Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH3:2].C([O-])(=O)C.[NH4+:39]>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:39])[C:8]=2[N:22]=1)[CH3:2]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCCCc1cccnc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCCCc1cccnc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
Under a nitrogen atmosphere, 2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridine (4.6 g) from Part A and ammonium acetate (46 g) were heated in a sealed tube to 150° C. After 65 hours, NMR analysis indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature, dissolved in ethyl acetate, and washed 3 times with 1N potassium hydroxide and once with water. The organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 10% hydrochloric acid and washed 3 times with dichloromethane (DCM). Potassium hydroxide was added to the aqueous layer to bring the pH to 14, and this was subsequently washed 4 times with DCM. The combined organic layers were washed twice with water, twice with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The oil was purified by column chromatography over silica using 98/2 DCM/methanol as the eluant. The oil was then triturated with ethyl acetate/hexane and the resulting solid was recrystallized from ethyl acetate/hexane to yield 2-(ethoxymethyl)-6,7-dimethyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine as a white solid, m.p. 78.0 78.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Cl:27][CH2:28][C:29]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Fc1cc(-c2ncccn2)ccc1N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Fluoro-4-piperazin-1-yl-phenyl)-pyrimidine (29AB) (675 mg, 2.61 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (5 mL), and triethylamine (1.32 mg, 1.82 mL, 13.05 mmol, 5 equiv) was added, followed by slow addition of a solution of chloroacetyl chloride (591 mg, 417 uL, 5.23 mmol, 2 equiv) in tetrahydrofuran at room temperature. The mixture was then stirred for about 1 hour at room temperature.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.[NH2:25][C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][C:29](/[CH:36]=[C:37](/[OH:41])\[C:38]([OH:40])=[O:39])=[CH:28][C:27]=1[Cl:42].C(N(CC)CC)C>C1COCC1>[NH2:25][C:26]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][C:29]([CH2:36][C@@H:37]([OH:41])[C:38]([OH:40])=[O:39])=[CH:28][C:27]=1[Cl:42]
Reactant: Nc1c(Cl)cc(/C=C(/O)C(=O)O)cc1C(F)(F)F
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](O)C(=O)O)cc1C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
33.5 g (104.3 mmol) (−)-DIP-chloride dissolved in 195 ml THF was added under protective nitrogen gas to a mixture of 24.5 g (86.9 mmol) (E)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-acrylic acid, 12.1 ml (86.9 mmol) triethylamine and 98 ml THF cooled to −20° C. The reaction mixture was stirred for 1.5 hours at −20° C., brought to ambient temperature and evaporated down under reduced pressure. The residue was combined with 200 ml aqueous 1-molar sodium hydroxide solution and 150 ml TBME and stirred thoroughly. The aqueous phase was separated off, acidified with 2-molar hydrochloric acid solution with stirring and extracted twice with 250 ml TBME. The combined organic phases were filtered through activated charcoal and evaporated down under reduced pressure. The residue was heated to boiling with 500 ml of water and the hot solution was filtered clear through Celite. The precipitate formed at ambient temperature was suction filtered and dried at 65° C. in the circulating air dryer.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2C(C=O)=CC=CC=2)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18].N1(C(OC(C)(C)C)=[O:26])CCNCC1>>[CH3:16][N:17]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:26])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: CNC
Product: CN(C)Cc1ccc(O)cc1

Procedure:
The title compound was prepared by substituting 4-hydroxybenzaldehyde for 4′-chlorobiphenyl-2-carboxaldehyde and dimethylamine for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][NH:28][CH3:29])=[CH:19]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:28]([CH3:29])[CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[CH:19]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Reactant: CNCc1cn(C)c2ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
EDC (0.35 g, 1.89 mmole) was added to a solution of 3-(6-aminopyridin-3-yl)acrylic acid (0.31 g. 1.89 mmole), 1-methyl-3-(methylaminomethyl)-1H-indole (0.30 g, 1.72 mmole), HOBt 1H2O (0.24 g, 1.89 mmole) and diisopropylethylamine (0.60 mL, 3.44 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (5% MeOHWCHCl3) gave the title compound (0.30 g, 55%) as a light yellow solid: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([C:9]([OH:11])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].Cl.O>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[OH:13][C:12]1[CH:14]=[C:15]([OH:16])[CH:17]=[CH:18][C:19]=1[C:9](=[O:11])[CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH3:1]
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C(=O)c1ccc(O)cc1O)c1ccccc1
Temperature: 110 °C
Yield: 41.3 %

