Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:19][C:20](Br)([F:22])[F:21]>C(OCC)(=O)C.O.C(#N)C>[Br:19][C:20]([F:22])([F:21])[CH2:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: FC(F)(Br)Br
Reactant: C=CC(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)CCC(F)(F)Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of acrylic acid (1.44 g) and acetonitrile (80 cm3) was added sodium dithionite (4.18 g), sodium bicarbonate (2.01 g), water (20 cm3) and finally dibromodifluoromethane (5 cm3). The biphasic mixture was stirred at the ambient temperature with the inorganic salts gradually dissolving. Gc analysis after 4 hrs indicated complete consumption of acrylic acid. The aqueous phase was saturated with solid sodium chloride. The organic phase was separated, dried (MgSO4), filtered and evaporated under reduced pressure to give a pale yellow oil with a small amount of a white solid. This mixture was taken up in ethyl acetate, filtered and evaporated under reduced pressure to give a pale yellow oil (2.54 g). 1H NMR (DMSO): δ2.65(2H,m); 2.45(2H, t).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:31]=[N:32][S:33][CH:34]=5)=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)=[N:9][CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:35]=[N+:36]=[N-:37].[Na+].O>[Zn+2].[Br-].[Br-].O>[C:1]1([C:7]2[C:8]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:31]=[N:32][S:33][CH:34]=5)=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)=[N:9][CH:10]=[C:11]([C:12]3[NH:37][N:36]=[N:35][N:13]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc(-c2ccc(CNCc3ccc(-c4csnn4)cc3)cc2)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: c1ccc(-c2cc(-c3nnn[nH]3)cnc2-c2ccc(CNCc3ccc(-c4csnn4)cc3)cc2)cc1

Procedure:
A mixture of 5-phenyl-6-[4({[4-(1,2,3-thiadiazol-4-yl)benzyl]amino}methyl)phenyl]nicotinonitrile (1-5; TFA salt) (69 mg, 0.1 mmol), 2M of NaN3 water solution (0.75 mL, 1.5 mmol), 2M of ZnBr2 water solution (0.5 mL, 1.0 mmol) was microwaved (Smith-Synthesizer) at 165° C. for 15 min. After this time, the solution was concentrated. The residue was re-dissolved in DMSO (1 mL) and purified by LCMS to afford the pure desired product (TFA salt) as a slightly yellow solid (1-6). Analytical LCMS: single peak (214 nm), 2.339 min. 1H NMR (500 MHz, DMSO-d6): δ 9.70 (s, 1H), 9.32 (d, J=2.1 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H), 8.22 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H), 7.42-7.48 (M, 4H), 7.35-7.40 (m,3H), 7.28-7.32 (m, 2H), 4.26 (s, 2H), 4.23 (s, 2H); HRMS, calc'd for C28H22N8S (M+1), 503.1761; found 503.1769.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17](=[O:29])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:26][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[OH:8])=[O:29])[CH:25]=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)C=Cc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(O)c(C(=O)CCc2cccc(N)c2)c1
Yield: 89 %

Procedure:
A mixture of 15.0 g (0.039 mole) of the title product from Example 120 and 1.5 g 5% palladium on charcoal in 300 ml tetrahydrofuran and 200 ml absolute methanol was shaken in a Parr hydrogenator under 10 psi hydrogen at ambient temperature for 3 hours. The reaction mixture was filtered through Celite and the filtrate was evaporated in vacuo to yield an oil. Column chromatography of the oil on silica gel eluting with ethyl acetate: hexanes (1:2, v/v) gave 9.42 g (90%) of the title product as an oil; 1H NMR (CDCl3): δ2.98 (t, J=8 Hz, 2H); 3.28 (t, J=8 Hz, 2H); 3.65 (s, br, 2H); 3.77 (s, 3H); 6.65 (m, 3H); 6.93 (d, J=9 Hz, 1H); 7.10 (m, 3H); 11.95 (s, 1H). Analysis calculated for C16H17NO3 : C, 70.83; H, 6.32; N, 5.16. Found: C, 70.51; H, 6.30; N, 4.97.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([NH:12][C:13](=O)[CH:14]=[N:15][O:16][CH3:17])=[C:4]([F:19])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C1C=CC=CC=1.ClCCl>[CH3:17][O:16][N:15]=[CH:14][C:13](=[N:12][C:5]1[CH:6]=[C:7]([O:8][CH2:9][C:10]#[CH:11])[C:2]([Cl:1])=[CH:3][C:4]=1[F:19])[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: C#CCOc1cc(NC(=O)C=NOC)c(F)cc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: C#CCOc1cc(N=C(C=NOC)N2CCCC2)c(F)cc1Cl
Yield: 64.2 %

