Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:17]2[CH:25]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16])C1C=CC=CC=1.[C:38](OCC)(=O)C.O1CCCC1.[H][H]>[Pd].CO>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([N:17]2[CH:25]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)=[CH:10][C:9]=1[OH:8])#[N:16]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1OCc1ccccc1
Reactant: CCOC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(O)c2)C1C1CCCC1

Procedure:
A mixture of 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (Example 31; 70 mg, 0.14 mmol), ethyl acetate, tetrahydrofuran, and methanol was treated with 10% palladium on carbon (10 mg) and hydrogenated for four hours at 30 psi hydrogen. The mixture was filtered through Celite, and concentrated to give methyl 2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate (57 mg, 0.14 mmol) as a yellow solid. The title compound was largely present as (±)-(3RS,3aSR)-methyl 2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.58 (m, 8H), 1.61-1.75 (m, 1H), 1.74-1.90 (m, 1H), 2.00-2.12 (m, 1H), 2.16-2.30 (m, 1H), 2.79-2.96 (m, 1H), 3.09 (d, J=16.11 Hz, 1H), 3.57 (ddd, J=13.76, 9.47, 4.70 Hz, 1H), 4.76 (dd, J=9.67, 5.37 Hz, 1H), 6.69 (dd, J=8.86, 1.61 Hz, 1H), 6.82 (s, 1H), 7.36 (d, J=8.59 Hz, 1H), 7.82-7.90 (m, 2H), 8.00 (d, J=8.06 Hz, 1H), 10.70 (s, 1H). ES-MS m/z 402 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=6)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(cnn2Cc2ccc(F)cc2)c1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Fc1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6nnc(C(F)(F)F)o6)cc45)ccc32)cc1

Procedure:
The title compound was prepared according to Procedure A from 1-(4-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.91(1H,bs), 9.55(1H,s), 8.91(1H,s), 8.69(1H,dd), 8.23(1H,s), 8.14(2H,m), 7.88(1H,d), 7.69(1H,dd), 7.36(2H,m), 7.18 (2H,dd), 5.71(2H,s); m/z (M+1+) 506.
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O.[CH:18]([N:21](CC)C(C)C)(C)[CH3:19].C(N)C>C1(C)C=CC=CC=1>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:21][CH2:18][CH3:19])=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CCCCBr
Agent: CCN
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)CCCCBr
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Dimethylformamide (116 μL, 1.5 mmol, 0.1 eq.) and thionyl chloride (1.63 ml, 22.5 mmol, 1.5 eq.) were added to a solution of 5-bromovaleric acid (2.71 g, 15 mmol, 1 eq.) in toluene (20 ml) and the reaction mixture was stirred at 50° C. for 4 h. The volatiles were removed under high vacuum, THF (130 ml) was added and the mixture was cooled to 0° C. N,N-Diisopropylethylamine (4.2 ml, 24 mmol, 1.6 eq.) and ethylamine (2 M solution in THF, 9.0 ml, 18 mmol, 1.2 eq.) were added dropwise. The reaction mixture was stirred for 1 h at 0° C. before being quenched by the addition of saturated aq. NH4Cl (100 ml). The reaction mixture was extracted with Et2O (4×75 ml) and the combined organic phases were washed with brine (100 ml) before being dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with petrol/EtOAc (4:6), giving the title product 95 as a clear, colourless oil (2.75 g, 88%). Analytical data consistent with the literature (Halazy, S. et al., WO 9612713, Pierre Fabre Medicament (1996)).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(O)CCC>[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccccc1-c1cc2c(Cl)ncnc2[nH]1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCO
Product: COc1ccccc1-c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 1.5 h

