Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([CH:13]=O)[C@H:9]2[CH2:10][C@H:5]([C@@H:6]([CH3:12])[C:7](=[O:11])[CH2:8]2)[O:4][O:3]1.[F:15][C:16]([F:52])([F:51])[C:17]1[CH:26]=[C:25]([C:27]2C=C[CH:30]=[CH:29][C:28]=2P(=C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:24]2[C:19](=[CH:20][C:21]([C:47]([F:50])([F:49])[F:48])=[CH:22][CH:23]=2)[N:18]=1>C(Cl)Cl>[F:51][C:16]([F:15])([F:52])[C:17]1[CH:26]=[C:25](/[CH:27]=[CH:13]\[C@:2]2([CH3:1])[C@H:9]3[CH2:10][C@H:5]([C@@H:6]([CH3:12])[C:7](=[O:11])[CH2:8]3)[O:4][O:3]2)[C:24]2[C:19](=[CH:20][C:21]([C:47]([F:50])([F:48])[F:49])=[CH:22][CH:23]=2)[N:18]=1.[F:15][C:16]([F:52])([F:51])[C:17]1[CH:26]=[C:25](/[CH:27]=[CH:28]/[C@:29]2([CH3:30])[C@H:9]3[CH2:10][C@H:5]([C@@H:6]([CH3:12])[C:7](=[O:11])[CH2:8]3)[O:4][O:3]2)[C:24]2[C:19](=[CH:20][C:21]([C:47]([F:50])([F:49])[F:48])=[CH:22][CH:23]=2)[N:18]=1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1-c1cc(C(F)(F)F)nc2cc(C(F)(F)F)ccc12
Reactant: C[C@H]1C(=O)C[C@@H]2C[C@H]1OO[C@]2(C)C=O
Solvent: ClCCl
Product: C[C@H]1C(=O)C[C@@H]2C[C@H]1OO[C@]2(C)/C=C/c1cc(C(F)(F)F)nc2cc(C(F)(F)F)ccc12
Product: C[C@H]1C(=O)C[C@@H]2C[C@H]1OO[C@]2(C)/C=C\c1cc(C(F)(F)F)nc2cc(C(F)(F)F)ccc12
Reaction time: 24 h

Procedure:
760 mg of (1R,4S,5S,8R)-4,8-dimethyl-7-oxo-2,3-dioxabicyclo[3.3.1]nonane-4-carboxaldehyde are dissolved in 80 ml of methylene chloride. 2.5 g of 2,7-bis(trifluoromethyl)quinolin-4-yl-methylidenetriphenylphosphorane are added thereto and the solution is left to stand at room temperature for 24 hours. The methylene chloride is distilled off and the residue is separated into the (E)- and (Z)-isomers by column chromatography on silica gel while eluting with methylene chloride. After crystallization from hot methanol there are obtained (1R,4S,5S,8R)-4-[(Z)-2-[2,7-bis(trifluoromethyl)-4-quinolinyl]vinyl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one as white crystals [m.p. 160°; [α]D25 =53.7° (c=1 in ethanol)] and (1R,4S,5S,8R)-4-[(E)-2-[2,7-bis(trifluoromethyl)-4-quinolinyl]vinyl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one [m.p. 188°].
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:45][C:46](=[N:49]C(OCC1C=CC=CC=1)=O)SC)(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:1].[C:29]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH:16][C:46](=[NH:45])[NH2:49])=[O:10])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 59.8 %

Procedure:
Prepared according to the method described in Example 1(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-(2-hydroxy-1-phenylethyl)ornithine amide hydrochloride (0.5 g; 1.12 mmol), N,N'-bis(Cbz)-S-methylisothiourea (0.603 g; 1.68 mmol), DiPEA (0.2 mL) and DMF (15 mL) yielding 0.351 g of sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C(OCC)(=O)C>[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(Br)cn1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Br)cn1
Reaction time: 72 h

Procedure:
A 2 g. portion of 5-bromo-2-aminopyridine was reacted with 2.5 g. of 2,6-difluorobenzoyl isocyanate under nitrogen in 50 ml. of ethyl acetate. The reaction mixture was stirred for 3 days, and was then filtered. The solids were washed with dichloromethane, ethyl acetate and diethyl ether and dried under vacuum to obtain the desired product, m.p. 232°-235° C. The elemental analysis showed:
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[N:9][C:10](Cl)=[CH:11][CH:12]=2)[N:7]=1.O>CN(C)C=O.C(O)C>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[N:9][C:10]([S:2][CH3:1])=[CH:11][CH:12]=2)[N:7]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc2ccc(N)nc2n1
Temperature: 0 °C

