Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:33]O)[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([Cl:32])[CH:23]=1>>[Cl:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Yield: 79.6 %

Procedure:
The title compound was prepared following procedure described for example 35, step 1, but starting from Intermediate 28 (1 076.46 mg; 4.20 mmol) and Intermediate 34 (960.27 mg; 4.20 mmol). The reaction mixture was cooled to RT and concentrated affording a brownish oil which was washed with MeOH (20 mL) affording a suspension that was filtered affording the title compound as a beige solid (1.5 g; 82%). 1H NMR (DMSO-d6, 300 MHz) δ 8.34 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.3 Hz, 1H), 8.21 (dd, J=3.6, 1.7 Hz, 1H), 8.18 (dd, J=3.5, 1.8 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.37-7.27 (m, 3H), 7.15 (d, J=7.0 Hz, 1H), 4.23 (d, J=12.8 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.92 (s, 3H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 449.1 (M+H)+. HPLC (Method A) Rt 6.14 min (Purity: 97.6%).
Reaction SMILES: O.C[O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([O:14]C)=[C:6]([CH3:16])[C:5]=1[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>C(#N)C>[CH3:13][O:12][C:8]1[C:7](=[O:14])[C:6]([CH3:16])=[C:5]([CH:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:4](=[O:3])[C:9]=1[O:10][CH3:11]
Reactant: COc1c(C)c(C(CCCCCCO)c2ccccc2)c(OC)c(OC)c1OC
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(C(CCCCCCO)c2ccccc2)=C(C)C1=O
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
A solvent mixture of acetonitrile (12 ml) and water (6 ml) was added to 2.01 g (5.0 mmole) of 7-(2,3,4,5-tetramethoxy-6-methylphenyl)-7-phenylheptanol and 2.51 g (5×3 mmole) of 2,6-pyridinecarboxylic acid, and a cooled solution of 8.22 g (5×3 mmole) of ceric ammonium nitrate in 50% aqueous acetonitrile (16 ml) was added dropwise to the mixture over the 20 minutes period under ice-cooling. After stirring was continued for another 20 minutes under ice-cooling, the insoluble matter was filtered out, and the acetonitrile was distilled off under reduced pressure. Isopropyl ether was added to the residue to carry out extraction. The isopropyl ether layer was separated out, washed with aqueuous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column to elute with isopropyl ether/ethyl acetate to give 1.56 g (84%) of 7-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)-7-phenylheptanol. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound No. 57 was prepared.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH2:29]([O:31][C:32](=[O:42])[C@H:33]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH2:34])[CH3:30].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C.C(O)(=O)C1C=CC=CC=1>CN(C=O)C.C(P(=O)(OCC)OCC)#N>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH:34][C@H:33]([C:32]([O:31][CH2:29][CH3:30])=[O:42])[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc3ccc(COc4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.7 %

