Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[CH:6][C:5]([F:12])=[CH:4][N:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C@H:23]1[CH2:26][C@H:25]([NH2:27])[CH2:24]1.CC(C)([O-])C.[Na+]>[Pd+2]>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C@H:23]1[CH2:24][C@H:25]([NH:27][C:2]2[C:7]([NH:8][CH:9]3[CH2:11][CH2:10]3)=[CH:6][C:5]([F:12])=[CH:4][N:3]=2)[CH2:26]1
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: Fc1cnc(Cl)c(NC2CC2)c1
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Fc1cnc(N[C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c(NC2CC2)c1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
2-Chloro-N-cyclopropyl-5-fluoropyridin-3-amine (intermediate 39, 0.230 g, 1.232 mmol), trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.270 g, 1.232 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl) 2-(2-aminoethyl)phenyl)palladium(II) (0.049 g, 0.062 mmol), and sodium t-butoxide (0.296 g, 3.08 mmol) were sealed in a microwave vial under argon. Dry, sparged dioxane (1 mL) was added and the reaction heated at 80° C. After 45 minutes the vial was opened and the crude and dry loaded on silica gel. Purification using silica chromatography (hexane to ethyl acetate gradient) gave N2-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-N3-cyclopropyl-5-fluoropyridine-2,3-diamine (0.304 g, 0.824 mmol, 66.8% yield).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([Si](C)(C)C)[S:4][C:3]=1[C:11]1[S:12][C:13]([Si](C)(C)C)=[CH:14][C:15]=1Br.C([Li])CCC.[CH3:26][CH:27]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][Si:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(Cl)Cl.O>O1CCCC1.CCCCCC>[CH3:26][CH:27]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:43])[CH3:44])[CH2:28][CH2:29][Si:30]1([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:11]2[S:12][CH:13]=[CH:14][C:15]1=2
Reactant: C[Si](C)(C)c1cc(Br)c(-c2sc([Si](C)(C)C)cc2Br)s1
Reactant: CCCCCC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCC[Si]1(CCC(C)CCCC(C)C)c2ccsc2-c2sccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
3,3′-dibromo-5,5′-bis(trimethylsilyl)-2,2′-bithiophene (Compound E4, synthesized in accordance with WO 2010/136353, 11.4 g, 24.3 mmol) was placed in a 500 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (200 mL). This was cooled to −78° C., and a solution of n-butyl lithium in hexane (KANTO CHEMICAL CO., INC., 1.59 M, 32.1 mL) was added dropwise. After about 20 minutes of agitation, the 3,7-dimethyloctyl-n-hexyl-dichlorosilane (Compound E24, 9.5 g) synthesized in Synthesis Example A22 was added dropwise. The temperature was raised gradually to room temperature over the course of about 2 hours, water was added, and the product was extracted with hexane. The organic layer was washed with water, and then dried over sodium sulfate and concentrated by filtration. The resulting oily substance was dissolved in chloroform (40 mL) and hexane (80 mL), trifluoroacetic acid (3.6 mL) was added, and the mixture was agitated for about 10 minutes at room temperature. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with hexane and then concentrated under reduced pressure. The resulting yellow oily substance was dissolved in hexane, and subjected to silica gel column chromatography (solvent: hexane) to obtain the target 4-(3,7-dimethyloctyl)-4-n-hexyldithieno[3,2-b:2′,3′-d]silole (Compound E25, 8.2 g, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: O=C(NC1CCCCC1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and cyclohexanamine (CAN 108-91-8) as starting materials, MS (EI) m/e: 315.1 [M+H]+.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[N:11]([C:14]2[S:15][C:16]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:19])[N:18]=2)[CH:10]=[N:9]1)(=O)=O.[C:30](=[O:33])([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1>O1CCCC1>[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH:44][C:30](=[O:33])[O:5][CH2:6][CH2:7][N:8]2[C:12](=[O:13])[N:11]([C:14]3[S:15][C:16]([C:20](=[O:29])[NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[C:17]([CH3:19])[N:18]=3)[CH:10]=[N:9]2)=[CH:39][CH:38]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Reactant: NCc1ccc(F)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(CCOC(=O)NCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 77 %

Procedure:
To the solution of 2-(4-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)thiazol-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl methanesulfonate (0.40 g, 0.91 mmol) in anhydrous tetrahydrofuran (10 mL) was added potassium carbonate (0.32 g, 2.28 mmol). The reaction mixture was stirred at ambient temperature for 1 minute, followed by the addition of (4-fluorophenyl)methanamine (0.10 mL, 0.91 mmol). The reaction mixture was stirred at ambient temperature for 17 hours, and then partitioned between ethyl acetate and brine. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 77% yield (0.36 g): mp 149-150° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 8.58 (br s, 1H), 8.49 (br s, 1H), 8.22 (s, 1H), 7.72-7.64 (m, 1H), 7.31-7.14 (m, 3H), 7.00-6.89 (m, 2H), 6.54 (t, J=5.8 Hz, 1H), 5.33 (t, J=5.9 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 4.38 (t, J=5.1 Hz, 2H), 4.25 (d, J=5.9 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 2.62 (s, 3H): MS (ES+) m/z 512.4 (M+1).