Procedure:
0.42 g of the obtained N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-(methoxyimino)acetamide was dissolved in 30 ml of benzene and after the addition of 0.36 g of phosphorus pentachloride, the resulting solution was refluxed for 4 hours. The concentrate obtained by concentrating the resulting reaction solution under reduced pressure was dissolved in 20 ml of dichloromethane and 0.32 g of pyrrolidine was added dropwise thereto at room temperature and the resultant solution was stirred at room temperature for 1 hour. The concentrate obtained by evaporating solvents from the resulting reaction solution under reduced pressure was purified by silica gel column chromatography to obtain 0.32 g of 2-(4-chloro-2-fluoro-5-propargyloxyphenylimino)-2-(pyrrolidine-1-yl)acetaldehyde O-methyloxime (1-5) (yield 64%). m.p. 73-75° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)=[O:4].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.O>C(#N)C>[O:4]=[C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: O=C1CCN(C(=O)CCl)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC(=O)CC2)CC1
Yield: 67.8 %

Procedure:
1-(2-Chloroacetyl)piperidin-4-one (5.17 g, 29.4 mmol) was dissolved in acetonitrile (50 ml). To this solution, tert-butyl piperazine-1-carboxylate (5.48 g, 29.4 mmol) and N-ethyldiisopropylamine (6.2 ml, 35.3 mmol) were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was allowed to return to room temperature, to which water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-[2-oxo-2-(4-oxopiperidin-1-yl)ethyl]piperazine-1-carboxylate (6.49 g, yield 68%) as a pale yellow crystalline powder.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: ClCCl
Product: CCCCC(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 1-[4′-(trifluoromethyl)-4-biphenylyl]-1-pentanol (250 mg, 0.81 mmol) in dry DCM (15 mL) under nitrogen at 0° C. (ice/water bath) was added thionyl chloride (590 μL, 8.09 mmol) drop-wise. After stirring the mixture for 30 minutes at rt under nitrogen, the reaction was quenched by cautious addition of saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3×30 mL). The organic extract was separated, washed with brine, dried (MgSO4) and the solvents removed under vacuum to afford the title compound as a yellow gum (251 mg).
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[C:13]#[CH:14])[CH3:10].[Na].C(O)CCC.O>O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[C:13]1[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:14]=1)[CH3:10]
Reactant: C#CC(OCC)OCC
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: [Na]
Solvent: O
Solvent: CCCCO
Product: CCOC(OCC)c1cn(C[Si](C)(C)C)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stir bar were added (azidomethyl)(trimethyl)silane (1.000 g, 7.740 mmol), 3,3-diethoxyprop-1-yne (0.992 g, 7.740 mmol), freshly made 1.0N sodium asorbate (0.774 ml, 7.740 mmol), and 1.0N Cu2SO4 (0.774 ml, 7.740 mmol) into 30.0 ml of a mixed solvent BuOH/H2O (1:1). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (1.620 g, 81% crude). ES-MS [M+1]+: 258.1 (M+H). This intermediate was carried over to the next step without further purifications and characterizations.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)([O-:40])=[O:39]>ClCCl>[N+:38]([C:41]1[CH:42]=[CH:43][C:44]([C:45]([O:22][C@H:14]2[CH2:15][CH2:16][C@@:17]3([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]4[C@@H:19]3[CH2:20][CH2:21][C@@:4]3([CH3:5])[C@H:6]4[CH2:7][CH2:8][C:3]3=[N:1][OH:2])[CH2:13]2)=[O:46])=[CH:48][CH:49]=1)([O-:40])=[O:39]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To the stirred solution of 17-oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml), p-nitrobenzoic acid (0.27 g, 1.6 mmol) was added. The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered and the solvent removed under vacuum. The resulting residue was crystallized from ethyl acetate:petroleum ether (60:80) to give 17-oximino-5-androsten-3β-yl 4-nitrobenzoate (11) (0.34 g, 68.0%) mp 185-188° C.
Reaction SMILES: F[C:2]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1.[N:20]1[CH:21]=[C:22]([C:29](O)=[O:30])[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.C(N1C2C=CC=C(N)C=2C=N1)C1C=CC=CC=1>>[CH2:4]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:29]([C:22]3[N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[N:20][CH:21]=3)=[O:30])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Agent: Nc1cccc2c1cnn2Cc1ccccc1
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2ccccn12