Procedure:
To a stirred suspension of 4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoic acid (0.19 g, 0.53 mmol) and L-glutamic acid diethyl ester hydrochloride (0.14 g, 0.58 mmol) (Aldrich) in DMF (3 ml) were added diethyl cyanophosphonate (0.09 ml, 0.6 mmol) (Aldrich) and triethylamine (0.15 ml, 1.1 mmol). Additional DMF (7 ml) was added but homogeneous solution was not obtained. The reaction mixture was stirred 45 minutes at room temperature and TLC analysis indicated remaining benzoic acid. Diethyl cyanophosphonate (2 drops) was added, the mixture stirred 45 minutes, and was then concentrated in vacuo. The residue was purified by chromatography on silica gel (50 g) eluting with ethanol:methylene chloride (1:9). The solid was filtered from a small volume of ethanol and dried under reduced pressure to give diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate (0.187 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.16 (t, J=7 Hz, 3H, ester CH3), 1.18 (t, J=7 Hz, 3H, ester CH3), 1.90-2.18 (m, 2H, glu CH2 ), 2.43 (t, J=7 Hz, 2H, glu CH2), 2.44 (s, 3H, C3 -CH3), 4.05 (q, J=7 Hz, 2H, ester CH2), 4.10 (q, J=6 Hz, 2H, ester CH2), 4.36-4.46 (m, 1H, glu CH), 5.43 (s, 2H, CH2O), 7.17 (d, J=9 Hz, 2H, Ar), 7.65 (d, J=9 Hz, 1H, Ar), 7.74 (dd, J=8,2 Hz, 1H, Ar), 7.88 (d, J=9 Hz, 2H, Ar), 8.08 (d, J=8 Hz, 1H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.58 (d, J=7 Hz, 1H, glu NH), 9.94 (s, 1H, Ar), 12.59 (s, 1H, N2H). Anal. Calculated for C30H31N3O7.1/4H2O: C, 65.50; H, 5.77; N, 7.64. Found: C, 65.54; H, 5.77; N, 7.61.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([O:14]C)=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:16]>C(O)C>[CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12](=[O:14])[NH2:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OC)cc(=O)[nH]1
Reactant: N
Solvent: CCO
Product: CCCCc1cc(C(N)=O)cc(=O)[nH]1

Procedure:
3 g (14.3mmol) of the compound from Example 1 are heated for a few minutes in 10 ml of ethanol and 20 ml of conc. ammonia. A further 5 ml of conc. ammonia are then added three times each and the mixture is again briefly heated to boiling. After cooling, the precipitate is filtered off with suction and dried over P2O5 in vacuo.
Reaction SMILES: I[C:2]([C:5]([O:8][C:9]([C:12]([S:15]([F:18])(=[O:17])=[O:16])([F:14])[F:13])([F:11])[F:10])([F:7])[F:6])([F:4])[F:3].[Si:19]([CH:26]=[CH2:27])([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>N#N>[Si:19]([CH2:26][CH2:27][C:2]([C:5]([O:8][C:9]([C:12]([S:15]([F:18])(=[O:17])=[O:16])([F:14])[F:13])([F:11])[F:10])([F:7])[F:6])([F:4])[F:3])([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]
Reactant: C=C[Si](OC)(OC)OC
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)I
Agent: N#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CO[Si](CCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)S(=O)(=O)F)(OC)OC
Temperature: 95 °C
Reaction time: 0.67 h

Procedure:
Following the teachings of Beckerbauer et al, op.cit., U.S. Pat. No. 5,958,822, (CH3O)3SiCH2CH2CF2CF2OCF2CF2SO2F was prepared as follows. To a stirred mixture of 85 g (0.2 mol) of ICF2CF2OCF2CF2SO2F available from the Shanghai Institute of Organic Chemistry, Shanghai, China, and 32 g (0.215 mol) of (CH3O)3SiCH═CH2 (Aldrich Chemical Company) was added 0.5 g of benzoyl peroxide (Aldrich) at 90 to 95° C. in N2 and the resulting mixture was stirred at 95° C. for 40 minutes. An additional 0.5 g of benzoyl peroxide was added and the mixture was stirred for 4 hours more and then evacuated to remove excess starting materials. After the mixture was cooled to room temperature, 59 g of (C4H9)3SnH was slowly added and the mixture was stirred at room temperature overnight and distilled to give 60.9 g of liquid (CH3O)3SiCH2CH2CF2CF2OCF2CF2SO2F having a purity of greater than 99% and boiling point of 55° C./3 mm Hg. 19F NMR(CDCl3): +44.9 (s, 1F), −82.6 (m, 2F), −87.4 (m, 2F), −112.6 (s, 2F), −120.7 (t, J=15 Hz, 2F), 1HNMR: 3.60 (s, 9H), 2.10 (m, 2H), 0.70 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[OH:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[F:11]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cc(Br)cc(F)c1O
Product: O=C(Nc1cc(Br)cc(F)c1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-bromo-6-fluorophenol (473 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([CH3:26])([CH3:25])[CH2:13][O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=O)=O)=CC=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:28]([CH2:11][C:12]([CH3:25])([CH3:26])[CH2:13][O:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])#[N:29]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)CC#N)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of toluene-4-sulfonic acid 3-toluene-4-sulfonyloxy-2,2-dimethylpropyl ester (5.0 g, 12.1 mmol) in DMSO (15 mL) is added KCN (789 mg, 12.1 mmol). The mixture is stirred at 80° C. for 18 h then cooled to RT. The mixture is poured into water and extracted with ether. The organic layer is dried over sodium sulfate the filtrate concentrated. The crude material is purified by column chromatography to give the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:11][C:10]=1[CH3:30])(=O)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]#[C:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:10]([CH3:30])[CH:11]=3)=[N:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Reactant: C1CCNC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
A solution of 110 mg (0.25 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl methanesulphonate in 2.11 mL (25 mmol) pyrrolidine is heated to 70° C. for 3 h. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated and after recrystallisation from EtOH the desired product is obtained.
Reaction SMILES: [C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([NH2:13])[C@@H:9]([OH:14])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2].C([O-])(O)=O.[Na+].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC#N>O>[C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([NH:13][C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:9]([OH:14])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2]
Reactant: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](N)C1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 5 °C
Yield: 91.1 %

