Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>CCOCC>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)[CH3:18]
Reactant: CCOC(=O)C1CNCCO1
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)CCN1CCOC(C(=O)OCC)C1
Temperature: 100 °C

Procedure:
A mixture of ethyl morpholine-2-carboxylate (3 g, 18.85 mmol) and ethyl acrylate (5 ml, 18.85 mmol) was heated at 100° C. for 14 h. The reaction was cooled to RT then diluted with Et2O and extracted with aqueous 3M HCl. The combined aqueous layers were basified by solid K2CO3 and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a pale-yellow oil, which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:19][C@H:18]([C:20]([O:22]C)=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C1COCC1.O>[CH3:31][C:30]([O:29][C:27]([N:19]1[C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[CH2:16][CH2:17][C@H:18]1[C:20]([OH:22])=[O:21])=[O:26])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a solution of methyl (5R)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate (D4, 120 mg, 0.38 mmol) in THF (2.3 ml) was added LiOH monohydrate (26 mg, 0.61 mmol) dissolved in water (1.1 ml), followed by methanol (1.1 ml). The resulting solution was stirred at room temperature for 2.5 hours, then left overnight at −18° C. Then the organic solvent was evaporated under reduced pressure maintaining the temperature at 38° C. and the aqueous residue containing the acid intermediate (D6, Rt (HPLC)=3.63 min. MS: (ES/+) m/z: 298 [MH+]. C18H19NO3 requires 297) was treated with BOC2O (168 mg, 0.77 mmol) dissolved in THF (1.1 ml). The reaction mixture was stirred at room temperature for 3.5 hours. The organic solvent was evaporated and the basic aqueous solution was acidified at 0° C. with aqueous 1N HCl solution to pH=3, this acidic aqueous solution was extracted with ethyl acetate (2×10 ml). The organic phase dried over Na2SO4 and evaporated under reduced pressure gave a solid, which was titurated in n-hexanes (3×6 ml) affording the title compound as a white powder (D7, 137 mg, 90% for two steps); Rt (HPLC): 5.81 min; Rf (cyclohexane:ethyl acetate=1:1): 0.34; MS: (ES/+) m/z: 420 [M+Na+] C23H27NO5 requires 397; MS: (ES/−) m/z: 396 [M−H] C23H27NO5 requires 397; 1H NMR (300 MHz, CDCl3) δ (ppm): 7.5-7.3 (m, 5H), 7.10 (bm, 2H), 6.90 (d, 2H), 5.08 (s, 2H), 4.65 (bm, 1H), 4.50 (bm, 1H), 2.58 (bm, 1H), 2.31 (bm, 1H), 2.11-1.90 (m, 2H), 1.16 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:5]=2[N:6]=1>C1COCC1.O=[Mn]=O>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(CO)ccc2s1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Cc1nc2cc(C=O)ccc2s1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A solution of (2-methylbenzo[d]thiazol-5-yl)methanol (400 mg; 2.23 mmol) in anh. THF (20 ml) was treated with MnO2 (3.026 g; 34.81 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 6.5 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with THF. The filtrate was concentrated to dryness under reduced pressure giving 2-methylbenzo[d]thiazole-5-carbaldehyde as a yellow solid. LC-MS (conditions B): tR=0.70 min.; [M+H]+: 178.03 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[C:5]([F:12])=[C:4]([Cl:13])[C:3]=1[OH:14].[H][H]>CO.[Ni]>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[C:5]([F:12])=[C:4]([Cl:13])[C:3]=1[OH:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(F)c(Cl)c(O)c(Cl)c1F
Agent: [Ni]
Solvent: CO
Product: Nc1c(F)c(Cl)c(O)c(Cl)c1F

Procedure:
18 g of 2,6-dichloro-3,5-difluoro-4-nitrophenol are hydrogenated in 100 ml of methanol in the presence of 1.5 g of Raney nickel at 25°-45° C. using 30-50 bar of hydrogen until the take-up of hydrogen is complete. After filtration, the solution is freed from solvent under reduced pressure. 13 g of aminophenol (GC purity 98.4%) remain; m.p. 151° C.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:19])[C:9](=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C1C2C(=CC=CC=2)CCC1>>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:19])[C:9](=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: c1ccc2c(c1)CCCC2
Product: Nc1cccc2c1C(=O)c1c(Cl)cccc1C2=O