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=368 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([NH:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=1)=[O:34].C(N(CC)C(C)C)(C)C.[NH2:54][CH2:55][C:56]1[C:61]([CH2:62][CH3:63])=[N:60][C:59]2[N:64]([CH2:67][CH3:68])[N:65]=[CH:66][C:58]=2[C:57]=1[NH:69][CH:70]1[CH2:75][CH2:74][O:73][CH2:72][CH2:71]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:54][CH2:55][C:56]2[C:57]([NH:69][CH:70]3[CH2:71][CH2:72][O:73][CH2:74][CH2:75]3)=[C:58]3[CH:66]=[N:65][N:64]([CH2:67][CH3:68])[C:59]3=[N:60][C:61]=2[CH2:62][CH3:63])=[O:42])=[CH:43][CH:44]=1)=[O:34]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(CCCCCCCBr)Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2.4 g, 6.3 mmol) was added to a solution of 4-[(8-bromooctanoyl)amino]benzoic acid (2.1 g, 6.1 mmol) in N,N-dimethylformamide (20 ml) followed by N,N-diisopropylethylamine (2.5 g, 19 mmol). The solution was stirred at room temperature for 15 min, and 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.7 g, 5.6 mmol. e.g. which can be substantially as prepared in Intermediate 7 including alternative preparation no. 1 thereof) was added as a solid. The solution was stirred at room temperature for 3 hours, and then was added to aqueous sodium bicarbonate solution (200 ml) and extracted with dichloromethane (2×100 ml). The dried (sodium sulphate) organic extract was evaporated gently to leave crude 4-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide mixed with N,N-dimethylformamide (about 5 ml).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][NH:42]2)=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2.[C:54]([O:58][C:59](=[O:68])[CH2:60][C@H:61]1[CH2:64][C@H:63]([C:65](O)=[O:66])[CH2:62]1)([CH3:57])([CH3:56])[CH3:55].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][N:42]2[C:65]([C@H:63]2[CH2:62][C@H:61]([CH2:60][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:68])[CH2:64]2)=[O:66])=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2
Reactant: COCc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (49.9 mg, 0.13 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (50 mg, 0.12 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (26.9 mg, 0.13 mmol) and DIEA (0.024 mL, 0.13 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the precipitate was collected by filtration, and washed with water to give tert-butyl 2-(trans-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (74.0 mg, 0.128 mmol, 107%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1([CH3:32])[CH:16]([CH2:17][CH2:18][OH:19])[S:15](=[O:21])(=[O:20])[C:14]([CH3:23])([CH3:22])[C:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:12]1.CN(C=O)C>C1COCC1>[CH3:23][C:14]1([CH3:22])[S:15](=[O:20])(=[O:21])[CH:16]2[CH2:17][CH2:18][O:19][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[C:11]2([CH3:32])[N:12]=[C:13]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc([N+](=O)[O-])ccc2F)C(CCO)S(=O)(=O)C1(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC2(C)c3cc([N+](=O)[O-])ccc3OCCC2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a solution of tert-butyl ((5RS,6RS)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120 mg, 0.253 mmol) in the mixture of THF (2 ml) and DMF (0.2 ml) sodium hydride (60% dispersion in mineral oil) (25.3 mg, 0.634 mmol) was added and the mixture was stirred for 10 min at RT. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine and concentrated. The residue was purified by FC on 12 g RediSep Gold column using 10-100% EtOAc/heptane to afford tert-butyl ((4aRS,11bRS)-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (100 mg, 0.221 mmol, 87% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[CH2:32]([O:39][C:40]([N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][C:46]([O:52][CH2:53]Cl)=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>O1CCCC1.O>[CH2:32]([O:39][C:40]([N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][C:46]([O:52][CH2:53][C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]3)=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc(OCCl)cc2C1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 47.9 %

