3, 300 MHz) δ 6.59–6.64 (1H, m), 6.48 (1H, d, J=7.3 Hz), 6.37 (1H, d, J=7.7 Hz), 3.4–3.7 (4H, m), 2.6–3.3 (10H, m), 1.7–2.2 (4H, m) ppm. MS (ESI): 244.2 (base, M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:8]=[C:5]2[N:6]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:7]=1
Reactant: Cc1c(-c2ccccc2)[nH]c2ncc(Br)cc12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: Cc1c2cc(Br)cn(CC(=O)c3ccccc3)c-2nc1-c1ccccc1
Yield: 72 %

Procedure:
5-Bromo-3-methyl-2-phenylpyrrolo[2,3-b]pyridine (0.34 g, 1.2 mmol) and phenacyl bromide (0.49 g, 2.4 mmol) in acetonitrile (20 ml) was refluxed over night to give a clear solution. The cooled solution was alkalized with sodium carbonate solution (10%) and extracted with methylene chloride. Drying over MgSO4, filtration and evaporation of solvents gave a residue which was dissolved in the minimum amount of ethanol. Crystallization was driven to completeness by keeping crystals and mother liquor in the fridge for a few days. Recrystallization by dissolving in hot ethanol and cooling in the fridge over night gave 0.35 g (73%) of yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(-c2ccccc2)nc(N)nc1N1CCOCC1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and morpholine in DME. EI-MS m/e (%): 281 (M+, 38), 280 ([M—H]+, 100).
Reaction SMILES: [N:1]1([C:7]2[O:11][C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[N:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1([C:7]2[O:11][C:10]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:20])=[N:9][N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1nnc(N2CCOCC2)o1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1nnc(N2CCOCC2)o1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (5-morpholin-4-yl-1,3,4-oxadiazol-2-yl)carbamate (269 mg, 0.777 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (211 mg, 0.854 mmol) and diisopropylethylamine (0.149 ml, 0.854 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 31 mg (9.0%) of the desired product as a solid.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1)C.[ClH:18]>>[ClH:18].[CH:12]1([C:7]2[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[N:8]=2)[C:4]([OH:17])=[O:3])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cc(C)nc(C2CCCC2)c1
Agent: Cl
Product: Cc1cc(C(=O)O)cc(C2CCCC2)n1

Procedure:
A solution of 2-cyclopentyl-6-methyl-isonicotinic acid ethyl ester (3.96 g, 17.0 mmol) in 25% aq. HCl (50 mL) is stirred at 75° C. for 16 h. The solvent is removed in vacuo and the remaining residue is dried under HV to give 2-cyclopentyl-6-methyl-isonicotinic acid hydrochloride (4.12 mg) as a white solid; LC-MS: tR=0.54 min, [M+1]+=206.08.
Reaction SMILES: [F:1][C:2]([F:36])([CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[OH:27])=[CH:7][CH:6]=1.Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=2[CH:54]=1>>[F:36][C:2]([F:1])([CH2:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=3[CH:54]=2)=[CH:7][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(OCC(F)(F)COc3ccccc3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCC(F)(F)COc4ccccc4)cc3)cc21

Procedure:
Analogously to Method D, 0.260 g of benzyl 4-[4-(2,2-difluoro-3-phenoxypropoxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 0.185 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benz[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellow oil. Rf=025 (1:1 EtOAc-heptane); Rt=5.67.
Reaction SMILES: N[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Br:10]Br.N([O-])=O.[Na+].N>Br.O>[Br:10][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)c(Cl)c1
Reactant: BrBr
Agent: Br
Agent: N
Agent: O=N[O-]
Solvent: O
Product: Cc1cnc(Br)c(Cl)c1

Procedure:
The product from paragraph (h) (5.7 g) in hydrobromic acid (48%; 50 ml) was cooled to -15° C. to -10° C. and bromine (2.6 ml) was added dropwise with stirring. The temperature was then kept at -5° C. to 0° C. while sodium nitrite (5.53 g) in water (12 ml) was added dropwise over a period of 45 minutes. When addition was complete, the mixture was stirred a further 30 minutes at 0° C. and poured on to ice. The mixture was made slightly alkaline by dropwise addition of concentrated ammonia, keeping the temperature at 0° C. with added ice. The mixture was extracted with ether (150 ml). The ether extract was washed with water, sodium bisulphite solution, and water, and then dried and evaporated. The residue was taken up in petroleum (b.p. 40°-60° C.) and the solution filtered and evaporated. The residue was identified as 2-bromo-3-chloro-5-methylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:27]#[C:26][CH2:25][OH:28])=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(4-chlorobenzyl)-8-fluoro4-hydroxy-6-iodo-3-quinolinecarboxamide of Preparation No. 1 (0.466 g) in 15 mL diethylamine is added CuI (0.010 g) and (Ph3P)2PdCl2 (0.035 g). Propargyl alcohol (0.058 mL) is then added and the reaction is stirred overnight at room temperature. The diethylamine is removed in vacuo. The residue is partitioned between EtOAc and water. The insoluble material is filtered off and saved. The organic layer is washed with brine, dried and condensed. The residue is combined with the insoluble material and adsorbed onto silica and chromatographed, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed to yield 0.192 g of the desired product as a tan solid.
Reaction SMILES: [CH:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)C1CCCC1
Reaction time: 2 h
Yield: 68.3 %

