Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:57][N:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][CH2:66][NH2:67])[CH2:60][CH2:59]1.[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:67][CH2:66][CH2:65][CH2:64][N:61]5[CH2:60][CH2:59][N:58]([CH3:57])[CH2:63][CH2:62]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(CCCN)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)NCCCN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.043 g (0.11 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 2.5 mL of dichloromethane, 0.05 mL of triethylamine was added followed by 0.0173 g (0.11 mmole) of 3-(4-methyl-piperazin-1-yl)-propylamine. After 2 hours, 6 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-methanol-ammonium hydroxide (83:17:1.5) to give 0.0333 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide (I-87).
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[OH-].[Na+].[C:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:17][CH2:18][C:19]([N:3]2[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CSCN1C(=O)CCc1ccccc1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of 2.66 g of (R)-(-)-thiazolidine-4-carboxylic acid in 10 ml of a 2N sodium hydroxide aqueous solution were added 5.5 g of 3-phenylpropionyl chloride and 15 ml of a 2N-sodium hydroxide aqueous solution with stirring under cooling at the same time. After adding, the mixture was stirred for 2 hours at room temperature, and then the reaction mixture was washed with diethyl ether. The mixture was acidified by adding hydrochloric acid. The acidic mixture was allowed to stand for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 4.06 g of (R)-(-)-3-(3-phenylpropionyl)thiazolidine-4-carboxylic acid. (yield: 76.5%)
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23](SC)=[N:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1>>[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23]([NH:2][CH3:1])=[N:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1
Reactant: CSc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Reactant: CN
Product: CNc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Temperature: 200 °C
Reaction time: 0.42 h
Yield: 50.5 %

Procedure:
Methylamine (2 mL, 16 mmol, 8.0M solution in ethanol) was added in one portion to (R)-4-(1-cyclopropylethylamino)-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (7 mg, 0.018 mmol). The resulting mixture was heated in the CEM microwave at 200° C. for 1 hour. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH4OAc; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.1 mg). 1H NMR (500 MHz, MeOD) δ 8.15 (s, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 4.07-3.78 (m, 1H), 3.10 (s, 3H), 1.50-1.36 (m, 3H), 1.19-1.04 (m, 1H), 0.70-0.48 (m, 2H), 0.43-0.23 (m, 2H). HPLC (method H) retention time=1.04 min. M+H=341.2.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1(C2C=CC(/C=C/C(C3C=C(Cl)C=C(Cl)C=3)=O)=CC=2)C=N[CH:30]=N1.FC([Si](C)(C)C)(F)F.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]([O:19][CH3:30])([C:15]([F:18])([F:17])[F:16])/[CH:13]=[CH:12]/[C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:7][CH:8]=2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: O=C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Reactant: OC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: COC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
(E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (DC69): To a solution of (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0° C. The reaction was slowly warmed to ambient temperature and allowed to stir for 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution was added and the reaction was stirred for an additional 4 h at ambient temperature. The reaction was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:32])[C:9](=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:7]2[C:8]([OH:32])=[C:9]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3[O:19][CH2:20][C:21]([CH3:23])([CH3:24])[N:22]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COC(c2ccccc2C2Oc3cccc(F)c3C(=O)C2=Cc2ccccc2)=N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2C2Oc3cccc(F)c3C(O)=C2Cc2ccccc2)=N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred solution of the compound from step A in THF (0.1M) at 0° C. was added LiAlH4 (1M in ether, 2.2 eq) dropwise over 10 minutes. The mixture was warmed to room temperature and stirred for 12 hours. The mixture was cooled to 0° C., quenched with Rochelles salt, and filtered through diatomaceous earth. The aqueous layer was extracted twice with ethylacetate, and the combined organic layers were washed with brine and dried over MgSO4. Filtration an solvent removal afforded a yellow oil. Chromatography over silica gel (ethylacetate:hexane) afforded a 60% yield of a white solid. M.P. 65°-70° C. (decomposed). Anal. calcd. for C27H26 NO3F: C, 75.15; H, 6.07; N, 3.25. Found: C, 74.75, H, 6.02, N, 3.09. 1H-NMR (300 MHz, CDCl3) :7.70 (1H, dd), 7.02-7.37 (8H, m), 6.96 (1H, dd), 7.91 (1H, d), 4.51 (1H, d), 4.23 (1H, dd), 4.39 (1H, dd) 3.87 (2H, dd), 2.74 (1H, dd), 2.55 (1H, dd), 2.18-2.28 (1H, m) 1.31 (6 H, d).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].I[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:14][CH2:15][CH3:16])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCCI
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(C)nc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 2.0 g 2-methylbenzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 0.9 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 3.9 g 1-iodopropane were added and the mixture was heated to 45 C for 6 hours. The mixture was quenched slowly with 40 ml water, extracted twice with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using pure ethyl acetate to 5% methanol in ethyl acetate. A pale yellow oil was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-:35])=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccccc1)COC3
Reaction time: 2 h
Yield: 99.5 %

