Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:24](S(C2C=CC=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=3[F:23])[N:9]=[C:4]2[CH:3]=1.[CH3:34][C:35]1[C:39](B(O)O)=[CH:38][NH:37][N:36]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[C:13]([F:23])[C:12]=1[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:39]3[CH:38]=[N:37][NH:36][C:35]=3[CH3:34])[NH:24][C:5]2=[N:6][CH:7]=1
Reactant: Cc1n[nH]cc1B(O)O
Reactant: COc1cc(OC)c(F)c(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c(F)c(CCc2cnc3[nH]c(-c4cn[nH]c4C)cc3n2)c1F
Temperature: 88 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (15 mg, 28 μmol), (3-methyl-1H-pyrazol-4-yl)boronic acid (4.2 mg, 33 μmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexed with dichloromethane (1:1) (1.8 mg, 2.2 μmol), and potassium phosphate (9.5 mg, 45 mmol) in water (0.2 mL)/1,4-dioxane (1 mL) was heated at 88° C. After 1 hour, the volatiles were removed under vacuum and the residue was dissolved in methanol (1 mL). Potassium carbonate (7.7 mg, 56 μmol) was added and the reaction mixture was warmed up to 60° C. After 0.5 hour, the reaction mixture was cooled to ambient temperature and was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (5.1 mg, 46%) as its TFA salt. LCMS calculated for C20H20F2N5O2 (M+H)+: m/z=400.2. Found: 400.2.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(NC(=O)OC(C)(C)C)cc(Cl)c(OC)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)cc(Cl)c(OC)c1Cl
Yield: 87 %

Procedure:
A solution of methyl 2-(tert-butoxycarbonylamino)-4,6-dichloro-5-methoxybenzoate (2.3 g, 6.6 mM) and trifluoroacetic acid (6.0 g, 53 mM) in methylene chloride (23 mL) was stirred at room temperature for 1.5 hr. The reaction mixture was then washed with saturated aqueous sodium bicarbonate, drie (MgSO4), filtered and concentrated to obtain (87%) the title compound as a yellow oil; MS(CI): 250 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:22]3[CH:21]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:20][CH2:19][C:18]([CH3:31])([CH3:30])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:21]2[CH2:20][CH2:19][C:18]([CH3:30])([CH3:31])[C:17]3[CH:16]=[C:15]([C:14]#[C:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[CH:12][CH:11]=4)[CH:24]=[CH:23][C:22]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)ccc21
Yield: 88.7 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 170, 0.08 g, 0.19 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of sodium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo and the residue was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.07 g,˜100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[Cl-].[Cl-].[Cl-].[Al+3].[F:16][C:17]1[CH:22]=[C:21]([CH:23]=[CH:24][N+:25]([O-])=O)[CH:20]=[C:19]([F:28])[C:18]=1[OH:29]>C1COCC1>[NH2:25][CH2:24][CH2:23][C:21]1[CH:20]=[C:19]([F:28])[C:18]([OH:29])=[C:17]([F:16])[CH:22]=1
Reactant: O=[N+]([O-])C=Cc1cc(F)c(O)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To lithium aluminum hydride 11.0M in ether (30 mL, 29.8 mmol) at 0° C. a solution of aluminum trichloride (4.0 g, 29.8 mmol) in THF (40 mL) is added. After 5 min a solution of compound obtained in step 1 above (2.0 g, 9.95 mmol) in THF (40 mL) is added and the reaction is allowed to stir at room temperature overnight. Add water and then 3 N HCL, the aqueous layer is extracted with 3/1 n-butanol/toluene. The combined organic layers are dried over sodium sulfate and concentrated. SCX ion-exchange chromatography afforded 1.50 g (87%) of the title compound. Electrospray MS M+1 ion=174. 1H-NMR (methanol-d4, 200 MHz): 6.95-6.78 (m, 2H), 3.14 (t, 2H, J=7.0 Hz), 2.86 (t, 2H, J=7.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[OH-].[Na+]>CN(C=O)C>[C:41]([O:40][C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[CH2:34][CH2:33]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Reaction time: 22 h
Yield: 86.9 %

