Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:18]=3)=[CH:11][C:10]=2[N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][C:41](Cl)([Cl:43])[Cl:42])=[O:38].O>ClCCl>[Cl:42][CH:41]([Cl:43])[CH2:40][O:39][C:37](=[O:38])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:18]=3)=[CH:11][C:10]=2[N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(NC(=O)OCC(Cl)Cl)cc3)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 239c (2.8 g, 6.8 mmol) in dichloromethane (40 mL) was added pyridine (1.1 g, 13.7 mmol) and 2,2,2-trichloroethyl chloroformate (1.7 g, 2.8 mmol). The mixture was stirred at room temperature for 72 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate/methanol (80:15:5) to give the desired product (2.0 g, 53%).
Reaction SMILES: ClCl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][S:13][C:14]1SC2C=CC=CC=2N=1.S[CH:24]([OH:26])C>ClC1C=CC=CC=1>[OH:26][CH2:24][CH2:14][S:13][S:12][C:4]1[S:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Reactant: CC(O)S
Agent: ClCl
Solvent: Clc1ccccc1
Product: OCCSSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 167.6 %

Procedure:
Chlorine gas (17.5 g/0.25 mole) was passed at 0 to 50C into a suspension of 2,2'-dithiobisbenzthiazole (83 g/0.25 mole) in chlorobenzene (600 ml). Mercaptoethanol (39 g/0.5 mole) was then added drop-wise to this solution, followed by stirring for 7 hours at room temperature. The precipitated product was filtered off, mixed with methylene chloride (500 ml) and washed with 5% NaHCO3 solution (500 ml). The organic phase was concentrated by evaporation. A yellowish-brown oil (102 g) was obtained, which crystallised after a short time. m.pt.: 65 to 68° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][C:21]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](Cl)=[O:30])=[CH:25][CH:24]=1)=[O:22]>O1CCOCC1>[CH:1]([NH:4][C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:32]=[CH:33][C:23]([C:21](=[O:22])[NH:20][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C(Cl)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reaction time: 5 h

Procedure:
0.71 g of isopropylamine and 3.0 g of triethylamine were dissolved in 20 ml of dioxane. To this solution, a solution prepared by dissolving 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetyl chloride prepared in the same manner as in Example 3 in 5 ml of dioxane, was dropwise added over a period of about 5 minutes at room temperature under stirring. After completion of the dropwise addition, the stirring was continued at room temperature for further 5 hours. After completion of the reaction, the reaction solution was treated in the same manner as in Example 3 to obtain 3.8 g of desired N-isopropyl-4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]([CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH2:15][CH:16]=[CH2:17].[OH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]=[CH:16][CH2:15][CH2:14][CH:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=1)[CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCCC(CCC=C)OCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCC(CCC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reaction time: 10 h
Yield: 64 %

Procedure:
3 g of the compound (7), 1.5 g of methyl 4-hydroxybenzoate and 4.1 g of potassium carbonate were dissolved in 50 ml of 2-butanone, and reflux was carried out for 10 hours in an atmosphere of argon. After the precipitated solid matter was filtered off, the solvent was evaporated, and the residue was purified by a chromatography using a column filled with alumina and silica gel, to obtain 2.3 g of the compound (8). (Yield: 64%)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][C@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18].CO.C(Cl)Cl.[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([O:18][CH2:17][C@H:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:30])[CH3:29]
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OC[C@@H](CC(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (5.50 g, 0.0259 mol), (R)-2-amino-4-methylpentan-1-ol (6.07 g, 0.0518 mol) and methanol (160 mL, 4.1 mol). The mixture was heated at reflux for 3 hours. The mixture was allowed to cool, reduced in vacuo and dried on high vacuum for approximately 1 hour. methylene chloride (200 mL, 3 mol) and acetyl chloride (4.1 g, 0.052 mol) were added and the mixture was heated at 50° C. for 3 hours. The resulting solution was reduced in vacuo and purified. The mixture was purified by column chromatography using a methanol:methylene chloride (0-3%) gradient. The combined pure fractions were reduced in vacuo to yield the title compound as a dark yellow solid which was taken to the next step without further purification.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1(/[C:19](/[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][CH:24]([CH2:23][CH2:22][CH2:21]/[CH:20]=[C:19](\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)CCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
A solution of diisopropylamine (0.21 ml, 1.46 mmole) in tetrahydrofurane (3 ml) was cooled at -60° C. under argon, and a hexane solution of n-butyl lithium (1.6M, 0.92 ml, 1.46 mmole) was added dropwise to the solution. After stirring for 10 minutes, a solution of methyl (E)-7-phenyl-7-(3-pyridyl)-6-heptenoate (360 mg, 1.22 mmole) in tetrahydrofuran (2 ml) was added dropwise to the solution, followed by stirring at -60° to -70° C. for 20 minutes. Subsequently, methyl iodide (0.12 ml, 1.83 mmole) was added, and the reaction was allowed to proceed at the same temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel, and development was effected with isopropyl ether:ethyl acetate (7:3) to yield methyl (E)-2-methyl-7-phenyl- 7-(3-pyridyl)-6-heptenoate (3-a) (270 mg, 71.6 %).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[S:19][C:18]([C:20]([OH:22])=O)=[CH:17][CH:16]=2)[CH:9]=1.C([NH2:25])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[S:19][C:18]([C:20]([NH2:25])=[O:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: NC=O
Reactant: O=C(O)c1ccc(-c2cc(-c3ccccc3Cl)[nH]c(=O)n2)s1
Product: NC(=O)c1ccc(-c2cc(-c3ccccc3Cl)[nH]c(=O)n2)s1
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
5-[6-(2-Chlorophenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]thiophene-2-carboxylic acid (100 mg, 0.30 mmol) was suspended in 1 mL of formamide. The reaction mixture was stirred for 30 minutes at 200° C. After cooling, the precipitate was filtered, dissolved in 1 mL dimethylformamide and purified by reverse phase HPLC. 30 mg of product were isolated.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24]CCCl>ClC(OC(Cl)C)=O>[ClH:24].[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:23]
Reactant: O=C(Cc1ccccc1F)C1CCN(Cc2ccccc2)CC1
Reactant: ClCCCl
Agent: CC(Cl)OC(=O)Cl
Product: Cl
Product: O=C(Cc1ccccc1F)C1CCNCC1
Reaction time: 0.67 h
Yield: 92 %