Reaction SMILES: Cl[C:2]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[C:8]2[CH2:7][C@:6]34[CH2:24][C@H:16]([C:17](=[O:23])[C:18]([C:19]([F:22])([F:21])[F:20])=[C:5]3[C:4]=2[CH:3]=1)[CH2:15][CH2:14]4.C1C=CC=CC=1.CO>CN(C=O)C.[OH-].[OH-].[Pd+2].[Pd]>[F:21][C:19]([F:20])([F:22])[C:18]1[C:17](=[O:23])[C@H:16]2[CH2:24][C@:6]3([CH2:7][C:8]4[C:9]5[N:10]=[CH:11][NH:12][C:13]=5[CH:2]=[CH:3][C:4]=4[C:5]=13)[CH2:14][CH2:15]2
Reactant: O=C1C(C(F)(F)F)=C2c3cc(Cl)c4[nH]cnc4c3C[C@@]23CC[C@@H]1C3
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CO
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]cnc4c3C[C@@]23CC[C@@H]1C3
Reaction time: 16 h

Procedure:
To a solution of (8R,10aS)-4-chloro-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d]imidazol-7(8H)-one (58 mg, 0.16 mmol) in DMF (5.8 mL) were added 20% Pd(OH)2 on carbon (27 mg) and 5% palladium on calcium carbonate (29 mg) and the mixture was hydrogenated at atmospheric pressure. After 16 hours, additional 20% Pd(OH)2 on carbon (12 mg) and 5% palladium on calcium carbonate (12 mg) were added. After another 3.5 hours, additional 20% Pd(OH)2 on carbon (5 mg) and 5% palladium on calcium carbonate (5 mg) were added. After 66 hours more, the mixture was filtered through a pad of Celite®, washing thoroughly with EtOAc. The filtrate was partitioned between EtOAc and water which had been acidified with a small amount of 1N hydrochloric acid. The aqueous layer was neutralized with 5% aqueous sodium bicarbonate and was then thoroughly extracted with EtOAc. After drying over MgSO4, the solvent was removed under reduced pressure to give a gum. Chromatography on silica gel (elution with 5% methanol in dichloromethane) gave a yellow oil which was lyophilized from benzene containing a small amount of methanol to provide (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d]imidazol-7(8H)-one as a yellow solid.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][N:25]=[C:24]([CH3:29])[CH:23]=1.C(I)C>C1COCC1>[Cl:21][C:22]1[C:27]([F:28])=[CH:26][N:25]=[C:24]([CH2:29][CH2:1][CH3:2])[CH:23]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(Cl)c(F)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c(F)cn1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Diisopropylamine (924 μL, 6.59 mmol) was dissolved in 9 mL of dry THF and the resultant solution was cooled to 0° C. in an ice bath. n-Butyllithium (3.07 mL of a 2.05M solution in THF, 6.29 mmol) was added via syringe to the amine solution and the resultant solution was stirred for 30 minutes at 0° C. The lithium diisopropylamide (LDA) solution was then cooled to -50° C. in an isopropyl alcohol/dry ice bath. To the cold LDA solution was added, dropwise from an addition funnel, over a 15 min period, a solution of 