Procedure:
28.8 parts of 1-nitro-8-chloroanthraquinone are heated for 5 hours at boiling temperature in 160 parts of tetrahydronaphthalene. The remainder of the process is carried out as described in Example 4 to yield 20.2 parts of 1-amino-8-chloroanthraquinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][C:21]#[N:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]#[N:22])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: N#CCN1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1

Procedure:
Example 46 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and bromoacetonitrile (2.8 μl) to give the title compound (0.0039 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Cl[C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])[CH2:12][O:13][C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1
Reactant: OCc1ccc(C(F)(F)F)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(C(F)(F)F)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].Cl.[NH2:13][OH:14]>C(O)C>[N:9]1[CH:10]=[CH:11][C:6]([C:2]2[CH:3]=[C:4]([NH2:5])[O:14][N:13]=2)=[CH:7][CH:8]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccncc1
Agent: Cl
Solvent: CCO
Product: Nc1cc(-c2ccncc2)no1
Temperature: 70 °C
Yield: 68.9 %

Procedure:
To 3-oxo-3-pyridin-4-yl-propionitrile (2.0 g, 13.7 mmol) in 20 mL of ethanol was added hydroxylamine hydrochloride (0.75 g, 10.8 mmol) and the resulting solution was heated at 70° C. overnight. The resulting white precipitate was collected and the solution was concentrated and dried in vacuum to afford the title compound (1.2 g, 54%) as a yellow solid. FIA MS: MH+162.2, M−160.0.
Reaction SMILES: [Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:15]Br>ClCCl>[Br:15][CH:9]1[C:10](=[O:11])[C:4]2[CH:3]=[C:2]([Br:1])[C:13]([F:14])=[CH:12][C:5]=2[O:6][CH2:7][CH2:8]1
Reactant: BrBr
Reactant: O=C1CCCOc2cc(F)c(Br)cc21
Solvent: ClCCl
Product: O=C1c2cc(Br)c(F)cc2OCCC1Br
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed 7-Bromo-8-fluoro-3,4-dihydro-2H-benzo[b]oxepin-5-one (1168 g, 4.51 mol, 1.00 equiv) and dichloromethane (8 L), followed by the addition of Br2 (724.3 g, 4.53 mol, 1.00 equiv) dropwise with stirring at −20° C. over 90 min. The resulting solution was stirred at −20° C. for 30 min and at room temperature for 3 h. The reaction was then quenched by the addition of 6000 mL of saturated aqueous Na2SO3 at 0° C. and extracted with 4×2 L of dichloromethane. The combined organic layers were washed with 2×3000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1170 g (77%) of 4,7-dibromo-8-fluoro-2,3,4,5-tetrahydro-1-benzoxepin-5-one as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CC[CH:33]([N:36]=[C:37]=NC2CCCCC2)CC1.CNC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([N:36]([CH3:37])[CH3:33])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of 15 g of (2S,4R)-1-(benzyloxy-carbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid, 7.64 g of HOBT and 11.65 g of DCC in 250 ml of DCM is stirred for 1 hour at RT. The reaction mixture is cooled on an ice bath, dimethylamine gas is added by sparging for 10 minutes and this mixture is stirred for 3 hours at RT. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in saturated Na2CO3 solution and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)[CH2:15][CH3:16].CC(C)=O>C(#N)C.ClCCl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:14][CH2:15][CH3:16])[N:22]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CCCc1cccc(N)n1
Solvent: CC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CCCc1cccc(Nc2cc(Cl)nnc2C(=O)OCC)n1
Temperature: 130 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (0.80 g, 3.62 mmol) and 6-propylpyridin-2-amine (739 mg, 5.43 mmol) was dissolved in acetonitrile (4 mL) and heated at 130° C. After 24 h, the reaction mixture was cooled and concentrated in vacuo, then purified by chromatography (silica, 80 g, 0 to 3% acetone in dichloromethane over 15 min, then 3 to 10% acetone in dichloromethane over another 15 min) to give ethyl 6-chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (335 mg, 1.04 mmol, 29%) as a pale yellow crystalline solid after drying under high vacuum at room temperature. LC-MS 321.