Procedure:
To a solution of 4-aminobenzoic acid (411 mg, 3.00 mmol) in DMF (3.0 mL) at room temperature was added EDC (862 mg, 4.50 mmol), HOBt (608 mg, 4.50 mmol), triethylamine (606 mg, 0.835 mL, 6.00 mmol) and tert-butyl piperazinecarboxylate (671 mg, 3.60 mmol). The mixture was stirred for 22 h, and then 2 N aq. NaOH was added to adjust the PH>10. The mixture was extracted with ethyl acetate, and the organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (50 to 90% EtOAc) to give 4-(4-amino-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (796 mg, 87%) as a colorless oil. MS (ES+): m/z=306.2
Reaction SMILES: [CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([Cl:16])[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O1CCOCC1.Cl>O>[ClH:16].[CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)c([N+](=O)[O-])c21
Reactant: CN1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(N(C)C)c3c2[N+](=O)[O-])CC1
Yield: 83.7 %

Procedure:
A mixture of 3.3 g of 1-dimethylamino-7-chloro-6-fluoro-8-nitro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 3.1 g of 1-methylpiperazine and 25 ml of dioxane is refluxed for 3 hours. The solvent is stripped off in vacuo, the residue is suspended in 25 ml of H2O and the pH is brought to 1 with 10% strength hydrochloric acid. The precipitate is filtered off with suction in the cold and washed with a little cold 10% strength hydrochloric acid and ethanol. 3.6 g of 1-dimethylamino-6-fluoro-8-nitro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochoride of decomposition point 292°-294° C. are obtained.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15].O>C(O)C>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CNCCO
Solvent: CCO
Solvent: O
Product: CN(C/C=C/c1ccccc1)CCO

Procedure:
12.5 Grams of cinnamyl chloride and 21 g of 2-methylaminoethanol were dissolved in 100 ml of ethanol, and the solution was refluxed for 5 hours. The solvent was removed by evaporation, to the residue thus obtained was added water and washed with n-hexane. To the water layer was added 3N-sodium hydroxide aqueous solution to adjust its pH to 10-11, and extracted with ether. The ether extract was washed with water and dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=25:1) to yield 15 g of 2-[N-methyl-N-(3-phenyl-2(E)-propenyl)amino]ethanol.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([CH3:11])(S(C)(=O)=O)[CH3:6].[F:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:17]=[CH:16][C:15]=1[C:27]([OH:33])([CH3:32])[CH2:28][C:29](=[NH:31])[NH2:30].C(=O)([O-])O.[Na+]>O1CCCC1.O>[F:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:17]=[CH:16][C:15]=1[C:27]([OH:33])([CH3:32])[CH2:28][C:29]1[NH:30][CH:2]=[C:3]([CH:4]=[C:5]([CH3:11])[CH3:6])[N:31]=1
Reactant: CC(C)(CC(=O)CBr)S(C)(=O)=O
Reactant: CC(O)(CC(=N)N)c1ccc(-c2ccc(F)cn2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=Cc1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2F)n1