Procedure:
3.0 g (20 millimols) of S-(+)-2-phenylpropionic acid was mixed with 3.3 g (24 millimols) of anhydrous zinc chloride and heated to 110° C. to dissolve the latter in the former. 2.64 g (24 millimols) of resorcinol was added to the solution and further heated to 150° C. over a period of 20 minutes while stirring the reaction mixture. The reaction mixture was then cooled to the room temperature. 10 ml of concentrated hydrochloric acid solution and 50 ml of water was added to the reaction mixture, and the reaction product was extracted for 3 times while using 50 ml of ethyl ether in each extraction operation. The extract in ethyl ether was rinsed with an aqueous solution of NaHCO3 for two times, and then rinsed with water for three times. The extract in ethyl ether was then dried by adding anhydrous Na2SO4. The drying agent was removed by filtration and ethyl ether was removed by distillation to obtain 3.6 g of a crude product. The crude product was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 2.0 g of 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenol was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:33])[F:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:35](N1C=CN=C1)([N:37]1C=CN=[CH:38]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:32])[F:33])[CH:21]=1)[CH2:16][C:17]([N:37]([CH3:38])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid (350 mg, 0.72 mmol) in tetrahydrofurane was added carbonyldiimidazole (175 mg, 1.08 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added dimethylamine in THF (0.73 ml, 1.45 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (200 mg, 55%): mp, 83-85° C.; 1H NMR (CDCl3): 2.25 (s, 3H, CH3CO), 2.91 (s, 3H, NCH3), 3.06-3.13 (m, 4H, CHHCO+NCH3), 3.85 (dd, J=10, 15 Hz, 1H, CHHCO), 5.85-5.91 (m, 1H, CHN), 6.80 (t, JH-F=75 Hz, 1H, OCF2H), 6.84 (t, JH-F=75 Hz, 1H, OCF2H), 7.23 (d, J=7.5 Hz, 1H, Ar), 7.41-7.47 (m, 3H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.72 (d, J=7.5 Hz, 1H, Ar), 9.51 (s, 1H, NHCO). 13C NMR (CDCl3): 24.8, 34.5, 35.4, 36.9, 50.5, 111.4, 111.5, 115.2, 115.6, 115.7, 117.9, 119.8, 119.9, 122.0, 122.4, 124.7, 126.1, 131.1, 135.8, 137.4, 138.2, 141.9, 142.2, 167.7, 168.8, 169.1, 169.7; Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22; Found: C, 53.89; H, 3.88; N, 8.13.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:24][CH3:25])[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (5.0 g, 16.3 mmol) and N-isobutyl-methylamine (7.09 g, 81.4 mmol) in DMSO (50 mL) at RT according to the general procedure C. Obtained as a brown oil (5.79 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.Cl.[CH:25]12[CH2:30][CH:29]1[CH2:28][NH:27][CH2:26]2.C(N(CC)CC)C.O>C1COCC1>[CH:25]12[CH2:30][CH:29]1[CH2:28][N:27]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[CH2:26]2
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)O)cc1Cl
Reactant: C1NCC2CC12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Temperature: 25 °C