4-chloro-5-fluoro-2-picoline (435 μL, 3.0 mmol), the product of Example 64, in 9 mL of THF. The reaction solution turned dark orange-brown in color. The reaction solution was stirred at a temperature in the range -50° C. to -45° C. for 5 hours and then was cooled over a 15 min period to -78° C. Ethyl iodide (792 μL, 9.9 mmol) was added in one portion and the reaction solution was stirred at -78° C. for 20 min. The reaction was then quenched by pouring the reaction solution into 60 mL of 10% aqueous ammonium chloride solution. The aqueous mixture was extracted with 2×50 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was distilled to afford the title compound, b.p. 80°-82° C. (12 mm Hg); MS DCI-NH3M/Z: 174 (M+H)+ 40%; 1H NMR (CDCl3) d 0.96 (t, 3H, J=7.5 Hz), 1.73 (spt, 2H, J=7.5 Hz), 2.73 (t, 2H, J=7.5 Hz), 7.21 (d, 1H, J=6.0 Hz), 8.38 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:23]([C:26]1[S:27][CH:28]=[C:29]([C:31]([N:33]2[CH2:38][C:37]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[O:36][CH2:35][CH2:34]2)=[O:32])[N:30]=1)([CH3:25])[CH3:24]>C(#N)C>[OH:11][CH2:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[C:12]([F:15])([F:14])[F:13])[CH2:2][N:41]1[CH2:42][CH2:43][C:37]2([O:36][CH2:35][CH2:34][N:33]([C:31]([C:29]3[N:30]=[C:26]([CH:23]([CH3:24])[CH3:25])[S:27][CH:28]=3)=[O:32])[CH2:38]2)[CH2:39][CH2:40]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cc(CBr)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(C(F)(F)F)c(CCO)c4)CC3)C2)cs1

Procedure:
The subtitled compound was prepared using a similar method to that described in Example 6 step (b) using a solution of 2-(5-(bromomethyl)-2-(trifluoromethyl)phenyl)ethanol (0.38 g) (Example 270 step a) in acetonitrile which was added dropwise over 30 minutes to (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (Example 22 step b). Purification was by silica gel chromatography eluting 5% triethylamine in ethyl acetate. Yield 0.32 g.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=2)[C:9]([C:20]2[C:25]([O:26]C)=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=[N:8][CH:7]=1.ClCCl>O>[F:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)[C:9]([C:20]2[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=[N:8][CH:7]=1
Reactant: COC(=O)c1ccc2c(F)cnc(-c3c(F)cccc3OC)c2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc2c(F)cnc(-c3c(O)cccc3F)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
Boron tribromide (1M dichloromethane solution, 2.5 mL) was added to a mixture of methyl 4-fluoro-1-(2-fluoro-6-methoxyphenyl)isoquinoline-7-carboxylate (270 mg) and dichloromethane (3 mL) under ice-cooling, and stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain 4-fluoro-1-(2-fluoro-6-hydroxyphenyl)isoquinoline-7-carboxylic acid (240 mg).
