Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15](Cl)=[O:16])[CH3:13]>>[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)=[O:16])[CH3:13]
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: CCCCC(CC)C(=O)Cl
Product: CCCCC(CC)C(=O)NC1=NC(=O)C2=CC=NC2=N1

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and 2-ethylhexanoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1F>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[CH:11][C:10]([C:23]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(C(F)(F)F)c3)n(-c3ccc(F)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 87A in analogy to the synthesis of the compound of Example 1. 28 mg (74% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][CH3:22])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1OC
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1OC)C1CCOCC1
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of methyl 5-chloro-2-methoxy-3-[(oxan-4-yl)amino]benzoate (220 mg, 0.73 mmol) in 1,2-dichloroethane (2 ml) at room temperature under nitrogen was added acetaldehyde (82 μl, 1.47 mmol) followed by acetic acid (0.25 ml, 4.4 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.47 g, 2.2 mmol) at room temperature. After stirring for 16 hours acetaldehyde (82 μl, 1.47 mmol) was added to the reaction mixture and stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.47 g, 2.2 mmol). After stirring for 24 hours, a further acetaldehyde (82 μl, 1.47 mmol) was added to the reaction mixture and stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.47 g, 2.2 mmol). The reaction was stirred for 24 h after which deionized water (10 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 127 mg (53%) of the title compound as a yellow oil. LC-MS 93%, m/z=328.4/330.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.35 (d, J=2.6 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 3.98 (dd, J=11.3, 4.2 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.48 (tt, J=11.6, 4.0 Hz, 1H), 3.36 (td, J=11.8, 1.9 Hz, 2H), 3.15 (q, J=7.0 Hz, 2H), 1.78 (qd, J=12.2, 4.6 Hz, 2H), 1.72-1.59 (m, 2H), 0.99 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([C:16]([OH:18])=O)[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>C(O)(=O)C>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:20]2[C:16](=[O:18])[C:9]3=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:15][CH:14]=[C:10]3[C:11]2=[O:13])=[CH:24][CH:25]=1
Reactant: CCCCCOc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCOc1ccc2c(c1)C(=O)N(CCc1ccc(O)cc1)C2=O
Temperature: 96 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
The crude product of 4-pentyloxyphthalic acid was dissolved in acetic acid (20 ml), and tyramine hydrochloride (2.74 g, 20 mmol) was added. The mixture was stirred at 96° C. for 4 hours, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=6/1) to give N-2-(4-hydroxyphenyl)ethyl-4-pentyloxyphthalimide (2.6 g, 9.4 mmol, 88%) as colorless crystals.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:25]C(=O)C)[CH2:6]1)(=O)C.C(O[C@H]1C[C@@H](C)[C@@]2(CO)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2OC(=O)C)C1)(=O)C>>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH:23]=[O:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:25])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(CO)[C@@H](CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(CO)[C@H](C)C1
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43C=O)[C@@H]1CC[C@@H]2O

Procedure:
Substituting 5α-androstane-3β,17β,19-triol 3,17-diacetate for the 1β-methyl-5α-androstane-3β,17β,19-triol 3,17-diacetate above results in the preparation of 3β,17β-dihydroxy-5α-androstan-19-one.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2C)[C@H:5]([OH:19])[C@@H:4]1[OH:20].[N:21]1C=CC=C[CH:22]=1.O=S(Cl)Cl>CC#N>[Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[NH:21][CH3:22])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O

Procedure:
