Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18](OCC)=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C[O-].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:16](=[CH:15][CH:14]=[C:13]([F:12])[CH:23]=2)[NH:24][C:10]1=[O:11]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(F)ccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1-c1ccc(Cl)cc1Cl
Yield: 96 %

Procedure:
2,4-dichlorophenyl isocyanate (18.8 g, 0.10 mol) is introduced in portions at room temperature into a solution of ethyl 5-fluoroanthranilate (18.3 g, 0.10 mol) in hexane (120 ml). After addition is complete, the mixture is stirred under reflux for 2 hours. 3.60 ml of a 30% strength solution of methanolic sodium methoxide (0.020 mol) are metered in and the mixture is stirred under reflux for a further 2 hours, ethanol and methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×15 ml of hexane. The hexane-moist precipitate is treated with dilute hydrochloric acid and the residual hexane is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 31.2 g of 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H) -quinazolinedione (yield: 96.0% of theory) of melting point 312° to 314° C. are obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23].F[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=1[F:35].C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[F:35][C:26]1[CH:27]=[C:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=[CH:30][C:25]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23]
Reactant: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)c(F)c1
Yield: 42.9 %

Procedure:
A solution of (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.0 g, 6.3 mmol), 1,2-difluoro-4-(methylsulfonyl)benzene (1.2 g, 6.3 mmol), and Na2CO3 (3.3 g, 32 mmol) in DMSO (20 mL) was stirred at 120° C. for 48 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered then concentrated in vacuo. The material was purified over silica gel (100% EtOAc) to yield (S)-benzyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.3 g, 2.7 mmol, 42%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Yield: 76.5 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (100 mg, 0.353 mmol) and tert-Butyl 1-piperazinecarboxylate (65.8 mg, 0.353 mmol) were combined and purified as per Preparation Hb to give tert-butyl 4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (116.9 mg, 76% yield). LC-MS (M+H)+=433.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:35]=[O:36])C.[NH4+].[Cl-]>C1COCC1>[C:23]([C@H:20]1[CH2:21][CH2:22][C@H:17]([O:16][C:7]2[C:8]([C:12]([F:14])([F:15])[F:13])=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([CH:35]=[O:36])[CH:11]=[CH:10]3)[CH2:18][CH2:19]1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2C(F)(F)F)CC1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene (1 g, 2.3 mmol) in THF (30 mL) was added n-BuLi (2.8 mL, 2.5M in THF, 3.0 equiv) dropwise at −78° C. in 30 min, then DMF (840 mg, 11.5 mmol, 5.0 equiv) was added slowly at −78° C. The reaction mixture was stirred at −78° C. for 1.5 h. Then saturated NH4Cl solution was added to the mixture to quench the reaction. The mixture was extracted with EtOAc and purified by silica gel chromatography (petroleum ether:ethyl acetate 10:1) to give product 6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde as a yellow solid (608 mg, 70%) ESI-MS: 379.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 10.13 (s, 1H), 8.28 (d, 2H), 8.08 (d, 1H), 7.98-8.01 (dd, 1H), 7.41 (d, 1H), 4.39 (m, 1H), 2.21 (d, 2H), 1.90 (d, 2H), 1.49-1.58 (q, 2H), 1.10-1.17 (m, 3H), 0.86 (s, 9H)
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:13]#[N:14].[K+]>CN(C=O)C.O>[Cl:12][C:4]1[C:3]([CH2:2][C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(CBr)c1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(bromomethyl)-2-chlorobenzoic acid (6.39 g) in DMF (75 mL) was treated with a solution of potassium cyanide (3.34 g) in water (25 mL) and the resulting solution was stirred at room temperature overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was carefully acidified with concentrated hydrochloric acid (25 mL), venting any liberated HCN through a bleach solution via a stream of nitrogen. After being stirred for 2 hours, the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled compound as a pale brown solid. Yield 4.12 g.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11](C2C=CC=CC=2)=[CH:10][C:9]=1[NH:20][C:21](=O)[CH2:22][C:23]([C:25]1C=C[CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[CH:26]=1)=O)(C)(C)C.[C:38](O)([C:40](F)(F)F)=[O:39]>C(Cl)Cl>[N:31]1([C:27]2[CH:28]=[C:22]([C:21]3[CH2:40][C:38](=[O:39])[NH:7][C:8]4[CH:13]=[C:12]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH:11]=[CH:10][C:9]=4[N:20]=3)[CH:23]=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccccc3)cc2N1