Procedure:
After dissolving 1.27 g of 1-(1-benzylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone in 8 ml of 1,2-dichloroethane, 0.53 ml of 1-chloroethyl chloroformate was added while stirring on ice, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, 8 ml of methanol was added to the residue, and heating to reflux was continued for 40 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the precipitate was filtered out to obtain the title compound (970 mg, 92% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1.[F:17][C:18]([CH3:32])([CH3:31])[CH2:19][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:21][OH:22]>>[F:17][C:18]([CH3:32])([CH3:31])[CH2:19][CH:20]([NH2:23])[CH2:21][O:22][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1
Reactant: CC(C)(F)CC(CO)NC(=O)OC(C)(C)C
Reactant: CC1Oc2cc(Cl)ccc2-c2ccncc21
Product: CC1Oc2cc(OCC(N)CC(C)(C)F)ccc2-c2ccncc21
Yield: 53.2 %

Procedure:
Prepared as described in Example 8, Part D using 8-chloro-5-methyl-5H-chromeno[3,4-c]pyridine (0.100 g, 0.432 mmol) and tert-butyl (4-fluoro-1-hydroxy-4-methylpentan-2-yl)carbamate (0.168 g, 0.712 mmol) to afford 4-fluoro-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-amine (80 mg, 0.23 mmol, 99% yield) as a yellow oil. 1H NMR (400 MHz, MeOD) δ 8.66 (d, J=6.4 Hz, 1H), 8.64 (s, 1H), 8.24 (d, J=6.4 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 6.94 (dd, J=2.4 Hz, 8.8 Hz, 1H), 6.78 (d, J=2.8 Hz, 1H), 5.57 (q, J=6.4 Hz, 1H), 4.38 (dd, J=6.4 Hz, J=10.8 Hz, 1H), 4.22 (dd, J=6.4 Hz, 10.8 Hz, 1H), 3.99 (m, 1H), 2.16 (m, 2H), 1.75 (d, J=6.8 Hz, 3H), 1.55 (s, 3H), 1.50 (s, 3H); LCMS (ESI) m/e 331.2 [(M+H)1, calcd for C19H24FN2O2 331.2] LC/MS retention time (method D): tR=0.97 min; HPLC retention time (method B): tR=8.04 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:12]4[CH:11]=[N:10][CH:9]=[C:8]([CH2:7][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:13]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: COCCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCCCOC)c4)cc23)CC1
Yield: 83 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [3-(methyloxy)propyl]amine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 22 mg of crude [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 31 mg of the title compound (83%).
Reaction SMILES: [CH:1]1(C2(CCC3C=CC(C(O)C)=C(F)C=3)OC(=O)C(CC3N=C4N=C(C)C=C(C)N4N=3)=C(O)C2)CCCC1.N1C=CC=CC=1S[C:45](=[O:54])[C:46]1[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][C:47]=1[Cl:53].N1C=CC=CC=1SC(=O)C1C=CC(Br)=CC=1F>>[Br:52][C:49]1[CH:50]=[CH:51][C:46]([C:45](=[O:54])[CH3:1])=[C:47]([Cl:53])[CH:48]=1
Reactant: O=C(Sc1ccccn1)c1ccc(Br)cc1Cl
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C(C)O)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Agent: O=C(Sc1ccccn1)c1ccc(Br)cc1F
Product: CC(=O)c1ccc(Br)cc1Cl

