Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([C:35]1[CH:36]=[C:37]([S:41]([C:44]2[CH:45]=[C:46]3[C:51](=[C:52]([CH3:54])[CH:53]=2)[N:50]=[CH:49][C:48]([C:55]([NH2:57])=[O:56])=[C:47]3[NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH3:66])[CH:60]=2)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1)=[O:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:66][O:65][C:61]1[CH:60]=[C:59]([NH:58][C:47]2[C:46]3[C:51](=[C:52]([CH3:54])[CH:53]=[C:44]([S:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([C:33](=[O:34])[NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=[O:23])[CH:36]=4)(=[O:43])=[O:42])[CH:45]=3)[N:50]=[CH:49][C:48]=2[C:55]([NH2:57])=[O:56])[CH:64]=[CH:63][CH:62]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Dess-Martin reagent (105 mg, 0.249 mmol) was added to a stirring solution of Intermediate 70 (77 mg, 0.124 mmol) in DMF (2 mL) at rt. The resulting solution was stirred for 3 h and poured into satd. NaHCO3 (50 mL). The precipitate was filtered, washed with H2O, and dried to give the title compound (70 mg) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C33H37N4O6S+ 617.2. Found m/z=617.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[C:7](=[O:9])[C:6]5[CH:10]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=5)=[CH:29][CH:30]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1cncc(C(=O)O)c1
Product: Cc1cncc(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)c1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 5-methylnicotinic acid (Lancaster) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid and 2 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione were used. The product was purified by chromatography using silica gel eluted with 96:4 chloroform/methanol. MS, m/z(M+)=553.2365.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[O:40]=[S:41]1(=[O:53])[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][N:47]([CH:44]4[CH2:43][CH2:42][S:41](=[O:53])(=[O:40])[CH2:46][CH2:45]4)[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazine dihydrochloride (prepared as described in Ding, Q. et al. WO2007063013) to give the title compound. HR-MS (ES, m/z) calculated for C38H48N5O4SCl2 [(M+H)+] 740.2799, observed 740.2802.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.O>C(Cl)Cl>[Br:19][C:3]1[S:4][C:5]2[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1csc2c1C(=O)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)sc2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzothiophene (500 mg, 3.01 mmol) in CH2Cl2 (15 mL) was added NBS (536 mg, 3.01 mmol) at room temperature, and the mixture stirred for 3 hours at room temperature. The reaction mixture was poured into water (50 mL) and the whole was extracted with diethyl ether (100 mL). The organic layer was washed with water (100 mL×2), brine, dried over MgSO4, and concentrated in vacuo to provide the title product (686 mg, 93% yield)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14](C(=O)C(F)(F)F)[CH2:15]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:12]12[CH2:21][CH2:20][CH:16]([CH2:15][NH:14][CH2:13]1)[C:17]1[C:11]2=[CH:10][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:28][C:29]3[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=3[C:31]([NH:33][CH3:34])=[O:32])[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:19][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-{5-Chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (402 mg, 0.739 mmol) was dissolved in methanol (30 mL) and potassium carbonate (612 mg, 4.43 mmol, 6.0 eq) was added. The reaction was stirred at room temperature for 48 hours and then concentrated under reduced pressure. Water (10 mL) was added and the product was collected by filtration. 2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide was obtained as a yellow solid (330 mg, 99%). m.p. dec. at 230° C.; LCMS (m/e) 449 (M+1); 1H-NMR (CD3OD, 400 MHz) δ 8.68 (d, 1H, J=8.3 Hz), 8.04 (s, 1H), 7.65 (d, 1H, J=7.8 Hz), 7.47-7.39 (m, 2H), 7.33 (dd, 1H, J=2.1 and 7.9 Hz), 7.23-7.17 (m, 1H), 7.16-7.08 (m, 3H), 7.04 (d, 1H, J=7.8 Hz), 3.34 (s, 1H), 3.03-2.98 (m, 1H), 2.97-2.80 (m, 8H), 2.11 (d, 2H, J=8.6 Hz), 1.86-1.79 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:14][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccccc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1OC
Reaction time: 2 h