Procedure:
To a solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid ethyl ester (300 mg) in tetrahydrofuran (3 ml) was dropwise added a 1.5M lithium diisopropylamide-tetrahydrofuran solution (0.97 ml) at −70° C., and the mixture was stirred at the same temperature for 50 min. Then, a solution of 7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (213 mg) in tetrahydrofuran (3 ml) was dropwise added at the same temperature, and the mixture was allowed to warm to room temperature in 2 hours in stirring. After completion of the reaction, aqueous ammonium chloride solution and water were added with ice-cooling. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=7:1) and dried under reduced pressure to give the title compound (170 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].[C:41](O)(=[O:44])[CH2:42][CH3:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([S:22]([NH:25][C:41](=[O:44])[CH2:42][CH3:43])(=[O:24])=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: CCC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(C(F)(F)F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C(F)(F)F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 87.5 %

Procedure:
Using 7-(2-chloro-5-trifluoromethylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.084 mmol) obtained in step 5 and propionic acid (0.031 mL, 0.419 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.048 g, 87%) was obtained.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:14]3[CH:15]4[CH2:18][CH2:19][N:11]([CH2:12][C:13]=3[C:4]=2[CH:3]=1)[CH2:17][CH2:16]4
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CCN2CCC1CC2
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 80 °C

Procedure:
In a 100 mL round-bottomed flask were combined p-tolylhydrazine hydrochloride (1.58 g, 10 mmol; Aldrich), 1-azabicyclo[3.2.2]nonan-4-one (1.392 g, 10.00 mmol; Example 2A), and concentrated sulfuric acid (5 mL) in dioxane (50 mL). The reaction mixture was heated to 80° C. for 2.5 hours, then cooled to room temperature. The solvent was decanted, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to pH ˜12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the resulting solid was further purified by silica gel column chromatography eluting with 20% methanol-dichloromethane to supply the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 2.07-1.97 (m, 4H), 2.43 (s, 3H), 2.89 (m, 1H), 3.1 (m, 2H), 3.3 (m, 2H), 4.25 (s, 2H), 6.9 (m, 1H), 7.17 (m, 2H), 76 (br s, 1H); MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=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+]>O1CCOCC1.C(Cl)Cl.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]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: COc1cc(Br)ccc1F
Reactant: Cc1cnc(Cl)nc1N
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
Solvent: ClCCl
Product: COc1cc(Nc2nc(Cl)ncc2C)ccc1F
Temperature: 25 °C
Yield: 13.8 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.2 g, 8.1 mmol), 4-bromo-1-fluoro-2-methoxy-benzene (1.8 g, 8.9 mmol), Pd2(dba)3 (0.74 g, 0.81 mmol), Xantphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (0.3 g, 14%) as a beige solid.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=CC=2N=1.C[N:27](C)CCN>>[C:14]([NH2:27])(=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:11][CH:12]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: NC(=O)c1ccccc1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with N,N-dimethylethlenediamine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)benzamide. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)benzamide (73 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 16 mg of 340. MS (Q1) 528.0 (M)+