Procedure:
The title compound was prepared analogously to Step 2 from Example X(X): 6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one where 4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (described in step 1 below) was substituted in place of 4-Bromo-2-fluoro-thiobenzoic acid S-pyridin-2-yl ester. 1H NMR (CDCl3) δ 2.64 (s, 3H), 7.46–7.48 (m,2H), 7.61 (s, 1H). ESIMS (MH+): 234.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:9]=2)[N:3]=1.[OH-:31].[Na+].O.Cl>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[N:11]=[C:12]([OH:31])[N:13]=2)[N:3]=1
Reactant: [OH-]
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(S(C)(=O)=O)n2)n1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(O)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylsulfonyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-6, 33.0 mg, 0.077 mmol, 1.0 eq.) in 1,4-dioxane (0.8 mL) was added 2 M NaOH in H2O (0.39 mL, 0.78 mmol, 10 eq.), and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was neutralized by the addition of aqueous concentrated HCl and the resulting precipitate was filtered, washed with 1,4-dioxane (2.0 mL) and dried to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-2-ol (20) as an amorphous white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (br s, 1H), 7.54 (br d, 11-1, J=7.5 Hz), 7.51 (br d, 1H, J=7.5 Hz), 7.22 (br t, 1H, J=7.5 Hz), 7.17 (br t, 1H, J=7.5 Hz), 6.73 (br s, 1H), 3.85 (s, 3H), 3.04 (m, 1H), 2.76 (s, 3H), 2.64 (m, 1H), 2.30 (s, 3H), 1.94-1.80 (m, 2H). LRMS m/z (M+H) 362 found, 362 required.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[OH:13])=[O:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1F)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1Oc1ccccc1[N+](=O)[O-]
Yield: 100.5 %

Procedure:
A solution of 2-methoxycarbonyl-5-methoxyphenol (34.1 g, 0.187 mol), 2-nitrofluorobenzene (19.7 mL, 0.187 mol), and K2CO3 (65 g, 0.467 mol) in DMF (200 mL) was heated at 110° C. for 18 h. The solution was diluted with water (200 mL) and extracted with EtOAc. The EtOAc layer was concentrated to give the crude title compound (57 g)which was used as is for the next step without further purification.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cr+3:4].[CH2:5]([N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Li])[CH2:8][CH3:9])[CH3:6]>>[CH2:5]([N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cr:4]([C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10][N:7]([CH2:8][CH3:9])[CH2:5][CH3:6])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:7]([CH2:8][CH3:9])[CH2:5][CH3:6])[CH2:8][CH3:9])[CH3:6]
Reactant: [Li]c1ccccc1CN(CC)CC
Reactant: [Cr+3]
Agent: [Cl-]
Product: CCN(CC)Cc1ccccc1[Cr](c1ccccc1CN(CC)CC)c1ccccc1CN(CC)CC

Procedure:
In Angew. Chem., 75, 94 (1963), Bahr and Zohm disclose reaction of chromium trichloride with 2-diethylaminomethylphenyllithium to give tris(2-diethylaminomethylphenyl)chromium. The product was highly unstable to atmospheric oxygen.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N2CCCCC2)n1
Yield: 22 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and piperidine in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 22% yield.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[C:6]([Cl:11])[N:5]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>O1CCCC1>[N+:22]([C:16]1[CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[CH:13]=[C:14]([C:25]([F:26])([F:27])[F:28])[C:15]=1[N:5]1[C:6]([Cl:11])=[CH:7][C:8]([NH2:10])=[N:9][CH:4]1[Cl:3])([O-:24])=[O:23]
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1=NC(Cl)N(c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)C(Cl)=C1
Temperature: 0 °C