Procedure:
A mixture of 14.6 g (81.2 mmol) of methyl (2-methoxyphenyl)acetate, 15.2 g (85.3 mmol) of N-bromosuccinimide and a catalytic amount of AIBN in tetrachloromethane (180 ml) was heated under reflux with stirring for 2 h. The cooled reaction solution was filtered, and the solvent was removed in vacuo. Yield: 21.6 g (100%) of yellow oil
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=2[CH2:22]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=3[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(N)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of 1.94 g of 4-chlorophenylsulfonyl chloride in 20 ml of ethyl acetate is added to a mixture of 30 ml of ethyl acetate, 20 ml of water, 3.46 g of potassium carbonate and 2.25 g of ethyl 6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate hydrochloride under stirring at room temperature. After the mixture is stirred at room temperature for 45 minutes, the organic layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform) to give 2.84 g of ethyl 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[OH:23][CH2:22][C@@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]1[NH:15][S:9]([C:6]1[CH:7]=[N:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Reactant: N[C@@H]1CCCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A solution of 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (190 mg, 0.78 mmol) in 2 mL dichloromethane was added dropwise to a solution of ((1R,2R)-2-aminocyclohexyl)methanol (100 mg, 0.78 mmol) and triethylamine (320 μL, 2.3 mmol) in 10 mL dichloromethane at 0° C. The reaction was stirred at 0° C. for 1 h, then concentrated and purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane to yield N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (150 mg, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 9.18 (d, J=2.01 Hz, 1H), 8.37 (dd, J=8.06, 1.76 Hz, 1H), 7.83 (d, J=8.31 Hz, 1H), 5.83 (d, J=6.80 Hz, 1H), 3.77 (ddd, J=11.21, 3.78, 3.65 Hz, 1H), 3.36 (dt, J=11.33, 5.67 Hz, 1H), 2.97-3.15 (m, 1H), 2.37 (t, J=5.41 Hz, 1H), 1.73-1.87 (m, 1H), 1.67 (d, J=2.01 Hz, 1H), 1.56-1.66 (m, 2H), 1.33-1.46 (m, 1H), 1.05-1.30 (m, 4H). MS [M+H]+=339. MS [M+Na]+=361.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.O.[Br-:21].[Li+]>CN(C)C=O.[Cl-].[NH4+]>[Br:21][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: [Br-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Br
Yield: 69 %

Procedure:
2,6-dimethyl-4-nitrophenyl trifluoromethanesulfonate (5.0 g, 17 mmol) was dissolved in N,N-dimethylformamide (40 mL). Lithium bromide monohydrate (4.7 g, 45 mmol) was added and the reaction was refluxed overnight. The reaction was diluted with saturated ammonium chloride and the layers were separated. The organics were washed with water (3×40 mL) and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (2% ethyl acetate in petroleum ether) gave 2-bromo-1,3-dimethyl-5-nitrobenzene (2.7 g, 69%) as a light yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.94 (s, 2H), 2.50 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH:19]1([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CC2)cc1F
Temperature: 90 °C
Yield: 81.1 %

Procedure:
A stirred suspension of trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester (5.6 g, 19 mmol), cyclopropyl boronic acid (2.09 g, 23.3 mmol) Pd(dppf)Cl2 (1.24 g, 1.5 mmol) and 2M aqueous cesium carbonate (30 mL, 60 mmol) in toluene (20 mL) was degassed before being heated at 90° C. under an argon atmosphere for 2.5 hours. The reaction mixture was allowed to cool to room temperature before filtering through a pad of Celite®, washing with ethyl acetate. The filtrate was washed (water, brine), and then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-30% ethyl acetate in pentane) to give the title compound as a yellow solid (2.79 g, 81%). 1H NMR (DMSO-d6, 400 MHz) 8.03 (1 H, t, J=8.39 Hz), 7.28 (1 H, dd, J=13.19, 1.91 Hz), 7.16 (1 H, dd, J=8.61, 1.90 Hz), 2.14-2.05 (1 H, m), 1.21-1.05 (2 H, m), 0.92-0.82 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)=O>C(O)(=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([C:8]([NH2:9])=[O:10])[C:2]2[N:1]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[NH:12][C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cc(Cl)cc(C(N)=O)c3N)cc2)CC1
Solvent: CC(=O)O
Product: NC(=O)c1cc(Cl)cc2[nH]c(-c3ccc(C4CCNCC4)cc3)nc12
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 74A (60 mg) in acetic acid (5 mL) at reflux was stirred for 60 minutes and concentrated. The concentrate was purified by chromatography on silica gel with 10% methanol/dichloromethane. 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 8.22 (d, J=7.98 Hz, 2H), 7.96 (s, 1H), 7.75-7.84 (m, 2H), 7.46 (d, J=8.29 Hz, 2H), 3.41 (d, J=12.27 Hz, 2H), 2.99-3.08 (m, 2H), 2.96 (t, J=3.53 Hz, 1H), 2.01 (d, J=12.27 Hz, 2H), 1.79-1.90 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1>C(OCC)(=O)C.[Pd]>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1ccc(CCC(=O)O)cc1

Procedure:
A solution of (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid in ethyl acetate is hydrogenated at 3 atmospheres pressure using 10% palladium on charcoal to yield 3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-propanoic acid, as an oil.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16])=S)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.OO>CO>[CH3:22][C:19]1[CH:18]=[C:14]2[C:13](=[CH:21][CH:20]=1)[NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:17][C:15]2=[O:16]
Reactant: Cc1ccc(NC(=S)NC(=O)c2ccccc2)c(C(N)=O)c1
Agent: N
Agent: OO
Solvent: CO
Product: Cc1ccc2[nH]c(NC(=O)c3ccccc3)nc(=O)c2c1
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a stirred mixture of 6 g of the above benzamide, 100 ml of methanolic ammonia and 200 ml of methanol was added dropwise, in increments, 20 ml of 30% hydrogen peroxide. After stirring overnight, the solid was collected, partially dissolved in 500 ml of hot acetonitrile and filtered. The filtrate was chilled, giving 1.2 g of the desired product as white crystals, mp 240°-242° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:21]=[C:20]([C:31]#[N:32])[CH:19]=1)=[O:17].S(O)(O)(=O)=[O:34].C(OCC)(=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([C:18]1[N:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:21]=[C:20]([C:31]([NH2:32])=[O:34])[CH:19]=1)=[O:17]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(-n2nc(C#N)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-n2nc(C(N)=O)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Reaction time: 2 h
Yield: 41 %