Procedure:
6.6 g (25.4 mmol) of 4-chloro-6-(2-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 5.34 ml (50.8 mmol) of 3-chloro-aniline in 100 ml of n-butanol are heated at boiling for 1.5 hours. The reaction mixture is cooled, then filtered and washed with diethyl ether and hexane. Flash chromatography (SiO2 ; applied dry; hexane/ethyl acetate [2:1] ethanol/acetone [1:1]) yields the title compound; m.p. 221-222° C.; TLC-Rf =0.3 (hexane/ethyl acetate [1:1]); FAB-MS: (M+H)+ =351.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Product: ON=Cc1ccc(F)cc1

Procedure:
In another embodiment, 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanol and 1-(3-(4-fluorophenyl)-isoxazol-5-yl) ethanone may be produced as described in Scheme 12A. 4-Fluoro-benzaldehyde is reacted with hydroxylamine hydrochloride to provide 4-fluorobenzaldehyde oxime. The isoxazole ring is then generated by reacting this intermediate with but-3-yn-2-ol and NCS to provide 1-(3-(4-fluorophenyl)isoxazol-5-yl) ethanol. 1-(3-(4-Fluorophenyl)isoxazol-5-yl)ethanol is then oxidized to the ketone, i.e., 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone, which may then be converted to a compound of formula (I-A) by the methods described herein.
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]([S:16][C:22]2[C:21]3[C:25](=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)[NH:24][CH:23]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Sc1cccc(Br)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1ccc2c(Sc3cccc(Br)c3)c[nH]c2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-chlorosuccinimide (1.93 g, 14.5 mmol) was dissolved in DCM (120 mL) and cooled to −78° C. 3-Bromothiophenol was added and the reaction was warmed to 0° C. After 1 hour, a solution of 6-chloroindole (2.0 g, 13.2 mmol) in DCM (20 mL) was added via canula. The reaction was stirred at 0° C. for 3 hours after which time it was submitted to aqueous workup and purification by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[C:12]1([C:18]2[O:19][CH2:20][CH:21]([OH:30])[CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([O:30][CH:21]2[CH2:20][O:19][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:23][CH:22]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCCl
Product: COc1ccc(NC(=O)OC2COC(c3ccccc3)=NC2c2ccccc2)cc1
Yield: 25.9 %

Procedure:
4-Methoxyphenyl isocyanate (1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.7 g) in 1,2-dichloroethane (20 cc). The solution obtained is stirred under reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 40 g) contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 2 to 6, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume), are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (4RS, 5RS)-5-(4-methoxyphenylcarbamoyloxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.7 g), m.p. 140° C., is obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26]C)=[O:25])[C:12]2=[O:28])=[CH:2]1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C)C(=O)C.[Zn]>[CH:24]([OH:26])=[O:25].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OCCN1CCOCC1)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Product: O=CO
Temperature: 25 °C
Yield: 28.6 %

