Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCN1CCOCC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of 1-chloro-3-bromopropane in dry tetrahydrofuran (2 mL) was added to a cold suspension of morpholine (200 mg, 2.29 mmol) and sodium carbonate (0.63 g, 4.56 mmol) in dry tetrahydrofuran (8 mL) at 0° C. The mixture was stirred at 45° C. overnight. The mixture was allowed to cool to rt, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (70:30), afforded 3-chloro-1-morpholin-4-yl-propane (156 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][CH:8]=[C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][C:10]2=[O:20])=[CH:4][CH:3]=1.[C:23](Cl)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>N1C=CC=CC=1.CN(C)C=O>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[CH:8][NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=2)[C:10](=[O:20])[NH:11]1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)CC(=O)Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a suspension of 4-[(4-Amino-benzylamino)-methylene]-4H-isoquinoline-1,3-dione (29.3 mg, 0.1 mmol) in pyridine (250 μL) is added isovaleryl chloride (26 μL, 0.2 mmol). The reaction mixture is shaken at room temperature for 1 hour. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (37.2 mg).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31][C:32](=[O:45])[C:33]1[CH:38]=[C:37]([S:39](=[O:42])(=[O:41])[NH2:40])[CH:36]=[CH:35][C:34]=1[O:43][CH3:44])[CH3:24]>>[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31][C:32](=[O:45])[C:33]1[CH:38]=[C:37]([S:39](=[O:41])(=[O:42])[NH:40][C:4](=[O:21])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[O:11][CH3:12])[CH:36]=[CH:35][C:34]=1[O:43][CH3:44])[CH3:24]
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC(=O)C(O)=CC(=O)N(Cc2ccc(F)cc2)OC)ccc1OC

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with N-(1-ethyl-pyrrolidin-2-ylmethyl)-2-methoxy-5-sulfamoyl-benzamide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 1.29 (t, 3, J=7), 1.86 (m, 1), 2.06 (m, 2), 2.26 (m, 1), 2.97 (m, 2), 3.50 (m, 1), 3.59 (s, 3), 3.64 (m, 1), 3.82 (m, 2), 3.95 (m, 1), 4.03 (s, 3), 4.72 (s, 2), 6.37 (s, 1), 6.95 (m, 2), 7.10 (m, 1), 7.23 (m, 2), 8.23 (m, 1), 8.71 (s, 1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:27])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1

Procedure:
tert-Butyl{1-[2-(6-fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 55) (640 mg, 1.56 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16].C[Si]([N:22]=[C:23]=[O:24])(C)C>>[NH2:22][C:23]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16])=[O:24]
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1ccc(-c2cc(N)c(C(N)=O)s2)cc1
Product: COc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(4-methoxyphenyl)-2-thiophenecarboxamide and trimethylsilylisocyanate.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]1[C:15]2([C@H:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][NH:17][CH2:16]2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:23]([O:22][C:21]([NH:20][C@H:19]1[C:15]2([CH2:14][CH2:13][CH2:12]2)[CH2:16][N:17]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:18]1)=[O:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC12CCC2
Reaction time: 0.75 h