Compound 3c was prepared by the same procedure as described for the preparation of 3a using 2c41 (2.9 g, 9.78 mmol), pyridine (1.54 g, 1.57 mL, 19.46 mmol), CH3CN (5 mL), and SOCl2 (5.82 g, 3.56 mL, 48.91 mmol): yield 1.95 g (63%); MS m/z 315 (M+H)+; 1HNMR (DMSO-d6) δ 7.91 (bs, 1H, H-2), 6.78 (q, 1H, 8CH3—NH), 6.50 (bs, 2H, 6-NH2), 5.70 (d, 1H, H-1′, J1′,2′=5.0 Hz), 5.41 (d, 1H, 2′-OH, J2′-2′OH=5.6 Hz), 5.32 (d, 1H, 3′-OH, J3′-3′OH=5.3 Hz), 5.18 (ddd, 1H, H-2′, J1′,2′=5.0 Hz, J2′,3′=5.4 Hz, J2′-2′OH=5.6 Hz), 4.33 (ddd, 1H, H-3′, J2′,3′=5.4 Hz, J3′,4′=4.4 Hz, J3′-3′OH=5.3 Hz), 3.91-4.02 (bm, 2H, H-4′,5′-CH2), 3.76-3.82 (m, 1H, 5′-CH2), 2.88 (d, 3H, 8NH—CH3, J=4.5 Hz).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.C[Sn](C)C.C[Sn](C)C.Br[C:25]1[N:30]=[C:29]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[CH:28]=[CH:27][CH:26]=1>COCCOC.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>[F:13][C:12]([F:15])([F:14])[C:6]1[N:7]=[C:8]2[C:3]([C:2]([C:25]3[N:30]=[C:29]([C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]#[N:34])[CH:28]=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccccc1-c1cccc(Br)n1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cccc(-c2ccnc3nc(C(F)(F)F)ccc23)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-Chloro-2-trifluoromethyl[1,8]naphthyridine (200 mg, 0.86 mmol) and hexamethylditin (178 μL, 282 mg, 0.86 mmol) in DME (5 mL) was degassed via three “freeze-thaw” cycles. Tetrakis(triphenylphosphine)palladium(0) (49.7 mg, 0.043 mmol) was added, and the mixture was degassed as before, then was heated under nitrogen at 80° C. overnight. 2-(6-Bromopyridin-2-yl)benzonitrile (126 mg, 0.48 mmol) was added and the mixture was degassed as before, then more tetrakis(triphenylphosphine)palladium(0) (49.7 mg, 0.043 mmol) was added, the mixture was degassed again, then was stirred at 80° C. under nitrogen overnight. Water (25 mL) and dichloromethane (15 mL) were added to the cooled mixture, and the aqueous layer was washed with more dichloromethane (2×15 mL). The combined organic layers were washed with saturated sodium chloride solution (1×25 mL) then were dried over magnesium sulfate and concentrated in vacuo. The residual material was purified by flash chromatography on silica gel, eluting with 10% to 40% ethyl acetate in dichloromethane, affording 2-[6-(7-trifluoromethyl[1,8]naphthyridin-4-yl)pyridin-2-yl]benzonitrile as a colourless solid, which was recrystallised from ethyl acetate/isohexane (44 mg, 24%). δH (400 MHz, CDCl3) 7.52-7.60 (1H, td, J 7.6 and 1.2), 7.71-7.77 (2H, m), 7.82 7.92 (5H, m), 8.12 (1H, t, J 7.8), 9.11 (1H, d, J 8.6), 9.35 (1H, d, J 4.3). m/z (ES+) 377 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[ClH:20]>C(O)C.CCOCC>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][Cl:20])=[N:5][N:6]=1
Reactant: Cl
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Solvent: CCOCC
Solvent: CCO
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CCl)s1
Reaction time: 12 h

Procedure:
1 g of 2-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-1,3,4-thiadiazole in a mixture of 100 ml of ethanol and 5 ml of a 3 N solution of hydrogen chloride in ether is left to stand for 12 hours. The precipitate formed is filtered off, washed neutral with ether and chromatographed over silica gel, using chloroform. The product eluates are evaporated to dryness, giving spectroscopically pure 2-methyl-5-[2-(2-hydroxy-3-chloropropoxy)-styryl]-1,3,4-thiadiazole of melting point 168°-170° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Di-tert-butylazodicarboxylate (1.64 g, 7.14 mmol) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-Chloro-6-methoxyquinazolin-7-ol (1.0 g, 4.76 mmol, prepared as described in WO2004041829, Example 1 therein (preparation of starting materials)), 4-hydroxy-1-tert-butoxycarbonylpiperidine (1.44 g, 7.14 mmol) and triphenylphosphine (1.87 g, 7.14 mmol) in methylene chloride (50 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 18 hours. The reaction mixture was then filtered and purified by flash chromatography on silica eluting with increasingly polar mixtures of isohexane/ethyl acetate/triethylamine (75/24/1 followed by 0/99/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate as a white solid (1.75 g, 93.4%); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.5-1.7 (m, 2H), 1.9-2.1 (m, 2H), 3.1-3.3 (m, 2H), 3.60-3.80 (m, 2H), 3.95 (s, 3H), 4.92 (m, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 8.83 (s, 1H); Mass Spectrum: (M+H)+ 394.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:14]([OH:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[CH:19]([F:21])[F:20]>CN(C)C=O>[F:20][CH:19]([F:21])[O:15][C:14]1[C:4]([F:3])=[C:5]([CH:11]=[C:12]([F:17])[C:13]=1[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(F)c(F)c(O)c1F