Procedure:
Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, N-(2-hydroxyethyl)morpholine (0.20 mL, 1.6 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.8 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 40 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0075 g, y. 15%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=3[F:34])[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=Nc1c(F)cccc1F
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2c(F)cccc2F)nn1
Yield: 28.2 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (48 mg, 0.14 mmol); 2-azido-1,3-difluorobenzene (24 mg, 0.15 mmol); CuSO4 (3.5 mg, 0.02 mmol); NaAsc (18 mg, 0.09 mmol); TBTA (12 mg, 0.01 mmol); in t-BuOH/EtOH/H2O (1:1:0.5); afforded 46 as a white solid (20 mg, 31.6%). 1H NMR (DMSO-d6, 400 MHz): δ 8.74-8.73 (d, 1H, J=1.79 Hz); 7.74-7.72 (m, 2H); 7.55-7.45 (m, 1H); 7.34-7.32 (m, 1H); 7.17-7.13 (t, 2H); 7.04-7.03 (d, 1H, J=1.72 Hz); 4.82-4.80 (q, 1H); 4.57-4.56 (d, 2H, J=5.97 Hz); 4.29-4.24 (m, 2H); 3.71-3.70 (d, 1H, J=1.78 Hz); 3.55-3.54 (d, 1H, J=1.78 Hz); 3.35-3.18 (m, 2H); 1.33-1.30 (t, 3H). 13C NMR (CDCl3, 100 MHz): 170.16, 166.65, 166.30, 158.01, 155.46, 153.29, 152.24, 144.36, 131.48, 129.14, 125.10, 116.01, 112.64, 62.24, 53.81, 52.74, 52.62, 34.74, 32.91, 13.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:23])[CH2:19][C@H:18]4[CH:24]([CH3:26])[CH3:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:35](=[N:37][OH:38])[NH2:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:23])[CH2:19][C@H:18]4[CH:24]([CH3:25])[CH3:26])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]3[NH:36][C:39](=[O:40])[O:38][N:37]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-N′-hydroxy-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (79 mg, 0.146 mmol) and 1,1′-carbonyldiimidazole (26.1 mg, 0.161 mmol) dissolved in acetonitrile (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 mL, 0.585 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C29H36ClN7O3 [M+H]+ 566. found 566. 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.96 (d, J=1.8, 1H), 8.78 (d, J=2.4, 1H), 8.50 (t, J=2.1, 1H), 7.82 (s, 1H), 4.39-4.34 (m, 1H), 3.98 (s, 1H), 3.85-3.81 (m, 1H), 3.77 (s, 2H), 3.53 (dd, J=5.9, 15.1, 1H), 3.20 (s, 3H), 2.31-2.27 (m, 1H), 2.09-2.00 (m, 1H), 1.80-1.72 (m, 1H), 1.37 (d, J=10.5, 2H), 1.12-1.05 (m, 1H), 1.05-0.96 (m, 1H), 0.89 (d, J=7.0, 3H), 0.87 (s, 1H), 0.76 (d, J=6.8, 3H), 0.6 (d, J=6.5, 3H), 0.61-0.55 (m, 1H), 0.54-0.48 (m, 1H), 0.48-0.44 (m, 1H), 0.40-0.34 (m, 2H).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:9]1[CH2:14][CH2:13][C:12]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)[CH2:11][CH2:10]1)[CH2:2]2.[C:31](Cl)(=[O:38])[O:32][C@@H:33]1[CH2:37][CH2:36][O:35][CH2:34]1.C(N(CC)CC)C.Cl>CCOCC>[O:35]1[CH2:36][CH2:37][C@@H:33]([O:32][C:31]([N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([N:9]2[CH2:10][CH2:11][C:12]4([C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]4)[CH2:13][CH2:14]2)[CH2:2]3)=[O:38])[CH2:34]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4)CC2)C1
Reactant: O=C(Cl)O[C@@H]1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 1′-(8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4c (205 mg, 0.5 mmol) was suspended in Et2O (10 mL) and treated with the (R)-tetrahydrofuran-3-yl carbonochloridate (150 mg, 1 mmol) and triethylamine (0.21 mL, 1.5 mmol, 3 eq). The reaction was stirred at room temperature for 30 min and was then treated with 1N aq. HCl. The phases were separated, the aqueous phase was brought to a basic pH by adding solid KOH, and the resulting suspension was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide crude tert-butyl 1′-(8-(((R)-tetrahydrofuran-3-yloxy)carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4d as a colorless, viscous oil (230 mg, 88% yield). LC/MS m/z [M+H]+ 526.2, retention time 2.54 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:13])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Br)cn2nccc12
Solvent: CC#N
Product: COc1cc(Br)cn2ncc(Cl)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (1010 mg, 4.43 mmol) in acetonitrile (40 ml) was added N-chlorosuccinimide (1180 mg, 8.86 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was partitioned between dichloromethane (100 ml) and 1N aqueous sodium hydroxide (100 ml). The organic layer was washed with brine (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 6-bromo-3-chloro-4-methoxypyrazolo[1,5-a]pyridine as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H); 8.03 (s, 1H); 6.84 (s, 1H); 3.94 (s, 1H). LRMS (ESI) calculated for C8H6BrClN2O [M+H]+, 260.9; found 261.0.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([CH:30]([NH2:32])[CH3:31])=[N:28][CH:29]=2)=[CH:20][C:19]=1[CH3:33].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[N:28][C:27]([CH:30]([NH:32][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:31])=[N:26][CH:25]=2)=[CH:20][C:19]=1[CH3:33]
Reactant: Cc1cc(-c2cnc(C(C)N)nc2)ccc1F
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(-c2cnc(C(C)Nc3nccc(N4C(=O)OC[C@@H]4C(C)C)n3)nc2)ccc1F
Yield: 27.4 %

