Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[CH3:28][O:29][CH2:30][CH2:31]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[I:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:31][CH2:30][O:29][CH3:28])=[CH:23][CH:22]=1
Reactant: Oc1ccc(I)cc1
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
Triphenylphosphine (2.8 g, 10.7 mmol) was added to an ice-cold solution of 4-iodophenol (2.2 g, 10.0 mmol) and 2-methoxyethanol (0.79 ml, 10.0 mmol) in tetrahydrofuran (10 ml). A solution of diethyl azodicarboxylate (1.88 ml, 11.5 mmol) in tetrahydrofuran (10 ml) was then added dropwise, and the reaction stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure, the residue partitioned between dichloromethane and hydrochloric acid (2N) and the phases separated. The organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with diethyl ether, the resulting suspension filtered and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using pentane:dichloromethane (75:25) as eluant to give the title compound, (2.0 g, 71%) as an oil.
Reaction SMILES: ClC1C=CC(C[N:7]2[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:28])[CH2:14][NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:8]2)=CC=1>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[F:26][C:23]([F:24])([F:25])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][CH2:14][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][NH:7][CH2:8]1)=[O:28])=[O:27]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCNC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of (S)-1-(4-chlorobenzyl)-3-[N-{3(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (2.93 g, 6.66 mmol) and Pd(OH)2 in 5% HCO2H/methanol (70 mL) was stirred at 60° C. for 3 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. To the residue was added 2 N aqueous NaOH solution (100 mL) and the mixture was extracted with ethyl acetate (100 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=85/10/5-60/30/5) gave (S)-3-[N-{3(trifluoromethyl}benzoyl)glycyl]aminopyrrolidine (1.70 g, 81%) as an oil: 1H NMR (CDCl3, 270 MHz) δ 1.76 (d, J=7.3 Hz, 1 H), 2.07-2.25 (m, 1 H), 2.81-2.98 (m, 2 H), 3.02-3.11 (m, 2 H), 4.12 (s, 2 H), 4.41 (br, 1 H), 6.90 (br, 1 H), 7.45 (br, 1 H), 7.58 (dd, J=7.3 and 7.3 Hz, 1 H), 7.77 (d, J =7.3 Hz, 1 H), 8.02 (d, J=7.3 Hz, 1 H), 8.11 (s, 1 H); ESI/MS m/e 316.0 (M++H, C14H16F3N3O2).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:20])[CH:12]=[CH2:13].C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.O.C1COCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:15]2[N:14]([CH2:11][CH:12]=[CH2:13])[CH:18]=[C:17]([CH:4]=[O:5])[CH:16]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: CN(C)C=O
Reactant: C=CCn1cccc1C(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCn1cc(C=O)cc1C(=O)c1ccc(OC)cc1
Reaction time: 0.25 h

Procedure:
Under nitrogen atmosphere, to a solution of the compound of Reference Example 5-2 (5 g) in THF (15 mL) was added KOtBu (3.07 g). Further, a solution of allyl bromide (4.51 g) in THF (9.0 mL) was added thereto, and the mixture was stirred at 45° C. for 2 hours. Water was added to the mixture, and the mixture was extracted twice with toluene. The organic layers were concentrated to give [1-(2-propenyl)-1H-pyrrol-2-yl][4-methoxyphenyl]ketone (6.00 g, 98%). To DMF (7.31 g) was added dropwise POCl3 (11.5 g) at 10° C., and the mixture was stirred for 15 minutes. To the mixture was added THF (5.41 g), and thereto was added dropise a solution of [1-(2-propenyl)-1H-pyrrol-2-yl][4-methoxyphenyl]ketone in toluene (10 mL). The mixture was stirred at room temperature for 5 hours, and thereto was added a solution of sodium acetate (11.2 g) in water (22 g), and the mixture was stirred for 3 hours. The precipitated crystals were collected by filtration, and dried to give (4-formyl-1-(2-propenyl)-1H-pyrrol-2-yl) (4-methoxyphenyl) ketone (3.31 g). The organic layer of the filtrate was collected, concentraed, and the precipitated crystals were collected by filtration, and dried (1.48 g, total 4.79 g, 71%).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C:8]([NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:18]2=[N:17][C:16]=1[CH3:34])=[O:14])([C:10]#[N:11])[CH3:9])(C)(C)C.[N-:47]=[N+:48]=[N-:49].[Na+].[Cl-].[NH4+].O>CN(C=O)C.C(OCC)(=O)C>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH2:25][O:24][C:23]1[C:18]2[N:19]([C:15]([C:13]([NH:12][C:8]([C:10]3[N:11]=[N:47][NH:48][N:49]=3)([CH3:9])[CH2:7][OH:6])=[O:14])=[C:16]([CH3:34])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(C#N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO)c1nn[nH]n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