Procedure:
Prepared from {3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K34) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (125 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH3:8][C:6]1[CH:5]=[C:4]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[N:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Cc1cc(Cl)nc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Yield: 65.2 %

Procedure:
To a degassed solution of 2-bromo-6-chloro-4-methyl-pyridine (1.45 g, 7.04 mmol), 4-trifluoromethylbenzeneboronic acid (3.8 g, 20 mmol), 2N Na2CO3 (10 mL) in DME (80 mL) was added tetrakis(triphenylphosphine)palladium (690 mg, 0.6 mmol) under argon. The mixture was heated to 85° C. for 4 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (0-20% methylene chloride in heptane) to give the product as an off white solid (1.75 g, 65%). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.91 Hz, 26H), 7.75 (d, J=8.29 Hz, 26H), 7.61 (s, 13H), 2.53 (s, 19H). MS m/e 382.2 (M+H)
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:48])[CH2:46][NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:45](=[O:48])[CH2:46][NH2:47])=[O:16])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: NCC(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NCC(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 34.2 %

Procedure:
Using the procedure described in example 3, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (104.6 mg, 0.36 mmol, 1.0 eq), triethylamine (150 uL, 1.07 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (51 uL, 0.39 mL, 1.1 eq), then with glycine N-benzylamide (88.2 mg, 537 umol, 1.5 eq). Workup as before provided 53.9 mg (34%) of glycine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide. as a white foam.
Reaction SMILES: ClC1C=C[CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.CC(=C)C[N:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16](=[O:18])[O-:17].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:3][C:4]1([CH2:5][O:17][C:16](=[O:18])[NH:15][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:8][O:10]1
Reactant: C=C(C)CN(C(=O)[O-])c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(COC(=O)Nc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.4 %

Procedure:
m-Chloroperbenzoic acid (1.6 g, 6.6 mmol) was added to a solution of 2-methyl-2-propenyl(4-chlorophenyl)carbamate (1.0 g, 4.4 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 4 hours. To which sodium thiosulfate aqueous solution was added and the mixture was filtered, and sodium hydrogencarbonate aqueous solution was added to the filtrate. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford (2-methyl-2-oxiranylmethyl)(4-chlorophenyl)carbamate (1.1 g, quantitative) as a pale yellow crystalline powder.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:22])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]#[N:21]
Reactant: N#Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: c1cc2[nH]ccc2cn1
Product: N#Cc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzonitrile (Compound No. 95) was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-cyanobenzoic acid.
Reaction SMILES: P([O-])([O-])([O-])=O.I[C:7]1[CH:8]=[C:9](/[CH:17]=[CH:18]\[C:19]2[CH:24]=[CH:23][C:22](OC)=[C:21](O)[CH:20]=2)[CH:10]=[C:11](OC)[C:12]=1OC>>[C:9]1(/[CH:17]=[CH:18]\[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=[CH:11][CH:12]=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C\c2cc(I)c(OC)c(OC)c2)cc1O
Agent: O=P([O-])([O-])[O-]
Product: C(=C\c1ccccc1)\c1ccccc1
Yield: 321.2 %