Procedure:
A solution of (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (1055 mg, 4.68 mmol), 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (1300 mg, 5.62 mmol, 1.2 equiv) and diisopropylethylamine (908 mg, 7.03 mmol, 1.5 equiv) in DMSO (20 mL) was heated at 110° C. for 1 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated directly onto silica gel. Silica gel chromatography provided the mixed distereomers of (S)-3-(2-(1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino) pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (560 mg). Chiral separation was carried out with SFC (ID, 5 μm, 20×250 mm) using 35% MeOH in CO2 to give (S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:6]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a mixture of 2-fluoro-5-methoxy-4-nitrobenzoic acid (53.8 g, 250 mmol), 1-methylpiperidin-4-amine (31.4 g, 275 mmol), DIEA (134 mL, 750 mmol) in 1 L of DCM at 0° C. was added HATU (114 g, 300 mmol) in four batches. The reaction mixture was stirred at room temp. for 16 h. After which, it was concentrated and diluted to IL of a mixture of MeOH in water (5%). The suspension was stirred vigorously for 2 h until seen a suspension of fine powder. The solid was filtered, washed with more water and dried to give 55 g of light yellow product. The filtrate was extracted with EtOAc, concentrated and re-suspended in water (5% of MeOH) and repeating the same procedure as above, after which another batch of solid was obtained (total 67 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (m, 2 H) 1.81 (m, 2 H) 2.04 (m, 2 H) 2.19 (s, 3 H) 2.77 (d, J=8 Hz, 2 H) 3.73 (m, 1 H) 3.94 (s, 3 H) 7.42 (d, J=5.6 Hz, 1 H) 7.98 (d, J=8.8 Hz, 1 H) 8.51 (d, J=7.6 Hz, 1 H). [M+H] calc'd for C14H18FN3O4, 312; found 312.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][CH2:16][C:17]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[N:22]2>COC(C)(C)C.ClCCl>[CH3:31][O:30][C:21]1[C:20]([O:32][CH3:33])=[N:19][C:18]2[C:23](=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:17]=2[CH2:16][NH:15][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH3:8])[N:22]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Reactant: CCCCC(=O)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NCc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
79 μl (0.567 mmol) of triethylamine and 55 μl (0.454 mmol) of n-valeroyl chloride are added to a suspension of 100 mg (0.378 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline in 2 ml of tert-butyl methyl ether and the mixture is stirred at room temperature for 16 hours. The mixture is then taken up in dichloromethane, washed with 1 N hydrochloric acid and with 1 N sodium hydroxide solution, dried over sodium sulfate and concentrated by evaporation. The title compound is obtained in the form of a yellowish powder.
Reaction SMILES: ClCCl.[CH3:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])(=[O:7])=[O:6].CS(C)=O>C(N(CC)CC)C>[CH3:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)CCCCCO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCCCC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a dichloromethane (15 ml) solution of 5-(methylsulfonyl)-1-pentanol (344 mg, 2.07 mmol), dimethylsulfoxide (0.441 ml, 6.21 mmol) and triethylamine (1.15 ml, 8.28 ml) was added a sulfur trioxide pyridine complex (659 mg, 4.14 mmol) at 0° C. and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was washed with water, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the ethyl acetate eluate was concentrated under reduced pressure, whereby the title compound (183 mg, 1.11 mmol, 54%) was obtained as a colorless oil.