To a solution of 60 mg of N-(1-{[tert-butyl (diphenyl)silyl]oxy}-2-cyanopropan-2-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 2 ml of DMF were added 70 mg of sodium azide and 60 mg of ammonium chloride, followed by stirring at 120° C. for 4 hours. The reaction mixture was left to be cooled to room temperature and water was then added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To the obtained crude product was added ethyl acetate, and the insoluble materials were collected by filtration and dried under reduced pressure to obtain 19 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(2H-tetrazol-5-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC(O)=O.[O:16]([C:18]#[N:19])[Na].[OH-].[Na+]>O>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:18]([OH:16])[N:19]=[C:4]2[OH:5]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: N#CO[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(O)c2cccc(Br)c2n1
Temperature: 35 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a 2000 mL flask charged with 2-amino-3-bromobenzoic acid (67.0 g, 310 mmol) was added water (750 mL) and AcOH (18.8 mL). The suspension was heated to 35° C. A solution of NaOCN (30.82 g, 403 mmol, 85% purity) in water (250 mL) was added dropwise at 35° C. The reaction mixture was stirred at 35° C. for 2 hrs. NaOH (415 g, 10.38 mol) was added in portions, the reaction temperature was kept below 40° C. during the addition. The mixture turned clear for a short time, then an off-white suspension was formed. The reaction mixture was cooled to room temperature, and filtered. The obtained solid was dissolved in hot water, pH was adjusted to 5 by addition of 6 N HCl. The resulting mixture was cooled to room temperature, and the precipitate was collected by filtration, rinsed with a small amount of DCM, cold MeOH, ether, then dried in vacuo to yield the title compound as a off-white solid (43.32 g, 58%). 1HNMR (DMSO-d6, 400 MHz): δ 11.60-11.40 (br s, 1H), 10.40-10.20 (br s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.12 (dd, J=7.6, 8.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43][NH2:44].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([NH:44][CH2:43][C:42]1[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=1[F:40])=[O:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1F
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(O)cc2)C(=O)CCC(=O)O)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(O)cc2)C(=O)CCC(=O)NCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A mixture of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl)succinamic acid (0.67 g, 1.2 mmols), 2-fluorobenzylamine (0.16 ml, 1.4 mmols), diethyl cyanophosphate (0.20 ml, 1.4 mmols), triethylamine (0.20 ml, 1.4 mmols) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an amorphous solid of N-[2-[3(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl)-N′-(2-fluorobenzyl)succinamide (0.69 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:22])[C:11](=[CH:17][NH:18][CH:19]1[CH2:21][CH2:20]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+]>CN(C)C=O>[CH:19]1([N:18]2[C:2]3[C:3](=[CH:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=3)[C:10](=[O:22])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17]2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O

Procedure:
In accordance with the above reaction scheme, a solution of 2-chloro-4,5-difluorobenzoic acid (V) in acetonitrile containing a catalytic amount of dimethylformamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride (VI) which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, followed by the addition to ice water and acidification to pH 2.5, giving (2-chloro-4,5-difluorobenzoyl)propanedioic acid diethyl ester (VII). A solution of compound (VII) in p-dioxane and water is heated at reflux, then evaporated and distilled, giving 2-chloro-4,5-difluoro-β-oxobenzenepropanoic acid ethyl ester (VIII). A solution of compound (VIII) and triethyl orthoformate in acetic anhydride is heated at 150° C. for 2 hours, giving 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (IX). Cyclopropylamine is added to a solution of compound (IX) in ethanol, giving 2-chloro-α-[(cyclopropylamino)methylene]-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (X). Compound (X) is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester (XI). Ester (XI) is then refluxed with acid, giving the desired 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XII).