Reactant: FC(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
1.76 g (0.044 moles) of a 60% w/w suspension of sodium hydride in mineral oil was added in small portions, whilst stirring and ice-cooling, to a solution of 8.83 g (0.04 moles) of ethyl 2,4,5-trifluoro-3-hydroxybenzoate [(XXIV), X=X'=F, R16 =C2H5O] [prepared as described in step (a) above] in 40 ml of dimethylformamide and, after the addition was complete, the mixture was stirred, whilst ice-cooling, for an additional 30 minutes. At the end of this time, the reaction mixture was transferred into a 200 ml stainless steel autoclave, and then 100 ml of dimethylformamide containing 28.0 g (0.32 moles) of chlorodifluoromethane were added thereto, and the mixture was stirred under pressure at 95°-100° C. for 5 hours. At the end of this time, the dimethylformamide was removed by distillation under reduced pressure, and water was added to the residue, which was extracted with toluene. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, using toluene as the eluent, to give 4.85 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoate as a colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:31]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:31]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)[CH2:40][CH2:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred mixture of 4-formylbenzoic acid (1 g, 6.66 mmol) in anhydrous dichloromethane (5 mL) was added triethylamine (1.4 mL, 7.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g, 7.99 mmol), and 1-benzyl-piperidin-4-ylamine (1.26 mL, 6.66 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was triturated with methanol. The resulting solids were collected by filtration, washed methanol and dried under reduced pressure to afford N-(1-benzylpiperidin-4-yl)-4-formylbenzamide as a white solid (1.7 g, 80%). 1H NMR (DMSO, 300 MHz): δ 8.41 (s, 1H), 7.85 (d, 2H), 7.77 (d, 2H), 7.28 (m, 5H), 3.78 (m, 1H), 3.4 (m, 2H), 3.80 (m, 2H), 2.05 (m, 2H), 1.45-1.80 (m, 4H); LCMS (m/z): 324 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12].[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:9]([NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([NH2:20])[CH2:14][CH2:15]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: Cc1sc2ncnc(Cl)c2c1Br
Reactant: NC1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1sc2ncnc(NC3CCC(N)CC3)c2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of 5-bromo-4-chloro-6-methylthieno[2,3-d]pyrimidine (79 mg, 0.30 mmol, 1.00 equiv) in anhydrous DMF (5 mL) was added cyclohexane-1,4-diamine (171 mg, 1.50 mmol, 5.00 equiv) and triethylamine (91 mg, 0.90 mmol, 3.00 equiv) successively at room temperature. The resulting solution was stirred overnight at ambient temperature and then quenched with water. The resulting solution was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the resulted 1-N-[5-bromo-6-methylthieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine (90 mg, 88%) as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:18]([O-:20])=[O:19])=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-])[CH:12]=2)=[N:2]1.P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:18]([O-:20])=[O:19])=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N:11][CH:12]=2)=[N:2]1
Reactant: O=[N+]([O-])c1c(Nc2ccon2)c[n+]([O-])c2c1COCC2