Procedure:
(11S)-11-[(Benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (0.92 g, 2.67 mmol) was dissolved in 25 mL of CH2Cl2 and treated with MCPBA (0.81 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of 5% Na2CO3 solution and the layers were separated. The aqueous portion was extracted with an additional 10 mL of CH2Cl2. The combined organic layers were washed successively with H2O (20 mL) and brine (20 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.96 g of (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide as a light-brown solid.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:22][CH2:21][CH2:20][CH2:19]2
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(C)ccc2C12CCCC2
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Reaction time: 1 h
Yield: 99 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 12.7 g of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one in 250 ml of anhydrous dichloromethane and 50 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.54 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 160 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 2.5 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloro-methane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 12.0 g (99%) of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one were obtained as a light red oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].[C:12](Cl)(Cl)=[S:13]>O.C(OCC)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[N:2]=[C:12]([SH:13])[O:11][C:4]=2[CH:5]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(O)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccc2nc(S)oc2c1

Procedure:
2-amino-5-methoxyphenol hydrochloride (6 g) in 80 ml of water was stirred at room temperature while thiophosgene (3.92 g) was added dropwise as a solution in 30 ml of diethyl ether at a rate such that the resultant exotherm was controlled.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)Nc2cccc(C(=O)C3CCN(C)CC3)c2)cc1
Yield: 96.1 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-methylbenzoyl chloride (91 μl, 0.687 mmol), 74.0 mg (96%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:30][NH:29][C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added benzohydrazide 181 (0.118 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g. 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N′-(phenylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 182 (0.35 g, 98%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[C:5]([O:10]C)=[N:6][CH:7]=[CH:8][CH:9]=1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCCCCCC>[F:12][CH:2]([F:1])[O:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ncccc1OC(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O
Product: Oc1ncccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
As shown in step 3(a)-iii of Scheme 3(a), 3-(difluoromethoxy)-2-methoxypyridine (270 mg, 1.54 mmol) was dissolved in 5 mL of DCM and BBr3 (540 μL; 1275 mg; 4.10 mmol) in heptane was added. The reaction mixture was stirred for 10 minutes at RT under an atmosphere of nitrogen, brought to reflux, and then stirred an additional 4 hours. The mixture was cooled and water was added to quench the reaction. The pH was adjusted to 7-8 with sodium bicarbonate, the organics partitioned, and the aqueous layer saturated with NaCl and extracted twice more with DCM. The combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography (DCM to 5% MeOH/DCM gradient) to yield 3-(difluoromethoxy)pyridin-2-ol as a white solid (Compound 2008, 986 mg, 97% yield): ESMS (M+H) 162.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH:10]=[CH2:11].I[C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH2:29].C(=O)([O-])O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)P(N(C)C)(N(C)C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:16]2[C:15](=[CH:14][CH:19]=[C:18]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]=2)[N:29]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1I
Reactant: C=CC(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=S(=O)(c1ccccc1)c1ccc2nc(-c3ccc(F)cc3F)ccc2c1
Temperature: 140 °C
Yield: 10.2 %