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:33]2)=CC=1.CCOC(C)=O.Cl>COCCOC>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](=[S:33])[NH2:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Agent: Cl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=S)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (340 mg, 1.0 mmol) obtained above in DME (10 mL) was added 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (485 mg, 1.2 mmol), and the mixture was stirred at 80° C. for 1 h. The reaction mixture was allowed to cool to rt, and then were added EtOAc (15 mL) and 1N hydrochloric acid (15 mL) and then the resulting suspension was filtered. The residue was washed with water (5 mL) and EtOAc (5 mL) to give the title compound (172 mg, 48%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:5][C:6]([OH:8])=O)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[CH:1]1([CH2:5][C:6]([N:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][C:23]([C:21]4[CH:22]=[C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]5)[N:18]=[C:19]([NH2:33])[N:20]=4)=[CH:24][CH:25]=3)[CH2:30]2)=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)CC1CCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from cyclobutylacetic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=421.1.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:42]1([S:48]([N:51]2[C:55]3=[CH:56][N:57]=[CH:58][C:59](Br)=[C:54]3[CH:53]=[C:52]2[CH2:61][CH3:62])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:42]1([S:48]([N:51]2[C:55]3=[CH:56][N:57]=[CH:58][C:59]([C:11]4[N:12]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[C:8]5[S:28][C:27]([CH2:29][N:30]6[CH2:35][CH2:34][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]6)=[CH:26][C:9]=5[N:10]=4)=[C:54]3[CH:53]=[C:52]2[CH2:61][CH3:62])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CCc1cc2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(C(C)(C)C(N)=O)CC5)cc4n3)cncc2n1S(=O)(=O)c1ccccc1
Yield: 62.2 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.241 g, 0.35 mmol), 1-benzenesulfonyl-4-bromo-2-ethyl-1H-pyrrolo[2,3-c]pyridine (0.14 g, 0.38 mmol), copper(I) 2-thiophene carboxylate (0.01 g, 0.069 mmol) and Pd(PPh3)4 (0.040 g, 0.035 mmol) in dioxane (3 mL) was subjected to microwave irradiation at 150° C. for 20 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 20:80) to give 2-{4-[2-(1-benzenesulfonyl-2-ethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl]piperazin-1-yl}isobutyramide as a yellow foam (0.15 g, 64%). LCMS (Method A): RT=3.53min, [M+H]+ 689.2
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[N:6]=2)[CH2:3][CH2:2]1.[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:24]4/[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18]/4)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[N:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CNC(=O)N1
Reactant: CSc1nc(NC2CC2)n2ncc(C=O)c2n1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reaction time: 3 h

Procedure:
4-(Cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde (1.0 eq, 3.00 g, 12.03 mmol) was suspended in ethanol (40 ml). Hydantoin (1.5 eq, 1.81 g, 18.08 mmol) and piperidine (1.5 eq, 1.78 ml, 18.01 mmol) were added. The mixture was heated at reflux under vigorous magnetic stirring for 3 hours. After cooling of the reaction mixture, the precipitate was filtered, washed with ethanol, then with a mixture of ethanol and water (1:1). After drying in vacuo, (Z)-5-((4-(cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a yellow solid (3.80 g, 95%). LCMS (ES):>85% pure, m/z 332 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][CH:17]=2)[C:10]=1[N+:31]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C1COCC1.CO.O.[Fe]>[NH2:31][C:10]1[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:13]=[N:14][C:9]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)cc1
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 4-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (37) (6 g, 11.1 mmol) in THF/MeOH/H2O (100 mL/100 mL/30 mL) was added Fe powder (3.11 g, 55.5 mmol) and NH4Cl (5.94 g, 111 mmol). The reaction mixture was heated at 60° C. for 4 h under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (100 mL×3), washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 4-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate (38) (5.4 g, yield 95%) as a yellow solid. LC-MS (ESI): m/z (M+1) 511.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 7 °C