Procedure:
Benzyl chloroformate (0.224 mL, 1.569 mmol) was added dropwise to a stirred solution of (S)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.2368 g, 1.046 mmol) in dichloromethane (7 mL) and a solution of sodium carbonate (69.1 mg, 0.652 mmol) in Water (1.05 mL) @ 0° C. Stirring of the biphasic reaction was continued @ 0° C. for 45 minutes. +/−MS analysis after 16 hrs indicated that essentially no starting material remained (m/e 361.3, M+H for desired product). A small amount of water was added and the layers were separated. The CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to yield 0.433 g of the desired product as a viscous yellow oil. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 12 g column), eluting with 100 mL ea of 95:5, 90:10, and 200 mL of 80:20 hexane:EtOAc yielded 0.324 g of the title compound as a viscous colorless oil that slowly solidifies upon standing under vacuum to a white solid. +/−MS: m/e 361.3 (M+H), 305.2 (M+H-56 isobutylene), 261.2 (M+H-Boc). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.45-7.32 (m, 5H), 5.15 (s, 2H), 4.53 (br. s., 1H), 4.14-4.01 (m, 1H), 3.70-3.50 (m, 2H), 3.47-3.24 (m, 2H), 2.19-2.09 (m, 1H), 2.05-1.83 (m, 5H), 1.49 (s, 9H).
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])[CH:9]=[CH:10]2)=[N:5]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+]>C1COCC1.C(OCC)(=O)C>[CH:30]1([NH:35][CH2:2][CH2:3][N:4]2[CH:12]=[C:11]3[C:6]([CH:7]=[C:8]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:19][CH:18]=4)=[O:15])[CH:9]=[CH:10]3)=[N:5]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=CCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1
Reactant: NC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2cn(CCNC3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-[2-(2-oxo-ethyl)-2H-indazol-6-yl]-3-(4-phenoxy-phenyl)urea (20 mg, 0.05 mmol) and cyclopentylamine (10 mL, 0.10 mmol) in THF (0.5 mL) was shaken at room temperature for 30 minutes. 1M Sodium cyanoborohydride in THF (104 μL, 0.10 mmol) was added and the solution was shaken at room temperature for 16 hours. The sample was diluted with ethyl acetate, washed with water, concentrated under reduced pressure and purified by RP-HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.6 (m, 6 H), 2.0 (m, 2 H), 3.55 (m, 2 H), 4.35 (m, 2 H), 4.70 (t, 2 H), 6.97 (m, 5 H), 7.12 (m, 1 H), 7.35 (m, 2 H), 7.52 (m, 2 H), 7.65 (d, 1 H), 7.95 (s, 1 H), 8.35 (s, 1 H) and 8.70 (m, 2 H.); MS (ESI) 456 (M+H)+.
Reaction SMILES: C(Cl)(=O)C.C(O)(=O)C.C(O)(=O)C(O)=O.[CH2:15]([NH:17][NH2:18])[CH3:16].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=O)[C:29]([O:31]C)=O)=[CH:20]1>C(O)C>[CH2:15]([N:17]1[CH:20]=[C:21]2[C:28]([C:29](=[O:31])[NH:19][C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=32)=[N:18]1)[CH3:16]
Reactant: CCNN
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: CCn1cc2c(n1)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Acetyl chloride (19 mL, 273 mmol), acetic acid (30 mL), and ethylhydrazine oxalate (41 g, 272 mmol) were added sequentially to a suspension of methyl 1H-indol-3-yl(oxo)acetate (37 g, 180 mmol) in ethanol (910 mL). The reaction mixture was heated at reflux for 18 hours, cooled to ambient temperature, and concentrated under reduced pressure to a small volume. Dichloromethane (100 mL) and ice were added, and the mixture was adjusted to pH 14 with the addition of 50% w/w sodium hydroxide. A precipitate formed. The dichloromethane was removed under reduced pressure, and the precipitate was isolated by filtration, triturated with hot acetonitrile, and isolated by filtration to provide 26 g of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCI
Reactant: OC1(c2ccc(F)c(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Example 22: 3-(3-chloro-4-fluorophenyl)pyrrolidin-3-ol (0.8 g, 3.72 mmol), potassium carbonate (1.03 g, 7.45 mmol), iodopropane (0.83 mg, 4.86 mmol), acetonitrile (20 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1 to 0:1). Yield: 520 mg. The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether: M.p. 157.9° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 8), 228 (bp), 198 (30), 157 (15), 84 (88).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)nc1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 104.4 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)-(6-fluoropyridin-3-yl)amine (571 mg, 2.27 mmol) in EtOAc (40 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (57 mg) and was stirred at RT under a hydrogen atmosphere for 22 h. The mixture was filtered through a phase separator and the filtrate concentrated in vacuo to afford the title compound as a dark oil (524 mg, quantitative). LCMS (Method C): RT 2.39 min [M+H]+ 222.2.
Reaction SMILES: [SH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:19]=1[CH2:20]O>C(Cl)Cl>[CH3:7][C:2]([S:1][CH2:20][C:19]1[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=1[O:17][CH3:16])([CH3:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: CC(C)(S)CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(CSC(C)(C)CC(=O)O)c(OC)c1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 3-mercapto-3-methylbutyric acid (Sweetman et al, J. Med Chem., 14:868 (1971), the disclosure of which is incorporated herein by reference in its entirety) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5° C. (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (Munson et al., J. Org. Chem., 57, 3013 (1992), the disclosure of which is incorporated herein by reference in its entirety) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5° C. After the addition was complete, the mixture was stirred for an additional 5 minutes at 5° C. and the volatiles were evaporated in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material evaporated in vacuo. The residue was treated with activated charcoal and recrystallized from diethyl ether/hexane. The product was isolated as a white solid in 70% yield (7 g) mp 103-105° C. 1H NMR(CDCl3) δ 6.12 (s, 2H), 3.80-3.85 (m, 11H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3) δ 173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:17][CH2:16]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:20]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N1CCC(CCN2CCCC2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N1CCC(CCN2CCCC2)CC1
Yield: 111.4 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1,5-naphthyridin-3-yl)ethanone (60 mg, 0.16 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (73 mg, 83%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.91 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.35 (d, J=8.9 Hz, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.89 (dd, J=11.7, 2.2 Hz, 1H), 4.66 (br s, 2H), 3.69-3.54 (m, 4H), 3.33-3.23 (m, 2H), 3.13-3.03 (m, 2H), 2.67 (s, 3H), 2.22-1.96 (m, 7H), 1.81-1.68 (m, 4H); ESI MS m/z 497 [M+H]+; HPLC>99% (AUC), tR=9.65 min.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 78.1 %