Procedure:
To a solution, close to saturation, of methyl mercaptan in dimethylformamide (200 cc) maintained at 0° C., sodium hydride (13.3 g) in 50% strength suspension in mineral oil is added in small portions. 2-Amino-7-chloro-1,8-naphthyridine (25 g) is then added to this solution, and the mixture is heated at 100° C. for 2 hours. After being cooled, the reaction mixture is poured into water (500 cc) and extracted with methylene chloride (5×250 cc). The organic extracts are then washed with distilled water (2×200 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (4 kPa). The product produced (22.9 g; m.p. 130° C.) is dissolved in boiling ethanol (150 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (10 cc) and then isopropyl ether (3×10 cc), and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-methylthio-1,8-naphthyridine (9.6 g) is produced, m.p. 158° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.28) (0.300 g, 0.86 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.247 g, 1.26 mmol) according to the general procedure VI. Obtained as a white solid (0.110 g, 31%). MS (ISP) 408.3 [(M+H)+]; mp>245° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])=[O:4].C1(C)C=CC=CC=1.S(Cl)([Cl:30])=O>CN(C)C=O>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:13]=1[O:14][CH3:15])[C:8]([Cl:30])=[O:9])=[O:4]
Reactant: COc1c(C(=O)N(C)C)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C(=O)N(C)C)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoic acid (333 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) was added, and then the mixture was stirred at 60° C. for 6 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (f).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10]C)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(OC)=O)=[CH:18][CH:17]=1>CO>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:8]([C:7]2[CH:12]=[CH:13][N:14]=[C:5]([CH3:4])[CH:6]=2)=[O:10])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)Cc2ccc(F)cc2)ccn1
Temperature: 95 °C
Reaction time: 17.5 h

Procedure:
To a freshly prepared solution of NaOMe (3.0 M in MeOH) was added a solution of methyl 2-methylisonicotinate (6.81 g, 45.1 mmol) in MeOH (10 mL). This was followed by the dropwise addition of a solution of methyl 4-fluorophenylacetate (8.34 g, 49.6 mmol) in MeOH (10 mL,). The MeOH was distilled off while heating the reaction mixture at 95° C. After 17.5 h, the solid residue was cooled. Concentrated HCl (15 mL) was added, and the mixture was heated at reflux. After 4 h, the mixture was cooled then diluted with H2O. The aqueous mixture was washed with Et2 O, adjusted to pH 5 with 1N NaOH, then adjusted to pH 8 with saturated NaHCO3. The alkaline aqueous was extracted with EtOAc. The EtOAc extracts were washed with saturated NaCl, then dried over Na2 SO4. Evaporation of solvent in vacuo afforded a red oil which was purified by column chromatography, eluting with a gradient of 0-3% MeOH/CHCl3. The title compound was isolated as a red oil (1.5 g, 15%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[CH3:33]OC(N(C1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)S(C1C=CC(F)=CC=1/C=C\CO)(=O)=O)=O.NC(C)C>>[CH3:2][CH:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:33]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Solvent: CC(C)N
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CNC(C)C)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and 2-aminopropane.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH:23]([NH:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[N:30]=[C:29]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[C:28]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:25])[CH3:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1>[CH:23]([NH:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[N:30]=[C:29]([C:36]2[CH:43]=[CH:42][C:39]([CH2:40][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:38][CH:37]=2)[C:28]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:25])[CH3:24]
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: CC(C)Nc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nccn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2nccn12
Reaction time: 1 h

Procedure:
253.8 mg (0.93 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 7.2 mL NMP. 0.26 mL (1.85 mmol) triethylamine are added and the reaction mixture is stirred for one hour. 300 mg (0.84 mmol) 4-(5-Isopropylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.12 mL (2.02 mmol) acetic acid are added. The reaction mixture is stirred for 24 hours at room temperature. 463.8 mg (2.2 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature over night. After the usual work-up and purification by column chromatography (silicagel, eluents: dichloromethane/methanol) 132 mg (27.5%) of the pure title compound and 42 mg (9.2%) of the slightly contaminated title compound are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4]1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4]1
Reactant: COC(=O)CCc1c[nH]c2ccccc12
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(CCCCl)c2ccccc12
Temperature: 55 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
Sodium hydride (60% dispersion) (236 mg, 5.91 mmol, 1.2 equiv) was slowly added to a cold mixture of methyl 3-(1H-indol-3-yl)propanoate (2 g, 4.92 mmol, 1 equiv) in N,N-dimethylformamide. After all the sodium hydride has reacted, 1-bromo-3-chloropropane (1.94 ml, 19.68 mmol, 4 equiv) was added and the reaction stirred at 55° C. for 16 h. Upon cooling the reaction was partitioned between water and ethyl acetate. The organic layer was further washed with 1N hydrogen chloride, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—1%-10% ethyl acetate in hexanes) to afford the title compound as a yellow oil (1.154 g, 83%); 1H NMR (400 MHz, DMSO-d6): δ 2.12-2.27 (m, 2H); 2.65-2.70 (m, 2H); 2.93-2.98 (m, 2H); 3.38-3.54 (m, 2H); 3.58 (s, 3H); 4.08-4.12 (m, 2H); 4.21-4.25 (m, 2H); 7.02 (t, 1H, J=7.6 Hz); 7.12-7.15 (m, 2H); 7.43 (dd, 1H, J=3.2 and 2.8 Hz); 7.52-7.55 (m, 1H); MS for C15H18ClNO2 m/z 280 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13]
Reactant: OCCCCCCCCCCCBr
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCCCCCCCCBr
Reaction time: 2 h