Procedure:
7.24 parts of 85% powdered potassium hydroxide are added to a solution of 8.2 parts of 2,6-dichloro-4-aminopyrimidine in 200 ml of absolute tetrahydrofuran. The mixture is cooled to 0° C. and then 13.5 parts of 2-chloro-3,5-dinitrobenzotrifluoride in 100 ml of absolute tetrahydrofuran are added in portions, with stirring, over half an hour. During this addition, the colour of the reaction solution turns from yellow to red. The reaction mixture is stirred for 12 hours and then poured into 500 ml of ice-water, acidified with 8 ml of hydrochloric acid, and extracted with two 200 ml portions of ethyl acetate. The combined extracts are washed with 50 ml of water, dried over sodium sulfate, filtered and concentrated. The crude product is crystallised from methanol. Melting point: 198°-200° C.
Reaction SMILES: Cl.Cl.CO[C:5]1[CH:22]=[CH:21][C:8]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][NH:19][CH2:18][CH2:17][NH:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:31]1[N:36]([CH3:37])[C:35](=[O:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:32]=1.[O:45]1CCC[CH2:46]1>>[CH3:46][O:45][C:12]1([C@H:15]2[NH:16][CH2:17][CH2:18][N:19]([C:31]3[N:36]([CH3:37])[C:35](=[O:38])[CH:34]=[C:33]([C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)[N:32]=3)[CH2:20]2)[CH:11]=[CH:10][C:9]([C:8]2[CH:7]=[CH:6][CH:5]=[CH:22][CH:21]=2)=[CH:14][CH2:13]1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2ccc([C@H]3CNCCN3)cc2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: COC1([C@@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCN2)C=CC(c2ccccc2)=CC1
Reaction time: 28 h
Yield: 96 %

Procedure:
To a suspension of (S)-2-(4′-methoxybiphen-4-yl)-piperazine dihydrochloride (237 mg, 0.694 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.40 mL, 2.9 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (128 mg, 0.579 mmol) at room temperature. After stirring for 28 h, the resulting mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was washed with hot ethanol to afford (S)-2-(3-(4-methoxybiphen-4-yl)piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (252 mg, 96%), which was treated with 4 N hydrogen chloride in ethyl acetate to yield its dihydrochloride salt (252 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH2:15][CH2:16][N:8]([C:9]=23)[C:7]2[CH:17]=[CH:18]C=[CH:20][C:6]=2[NH:5]1.[C:21]([O:28]CC)(=O)[C:22]([O:24]CC)=O.Cl[CH2:32]Cl>>[CH3:18][C:17]1[C:22](=[O:24])[C:21](=[O:28])[CH:20]=[C:6]2[N:5]3[CH:32]=[CH:1][N:2]=[CH:3][C:4]3=[C:10]3[CH2:11][CH2:12][CH2:13][C:14]4[CH:15]=[CH:16][N:8]([C:9]=43)[C:7]=12
Reactant: ClCCl
Reactant: CNCC1Nc2ccccc2N2CCc3cccc1c32
Reactant: CCOC(=O)C(=O)OCC
Product: Cc1c2n3ccc4c3c(c3cnccn3c-2cc(=O)c1=O)CCC4
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
N-methyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-methanamine (2.5 g), and diethyl oxalate (1.6 g), were combined and heated to 140° C. over a period of 45 min, then to 180° C. over 15 min. The reaction mixture was maintained at this temperature for 1 hr. The reaction mixture was cooled, dissolved in a small volume of dichloromethane, placed on a column of silica gel and eluted with 2.5% methanol-dichloromethane to yield 1.4 g, (46.7%) of product.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[OH2:13].[C:14](#[N:16])[CH3:15]>>[O:12]=[C:5]1[CH:6]2[CH2:7][CH:8]3[CH2:9][C:2]([NH:16][C:14](=[O:13])[CH3:15])([CH2:3][CH:4]1[CH2:10]3)[CH2:11]2
Reactant: O
Reactant: O=C1C2CC3CC1CC(Br)(C3)C2
Reactant: CC#N
Product: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2

Procedure:
A solution of 1.2 g of nitryltetrafluoroborate in 15 ml of acetonitrile is cooled to 0° C. and a solution of 2.17 g of 5-bromo-2-oxoadamantane [preparation is described in H. W. Geluk, SYNTHESIS, p. 374 (1972)] in 15 ml of acetonitrile is added with rapid stirring and cooling. The reaction mixture is stirred for 30 minutes then poured into water and extracted with diethyl ether. The diethyl ether extract is washed with 5% sodium bicarbonate solution and water and dried over magnesium sulfate. The solvent is removed under reduced pressure to give N-(2-oxoadamantan-5-yl)acetamide. Substitution of an equivalent quantity of N-(2-oxoadamantan-5-yl)acetamide for the methyl 2-oxoadamantane-1-carbamate of Example 57 and substantial repetition of the procedures detailed therein provides methyl L-tyrosyl-D-methionylglycyl-L-phenylalanyl-5-amino-2-adamantanecarboxylate hydrochloride which is represented by the formula ##STR68##