Procedure:
The phosphorylation reaction used to obtain phosphate 15 was repeated with Z-stilbene 14a (2.39 g, 0.95 mmol) to obtain 0.55 g of Z-stilbene 17 in 86% yield as a colorless oil. b.p. dec. 274° C. (0.01 mmHg); HRMS calc for C31H31PO7 [M+H]+ 673.0852; found [+H]+, 673.0808. 1H-NMR (300 MHz, CDCl3) δ 3.51 (s, 3H), 3.65 (s, 3H), 3.72 (s, 3H), 5.04 (s, 2H), 5.06 (s, 2H), 6.36 (d, 1H, J=9 Hz), 6.42 (d, 1H, =9 Hz), 6.77 (d, 1H, J=1.2 Hz), 6.89 (d, 1H, J=6 Hz), 7.02 (d, 1H, J=6 Hz), 7.01 (s, 1H), 7.19 (d, 1H, J=1.2 Hz), 7.28 (m, 10H); and 13C-NMR (75 MHz, CDCl3) δ 56.20, 56.50, 60.73, 71.18, 71.24, 92.73, 113.72, 114.23, 122.58, 122.61, 128.10, 128.93, 129.50, 129.56, 130.18, 130.85, 130.86, 131.87, 136.26, 136.66, 136.73, 140.32, 140.3, 149.12, 151.21, 151.25, 153.26.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:42]=[N:41][CH:40]=[C:39]([Cl:43])[C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]2[C:25]3([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:24](=[O:31])[C:23]=2[C:32]2[CH2:33][N:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:6].[H][H]>CCO.[Pt](=O)=O>[Cl:43][C:39]1[CH:40]=[N:41][CH:42]=[C:3]([Cl:2])[C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]2[C:25]3([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[C:24](=[O:31])[C:23]=2[CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([CH3:38])[CH2:33]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=C(C2=CC=CN(C)C2)C(=O)C12CCCCC2
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=C(C2CCCN(C)C2)C(=O)C12CCCCC2
Yield: 100.1 %

Procedure:
The compound of Example 86 (127 mg, 0.21 mmol) was dissolved in EtOH (10 ml) and hydrogenated over platinum dioxide (50 mg) at room temperature and 1 atmosphere hydrogen for 5 days. The catalyst was removed by evaporation in vacuo to afford the title compound as a yellow oil (129 mg, 100%). δH (DMSO d6) 10.48 (1H, brs), 8.70 (2H, s), 7.59 (2H, d, J 8.1 Hz), 7.30 (2H, d, J 8.1 Hz), 4.25 (1H, m), 4.22 (2H, q, J 4.0 Hz), 3.23 (1H, m), 3.08 (1H, m), 1.70–1.50 (22H, m), 1.26 (3H, m); m/z (ES+, 70V) 613.2 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][C:15]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1CCOCC1
Product: O=C1CCOCC1C(=O)Cc1ccccc1
Yield: 61 %

Procedure:
3-(2-Phenylacetyl)dihydro-2H-pyran-4(3H)-one (0.855 g, 61%) was obtained from tetrahydro-4H-pyran-4-one and phenylacetyl chloride using the general procedure for the preparation of diketones. MS (ES+) m/z 219.1 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(O)=[O:2].Cl.[C:24]1([CH2:30][O:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:24]1([CH2:30][O:31][NH:32][C:1]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:8][CH:9]=2)=[O:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NOCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A mixture of 4-(4-carboxyphenyl)-1-piperazinecarboxylic acid, 1-(1,1-dimethylethyl) ester (0.032 mol), O-(phenylmethyl)-hydroxylamine hydrochloride (0.064 mol), DMAP (0.03 mol) in DCM p.a. (250 ml) and TEA (14 ml) was stirred at room temperature. DIC (0.064 mol) was added. The reaction mixture was stirred at room temperature for 8 hours, then washed with water, HCl (0.5N) and water. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 98/2). The desired fractions were collected and the solvent was evaporated, yielding 13.7 g of 4-[4-[[(phenylmethoxy)amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (interm. 4).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N+:11]([O-])=O)=[C:5]2[CH:4]=[CH:3]1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[CH:4]=[CH:3]1
Reactant: [H][H]
Reactant: Cn1ccc2c([N+](=O)[O-])ccnc21
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc2c(N)ccnc21