Procedure:
To a solution of the amino acid 13 (0.290 g, 1.36 mmol) and NaHCO3 (0.343 g, 4.08 mmol) in water (7 mL), a solution of phenylacetyl chloride (0.191 g, 1.24 mmol) in abs. MeCN (3 mL) was added dropwise with cooling (−5˜−6° C.) and stirring. The reaction mixture was stirred for 2 h at 0˜−2° C. and for 1 hour at room temperature and was concentrated in vacuo to a volume of circa 5 mL. The solution was cooled to ca. 5° C. and adjusted to pH 2-3 with 1M aqueous HCl. (2.8 mL). The white precipitate was filtered off, washed with water and dried in vacuo to afford 0.364 g (91%) of the product 14 as a white solid with mp 194-195° C. (decomp.) (from iso-PrOH). 1H NMR (400 MHz) in CD3OD (J, Hz): δ 1.47 (3H, d, 3J=7.3, α-MeCH), 3.62 (1H, d, 2J=−14.8, CHAPh), 3.67 (1H, d, 2J=−14.8, CHBPh), 4.06 (1H, dd, 2J=−11.4, 3J=3.7, 6-HA), 4.12-4.06 (1H, m, 5-H), 4.33 (1H, dd, 2J=−11.4, 3J=5.6, 6-HB), 4.66 (1H, d, 3J=8.0, 4-H), 4.96 (1H, q, 3J=7.3, α-CH), 7.38-7.17 (5H, m, Ph). 13C (100 MHz) in CD3OD: δ 1371, 43.63, 55.70, 57.54, 71.84, 79.10, 127.85, 129.51, 130.37, 136.63, 169.61, 172.71, 174.89. IR (KBr), cm−1: 3361, 2913, 1729, 1666, 1630, 1542, 1440, 1233. MS (CI, isobutane), m/Z: 323 (M++1). Anal. Calcd for C15H18N2O6: C, 55.9; H, 5.6; N, 8.7. Found: C, 55.7; H, 5.7; N, 8.6%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:24])[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:24])[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1CCC(N(C)CCNC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCNC(=O)OC(C)(C)C)C1CCC(CC(=O)O)CC1
Reaction time: 2.75 h