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Nc2ccon2)cnc2c1COCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 473 mg of Compound 6 obtained in the above step (2) in 30 ml of methylene chloride is added a solution of 935 mg of phosphorus tribromide in 1 ml of methylene chloride under ice cooling. The reaction mixture is stirred for 2 hours, mixed with ice water and neutralized with aqueous potassium carbonate under ice cooling. The organic layer is separated, and the aqueous layer is extracted with methylene chloride. The organic layers are combined, washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is recrystallized from methylene chloride-isopropanol to give 407 mg of the titled compound 7 as yellow crystals. Yield: 93% mp.: 143° to 145° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7](C(=O)C)[C:6](=[O:11])[N:5]([C:12](=[O:14])[CH3:13])[C:4]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>Br.C(O)(=O)C>[C:12]([N:5]1[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([CH2:2][Br:1])[NH:7][C:6]1=[O:11])(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1c(CBr)n(C(C)=O)c(=O)n1C(C)=O
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Reaction time: 4 h

Procedure:
Crude ethyl 5-(bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate is dissolved in 30% hydrobromic acid in acetic acid and the solution is allowed to stand at room temperature for 4 hours. The product precipitates, is collected and dried in vacuo at 80° C. over KOH, m.p. 193°-194° C. (dec.).
Reaction SMILES: [C:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH:29]([C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:30]([CH:29]([C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1)[O:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]2=[O:15])=[CH:45][CH:44]=1)([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reactant: CCOC(=O)C(Oc1ccc(CBr)cc1)c1ccc2c(c1)OCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc1)c1ccc2c(c1)OCO2
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of 0.020 g (0.10 mmol) of 1-carboethoxy-2-benzimidazolinone dissolved in 250 gL DMF was added 0.035 g (0.11 mmol) of cesium carbonate and the resulting suspension was stirred under a nitrogen atmosphere for 10 minutes. A solution of the product of step B in 300 aL DMF was then added and the reaction mixture was stirred for an additional 1 hour. The mixture was suspended in 10% aqueous citric acid and extracted into ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered, evaporated, and the residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.029 g (58%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)[CH:12]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][NH:23]1>CO>[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][N:23]1[CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:12]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: Cn1cnc2ccc(-c3cccc(OCC4CO4)c3)cc21
Solvent: CO
Product: Cn1cnc2ccc(-c3cccc(OCC(O)CN4Cc5ccccc5C4)c3)cc21
Reaction time: 16 h
Yield: 11 %

Procedure:
To a solution of 1-methyl-6-(3-(oxiran-2-ylmethoxy)phenyl)-1H-benzo[d]imidazole (500 mg, 1.78 mmol) in MeOH (5 mL) was added isoindoline (213 mg, 1.78 mmol) at 25° C., and the mixture was heated to reflux and stirred for 16 h. The reaction mixture was cooled, concentrated and purified by preparative HPLC purification. (80 mg, yield 11%) MS (ESI+) e/z: 400.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.22 (s, 1H), 7.87 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.41-7.19 (m, 7H), 6.97-6.95 (m, 1H), 4.16-4.04 (m, 7H), 3.89 (s, 3H), 3.04-2.87 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.Cl.[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 30, 0.2 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.15 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.2 g of title compound. MS (electrospray): 404 (M+1) for C16H18FN9O3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][N:31]1[CH2:32][CH2:33][CH:28]([C:26](=[O:27])[C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=2)[CH2:29][CH2:30]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A solution of ((R)-1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.0 mmol), (4-fluoro-phenyl)-piperidin-4-yl-methanone (0.414 g, 2.0 mmol) and sodium triacetoxyborohydride (0.638 g, 3.0 mmol) in tetrahydroftiran (20 ml) is stirred at ambient temperature for 24 hours. The solvent is evaporated and the residue redissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The dichloromethane is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (ethylacetate:hexane, 3:1 elution) to afford {(R)-1-benzyl-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}carbamic acid tert-butyl ester. [MH]+441.3.