Reaction SMILES: [Cl:1][C:2]1[N:3](C)[CH2:4][C:5](=[CH:9][CH:10]=1)[C:6](Cl)=[O:7].CN.[CH2:14]([N:16](CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH3:14])=[O:7])=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: CN1CC(C(=O)Cl)=CC=C1Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cl)nc1
Yield: 91 %

Procedure:
To a solution of 6-chloro-N-methylnicotinoyl chloride (7.39 g, 42.0 mmol) in tetrahydrofuran (50 mL), methylamine (42 mL, 84.0 mmol) and triethylamine (6.4 mL, 46.2 mmol) were added under ice-cold conditions, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated in vacuo, then filtered, and washed with tetrahydrofuran. The obtained residue was recrystallized (ethyl acetate/hexane) and 6-chloro-N-methylnicotinamide (6.52 g, yield 91%) was obtained as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>C(O)C.[Fe]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(N)cc2)cc1C
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Iron powder (1.04 g, 18.6 mmol) was added to a solution of methyl 3-methyl-4′-nitrobiphenyl-4-carboxylate (0.63 g, 1.9 mmol) in ethanol (20 mL). Concentrated HCl (0.93 mL, 1.9 mmol) was added, and the mixture was heated at reflux for 3 h. Upon cooling to rt, the mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The material was purified by column chromatography (33% EtOAc in hexanes), yielding 0.338 g (75%) of the title compound. LC/MS m/z 242.3 (MH+); retention time 2.27 min. 1H NMR (400 MHz, CD2Cl2) 2.81 (s, 3H), 3.95 (s, 3H), 6.83 (d, 2H), 7.41-7.51 (m, 4H), 7.85 (d, 1H).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[CH2:9][C:10]1[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:12][C:13]([NH2:17])=[N:14][C:15]=1[CH3:16]>CS(C)=O.CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:17][C:13]1[N:14]=[C:15]([CH3:16])[C:10]([CH2:9][C:8]2[CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:26]=[CH:25][CH:24]=2)=[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:12]=1
Reactant: [C-]#N
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CCl)c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Potassium cyanide (0.61 g) was added to a stirred solution of the product from step (v) (0.62 g) in DMSO (5 mL) and DMF (5 mL) and the mixture stirred at rt for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, dried and evaporated under reduced pressure to give the subtitle compound as a yellow oil 0.59 g that was used without further purification.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:33](=[O:34])[CH2:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:37])[CH:27]=2)[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: CCCC(NC(=O)Cc1cccc(C(F)(F)F)c1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3-trifluoromethylphenyl)-acetic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 25.9, 35.9, 43.2, 53.1, 55.5, 59.2, 67.4, 68.8, 105.3, 112.5, 124.1, 124.2, 126.2, 126.3, 129.3, 131.7, 132.9, 136.1, 137.5, 169.3, 169.7; MS m/z 510.4 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([O:10][CH3:11])[C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc(OC)c(Br)cn1
Product: COc1ccc(-c2cnc(OC)cc2OC)cc1
Yield: 99.3 %

Procedure:
According to Scheme 23 Step 3: The title compound was prepared from 5-bromo-2,4-dimethoxypyridine (1 eq, 1.40 mmol, 0.30 g) and 4-methoxyphenylboronic acid (1.5 eq, 2.10 mmol, 0.32 g) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 98/2 to afford 2,4-dimethoxy-5-(4-methoxyphenyl)pyridine (1.39 mmol, 0.34 g, 99%) as a brown oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][C:9]=1[NH2:17]>C(#N)C.C(OCC)C.S([O-])([O-])(=O)=O.[Cu+2]>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][C:9]=1[NH:17][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: Nc1cc2cn[nH]c2cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)CC(=O)Nc1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diketene (stabilized w/copper sulfate, 1.0 mL, 12.9 mmol, 1.5 equiv) was added to a suspension of 6-fluoro-1H-indazol-5-amine (1.3 g, 8.6 mmol, 1 equiv) in acetonitrile (8 mL) at 0° C. over 30 minutes. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was diluted with cold diethyl ether (20 mL) and the solid product was collected by filtration and washed several times with cold diethyl ether. The title compound was isolated as a pale brown powder (1.49 g, 74%). MS m/z 236 [M+H]+