Procedure:
A mixture of N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,4-diamine (Intermediate 159, 440 mg, 0.95 mmol), iron (319 mg, 5.71 mmol), NH4Cl (38.2 mg, 0.71 mmol), ethanol (15 mL) and water (5 mL) was heated at reflux for 1.5 h. After cooling, the mixture was concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (20 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (20 mL) and then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (321 mg, 78%) as a brown gum after trituration with diethyl ether; 1H NMR: 2.18 (6H, s), 2.37 (2H, t), 2.65 (3H, s), 2.91 (2H, t), 3.72 (3H, s), 4.57 (2H, br s), 6.77 (1H, s), 7.07 (1H, td), 7.22 (1H, d), 7.29 (1H, s), 7.37-7.42 (1H, m), 7.97 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H, s), 8.77-8.80 (1H, m); m/z: ES+ MH+ 433.36.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:14]([NH:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.CCN(C(C)C)C(C)C.C(OC(ON1C(=O)CCC1=O)=O)(C)(C)C>>[NH2:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[N:11]1[CH2:12][C@H:13]([CH3:20])[C@H:14]([NH:15][C:16](=[O:17])[O:18][CH3:19])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of di-tert-butyl (4-{(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-4-[(methoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (1.41 g, 2.43 mmol) and 4.0 M HCl in dioxane (40.0 mL, 1.60E2 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the solid was dried under high vacuum for 10 min. DCM (25.0 mL) was added to the residue, followed by DIPEA (1.94 g, 15.0 mmol) and 1-[(tert-butoxycarbonyl)oxy]pyrrolidine-2,5-dione (579 mg, 2.69 mmol). The mixture was then stirred room temperature for 16 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aq. Na2CO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (40 g, eluting with 100% EtOAc, then 10% MeOH in DCM with 1% Et3N) to give the sub-title compound as a yellow foamy solid (701 mg, 76%). LCMS calc. for C18H30N5O4 (M+H)+: m/z=380.2. Found: 380.3.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16][CH2:15]1>>[CH:8]1([CH2:7][N:6]2[C:2]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16][CH2:15]3)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=[N+]([O-])c1cnn(CC2CC2)c1Cl
Product: CC(C)(C)OC(=O)NCC1CCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1
Yield: 95 %