Procedure:
To a solution of ethyl 2-[4-[2-(tert-butoxycarbonylamino)ethyl-methyl-amino]cyclohexyl]acetate (231 mg, 0.67 mmol) in methanol (2 mL) and THF (2 mL) was added NaOH (1 mL, 2M aqueous solution). The resulting solution was stirred for 2.75 hours then concentrated under reduced pressure to approximately ¼ the original volume. The residue was acidified with HCl (3 mL, 1M aqueous solution). This solution was purified directly by reverse phase silica chromatography (30 g of C18 silica; eluted with 5-100% acetonitrile/water/0.1% TFA) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:20][CH2:21][CH:22]([Mg]Br)[CH2:23][CH3:24].CCOCC.[NH4+].[Cl-]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH:22]([CH2:23][CH3:24])[CH2:21][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: CCC(CC)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CC)[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (0.8 g, 3.8 mmol;) and THF (8 mL, 90 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 2M 3-Pentylmagnesium bromide in ether (4.70 mL, 9.4 mmol) was then added dropwise over 1 hour. The mixture was allowed to warm to room temperature slowly overnight. Then aqueous saturated NH4Cl (5 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×25 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (25 mL) and saturated aqueous NaCl (25 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (5-25% EtOAc in Hexanes) to yield the following as clear oils:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH2:21]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)c1ccccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
24 g of 3-bromocarbazole was dissolved in 100 ml of tetrahydrofuran. To this was added 14 g of potassium carbonate followed by 14 g of benzylchloride and allowed the reaction to stir at room temperature overnight. The reaction mixture was poured into water and the precipitated white solid was filtered, washed with methanol and dried under vacuum to obtain 30 g 9-benzyl-3-bromocarbazole (89%).
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1([C@H:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][NH:25][CH2:24][CH2:23][NH:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:35]1[N:40]([CH3:41])[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][N:44]=2)[N:36]=1>O1CCCC1>[CH3:41][N:40]1[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][N:44]=2)[N:36]=[C:35]1[N:25]1[CH2:24][CH2:23][NH:22][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH2:13][CH2:14][CH:10]([N:5]4[CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:11]3)=[CH:20][CH:19]=2)[CH2:26]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: c1cc(N2CC[C@H](N3CCCC3)C2)ccc1[C@H]1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCC(N5CCCC5)C4)cc3)C2)nc(-c2ccncn2)cc1=O
Reaction time: 24 h
Yield: 66.8 %

Procedure:
To a suspension of (S)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl) piperazine tetrahydrochloride (99 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.20 mL, 1.40 mmol) and 2-chloro-3-methyl-6-(4-pyrimidinyl)-3H-pyrimidin-4-one (45 mg, 0.20 mmol) at room temperature. After stirring for 24 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated, and the resulting crystals were washed in a mixture of diisopropyl ether and ethanol to afford (S)-3-methyl-6-(4-pyrimidinyl)-2-(3-(4-(3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazin-1-yl)-pyrimidin-4-one (65 mg, 66%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8](/[C:10](=[CH:18]/[CH3:19])/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=1)(=[O:3])[CH3:2].S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:23])=[C:8](/[C:10](=[CH:18]/[CH3:19])/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: C/C=C(\C(=O)OC(C)(C)C)c1csc(NC(C)=O)n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: C/C=C(\C(=O)OC(C)(C)C)c1nc(NC(C)=O)sc1Cl
Yield: 6.8 %

Procedure:
78 g (0.28 mol) of tert.-butyl Z-2-(2-acetamidothiazol-4-yl)but-2-enoate are suspended in a mixture of 2 l of carbon tetrachloride and 15 ml of glacial acetic acid at 0° C. 43 g (0.32 mol) of sulphuryl chloride, dissolved in 600 ml of carbon tetrachloride, are added dropwise in the course of five hours, while stirring. The solution is extracted once with saturated sodium bicarbonate solution and once with water, dried and concentrated to about 200 ml. The product which has precipitated is filtered off with suction and washed with ether (53.4 g). The mother liquor is evaporated completely and a second fraction of the product (6 g) is obtained by crystallization of the residue with ether/ligroin. Yield: 59.4 g=67.8% of theory.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>C(OCC)C>[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:9]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CCN(C)C1=O
Temperature: 40 °C
Reaction time: 21 h