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])(=O)=O.O>C1COCC1>[CH2:33]([O:32][CH2:31][CH2:30][CH2:29][O:1][C@@H:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1)[CH3:34]
Reactant: CCOCCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
An oven dried flask was charged with (R)-tert-butyl 3-((R)hydroxy(phenyl)methyl)-piperidine-1-carboxylate (3.18 g, 10.9 mmol) and 60% NaH in mineral oil (2.19 g, 54.8, 5 equiv). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (100 mL) was added slowly. The mixture was allowed to warm to rt slowly. A solution of 3-ethoxypropyl methanesulfonate (6.0 g, 32.9 mmol, 3 equiv) in anhydrous THF (50 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction completed. The reaction mixture was cooled to 0° C. slowly and water was added dropwise to quench the reaction. After separation, the aqueous layer was extracted with ether three times. The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3, brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel cartridge eluted with a 0-30% EtOAc in hexanes gradient) to afford (R)-tert-butyl 3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (3.70 g, 90%) as a clear oil. Chiral HPLC indicated 95.5% purity. LC-MS (3 min) tR=2.38 min, m/z 400 (M+Na). 1H NMR (CDCl3) □ 7.26 (m, 5H), 4.39 (d, 1H), 3.89 (t, 2H), 3.53-3.40 (m, 4H), 3.38-3.23 (m, 2H), 2.75-2.60 (m, 2H), 1.85-1.47 (m, 4H), 1.45 (s, 9H), 1.40-1.22 (m, 2H), 1.15 (t, 3H), 1.10-0.96 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[F-].C([N+:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])CCCC)CCC.ClN1C(=O)CCC1=O.N1C2C(=CC=CC=2)C=C1.C([O-])(O)=O.[Na+]>C1COCC1.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][C:48]2[C:49]3[C:43](=[CH:44][CH:45]=[CH:46][CH:50]=3)[NH:38][CH:47]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)[Si](Sc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [F-]
Solvent: O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2Sc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
1.58 g 4-(2-Triisopropylsilanylsulfanyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.51 mmol) in 10 mL THF was added to 1.21 g tetrabutylammonium fluoride dihydrate (3.85 mmol) in 5 mL THF at 0° C. The reaction mixture was stirred 1 hour at 0° C., filtered through a plug of silica (eluted with EtOAc/heptane 1:1) and concentrated in vacuo. The residue was redissolved in 14 mL THF. 2 mL of this solution (≈0.5 mmol) was added to 67 mg N-chloro succinimide (0.50 mmol) in 2 mL 1,2-dichloro-ethane at 0° C. The reaction mixture was stirred 30 minutes at room temperature. The resulting solution was added to 90 mg indole (0.75 mmol) in 2 mL THF at 0° C. The reaction mixture was stirred 2 hour at 0° C., poured into 20 mL saturated NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; ethyl acetate/heptane) to give 89 mg 4-[2-(1H-indol-3-ylsulfanyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.22 mmol, ≈44%). 2 mL diethyl ether saturated with HCl was added to 4-[2-(1H-indol-3-ylsulfanyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester and stirred over night at room temperature. The reaction mixture was neutralized with saturated NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. 3-(2-piperidin-4-yl-phenylsulfanyl)-1H-indole was isolated after preparative HPLC.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[S:24][C:25]([CH2:33][CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12].CO.C1COCC1.[Li+].[OH-]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[S:24][C:25]([CH2:33][CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylate in 1:1 MeOH and THF (2 mL) was added LiOH (5 mg, 0.21 mmol) dissolved in water (2 mL). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To this crude material was added water and MeOH and allowed to sit overnight. The resulting precipitate was filtered and washed with water. To this solid was added water and acetonitrile and lyophilized to give 12 mg of the desired product 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (24). 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.60 (s, 2H), 7.51-7.33 (m, 3H), 7.27 (t, J=8.0, 3H), 7.17 (t, J=7.7, 2H), 6.92 (dd, J=7.5, 14.2, 5H), 4.03 (t, j=6.4, 3H), 3.95 (s, 2H), 3.42 (d, J=7.8, 4H), 2.78 (s, 2H), 2.10 (s, 3H), 1.88 (d, J=9.5, 3H).