Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2=[N:6][CH:7]=1.Br[C:29]1[CH:30]=[C:31]([NH:35][C@H:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:30]=[C:31]([NH:35][CH:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[C@@H](Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Reactant: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 100 °C
Yield: 73.8 %

Procedure:
To a nitrogen gas purged mixture of 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (231 mg, 0.565 mmol), (R)-2-(5-bromopyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide (200 mg, 0.565 mmol), and Na2CO3 (847 μl, 1.694 mmol) in DME (3765 μl) was added Tetrakis (131 mg, 0.113 mmol). The reaction mixture was heated at 100° C. in a sealed microwave vessel for 1 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, and concentrated under reduced pressure. Purification of the residue on silica (0-5% methanol/ethyl acetate, 25 gm silica) to give 232 mg foam, (2-1a).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:12][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1n[nH]c(C)c1Cl
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (Maybridge, 4.41 g, 28.6 mmol) in DMF (14 mL) was added N-chlorosuccinimide (3.86 g, 28.9 mmol). The resulting solution was heated at 60° C. for 3 h and then cooled to room temperature. Water was added until a white precipitate formed, and the solid was collected by filtration washing with water. The solid was dissolved in CH2Cl2, washed with water (2×), dried over MgSO4 and concentrated in vacuo to provide the title compound (5.14 g, 90%) as a white solid. 1H NMR (CDCl3) δ 8.03 (s, 1H), 4.42 (q, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.42 (t, J=7.1 Hz, 3H); MS(ESI+) m/z 188.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]3[N:21]=[CH:22][C:23]([CH:24]=O)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:19][CH2:20]3)[N:13]3[N:21]=[CH:22][C:23](/[CH:24]=[C:32]4/[C:30](=[O:31])[NH:29][C:27](=[O:28])[NH:26]/4)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1cnn2c(NCC3CC3)cc(Nc3ccc(F)c(Cl)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cnn3c(NCC4CC4)cc(Nc4ccc(F)c(Cl)c4)nc23)N1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To 5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.09 mmol) in 1.0 mL of ethanol was added hydantoin (9 mg, 0.09 mmol) and piperidine (8 ul). The reaction was heated at 80° C. overnight, cooled to room temperature, filtered, and washed with ethanol to yield 20 mg (31% yield) (Z)-5-((5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino) pyrazolo[1,5-a]pyrimidin-3-yl) methylene)imidazolidine-2,4-dione as a yellow powder. LCMS (M+1=442)
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([O:32]C)=[C:26]([O:34]C)[CH:25]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO.O>ClCCl>[CH2:20]([C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[C:9]([OH:8])=[C:10]([C:24]3[CH:29]=[C:28]([OH:30])[C:27]([OH:32])=[C:26]([OH:34])[CH:25]=3)[O:11]2)=[CH:16][CH:15]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a stirring solution of 39d (0.389 g, 1 mmol) in dichloromethane (15 ml) under Ar was added boron tribromide in dichloromethane (1.0M, 5.0 ml, 5 mmol, 4.9 equ). The mixture was then stirred for 18 hours. Methanol (5 ml) was then added. The reaction was heated to reflux for 2 hours, then concentrated in vacuo to give a brown solid. Water (25 ml) was added and the mixture sonicated then extracted into ethyl acetate (3×). The organic layer was washed with brine then dried (MgSO4) and concentrated in vacuo to give 9d (0.302 g, 77%) as a brown solid.