Reaction SMILES: [C:1]([O-:10])(=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+].Cl[CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC>[C:1]([S:9][CH2:13][CH2:14][CH2:15][Si:16]([O:17][CH2:18][CH3:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC([O-])=S
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C

Procedure:
The aqueous solution of sodium thiooctanoate was heated to 50° C. and stirred with a mechanical stirrer throughout this procedure. To this solution was added 3-chloro-1-propyltriethoxysilane (444 grams, 1.84 moles) all at once. Immediately thereafter was added 0.15 grams of a concentrated aqueous solution of methyltrioctylammonium chloride. A temperature of 50° C. was maintained for 9 hours, with continued stirring, whereupon the temperature was raised to and subsequently maintained at 74° C. for an additional 15 hours, with continuous stirring. At this point, the solution was allowed to cool to ambient temperature, the stirring was stopped, and the organic phase separated from the aqueous phase by decantation in a separatory funnel. Gas chromatography and mass spectrometry (GC and GCMS) revealed a product containing 80% 3-octanoylthio-1-propyltriethoxysilane and 15.5% residual 3-chloro-1-propyltriethoxysilane (reported purities are based on area percent GC responses). The product was vacuum stripped at 110° C. at 0.1 torr to remove volatiles, primarily 3-chloro-1-propyltriethoxysilane, to yield a product of 94% purity. Product identity using this process confirmed by nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>[CH3:1][NH:2][C:3](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CNC(=O)C(C)(C)C
Reactant: Nc1ccccc1N1CCCCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=Nc1ccccc1N1CCCCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-methylpivalamide (11.5 g) in benzene (120 ml) and phosphorus oxychloride (9.2 ml) was stirred at room temperature for 3 days. A solution of 1-(2-aminophenyl)piperidine (14 g) in benzene (80 ml) was added and the mixture heated at 65°-70° C. for four days to give N-methyl-N'-(2-piperidinophenyl)pivalamidine (m.p. 78° C.) which was recrystallised from hexane. The product was obtained as a 0.25 hydrate.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].C(O)(C)C.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>O>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:33]([O-:38])(=[O:37])[C:34]([O-:36])=[O:35]
Reactant: O=C(O)C(=O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: O
Solvent: CC(C)O
Product: O=C([O-])C(=O)[O-]
Temperature: 80 °C
Reaction time: 22 h

Procedure:
Sitagliptin (5 g) and isopropanol (75 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 30 minutes to obtain a clear dissolution. Oxalic acid (1.54 g) dissolved in water (5 mL) is added and the reaction mixture is refluxed for about 1 hour. The reaction mixture is cooled to about 30° C. and stirred for about 22 hours. The separated solid is filtered, washed with isopropanol (5 mL), and dried under reduced pressure at about 40° C. for about 2.5 hours to afford the title compound. (Yield: 5.8 g; MC: 6.54% w/w; HPLC purity: 99.95%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21]Br>CN(C=O)C>[CH3:18][O:19][CH2:20][CH2:21][O:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1nc2ccccn2c1CO
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1c(C(=O)OC)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of methyl 3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (0.30 g) in DMF (5 ml) was added sodium hydride (60 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min, 2-methoxyethyl bromide (220 mg) was added under ice-cooling, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with aqueous potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-10:0) was concentrated under reduced pressure to give the object product (0.16 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[C@H:23]([CH:24]=O)[CH2:22][C@H:21]2[C@@H:17]1[CH2:18][CH2:19][CH2:20]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(O)(=O)C>[C:9]([O:13][C:14]([N:16]1[C@H:23]([CH2:24][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][C@H:21]2[C@@H:17]1[CH2:18][CH2:19][CH2:20]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@@H]2CCC[C@@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@H](CNCc2ccccc2)C[C@@H]2CCC[C@@H]21
Reaction time: 0.08 h

Procedure:
Benzylamine (2.76 mmol, 2.3 eq) is added to a solution of (1S,3S,5S)-3-formyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester (1.2 mmol, 1.0 eq) in chloroform (10 mL). The mixture is stirred for 5 min, treated with sodium triacetoxyborohydride (4.8 mmol, 4.0 eq) and acetic acid (0.05 mL), stirred for additional 14 h and poured into sat. NaHCO3 solution. DCM is added, the layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are washed with water (100 mL) and concentrated in vacuo. The residue is dissolved in ether and extracted three times with hydrochloric acid (0.1 M). The combined aqueous layers are extracted once with ether, made basic (pH 9-10) by addition of NaOH solution (1.0M) and extracted three times with ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired benzylamine which is used without further purification. LC-MS: tR=0.89 min; [M+H]+=331.5.