Procedure:
13.20 g of 60% NaH (in paraffin oil) (0.33 mol) was added to 100 ml of dry diethyl ether. With vigorous stirring, 19.83 g (0.20 mol) of N-methylpyrrolidone were added. Then within one hour 121.30 g (0.83 mol) of diethyl oxalate were added dropwise. After the addition the suspension was heated to 40° C. and stirred for 21 hours. The reaction mixture was then cooled in an ice bath, mixed with 66 ml 5M HCl and the resulting 2-phase mixture was filtered once. Then the two phases were separated, and the aqueous phase was extracted twice with 100 ml diethyl ether. The combined ethereal phases were dried over Na2SO4 and concentrated on a rotary evaporator to dryness. The oily residue was cooled to −80° C. and mixed with 200 ml diethyl ether. The resulting brown solid was filtered off and recrystallized from heptane. This gave 5.2 g product as white needles.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[CH:9][Cl:10].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])(=[O:19])=[O:20])=[CH:9][Cl:10]
Reactant: CN(C)C(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CN(C)C(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Yield: 89.4 %

Procedure:
A solution of 10.2 g of dimethylcarbamyl chloride in 10 ml of methylene chloride is added dropwise to a mixture of 10.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide, 12.2 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of methylene chloride at 20° to 25° C. and the mixture is refluxed for 2 hours. The solvent is then evaporated off and the residue is dissolved in 5% sodium carbonate solution. The solution is filtered and acidified with 10% hydrochloric acid, whereupon the product precipitates as crystals. After filtration and drying, 12.1 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N',N'-dimethylurea are obtained. Melting point: 218°-220° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]=[N+]=[N-].[H][H]>O1CCOCC1.[Pd]>[F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[NH2:10]
Reactant: [H][H]
Reactant: [N-]=[N+]=NC1O[C@H](CO)[C@@H](O)[C@@H]1F
Agent: [Pd]
Solvent: C1COCCO1
Product: NC1O[C@H](CO)[C@@H](O)[C@@H]1F
Yield: 92 %

Procedure:
Compound (45) (65.0 mg) was dissolved in dioxane (2 ml) and the solution was catalytically reduced by blowing hydrogen therein in the presence of palladium black as catalyst at room temperature for 1 hour. The resulting reaction solution was filtered and the filtrate was concentrated to afford the titled compound (46) (51.0 mg) as a colorless solid. Yield: 92%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([NH2:19])=[C:17]([Cl:20])[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:2].[CH:22](OCC)(OCC)OCC>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:22]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[Cl:20])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)Cc1ccc(Nc2ncnc(Cl)c2N)cc1
Product: CCOC(=O)Cc1ccc(-n2cnc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(5-amino-6-chloro-pyrimidin-4-ylamino)-phenyl]-acetic acid ethyl ester (0.178 g, 0.58 mmol) and triethyl orthoformate (4 mL, 23.3 mmol, 40 equiv) is stirred for 1 h at reflux. The resulting mixture is allowed to cool to rt and concentrated in vacuo to provide the title compound as a red solid: ES-MS: 317.0 [M+H]+; tR=4.06 min (System 1).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:6]=1>N1C=CC=CC=1>[C:13]1([C:8]2[CH:9]=[C:10]3[C:11]([NH2:12])=[N:3][NH:2][C:5]3=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc(-c2ccccc2)ncc1Cl
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: Nc1n[nH]c2cnc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (0.3 mL, 5.9 mmol) was added to a stirred solution of 5-chloro-2-phenyl-isonicotinonitrile (420 mg, 1.9 mmol) in pyridine (5 mL). The reaction mixture was stirred at reflux for 3 hours, cooled and the resulting solid was filtered and dried in vacuo, affording a crude residue. Purification by column chromatography using a gradient elution of 0–5% methanol in dichloromethane as eluent afforded the title compound as a solid.