Procedure:
Step C In a quartz tube, 1-bromo-4-methyl-4-(methylsulfonyl)pentan-2-one (26 mg, 0.10 mmol), the di(trifluoroacetate) salt of (±)-3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (105 mg, 0.202 mmol), and sodium hydrogen carbonate (53 mg, 0.63 mmol) were suspended in a mixture of tetrahydrofuran (1.5 mL) and water (0.5 mL). After being irradiated by microwave (120° C., 10 min), the reaction mixture was purified by reversed-phase high performance liquid chromatography to afford the di(trifluoroacetate) salt of the title compound. (M+H) found 370.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH2:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>CC#N.CCN(CC)CC>[Cl:19][C:4]1[N:3]=[C:2]([NH:31][CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: NCc1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of tert-butyl 2,6-dichloro-3-nitropyridin-4-ylcarbamate (1.2 g, 3.9 mmol) and quinolin-6-ylmethanamine (616 mg, 3.9 mmol) in CH3CN (15 mL) and Et3N (1 mL) was stirred at 80° C. for 1 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography to afford the title compound (1.60 g). MS (m/z): 430 (M+1)+.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6]1)[CH2:2][CH3:3].[Li+].CCC[CH2-].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=[CH:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCOC1C=CC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of 3 g of 1,5-dihydro-5-n-propyloxy-2H-pyrrol-2-one, in 80 cm3 of tetrahydrofuran, cooled to -45° C., there is added 13.25 cm3 of a 1.6M solution of N-butyllithium in n-hexane, while maintaining the temperature between -35° and -45° C. After 30 minutes, a solution of 3.74 g of benzenesulphonyl chloride in 12 cm3 of tetrahydrofuran is added at a temperature between -45° and -35° C., then the temperature is allowed to return to the ambient over two hours, followed by evaporating to dryness and chromatographing on silica (eluent: ethyl acetate-n-hexane, 1--1). 2.2 g of the expected product is recovered. m.p. 56°-58° C., crystallized from a mixture of ethyl ether-n-hexane, 1-2. By crystallizing from isopropanol, 1.4 g of the expected product is obtained, m.p. 66°-67° C.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:63]=[CH:62][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:55][CH:54]=1)[CH2:37]2>O>[CH3:43][O:42][C:41]1[C:33](=[O:32])[C:34]2[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:63]=[CH:62][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:55][CH:54]=3)[CH2:37][C:38]=2[C:39](=[O:46])[C:40]=1[O:44][CH3:45]
Reactant: CCOC(=O)c1ccc(OCCCCC2Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(OCCCCC2CC3=C(C2)C(=O)C(OC)=C(OC)C3=O)cc1
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
A water (1.0 ml) solution of CAN (299 mg, 0.545 mmols) was dropwise added to an acetonitrile (2.0 ml) solution of ethyl 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoate (100 mg, 0.218 mmols), with cooling with ice, and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 8:1) followed by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (45.0 mg) as crystals.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][C:5]=12.Br[C:12]1[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:18][C:16]1[CH:17]=[C:12]([NH:10][C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[N:6]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1ccn2ccnc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccn3ccnc3n2)c1=O
Yield: 31 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 199a (2.2 g, 16.4 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (8.77 g, 32.8 mmol), Pd2dba3 (1.5 g, 1.64 mmol), Xantphos (1.88 g, 3.28 mmol), Cs2CO3 (10.7 g. 32.8 mmol), and 1,4-dioxane (150 mL). The system was evacuated and then refilled with N2. It was then heated at reflux for 3 h. After the completion of the reaction, the mixture was filtered off and the solid was washed with methanol (60 mL). The combined filtrate was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 199b as a light green solid (1.63 g, 31%). MS: [M+H]+ 320.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][CH:19](O)[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH:19]([CH3:20])[CH3:18])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)c(F)c1
Reactant: CC(C)O
Product: CC(C)OC(=O)Cc1ccc(-c2ccccc2)c(F)c1