Procedure:
1-(2,4-Difluorophenyl)prop-2-en-1-ol (Step 3, 260 mg, 1.41 mmol), [2-iodo-4-(phenylsulfonyl)phenyl]amine (Step 2, 359 mg, 1 mmol), palladium acetate (22 mg, 0.1 mmol), sodium hydrogencarbonate (162 mg, 3 mmol) and triphenylphosphine (26 mg, 0.1 mmol) were combined in hexamethylphosphoramide (5 mL) and heated to 140° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine (x5), dried over MgSO4 and evaporated. The residue was purified by preparative HPLC to give the title compound (39 mg). 1H NMR (500 MHz, CDCl3) δ 8.59 (1H, d), 8.32 (1H, d), 8.21-8.14 (2H, m), 8.10 (1H, dd, J=2.1, 8.9 Hz), 8.03-7.98 (3H, m), 7.61-7.52 (3H, m), 7.09-7.05 (1H, m), 6.99-6.94 (1H, m).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>O>[N:6]1([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 250-mL round-bottomed flask was charged with a solution of NaHCO3 (10.7 g, 127.38 mmol, 2.00 equiv) in H2O (80 mL), ethyl piperidine-3-carboxylate (10 g, 63.69 mmol, 1.00 equiv) and benzyl carbonochloridate (11.9 g, 70.00 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The progress was monitored by TLC (EtOAc: PE=1:5). Upon completion, the resulting solution was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:100) afford 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate as pale yellow oil (11.4 g, (62%).
Reaction SMILES: Br[CH:2]([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K].C(OCC)(=O)C>CN(C=O)C>[CH3:3][CH:2]([N:12]1[C:8](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:13])[C:4](=[O:7])[CH2:5][CH3:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(=O)C(C)Br
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 79 %

Procedure:
2-Bromo-pentan-3-one obtained in Example (15a) (8.47 g, 35.57 mmol) was dissolved in DMF (120 mL). Potassium phthalimide (6.9 g, 37.25 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with 1 N hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was washed with hexane to obtain 6.5 g of the title compound as a white solid (79%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:18][C:17](=[O:19])[CH2:16][CH:15]3[N:11]2[C:12](=[O:20])[CH2:13][CH2:14]3)=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:18][CH:17]([OH:19])[CH2:16][CH:15]3[N:11]2[C:12](=[O:20])[CH2:13][CH2:14]3)=[CH:6][CH:5]=1
Reactant: O=C1CC2CCC(=O)N2C(c2ccc(F)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC2CC(O)CC(c3ccc(F)cc3)N12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (230 mg) was added to a solution of 5-(4-fluorophenyl)hexahydroindolizine-3,7-dione obtained above (500 mg) in ethanol (75 mL) at room temperature, and the reaction solution was stirred for one hour. The reaction solution was added to ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 500 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]1=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH2:21])=[S:20].CCOC(C)=O.CO>CC(C)=O>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[S:20][C:2]2[CH2:10][CH2:9][C:8]3[NH:7][N:6]=[CH:5][C:4]=3[C:3]=2[N:21]=1
Reactant: NC(=S)Nc1ccccn1
Reactant: O=C1c2cn[nH]c2CCC1Br
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(Nc2nc3c(s2)CCc2[nH]ncc2-3)nc1
Yield: 56.9 %

Procedure:
According to Scheme 1 Step 4: A solution of 5-bromo-6,7-dihydro-1H-indazol-4(5H)-one (23.3 mmol, 5.00 g) and of 1-(pyridin-2-yl)thiourea (20.9 mmol, 3.21 g) in acetone (60 mL) was stirred at 60° C. for 5 hours. The precipitate formed was filtered and partitioned between AcOEt and a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated to yield a grey solid. The crude residue was purified by flash chromatography over silica gel using DCM/MeOH (95:5) as eluent and by two recristallizations with AcOEt/MeOH (50:50) to yield N-(pyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (11.9 mmol, 3.20 g, 51%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:15]
Reactant: Oc1ccnc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2ccc(Br)cc12
Temperature: 25 °C
Yield: 98.5 %

Procedure:
The solid 6-bromo-quinolin-4-ol (52 g, 232.1 mmol) was added to phosphorus oxychloride (213.5 mL) and then the mixture was heated to reflux for 6 h to afford a light brown solution. After cooling to room temperature, the excess phosphorus oxychloride was removed under the vacuum. The remaining residue was poured into an ice-containing beaker (2 L). Then, it was slowly neutralized with solid potassium carbonate and the resulting solids were collected by filtration and washed with water. After drying in air, 55.46 g (98.5% yield) of 6-bromo-4-chloro-quinoline was isolated as a light yellow solid: EI-HRMS m/e calcd for C9H5BrClN (M+) 240.9294, found 240.9297.