Procedure:
In THF (15 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl) pyrimidine-5-carboxylic acid (196 mg, 0.55 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride salt (79 mg, 0.66 mmol). The solution was cooled in an ice bath, and triethylamine (167 mg, 1.65 mmol) was added dropwisely. The reaction was allowed to warm to ambient temperature for 5 h, followed by addition of water and extracted with DCM. The organic phase was dried and concentrated to give a solid which was used in the subsequent procedure without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:7])C.[OH-].[Na+].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>CN(C=O)C.[H][H]>[NH2:7][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(N)CCCN
Reactant: [H][H]
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
To a solution of 1,4-diaminopentane (25 g, 155 mmol) in 100 mL DMF/H2 O (1:1) was added 5N NaOH to adjust the pH to 9. CBZ-Cl (3.7 mL, 26 mmol) was added as one portion and stirred at room temperature for 16 hrs. The reaction was acidified to pH 1.25 and washed with diethyl ether. The pH of the reaction was then adjusted to 9.5 and the reaction extracted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4 and evaporated to give title compound (1.57 g, 30%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCOCC1.O>[CH3:12][C:4]1[N:3]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: C1CNCCN1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)cc(N2CCNCC2)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
A solution of 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.0 g, 5.11 mmol), piperazine (1.32 g, 15.3 mmol), and triethylamine (0.71 mL, 5.1 mmol) were mixed in 1,4-dioxane (10 mL). After stirring at 100° C. for 5 h, the reaction solution was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (10% MeOH/5% Et3N/EtOAc) to yield the desired product (880 mg, 70.2%). LCMS calculated for C11H15F3N3: (M+1) 246.1; found 246.1.
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([S:11][CH3:12])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=1
Reactant: CSSC
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1C(F)(F)F
Temperature: 85 °C
Yield: 87.2 %

Procedure:
A solution of isoamyl nitrite (4.02 mL, 30 mmol) in dimethyl disulfide (19.8 mL, 220 mmol) at 25° C. was slowly treated with 4-bromo-2-(trifluoromethyl)aniline (4.8 g, 20 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis i-of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (4.73 g, 87%) as a brown oil: EI-HRMS m/e calcd for C8H6BrF3S (M+) 269.9326, found 269.9327.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C1C(=O)N([I:18])C(=O)C1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:18])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c(I)n[nH]c2cn1
Temperature: 25 °C

Procedure:
A solution containing 5-bromo-1H-pyrazolo[3,4-c]pyridine (168.0 g, 848.4 mmol) and NIS (286.3 g, 1.27 mol) in DMF (1.2 L) was stirred on at room temperature. The reaction mixture was poured into water then filtered. The solid was washed with water and 5% Na2S2O5. The crude product was dried under high vacuum overnight to give 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=NN(C)C)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: CN(C)N=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Product: O=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Temperature: 45 °C
Yield: 92 %

Procedure:
3-(4-bromophenyl)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (2.0 g, 6.2 mmol) was suspended in 5N sulfuric acid (60 mL) and heated at 45° C. for 6 h. The temperature was raised to 85° C. for 2 h, and upon cooling a precipitate formed. This material which was isolated by filtration to give 1-(4-bromophenyl)-3,3,3-trifluoropropane-1,2-dione 1.6 g (92%) as a yellow solid. The dione (1.6 g, 5.7 mmol) was taken up in methanol (30 mL), N-(tert-butoxycarbonyl)-L-prolinal (1 g, 5.0 mmol) was added, followed by addition of 28% ammonium hydroxide solution (10 mL). The reaction was stirred at room temperature for 18 h, poured onto dichloromethane (200 mL), washed with water and dried with MgSO4. Filtration, concentration and application to a 40 M Biotage cartridge, gradient elution with 5%-30% ethyl acetate/Hexanes, gave J32.a 1.3 g (50%). 1H NMR (300 MHz, DMSO-d6) δ 12.88 (br. s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.84-4.70 (m, 1H), 3.57-3.49 (m, 1H), 3.39-3.29 (m, 1H), 2.31-2.20 (m, 1H), 1.98-1.78 (m, 3H), 1.39/1.13 (m, 9H). LRMS: Anal. Calcd. for C19H20BrF3N3O2 458.07. found: 458.06 and 460.06 (M−H)−. HRMS: Anal. Calcd. for C19H22BrF3N3O2 460.0847. found: 460.0866 and 462.0840 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:8]([O:15][CH3:16])(=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].C[O-].[Na+]>>[CH3:4][CH:3]([CH2:2][C:1]([O:6][CH3:7])=[O:5])[CH:9]([C:8]([O:15][CH3:16])=[O:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)OC
Reactant: C/C=C/C(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(C)C(C(=O)OC)C(=O)OC