Reaction SMILES: C1(C2N3C=CN=C(N)C3=C(I)[N:6]=2)CCC1.Cl[C:17]1[C:18]2[N:19]([C:23]([CH:27]3[CH2:30][C:29]([F:32])([F:31])[CH2:28]3)=[N:24][C:25]=2[I:26])[CH:20]=[CH:21][N:22]=1>>[F:31][C:29]1([F:32])[CH2:30][CH:27]([C:23]2[N:19]3[CH:20]=[CH:21][N:22]=[C:17]([NH2:6])[C:18]3=[C:25]([I:26])[N:24]=2)[CH2:28]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: FC1(F)CC(c2nc(I)c3c(Cl)nccn23)C1
Product: Nc1nccn2c(C3CC(F)(F)C3)nc(I)c12

Procedure:
Prepared according to the procedure described above for 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine, except using 8-chloro-3-(3,3-difluoro-cyclobutyl)-1-iodo-imidazo[1,5-a]pyrazine. HPLC: tR=1.87 min. (Open Lynx polar—5 min). MS (ES+): m/z 350.74 (100) [MH+].
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)O1.Br[C:32]1[CH:33]=[C:34]([O:38][CH2:39][CH2:40][NH:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])[CH:35]=[N:36][CH:37]=1>[Pd].C1COCC1>[C:25]([NH:24][C:22]1[S:23][C:19]2[CH:18]=[C:17]([C:32]3[CH:33]=[C:34]([O:38][CH2:39][CH2:40][NH:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])[CH:35]=[N:36][CH:37]=3)[CH:29]=[CH:28][C:20]=2[N:21]=1)(=[O:27])[CH3:26]
Reactant: COCC(=O)NCCOc1cncc(Br)c1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(=O)NCCOc1cncc(-c2ccc3nc(NC(C)=O)sc3c2)c1
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A Biotage high recovery microwave vessel was charged with sodium carbonate hydrate (0.048 g, 0.38 mmol), 0.15 mL water and a stirbar. The slurry was sonicated and stirred for 10 minutes. An inert atmosphere inlet was placed over the vessel and the remaining reagents were added under a flow of nitrogen. To the vessel was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.043 g, 0.14 mmol), 100 mg Pd FibreCat® palladium catalyst, and N-(2-(5-bromopyridin-3-yloxy)ethyl)-2-methoxyacetamide (0.0247 g, 0.085 mmol) dissolved in 1 mL THF. The vessel was sealed, and irritated using a Biotage personal chemistry microwave reactor to 130° C. for 25 minutes. The cooled reaction was diluted with 5 mL THF, and filtered through a 0.22 μm PTFE membrane. The catalyst was washed with THF (2×5 mL), and the combined filtrates were concentrated in vacuo. The residue was sonicated in 2 mL water, and filtered. The precipitate was then dissolved in 3 mL MeOH, filtered, and concentrated in vacuo. The crude was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 10% B; 5.0→35 min@20 mL/min, linear gradient to 40% B; 35→45@20 mL/min, isocratic at 40% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 10% B; 60 min end; A=10.7 mM NH4HCO3 in water, pH adjusted to 8.6 with concentrated NH4OH; B acetonitrile). A band that eluted from 24.2 to 26.0 minutes was isolated. The solvent was removed in vacuo to afford N-(2-(5-(2-(N-actyl)aminobenzo[d]thiazol-6-yl)pyridin-3-yloxy)ethyl)-2-methoxyacetamide. (0.0090 g, 26% yield). 1H NMR (400 MHz, DMF) δ ppm 2.34 (s, 3H) 3.37 (s, 3H) 3.70 (q, J=5.84 Hz, 2H) 3.89 (s, 2H) 4.35 (t, J=5.97 Hz, 2H) 7.81 (dd, J=2.54, 1.96 Hz, 1H) 7.83 (s, 1H) 7.85 (s, 1H) 7.86-7.90 (m, J=8.41, 1.86 Hz, 1H) 8.32 (d, J=2.25 Hz, 1H) 8.47 (d, J=1.47 Hz, 1H) 8.62 (br. s., 1H) 12.35 (br. s., 1H). 13C NMR (101 MHz, DMF) δ ppm 22.46 (s, 1 C) 38.02 (s, 1 C) 58.54 (s, 1 C) 66.92 (s, 1 C) 71.91 (s, 1 C) 118.91 (s, 1 C) 120.35 (s, 1 C) 121.07 (s, 1 C) 125.49 (s, 1 C) 132.82 (s, 1 C) 133.22 (s, 1 C) 136.79 (s, 1 C) 137.04 (s, 1 C) 140.37 (s, 1 C) 149.26 (s, 1 C) 155.35 (s, 1 C) 159.21 (s, 1 C) 169.69 (s, 1 C) 169.72 (s, 1 C). HPLC-MS: retention time=1.12 min (99.3%@215 nm; 98.1% @254 nm; m/z=401.1, calculated for C19H20N4O4S+H+=401.1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29]Br)[CH2:25][CH2:24]1)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][N:13]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CCC[C@H]1CC[C@H](CBr)CC1