Procedure:
1-Bromo-11-hydroxyundecane (5 g, 20 mmoles) dissolved in methylene chloride (30 ml) was added to a suspension of pyridinium chlorochromate (6.4 g, 30 mmoles) in methylene chloride (25 ml) and stirred for 2 hours. The mixture was diluted with ether, filtered and concentrated in vacuo to afford 1-bromo-11-oxoundecane.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8]C)C(O)=O.[C:10](Cl)(=O)[C:11]([Cl:13])=[O:12]>CN(C)C=O>[Br:1][CH2:2][CH2:6][CH2:7][CH2:8][CH2:10][C:11]([Cl:13])=[O:12]
Reactant: CCCCC(Br)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCBr

Procedure:
58.5 g of (0.3 moles) of 6 bromohexanoic acid and 85 ml of oxalyl chloride are placed in a 250-ml flask with a magnetic agitator. The mixture is agitated and 1 milliliter of dimethylformamide (DMF) is added.
Reaction SMILES: CC([N:5]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][C@@H:28]([C:30]([NH:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:31])[CH2:27][CH2:26][C@H:25]4[CH3:39])[N:21]=[C:20]([NH:40][CH3:41])[N:19]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)C(=O)[O-])(C)C.C([O-])(O)=O.[Na+]>CO.Cl.O>[NH2:5][C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[N:19]=[C:20]([NH:40][CH3:41])[N:21]=[C:22]([N:24]4[C@H:25]([CH3:39])[CH2:26][CH2:27][C@H:28]([C:30]([NH:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[O:31])[CH2:29]4)[CH:23]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: CNc1nc(-c2ccc3c(N(C(=O)[O-])C(C)(C)C)n[nH]c3c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Temperature: 50 °C
Yield: 51 %

Procedure:
A mixture of 1,1-dimethylethyl[6-(2-(methylamino)-6-{(2R,5S)-2-methyl-5-[(phenylamino)carbonyl]-1-piperidinyl}-4-pyrimidinyl)-1H-indazol-3-yl]carbamate (530 mg, 0.95 mmol) in CH3OH (15 mL) and conc. HCl (0.5 mL) was heated at 50° C. for a total of 6 hours. The residue was taken up in 5 mL of water, to which was added 5 mL of sat. NaHCO3. The resulting suspension was sonicated, and filtered. The yellow solids collected underwent purification by silica gel column chromatography using elution of gradient 1% A in CHCl3 to 60% A in CHCl3 (A was 200/800/20 CH3OH/CHCl3/NH4OH). Trituration of the residue obtained from the chromatography in MTBE (6 mL), followed by drying under vacuum at 50° C. for 20 hours afforded the title compound (221 mg) as a yellow solid. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.33 (d, J=6.8 Hz, 3H), 1.82-1.97 (m, 3H), 2.06-2.16 (m, 1H), 2.57-2.65 (m, 1H), 2.98 (s, 3H), 3.15-3.25 (m, 1H), 6.51 (s, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.34 (t, J=8.1 Hz, 2H), 7.54 (dd, J=8.5, 1.1 Hz, 1H), 7.60 (dd, J=8.6, 1.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.87 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[CH3:50][N:51]([CH3:62])[C@H:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53](O)=[O:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH3:50][N:51]([CH3:62])[C@H:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:4](=[O:42])[C@@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:41])=[CH:17][CH:16]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:22][CH:23]=1)=[O:29])=[O:54]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Reactant: CN(C)[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N(C)C)cc2)c2ccccc2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43.8 %