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][F:27])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[F:35][CH:36]([F:42])[C:37](OCC)=[O:38]>CO>[F:35][CH:36]([F:42])[C:37]([NH:1][C@H:2]([CH2:26][F:27])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)=[O:38]
Reactant: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@H](N)CF)cc3)cc2n1
Reactant: CCOC(=O)C(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 3.1 %

Procedure:
To a stirred solution N-{7-[4-((1R,2S)-2-Amino-3-fluoro-1-hydroxy-propyl)-phenyl]imidazo[1,2-a]pyridin-2-ylmethyl}-methane sulfonamide (88 mg, crude) in methanol (1 mL) is added triethyl amine (0.05 mL, 0.346 mmol) followed by addition of ethyl difluoroacetate (0.02 mL, 0.208 mmol) at 0° C. then stirred at room temperature for 20 h. The reaction mixture is concentrated and purified by flash column chromatography eluting in 2.1% MeOH in CH2Cl2 followed by re-purification by preparative TLC to afford 5 mg and which is re-crystallized in Chloroform: hexane to afford 3 mg of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 2.94 (s, 3H), 4.31-4.35 (m, 3.5H), 4.41-4.45 (m, 0.5H), 4.54-4.57 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=3.96 Hz, 1H), 5.92 (d, J=4.52 Hz, 1H), 6.20 (t, J=53.8 Hz, 1H), 7.34 (d, J=6.16 Hz, 1H), 7.46 (d, J=8.24 Hz, 2H), 7.60 (t, J=6.12, 1H), 7.78-7.83 (m, 3H), 7.90 (s, 1H), 8.63 (d, J=7.16 Hz, 1H), 8.84 (d, J=8.8 Hz, 1H), 8.93 (bs, 1H). LC-MS (m/z): [M+H]=471.2.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:15][CH3:16])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9]C(=O)[C:7]2=[O:14])([O-:3])=[O:2].[OH:17]O.Cl>[OH-].[Na+]>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([NH2:9])=[C:6]([C:5]=1[CH2:15][CH3:16])[C:7]([OH:14])=[O:17])([O-:3])=[O:2]
Reactant: CCc1c([N+](=O)[O-])ccc2c1C(=O)C(=O)N2
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 1.0 g (4.5 mmoles) of 5-nitro-4-ethylisatin in 8.0 mL of 5% NaOH was slowly added 1.25 mL (11 mmoles) of 30% hydrogen peroxide over 10 minutes. A mild exotherm was detectable. The solution was stirred at room temperature for 60 minutes, then poured over crushed ice. The solution was acidified with 10% HCl until the `cloud point`. The suspension was extracted 3× with ethyl acetate. The combined organic extracts were washed 1× with water, dried over MgSO4, and concentrated in vacuo. There was obtained a dark oil, which upon standing at room temperature, became an orange-rust colored solid. 0.78 g (82% yield) of 5-nitro-6-ethyl-2-aminobenzoic acid was obtained. NMR(DMSO-d6): 1.16(t,3H,J=7.2 Hz), 2.88(q,2H,J=7.2 Hz), 3.34(bs,2H), 6.66(d,1H,J=9.3 Hz), 7.84(d,1H,J=9.3 Hz). MS(m/z): 210(M+).
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[S:23]1[CH2:27][CH2:26][S:25][CH:24]1NC.C[CH2:31][N:32](C(C)C)C(C)C>C(O)CCC>[S:25]1[CH2:26][CH2:27][S:23][CH:24]1[CH2:31][NH:32][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC1SCCS1
Solvent: CCCCO
Product: c1ccc(-c2oc3ncnc(NCC4SCCS4)c3c2-c2ccccc2)cc1
Temperature: 120 °C
Yield: 34.7 %

Procedure:
A mixture of 69 (150 mg, 0.86 mmol), 1,3-dithiolan-2-yl-methylamine (240 μL, 1.78 mmol), and DIEA 0.31 mL (1.78 mmol) in 1-butanol (1 mL) was heated to 120° C. for 2 h. After cooling, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography, affording 110 (121 mg). LCMS and 1HNMR are identical with the product obtained from method 1.