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCc1cnc(-c2ccc(OC[C@H]3CC[C@H](CCC)CC3)cc2)nc1

Procedure:
A mixture of 11 g of a 2-p-hydroxyphenyl-5-n-hexylpyrimidine, 7.8 g of trans-4-n-propyl-1-bromomethylcyclohexane, 8.6 g of potassium carbonate and 50 ml of dimethylformamide is warmed at 90° for 10 hours. Customary working up gives 4-(5-n-hexylpyrimidin-2-yl)-phenyl trans-4-n-propylcyclohexylmethyl ether.
Reaction SMILES: C(OCC)C.[H-].[Na+].[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=1)=[O:12])[CH3:9].[C:25]([O:29][C:30](=O)[O:31]C(C)(C)C)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30]([N:14]1[C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=[C:13]1[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1cc2c([nH]1)CN(C(C)=O)CC2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1C(=O)OC(C)(C)C)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
A suspension of diethyl ether washed sodium hydride (0.28 g, 0.009 mole) in dry dimethylformamide (8 ml) at 0° C. was treated with a solution of 2-ethoxycarbonyl-6-acetyl-4,5,6,7-tetrahydro-6-azaindole from Example 2 (2 g, 0.0085 mole) in dry dimethylformamide (2 ml) and stirred for 20 minutes. The mixture was warmed to room temperature and stirred for 1 hour by which time solution was complete. The solution was cooled to 0° C., a solution of di-tert-butylcarbonate (1.85 g, 0.0085 mole) in dry dimethylformamide (2 ml) added dropwise over 10 minutes, and the solution stirred at room temperature for 4 hours. The mixture was quenched with water (200 ml), extracted with ethyl acetate (4×100 ml) the organic extracts washed with brine (3×100 ml), dried over sodium sulphate, and evaporated to give a yellow oil which was chromatographed on silica gel (20 g) eluting with dichloromethane:hexane (9:1) to give the title product as a pale yellow oil (1.4 g, 49%). Found: C, 60.12; H, 7.32; N, 8.15. C17H24N2O5 requires C, 60.70; H, 7.19; N, 8.33%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.[CH:21]([N:24]([CH:27]([CH3:29])C)CC)([CH3:23])C.N1CCCC1.[I-].[Na+]>CN(C)C=O>[C:13]1([C:10]2[C:9]3[C:19](=[O:20])[CH:5]([CH2:4][CH2:3][CH2:2][N:24]4[CH2:21][CH2:23][CH2:29][CH2:27]4)[CH2:6][CH2:7][C:8]=3[O:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCCC1
Temperature: 25 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (3.75 g) and dimethylformamide (37.0 ml) was added diisopropylethyl amine (6.81 ml), pyrrolidine (2.17 ml) and sodium iodide (5.85 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 73°-76° C. for 1.25-2 hours. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/0-10% methanol/ether) afforded 3.10 g of 6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. The salicylate was prepared with 1.07 eq. salicylic acid in ether. The resulting solid was redissolved with methanol. Addition of pentane led to precipitation of the target salt. Filtration and washing with pentane gave 6,7-dihydro-3-phenyl-5-[3(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one salicylate, m.p. 106°-107° C.
