Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCP(=O)=O.[Cl:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[C:10]([Cl:18])[C:9]=1[C:19]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2.[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1)[CH3:33].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O.O>[CH2:32]([N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:46]=[CH:45][C:43]([NH:44][C:29]([C:26]3[CH:27]=[CH:28][C:19]([C:9]4[C:10]([Cl:18])=[C:11]([O:16][CH3:17])[CH:12]=[C:13]([O:14][CH3:15])[C:8]=4[Cl:7])=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)=[O:30])=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)[CH3:33]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c4cccnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of propylphosphonic anhydride (50% in DMF, 0.41 mL, 0.70 mmol, 2 equiv), 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1) (132 mg, 0.35 mmol), 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) (79 mg, 0.39 mmol, 1.1 equiv), DMAP (3 mg), and Et3N (0.49 mL, 3.5 mmol, 10 equiv) in DMF (3 mL), was stirred for 16 h at rt, under an argon atmosphere. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by trituration in EtOAc to afford the title compound as a yellow solid: ES-MS: 564.9/566.9 [M+H]+; tR=4.45 min (System 1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>O1CCCC1>[CH:9]1([C:5]2[CH:6]=[C:7]([F:8])[C:2]3[NH:1][C:31](=[O:32])[N:12]([CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]4)[C:3]=3[CH:4]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C3CC3)cc(F)c2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(F)cc(C4CC4)cc32)CC1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-cyclopropyl-3-fluorophenyl)amino]-1-piperidine-carboxylate (D27, 0.80 mmol, 280 mg) was dissolved in 4 ml of tetrahydrofuran and CDI (1,1′-(oxomethanediyl)bis-1H-imidazole) (2.5 eq., 2.0 mmol, 0.33 g) at room temperature and the mixture was stirred at 50° C. for one overnight under argon. Extra CDI (1 eq., 0.13 g, 0.80 mmol) was added and the mixture was refluxed for two extra hours. The mixture was cooled to room temperature and the solvent was evaporated to afford the crude compound which was purified by chromatography (ethyl acetate (50)-n-hexane (50)) to yield the title compound, 102 mg, 36%, M−−H=374.
Reaction SMILES: [Br:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=[C:3]1[CH:18]([CH3:20])[CH3:19].C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:28]([O:7][C:6]1[N:5]([C:8]([CH3:16])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=[C:3]([CH:18]([CH3:20])[CH3:19])[C:2]=1[Br:1])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C1=NN(C(C)(C)Cc2ccccc2)C(=O)C1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nn(C(C)(C)Cc2ccccc2)c(OC(=O)c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
4-Bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (3.00 g, 8.90 mmol) was dissolved in 39 mL of tetrahydrofuran and cooled with ice to 0° C., and after dropwise addition of 1.80 g (17.8 mmol) of triethylamine and 1.38 g (9.82 mmol) of benzoyl chloride, stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction was quenched with distilled water, and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:20) to give 3.34 g of the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:16]([O:23][C@H:24]([CH3:37])[C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:24]([O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:37])([CH3:35])([CH3:34])[CH3:36]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.9 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (525 mg, 2.6 mmol), (2S,3R)-3-benzyloxy-2-tertbutoxycarbonylaminobutyric acid (880 mg, 2.9 mmol), HOAt (390 mg, 2.9 mmol), 4-methylmorpholine (0.60 mL, 5.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (560 mg, 2.9 mmol) in DCM (13 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(1S,2R)-2-benzyloxy-1-(4-fluoro-2-phenylaminophenylcarbamoyl)propyl]carbamic acid tert-butyl ester (1.32 g). LCMS (Method B): RT 4.32 min [M+H]+ 494.3.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C:9]1[N:10](C(OCC(C)C)=O)[C:11]2[C:12]([N:28]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:18]=[CH:19][C:20]3[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=3[CH:27]=1)[CH:16]=2.[C@H:36]([N:40]([CH2:51][C:52]1[N:61]=[C:60](Cl)[C:59]2[CH2:58][C:57]([CH3:64])([CH3:63])[CH2:56][CH2:55][C:54]=2[N:53]=1)C(=O)OCC1C=CC=CC=1)([CH2:38][CH3:39])[CH3:37]>>[CH3:64][C:57]1([CH3:63])[CH2:56][CH2:55][C:54]2[N:53]=[C:52]([CH2:51][NH:40][C@@H:36]([CH2:38][CH3:39])[CH3:37])[N:61]=[C:60]([N:23]3[CH2:22][C:21]4[CH:27]=[C:17]([C:15]5[CH:16]=[C:11]6[NH:10][C:9]([CH3:8])=[N:28][C:12]6=[N:13][CH:14]=5)[CH:18]=[CH:19][C:20]=4[O:26][CH2:25][CH2:24]3)[C:59]=2[CH2:58]1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CC[C@@H](C)N(Cc1nc(Cl)c2c(n1)CCC(C)(C)C2)C(=O)OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: CC[C@@H](C)NCc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as a trifluoroacetate salt according to the method of example 6 by using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and (R)-benzyl sec-butyl((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)carbamate (reagent preparation 17) in step 3 followed by Cbz deprotection. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (br s, 3H), 8.24 (br s, 1H), 7.80 (s, 1H), 7.62 (d, 1H), 7.09 (d, 1H), 4.79 (s, 2H), 4.43-4.36 (m, 2H), 4.17-4.11 (m, 2H), 4.00-3.94 (m, 2H), 3.15 (br s, 1H), 2.75 (t, 2H), 2.67 (s, 2H), 2.50 (s, 2H, buried), 1.79-1.66 (m, 1H), 1.62 (t, 2H), 1.46-1.33 (m, 1H), 1.17 (d, 3H), 0.89-0.78 (m, 9H); MS (EI) for C31H39N7O: 526 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([N:13]([CH2:15][CH3:16])[CH3:14])=[O:12])=[C:4]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])(=[O:20])=[O:19])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][C:11]([N:13]([CH2:15][CH3:16])[CH3:14])=[O:12])=[O:37])=[C:4]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])(=[O:20])=[O:19])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CCN(C)C(=O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]-N-ethyl-N-methylpropanamide (119 mg, 0.256 mmol) in CH2Cl2 (5 ml) was added mCPBA (61 mg, ˜0.26 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 10% MeOH in CH2Cl2) to yield the title compound (53 mg, 43%) as a mixture of amide bond cis-trans isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH:14]=[C:15]([C:18]3[O:22][C:21]([SH:23])=[N:20][N:19]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=1.I[CH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH:14]=[C:15]([C:18]3[O:22][C:21]([S:23][CH3:25])=[N:20][N:19]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=1
Reactant: CI
Reactant: Fc1ccc(F)c(-c2coc3ccc(-c4nnc(S)o4)cc23)c1
Product: CSc1nnc(-c2ccc3occ(-c4cc(F)ccc4F)c3c2)o1
Yield: 89 %