Procedure:
Reaction of 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and tert-butyl piperidin-4-ylmethylcarbamate gave tert-butyl (1-(1-(cyclopropylmethyl)-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a pale yellow gum (0.57 g, 95%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (m, 1H), 4.63 (s, 1H), 3.91 (d, J=7.1 Hz, 2H), 3.40-3.32 (m, 2H), 3.13-3.06 (m, 2H), 2.95 (d, J=11.5 Hz, 2H), 1.81 (d, J=12.9 Hz, 2H), 1.46 (s, 9H), 1.42-1.14 (m, 3H), 0.95-0.82 (m, 1H), 0.63-0.57 (m, 2H), 0.42-0.35 (m, 2H)
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.C(O)C.[NH2:19]N>>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[N:19]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1cccc(C#N)c1
Solvent: CCO
Product: N#Cc1cccc(-c2cc[nH]n2)c1
Yield: 84.7 %

Procedure:
The 3-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (0.600 g, 0.00300 mol) was dissolved in ethanol (20.0 mL, 0.342 mol) and hydrazine (0.56 mL, 0.018 mol) under an atmosphere of nitrogen was stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo to give a dark product which was purified by FCC on silica gel, eluting with ethyl acetate-hexane 1:1 to give 3-(1H-pyrazol-3-yl)benzonitrile as an oil (0.430 g, 84%), LC/MS (M+H)+: 170.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:29]([C:26]1[CH:25]=[N:24][C:23]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:19][CH:18]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:28][CH:27]=1)[CH3:30]
Reactant: Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Yield: 85.9 %

Procedure:
Condensation of 4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol (1.20 g; 4.06 mmol) with 2-chloro-5-ethyl-pyrimidine (0.52 ml; 4.27 mmol) as per general procedure E (conditions: 1.1 eq. DIEA, toluene, 210C, 16 hr) provided the title compound (1.40 g; 85% yield).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9]C)=O)[N:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:9])[N:6]=1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Cl)sc1-c1ccccc1
Yield: 22.5 %

Procedure:
5.4 g (21.3 mmol) of methyl 2-chloro-5-phenyl-4-thiazolecarboxylate and 3.6 g (22.3 mmol) of t-butyl (2-aminoethyl)carbamate were stirred under reduced pressure for 22 hours at a bath temperature of 110°, whereby the methanol formed was distilled off continuously. The reaction mixture was cooled, dissolved in methylene chloride and chromatographed on 150 g of silica gel with methylene chloride and a 4:1 mixture of methylene chloride and ethyl acetate as the eluting agent. The fractions which were pure according to the thin-layer chromatogram were combined and evaporated. Crystallization of the residue from ethyl acetate/hexane yields 1.83 g (27.5%) of t-butyl [2-(2-chloro-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as white crystals, melting point 114°-116°.
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].N1C=CC=CC=1.[NH2:11][C:12]1[N:17]=[C:16]([S:18][C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH3:20])[N:15]=[C:14]([OH:28])[CH:13]=1.BrBr>CN(C=O)C.O>[NH2:2][C:1]1[S:3][C:13]2[C:14]([OH:28])=[N:15][C:16]([S:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH3:20])=[N:17][C:12]=2[N:11]=1
Reactant: N#C[S-]
Reactant: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1F
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(O)c2sc(N)nc2n1)c1ccccc1F
Temperature: 0 °C
Yield: 81 %

Procedure:
KSCN (10.76 g, 110.7 mmol) and pyridine (3.9 mL, 49.2 mmol) was added to 6-amino-2-{[(1S)-1-(2-fluorophenyl)ethyl]thio}pyrimidin-4-ol (6.53 g, 24.6 mmol) in DMF (70 mL). The mixture was cooled to 0° C. and Br2 was added dropwise. After 3.5 h the reaction mixture was poured into water and the formed precipitate was collected by filtration. The solid was suspended in a mixture of DMF (75 mL) and water (15 mL) and heated to 120° C. for 8 h. The reaction mixture was poured into water and the solid was collected by filtration and dried in vacuum at 40° C. to give the title compound (6.42 g, 81% yield).