Procedure:
Part I. To 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)-phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile (75 mg, 0.175 mmol) was added concentrated aqueous dihydrogen sulfate (4.5 mL). After 2 h, the reaction was poured into ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and concentrated to dryness. The resulting residue was purified by radial chromatography (2% methyl alcohol in dichloromethane) to afford 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide (32 mg, 41%) as a white solid upon lyophilization from 10% acetonitrile in water. LC/MS (ESI+): 448.2 (M+H)+. 1H NMR (CD3OD) δ 7.70 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.16-7.32 (m, 4H), 6.97 (d, 2H), 6.60 (d, 1H), 6.45 (t, 1H), 4.40 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([I:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.O1CCOCC1.Cl.[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[ClH:2].[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:3]2[C:12]3[C:7](=[CH:8][C:9]([F:14])=[C:10]([I:13])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:35][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cc2ncnc(Cl)c2cc1I
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Temperature: 110 °C
Yield: 79.1 %

Procedure:
Prepared according to Procedure A from 4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml), and 4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixture was stirred and heated to 110° C. (oil bath temperature) for 16 hours, cooled to room temperature and filtered to remove the precipitated solids. The solids were washed with cold anhydrous dioxane (100 ml) followed by cold anhydrous diethyl ether. The yellowish solid was collected and dried under vacuum at room temperature to yield 4.68 grams (79%) of the title compound. δH NMR (400 MHz, DMSO-d6): 11.2(s, 1H), 9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m, 2H), 7.31(m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([NH2:21])=[CH:13][C:12]=1[NH2:22])[C:6](=[O:10])OCC.[H-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:21][C:14]1[CH:15]=[C:16]([C:17]([F:18])([F:20])[F:19])[C:11]2[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[Cl:1])[C:6](=[O:10])[NH:22][C:12]=2[CH:13]=1
Reactant: CCOC(=O)N(Cc1ccccc1Cl)c1c(N)cc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1ccccc1Cl
Yield: 61 %

Procedure:
Ethyl 2-chlorobenzyl[2,4-diamino-6-(trifluoromethyl)phenyl]carbamate (85.6 mg) was dissolved in ethanol (10 ml), and to the solution was added sodium hydride (17.7 mg). The reaction mixture was heated at reflux for 24 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted 4 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3-methanol=5:1) to give the title compound (46.0 mg).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:3]=1[C:4](=[O:84])[C:5]1[C:6]([NH:51][CH2:52][CH2:53][NH:54][C:55](=[O:83])[C@H:56]([CH2:79][CH:80]([CH3:82])[CH3:81])[NH:57][C:58](=[O:78])[C@H:59]([CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[NH:60]C(OCC3C=CC=CC=3)=O)=[CH:7][CH:8]=[C:9]([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:50])[C@H:23]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:24][C:25](=[O:45])[C@H:26]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:27]C(OCC3C=CC=CC=3)=O)[C:10]=1[C:11]2=[O:17].[BrH:85]>C(O)(=O)C>[BrH:85].[BrH:85].[OH:1][C:2]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:3]=1[C:4](=[O:84])[C:5]1[C:6]([NH:51][CH2:52][CH2:53][NH:54][C:55](=[O:83])[C@H:56]([CH2:79][CH:80]([CH3:82])[CH3:81])[NH:57][C:58](=[O:78])[C@H:59]([CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[NH2:60])=[CH:7][CH:8]=[C:9]([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:50])[C@H:23]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:24][C:25](=[O:45])[C@H:26]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH2:27])[C:10]=1[C:11]2=[O:17]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NCCNc1ccc(NCCNC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Agent: Br
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)NCCNc1ccc(NCCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc2ccccc2)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A 2.75 g portion of N,N'-[(9,10-dihydro-5,8-dihydroxy-9,10-dioxo-1,4-anthracenediyl)bis(imino-2,1-ethanediyl)]bis[N-[(phenylmethoxy)carbonyl]-L-phenylalanyl-L-leucinamide] was reacted by a modification of the procedure of Example 31, by being dissolved in 75 ml of glacial acetic acid previously saturated for 5 minutes with anhydrous hydrogen bromide. The mixture was reacted for 2.5 hours, then more hydrogen bromide was bubbled into the solution for 15 minutes and after another 2 hours the solid was collected, giving 2.7 g of the desired product, mp 180° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:21][CH2:19][CH3:20])[N:3]=1
Reactant: CCN
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 80 °C

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.544g, 2 mmol) was added to an ethyl amine-saturated methanol solution (14 mL). The solution was heated at 80° C. in a Parr bomb for 2.5 hours. 1 N NaOH (2 mL) was added, and solvent evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 10% methanol-chloroform; white crystals after crystallization from acetonitrile-methanol (0.365 g, 67%); mp 171-173° C.;