Procedure:
300 mg (1.69 mmol) of 1-methyl-4-nitro-1H-pyrrolo[2,3-b]pyridine are dissolved in a mixture of 20 ml of ethanol/THF (1:1). 38 mg (0.17 mmol) of platinum(IV) oxide are added, and the mixture is hydrogenated in a hydrogen atmosphere at atmospheric pressure overnight. The mixture is filtered through Celite and the solvent is removed under reduced pressure.
Reaction SMILES: [CH3:1][NH:2][N+:3]([O-:5])=[O:4].S(=O)(=O)(O)O.[N+:11]([N:14]([CH3:17])[CH2:15]O)([O-:13])=[O:12]>>[N+:3]([N:2]([CH2:15][N:14]([N+:11]([O-:13])=[O:12])[CH3:17])[CH3:1])([O-:5])=[O:4]
Reactant: CN[N+](=O)[O-]
Reactant: CN(CO)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CN(CN(C)[N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The solution of 2-nitro-2-aza-1-propanol in methylene chloride produced in Example 2 was combined with an additional 56 grams of methylnitramine. This mixture was slowly added to 300 ml of stirred concentrated sulfuric acid which had previously been cooled to -5° C. to -10° C. The temperature of the reaction mixture was kept at from 0° C. to -5° C. throughout the controlled addition. After the addition was completed, the mixture was poured into a large excess of ice water. Following the separation of the methylene chloride phase, the water phase was repeatedly extracted with methylene chloride. All the methylene chloride fractions were then combined, twice washed with water, and then dried with magnesium sulfate. The magnesium sulfate was filtered out and then the methylene chloride was removed by evaporation under vacuum, leaving an oily liquid. The oily liquid was converted into solid white crystals of 2,4-dinitro-2,4-diazapentane (m.p. 56° C., 65 grams pure) by precipitation from a chloroform/hexane solvent mixture.
Reaction SMILES: [CH2:1]([N:4]([C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=C)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C>C(Cl)Cl>[CH3:13][C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:21]=[CH:2][CH2:1][N:4]1[C:5]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:11]
Reactant: C=CCN(C(=O)OC(C)(C)C)C(C)(C=C)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=CC1(C)c1ccccc1

Procedure:
A solution of 20-3 (0.78 g, 2.7 mmol) and tricyclohexylphosphine[1,3-bis(2,4,6-trinmethylphenyl)-4,5-dihydroimidazol-2-ylidene][benylidine]ruthenium (IV)dichloroide (0.04 g, 0.05 mmol) in CH2Cl2 (500 mL) was stirred 1 hour. at 40° C. under N2. The reaction mixture was concentrated under reduced pressure and purified by flash column chromotography (SiO2, O-30% EtOAc/Hexanes gradient) to give tert-butyl 2-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate, 20-4. 1H NMR (300 MHz, CDCl3) δ 7.25 (m, 5H), 5.79 (m, 1H), 5.58 (m, 1H), 4.32 (m, 1H), 4.43 (m, 1H), 1.8 (s, 3H), 1.5 (s, 9H); LRMS m/z (M+H) 260.1 found, 260.2 required.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][N:3]=1.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:14]=[C:12]1[NH:11][C:10](=[O:15])/[C:9](=[CH:8]/[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26]([C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=3)=[O:27])[N:7]=2)/[S:13]1
Reactant: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1NC(=O)/C(=C/c2ccnc(NC(=O)c3ccc4ccccc4n3)n2)S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)quinoline-2-carboxamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), quinoline-2-carbonyl chloride (74.6 mg, 0.389 mmol, 3.8 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (3 mg, 37.7 mg theoretical, 8%). LC-MS m/z 378.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:15]1[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=1)=[O:14])[CH:7]=[CH:6]2.C(O)=O.[CH2:42]1[CH2:46]OC[CH2:43]1>>[NH:18]1[CH:19]=[C:15]([C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)([OH:14])[CH:42]([CH3:46])[CH3:43])[N:16]=[CH:17]1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: C1CCOC1
Solvent: O=CO
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (15.0 g) was dissolved in THF (80 ml). To the solution was added 90% formic acid (20 ml), and the mixture was stirred at 50° C. for 2 h. After removal of the solvents by evaporation, 1N-hydrochloric acid (60 ml) was added and the precipitate was filtered off. The filtrate was washed with ether, and neutralized with potassium carbonate. The resulting precipitate was collected by filtration, dried under reduced pressure to give the titled compound (7.54 g) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccccn1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Ic1ccc(N(Cc2ccccn2)c2ncccn2)cc1
Yield: 71.9 %

Procedure:
In the same manner as in Reference Example 22, N-(4-iodophenyl)pyrimidin-2-amine (300 mg) and 2-bromomethylpyridine hydrobromide (307 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-((pyridin-2-yl)methyl)pyrimidin-2-amine (282 mg).