Procedure:
The product from Example 10A (15 mg, 0.022 mmol) was combined with (R)-2-(dimethylamino)-2-phenylacetic acid (4.82 mg, 0.027 mmol), HATU (9.38 mg, 0.025 mmol) and Hunig's base (0.014 mL, 0.078 mmol) in DMSO (0.5 mL) and the mixture was stirred at room temperature for 45 min. Diluted with water and collected the solid by filtration. The product was purified by chromatography on silica gel, eluting with 0-4% MeOH in CH2Cl2 to give the title compound (8 mg, 43% yield). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.02 (s, 9 H) 1.65-1.73 (m, 1 H) 1.86-1.95 (m, 2 H) 1.99-2.08 (m, 1 H) 2.13-2.20 (m, 2 H) 2.26 (s, 6 H) 2.49 (dd, J=12.21, 6.56 Hz, 1 H) 2.53-2.60 (m, 1 H) 3.32-3.39 (m, 1 H) 3.65-3.68 (m, 1 H) 3.69 (s, 3 H) 3.74-3.80 (m, 1 H) 3.81-3.87 (m, 1 H) 4.01 (s, 1 H) 4.38 (d, J=9.77 Hz, 1 H) 4.56 (s, 4 H) 4.76 (d, J=7.17 Hz, 1 H) 4.80 (dd, J=8.01, 2.52 Hz, 1 H) 5.39 (d, J=9.61 Hz, 1 H) 6.70 (t, J=7.25 Hz, 1 H) 6.73 (d, J=7.93 Hz, 2 H) 7.12-7.19 (m, 6 H) 7.36-7.43 (m, 5 H) 7.47-7.51 (m, 4 H) 9.30 (s, 1 H) 9.71 (s, 1 H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([N:21]1[CH2:24][C:23](=O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[B][B][B][B][B][B][B][B][B][B]>CO>[C:17]([O:16][C:14]([N:21]1[CH2:24][CH:23]([N:4]2[CH2:3][CH2:2][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][N:13]=3)=[O:8])[CH2:6][CH2:5]2)[CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: O=C(c1nccs1)N1CCNCC1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 18 h

Procedure:
A solution of compound 7b (6.1 g, 0.031 mol) and (5.1 g, 0.03 mol) compound 4a in MeOH (30 mL) was stirred for 15 min. Decaborane (1 g, 0.008 mol) was added and the reaction was stirred for 18 h. The solvent was evaporated in vacuo. The residue was used without further purification for the next step. MS m/z (M+H+) 353.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C.CN(C)C=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:24][CH:21]2[CH2:20][CH2:19][N:18]([CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH2:23][CH2:22]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 200 °C
Reaction time: 0.02 h

Procedure:
400 mg (0.0018 mol, 1 eq) of 4-bromo-2-fluoro-1-nitro-benzene, 330 mg (0.0018 mol, 1 eq) of D9, 350 mg (0.0027 mol, 1.5 eq) of diisopropylethylamine, and 5 mL of dimethylformamide were combined, heated to 200° C. and held for 1 min in a microwave reactor. 80 mL of water was then added and the reaction extracted with 2×75 mL of dichloromethane. The dichloromethane layers were combined, dried with sodium sulfate, and evaporated to yield N-(5-bromo-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine which was used without further purification in the next step. MS (ESI): 385 [M+H]+.
Reaction SMILES: [N:1]1([C:8]2[N:16]3[C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][O:19][C:14]4=[C:15]3[C:10](=[CH:11][CH:12]=[C:13]4[C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:33](N)([NH2:36])(=[O:35])=[O:34]>N1C=CC=CC=1.CO>[CH3:32][C:27]1[C:26]([C:13]2[C:14]3[O:19][CH2:18][C@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:16]4[C:8]([N:1]5[CH2:7][CH2:6][CH2:5][N:4]([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:3][CH2:2]5)=[N:9][C:10]([C:15]=34)=[CH:11][CH:12]=2)=[C:30]([CH3:31])[O:29][N:28]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CCCN(S(N)(=O)=O)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 120 °C
Yield: 77 %

Procedure:
(4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (5.8 mg, 0.013 mmol) and sulfamide (7.8 mg, 0.081 mmol) were dissolved in pyridine (0.71 mL) and the solution was heated at 120° C. for 3 min in a microwave. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (5.1 mg, 74%). LCMS calc. for C24H27N7O4S (M+H)+: m/z=510.2. found: 509.7.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C.[C:53](OC(=O)C)(=[O:55])[CH3:54]>ClCCl>[C:53]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9])(=[O:55])[CH3:54]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(C(=O)CCCCCOc2ccccc2N(C)C(=O)c2ccc(NC(=O)c3ccccc3OCCCN)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N(C)c2ccccc2OCCCCCC(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To an ice bath cooled solution of 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in dichloromethane (10 ml) were added triethylamine (36.2 mg) and acetic anhydride (36.5 mg) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was washed successively with water (10 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and brine (10 ml), and dried over magnesium sulfate. The solvent was evaporated to give 4-[2-[(3-acetylaminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (201 mg) as a colorless amorphous.