Procedure:
Scheme 2 illustrates an alternative exemplary method for making a compound of the formula 1.3. Starting from (E)-methyl but-2-enoate, reaction with dimethyl malonate and sodium methoxide gives trimethyl 2-methylpropane-1,1,3-tricarboxylate, which can be resolved, by for example, a lipase, to give compound 1.3.
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH3:13][O:14][CH2:15][CH2:16][Br:17]>>[BrH:17].[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8](=[NH:10])[N:7]([CH2:16][CH2:15][O:14][CH3:13])[C:6]=2[CH:11]=1
Reactant: COCCBr
Reactant: Nc1nc2cc(F)c(F)cc2s1
Product: Br
Product: COCCn1c(=N)sc2cc(F)c(F)cc21

Procedure:
Commercially available 5,6-difluoro-benzothiazol-2-ylamine and 2-bromoethyl methyl ether were processed as described for Example 46A to afford the title compound. MS (ESI+) m/z 245 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[OH:25])([O-:15])=[O:14].Cl>O>[OH:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[N:21]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:20]=1
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl chloroformate (5 ml) was added to a pyridine (30 ml) solution containing 5-nitro-1H-indazol-3-ol (5.42 g) obtained in the 1st step, followed by stirring at room temperature for 1.5 hours. Water and concentrated hydrochloric acid (32 ml) were added dropwise to the reaction solution and a solid precipitate was collected by filtration. The obtained residue was washed with water. A brown solid of ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (7.5 g) was thus obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[CH2:25]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:41]([O-:44])(=[S:43])[CH3:42].[K+]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:41]([S:43][CH2:25][C@H:13]1[N:12]([CH2:11][CH:10]([C:5]2[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[C:4]=2[CH3:28])[OH:27])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)(=[O:44])[CH3:42]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Reactant: CC([O-])=S
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(O)c1ccc(F)c(C#N)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S)-tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (synthesis described above, 0.090 g, 0.23 mmol) was dissolved in THF (2.3 mL) and cooled to 0° C. Triethylamine (0.038 mL, 0.274 mmol) was added followed by addition of Ms-Cl (0.020 mL, 0.252 mmol), and DMAP (2.79 mg, 0.023 mmol). The ice bath was removed and stirring was continued for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting material was re-dissolved in DMSO (2 mL) and treated with potassium thioacetate (0.035 g, 0.306 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight and then heated at 45° C. for 2 h. The mixture was diluted with ethyl acetate and washed with water (3 times) and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (100% hexane to 80% EtOAc/Hexane) to give the desired product LC/MS: M+1=452.3.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[O:3]1.Cl.[CH2:15]([NH2:17])[CH3:16].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:15]([NH:17][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[S:1])[O:3][C:4]=2[CH:10]=1)=[O:13])[CH3:16]
Reactant: O=C(O)c1ccc2[nH]c(=S)oc2c1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Example 92B, 424 mg, 2.17 mmol), ethanamine hydrochloride (266 mg, 3.26 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (991 mg, 2.61 mmol) were combined in tetrahydrofuran (5 mL). Triethylamine (1.4 mL, 977 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of hydrochloric acid, and absorbed on silica gel. The crude mixture was purified with silica gel chromatography eluting with a gradient of methanol in dichloromethane (2-20%). The chromatographed material was triturated with dichloromethane to afford the title compound. MS (ESI−) m/z 220.9 (M−H)−.