Reaction SMILES: [OH2:1].C[N+]1([O-])CCOCC1.C[N+]1([O-])CCOCC1.[C:18]([O:22][C:23]([NH:25][C@@:26]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:31]=[CH:30][C@@H:29]2[C@H:27]1[C@H:28]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])([CH3:21])([CH3:20])[CH3:19].CCCCCC.C(OCC)(=O)C.[OH2:58]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:18]([O:22][C:23]([NH:25][C@@:26]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:31]([OH:1])[C@H:30]([OH:58])[C@@H:29]2[C@H:27]1[C@H:28]2[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C=C[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1O
Temperature: 23 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Osmium tetraoxide (4% wt/wt in water, 231.78 mL, 241.05 g, 37.93 mmol,) is added at 23° C. to a solution of N-methylmorpholine-N-oxide hydrate (101.62 mL; 114.83 g, 424.78 mmol), N-methylmorpholine-N-oxide hydrate (116.88 g, 864.74 mmol), 4-methylmorpholine-4-oxide (198.88 mL; 195.50 g, 1.67 mol), and di-tert-butyl (1S,2S,5R,6S)-2-[(tert-butoxycarbonyl)amino]bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylate (600.00 g, 1.52 mol) in acetone (12.00 L) and water (1.80 L). The mixture is stirred at 23° C. overnight. Thin layer chromatograph (hexane/ethyl acetate 3:2; stain: PMA) analysis of the reaction mixture revealed complete consumption of di-tert-butyl (1S,2S,5R,6S)-2-[(tert-butoxycarbonyl)amino]bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylate. The reaction is quenched with saturated aqueous Na2S2O3 (1 L) and extracted with methyl tert-butyl ether (15 L). The organic phase is washed with an aqueous solution (1.5 L) prepared from 37% aqueous HCl (300 mL) and brine (1.2 L), dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue is slurried in heptane (1.5 L), filtered, washed with heptane (2×500 mL), and resulting solid. The solid is dried under vacuum to yield the title compound (450 g, 69% yield).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C4C=CC=C5C(NC(=O)C=45)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.[NH2:31]N.Cl.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>CO.C(O)C.O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c(CCN3CCC(c4noc5cc(F)ccc45)CC3)cccc21
Reactant: NN
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Solvent: O
Product: NCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl phthalimide (4.6 gm, 11.7 mmol) and hydrazine monohydrate (1.17 gm, 23.4 mmol) in methanol (50 ml) was heated at reflux overnight. At the end of the reaction, methanol was removed to leave a crude solid. This was stirred with water (15 ml) and acidified with HCl to pH=2. The insolubles were filtered. The aqueous solution was basified with 50% NaOH then extracted with DCM (2×250 ml). The DCM solution was washed with brine and dried over MgSO4. The solvent was removed to produce a colorless oil: 2.12 gm. This oil was treated with a solution of fumaric acid (935 mg, 1.0 eq) in ethanol. The salt crystallized out: 0.99 gm, m.p.=203°-205° C. A second crop of 0.73 gm (m.p.=198°-200° C.) was collected later.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[C:26]4[CH2:37][CH2:36][N:35]([C:47]([N:46]([CH3:50])[CH3:45])=[O:48])[CH2:34][C:27]4=[N:28][C:29]=3[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]2)=[C:9]([F:8])[CH:10]=1)#[N:13]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCNC2