Procedure:
Cyclopentanesulfonamide (9.7 g) was dissolved in acetone (300 ml) and 1N NaOH (65 ml) was added. To the resulting solution was added p-chlorophenylisocyanate (9.5 g) dissolved in acetone (100 ml). The solution was allowed to stir for two hours and was then treated with 1N HCl (65 ml). The resulting solid was collected and treated with 1N NaOH (100 ml). This mixture was treated with 1N HCl (100 ml) and the resulting solid collected. The solid was dissolved in acetone, water was added and the acetone was stripped off. The solid material was collected and dried to provide 12.8 g of product.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3]([CH:1]=[O:2])=[N:4][NH:5]3)=[CH:10][CH:9]=2)=[O:14])=[CH:17][CH:18]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1n[nH]c2cc(C(=O)Nc3ccc(O)cc3)ccc12
Reaction time: 2 h

Procedure:
To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4-aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-(4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d6) δ 6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=[O:30])OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.O.Cl.[NH:49]1[CH2:54][CH2:53][C:52](=[O:55])[CH2:51][CH2:50]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:49]4[CH2:54][CH2:53][C:52](=[O:55])[CH2:51][CH2:50]4)=[O:30])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: O=C1CCNCC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(=O)CC4)c3)ccc21
Reaction time: 2 h
Yield: 59 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (440 mg, 0.841 mmol) synthesized in Production example 5-2 was dissolved in N,N-dimethylformamide (5 ml); triethylamine (0.543 ml, 3.90 mmol) and 4-piperidone hydrochloride monohydrate (0.530 g, 3.93 mmol) were added thereto; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was concentrated to yield the title compound (0.202 g, 0.496 mmol, 59%) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCCCCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NCCCCCCCNC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 1,9-diazanonane (13 g, 0.1 mol) in pyridine (200 mL) and cool to 0° C. Add, by dropwise addition, benzoyl chloride (31 g, 0.22 mol) and stir overnight. Extract into chloroform, wash with water, 5% hydrochloric acid, 5% sodium hydroxide, water and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 1,9-bis(benzoyl)-1,9-diazanonane.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:20])[NH:9][C@H:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15](Br)=[CH:14][N:13]=1)[CH3:11])([CH3:6])([CH3:5])[CH3:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[C:3]([O:7][C:8](=[O:20])[NH:9][C@H:10]([C:12]1[N:13]=[CH:14][C:15]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=2)=[C:16]([CH3:18])[CH:17]=1)[CH3:11])([CH3:6])([CH3:5])[CH3:4]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
N2 was bubbled through a solution of (S)-tert-butyl(1-(5-bromo-4-methylpyridin-2-yl)ethyl)carbamate (200 mg, 0.635 mmol), (2-(trifluoromethyl)pyridin-4-yl)boronic acid (145 mg, 0.761 mmol) and Na2CO3 (2.0 M, 635 μl, 1.269 mmol) in dioxane for 5 min. Cl2Pd(dppf) (CH2Cl2 adduct) (51.8 mg, 0.063 mmol) was added. The reaction mixture was stirred at 90° C. for 16 hr. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, concentrated and purified through flash column chromatography (0-100% EtOAc/Heptane) to give 200 mg (S)-tert-butyl(1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)carbamate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=4.9 Hz, 1H), 8.36 (s, 1H), 7.66 (s, 1H), 7.51-7.42 (m, 1H), 7.21 (s, 1H), 5.60 (d, J=7.7 Hz, 1H), 4.87 (p, J=6.9 Hz, 1H), 2.30 (s, 3H), 1.48 (d, J=6.9 Hz, 3H), 1.45 (s, 9H). MS m/z 382.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH2:9])[CH2:11]2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: Cc1cccc(Br)c1
Product: Cc1cccc(N2C=CC=C(N)C2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.6 %

Procedure:
Following the general procedure using 3-bromotoluene (121 μL, 1.00 mmol) and 3-aminopyridine (113 mg, 1.20 mmol), the reaction was stirred for 20 h at rt. Column chromatography on silica gel (eluting with 40% EtOAc/hexanes) afforded the product as an off-white solid (180 mg, 98%).