Procedure:
2-propyl (2-fluorobiphenyl-4-yl)acetate (20) was synthesized from 2-(2-fluorobiphenyl-4-yl)acetic acid and 2-propanol according to a similar procedure to step 1 of Example 15. The 1H NMR spectrum of this substance is shown below.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:7](F)=[N:8][CH:9]=[CH:10][CH:11]=2)=O)[CH2:3][CH2:2]1.Cl.Cl.[NH:15]([C@H:17]1[CH2:20][C@H:19]([NH:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:18]1)[NH2:16].C([O-])(=O)C.[K+].O1CCOCC1>C1(C)C=CC=CC=1.C(O)C>[CH:1]1([C:4]2[C:6]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:15]([C@H:17]3[CH2:18][C@H:19]([NH:21][C:22]4[S:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH2:20]3)[N:16]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1cccnc1F)C1CC1
Reactant: NN[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2sc(N[C@H]3C[C@H](n4nc(C5CC5)c5cccnc54)C3)nc2c1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
Cyclopropyl(2-fluoropyridin-3-yl)methanone (intermediate 53, 0.270 g, 1.635 mmol), N-(trans-3-hydrazinylcyclobutyl)benzo[d]thiazol-2-amine dihydrochloride (intermediate 52, 0.502 g, 1.635 mmol), and potassium acetate (0.462 ml, 7.39 mmol) were suspended in a mixture of dry dioxane (5 mL), dry ethanol (5 mL), and dry toluene (5 mL) and heated at 105° C. for 30 minutes. The temperature was lowered to 90° C. and additional potassium acetate (1.2 g, 6.6 eq) was added. The mixture was stirred for another 90 minutes. After another 3 hours the reaction was evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% (2 N ammonia in methanol) in dichloromethane gradient) followed by repurification using reverse phase HPLC and free basing (ethyl acetate/saturated sodium bicarbonate) gave the desired N-(trans-3-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.170 g, 0.470 mmol, 28.8% yield) as a white solid. M+1: 362.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87-1.20 (m, 4 H) 2.12-2.22 (m, 1 H) 2.49-2.71 (m, 2 H) 3.00-3.26 (m, 2 H) 4.36-4.58 (m, 1 H) 5.63 (quin, J=7.24 Hz, 1 H) 6.61 (br. s., 1 H) 6.89-7.12 (m, 2 H) 7.21 (br. s., 1 H) 7.53 (m, J=7.80 Hz, 2 H) 7.94 (dd, J=7.82, 1.17 Hz, 1 H) 8.39 (dd, J=4.40, 1.08 Hz, 1 H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cl-].[Zn+2].[Cl-]>[C:14]([C:11]1[CH:10]=[C:9]([Cl:13])[CH:8]=[C:7]2[C:12]=1[NH:4][CH2:5][CH2:6]2)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N1CCc2cc(Cl)ccc21
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(c1ccccc1)c1cc(Cl)cc2c1NCC2

Procedure:
7-Benzoly-5-chloroindoline was prepared by treating 1-acetyl-5-chloroindoline with benzoyl chloride at 120°-175°C. using zinc chloride as a catalyst. The acetyl group was removed by acid hydrolysis to give the yellow colored 7-benzoyl-5-chloroindoline. The yellow solid melted at 112°-115°C. A mixture melting point with material prepared in Example 2 showed no depression.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1([CH2:21]O)[CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: CC1(CO)CC1
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCC1(C)CC1

Procedure:
Following General Procedure C above, and using N-(3-chloroph,enylacetyl alanine (from Example D above) and (1-methylcyclopropyl)methanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:9])[S:8][C:4]=2[CH:3]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[Cl:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][CH2:12][CH2:13][CH2:14][CH3:15])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Nc1ccc2nc(Cl)sc2c1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCNc1ccc2nc(Cl)sc2c1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of (29) (0.2 mmol, 36.8 mg) in 2 ml dichloroethane was added 0.2 mmol butyraldehyde (18 followed by 63.6 mg sodium triacetoxyborohydride, and 12 μl acetic acid. After 2 h, the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and the solvent removed by rotary evaporation, yielding 44.2 mg of a yellow solid. 1H-NMR (CDCl3): δ 7.67 (d, 1H, J=9.2 Hz), 6.84 (d, 1H, J=2.4 Hz), 6.72 (dd, 1H, J=2.4, 9.2 Hz), 3.35 (bt, 1H), 3.15 (t, 2H), 1.65 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H, J=7.6 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.[Si:27]([O:34][CH2:35][CH2:36][C:37]1[S:41][C:40]([CH2:42][CH:43]=O)=[CH:39][CH:38]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Si:27]([O:34][CH2:35][CH2:36][C:37]1[S:41][C:40]([CH2:42][CH2:43][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]4[N:13]=[C:9]([CH3:8])[S:10][CH:11]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:39][CH:38]=1)([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28]
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CC=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO[Si](C)(C)C(C)(C)C)s4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
(2-Methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.25 g) was added to a solution of 2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)acetaldehyde (0.2 g) (example 4, step g) in a mixture of NMP (5 mL) and acetic acid (0.04 mL). The resulting mixture was stirred for 5 min then sodium triacetoxyborohydride (0.22 g) was added. The mixture was stirred for 1 h and poured into pH 7.2 buffer (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organics were washed with pH 7.2 buffer (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 4:1:0.05 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine to give the subtitled compound as a yellow oil. Yield 0.23 g.