Procedure:
A 100 mL Schlenk tube was charged with methanol (30 mL) and codeine free base (5.3 g, 17.7 mmol). The stirred solution was heated to reflux under nitrogen for 15 min and treated with the solution of the catalyst added by a pipette. The resulting brown solution was stirred and heated to reflux under nitrogen for 1 hour, cooled to 7° C. in an ice bath, stirred at this temperature for another 30 min and filtered. The filtered solid was washed with cold isopropanol (3×6 mL) and dried in an oven at 95° C. to give hydrocodone free base as a white solid. The yield was 4.48 g, 84.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClC1C=CC=C(C(OO)=[O:20])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:20])=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc2cccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 40 mL of a chloroform solution containing 2.0 g of 8-methylquinoline, 3.6 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature overnight. Thereto was added 1.0 g of m-chloroperbenzoic acid, and the mixture was stirred at room temperature overnight. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 2.2 g of a brown oily substance, 8-methylquinoline N-oxide.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[CH3:12].CCO.[Cl-].[NH4+]>[Fe].O>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([Cl:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(Cl)cc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)cc(N)c1Br
Temperature: 50 °C
Yield: 77.1 %

Procedure:
2-Bromo-5-chloro-1-methyl-3-nitro-benzene (721 mg, 3.5 mmol, Example 135: step b) was dissolved into EtOH (6 mL). To this was added ammonium chloride (1.9 g, 35 mmol) dissolved into water (10 mL). The reaction was heated to 50° C., iron (9.6 mg, 0.34 mmol) was added and the reaction was then heated to 80° C. for 12 hours. The reaction mixture was filtered through celite, washed with methanol and EtOAc and the solvents were removed in vacuo. The residue was dissolved into EtOAc and washed with brine to remove salts. The organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in the title compound (595 mg, 78%) as a brown solid. 1H-NMR (CDCl3): δ 6.63–6.61 (m, 2H), 2.33 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:25][NH2:26])[CH3:24]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:26][N:25]([CH2:23][CH3:24])[C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNN
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Product: CCc1nn(CC)c(CC)c1Cc1cncn1Cc1ccccc1

Procedure:
4-(3-Benzyl-3H-imidazol-4-ylmethyl)-1,3,5-triethyl-1H-pyrazole was prepared from 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione and ethylhydrazine in analogy to Example 55 b): off-white solid; MS (ISP): 323.3 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([F:20])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[I:12].O.O.[Sn](Cl)Cl>CCO>[NH2:17][C:15]1[C:14]([F:20])=[CH:13][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=2[I:12])=[C:2]([F:1])[CH:16]=1
Reactant: Nc1nccc(Oc2cc(F)c([N+](=O)[O-])cc2F)c1I
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Oc2ccnc(N)c2I)cc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a solution of 4-(2,5-difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (0.78 g, 1.78 mmol) in EtOH (15 mL) added tin(II) chloride dihydrate (2.0 g, 8.93 mmol) and the reaction mixture was stirred at 80° C. for 3 h. The mixture was cooled to RT, the solvent was removed in vacuo and crude residue was basified with NaHCO3 solution (40 mL). EtOAc (50 mL) was added to the resultant white suspension and the mixture was stirred for few minutes. It was filtered though a Celite® pad which was washed with EtOAc (4×5 mL), and water (3×4 mL). The organic layer was separated and was washed with brine, dried (Na2SO4) and concentrated to afford crude product which was purified by silica gel chromatography (EtOAc-hexanes) to afford 4-(4-amino-2,5-difluorophenoxy)-3-iodopyridin-2-amine as an off-white solid (0.33 g, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=5.6 Hz, 1H), 7.12 (dd, J=11.2 Hz, 7.6 Hz, 1H), 6.69 (dd, J=12.0 Hz, 8.0 Hz, 1H), 6.13 (s, 2H), 5.74 (d, J=5.6 Hz, 1H), 5.47 (s, 2H); MS (ESI) m/z: 364.0 (M+H+).