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCN(C(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (32.5 mg, 0.062 mmol) in DCM (620 μL) at 0° C. was treated with triethylamine (25.9 μL, 0.186 mmol) and dimethylcarbamic chloride (11.4 μL, 0.124 mmol). The reaction mixture was allowed to gradually warm to room temperature and stir for 1 h. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 40% to 70% ACN gradient to give the title compound in (about 90% purity), as a TFA salt, as a yellow solid (6.8 mg, 18%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (m, 6H), 2.02 (m, 2H), 2.19 (m, 2H), 2.81 (t, J=5.3 Hz, 2H), 2.91 (s, 5H), 3.17 (m, 3H), 3.43 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 4.13 (m, 1H), 4.32 (s, 2H), 4.80 (m, 1H), 7.34 (m, 1H), 7.54 (t, J=10.9 Hz, 2H); ESI-MS m/z [M+H]+ 482.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([O:25][C@@H:26]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=4[Cl:36])[CH3:27])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[O:39]1CCOCC1>CO.ClCCl>[C:26]([OH:39])(=[O:25])[CH3:28].[Cl:36][C:29]1[C:30]([F:35])=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C@H:26]([O:25][C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1)[CH3:27]
Reactant: C1COCCO1
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)O
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (566.7 mg, 1.03 mmol) in methanol (5 mL) or dichloromethane (30 mL) was added 4N HCl/dioxane (15 mL). The solution was stirred for about 1 hour or until the de-protection was complete. The solvents were evaporated and the residue was dissolved in methanol and purified on a reversed phase C-18 preparative HPLC eluting with acetonitrile/water with 0.1% acetic acid from 5% to 30% with a linear gradient. After lyophilization, 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine acetate was obtained as a white solid (410 mg, 78% yield, 100% HPLC purity, 96.4% ee). 1H NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.68 (d, 1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (q, 1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m, 2H), 1.88 (m, 2H), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e 450 (M+1)+.
Reaction SMILES: [C:1](NCC(O)=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1(O)C2C=CC=CC=2N=N1.[OH:33][C:34]([C:36](F)(F)F)=O.[CH3:40][O:41][C:42]([C@@H:44]1[CH2:48][C:47]([F:50])([F:49])[CH2:46][NH:45]1)=[O:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([CH2:36][C:34]([N:45]3[CH2:46][C:47]([F:50])([F:49])[CH2:48][C@@H:44]3[C:42]([O:41][CH3:40])=[O:43])=[O:33])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC(F)(F)CN1C(=O)CC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with Fmoc-glycine (756 mg, 2543 μmol), 1H-benzo[d][1,2,3]triazol-1-ol (412 mg, 3052 μmol), (S)-methyl-4,4-difluoropyrrolidine-2-carboxylate TFA salt (710 mg, 2543 μmol), Hunig'sBase (2221 μl, 12717 μmol) and 10.2 mL DMF. The mixture was stirred for 5 min at RT, and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (1350 mg, 3052 μmol) was added. The reaction mixture was stirred overnight at RT. The solution was diluted with DCM and washed with water. The organic layer was dried, filtered, and concentrated. The crude oil was purified by silica gel chromatography, 0-5% MeOH/DCM to provide (R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate. MS: [M+H]=445.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH2:10])=[N:6][O:7][C:8]=1[CH3:9].[CH2:11]([C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Cl:3][C:4]1[C:5]([NH:10][S:22]([C:14]2[C:15]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[S:21][C:13]=2[CH2:11][CH3:12])(=[O:24])=[O:23])=[N:6][O:7][C:8]=1[CH3:9]
Reactant: Cc1onc(N)c1Cl
Reactant: CCc1sc2ncccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ncccc2c1S(=O)(=O)Nc1noc(C)c1Cl
Yield: 35.2 %

Procedure:
N-(4-chloro-5-methyl-3-isoxazolyl)-2-ethylthieno[2,3-b]pyridine-3-sulfonamide was prepared according to Example 1(C), using NaH (44 mg, 1.9 mmoles), THF (5 ml), 4-chloro-5-methyl-3-aminoisoxazole (82 mg, 0.62 mmoles) and 2-ethylthieno[2,3-b]pyridine-3-sulfonyl chloride (0.19 g, 0.71 mmoles). Flash chromatography (50% EtOAc/hexanes) followed by recrystallization from EtOAc/hexanes provided 78 mg (35%) of the title compound as a light yellow solid, m.p. 172-174° C.