Procedure:
In the same manner as in Example 7 and using 5-[3-(2,5-difluorophenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and using iodomethane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH:46][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=3)[O:45][C:41]=2[C:40]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: COc1ccc(N2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2oc(NC(=O)c3ccc(C)nc3)nc12

Procedure:
From 6-methyl-nicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-morpholin-4-yl-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 369 (M+H+, 100).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH3:34])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH3:34])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: CCOc1ccc2cc(C3(O)CCNCC3)ccc2c1
Product: CCOc1ccc2cc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 59.2 %

Procedure:
Beginning with 0.139 gm (0.70 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.200 gm (0.70 mMol) 4-hydroxy-4-(6-ethoxynaphth-2-yl)piperidine, 0.191 gm (56%) of the title compound were recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: C1CNCCN1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: O
Product: COc1cc(NC(=O)CCCCCN2CCNCC2)c2nccc(C)c2c1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A mixture of 8 g (0.022 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)-hexanamide and 35 g (0.41 mole) of piperazine was stirred at 125° for 1 hr, cooled and suspended in water. The resulting fine precipitate was collected and dissolved in dichloromethane. The solution was washed with water, dried, and concentrated to dryness in vacuo. The residue was chromatographed over 560 g of alumina with 500 ml each of the following solutions of methanol in an ethyl acetate:dichloromethane (1:9) mixture: 2%, 3%, 4%, 5% and 10% to afford 2.6 g of crude product, Rf(alumina--75 parts of ethyl acetate:25 parts of methanol:1 part of triethylamine)=0.38. Recrystallization from toluene afforded 1.9 g (23%) of the title compound, mp 122°-124°.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:55][CH2:56][C:57]1[CH:65]=[CH:64][C:60]([C:61](Cl)=[O:62])=[CH:59][CH:58]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C(Cl)Cl.CO>[Cl:55][CH2:56][C:57]1[CH:65]=[CH:64][C:60]([C:61]([O:54][CH:27]([CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:62])=[CH:59][CH:58]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(OC(=O)c1ccc(CCl)cc1)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 46.1 %

Procedure:
The resultant compound of Example 70 (1.3 g, 1.76 mmol) was combined with 4-(chloromethyl)benzoyl chloride (1.0 g, 5.3 mmol) and pyridine (418 mg, 5.3 mmol) in 10 mL of freshly distilled methylene chloride. The reaction mixture was heated at reflux under nitrogen for approximately 10 h and then diluted with 150 mL of chloroform. The chloroform solution was washed with 75 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (2.1 g) was taken up in ~10 mL of chloroform and applied to a 1.8×45 cm column of 40 mesh silica gel. The column was eluted @~5 p.s.i. sequentially with 200 mL of methylene chloride, 250 mL of 0.5% methanol in methylene chloride and 600 mL of 1% methanol in methylene chloride to give 721 mg (46% yield) of the title compound; FAB MS M/Z: 889 (M+H) +. The 300 MHz 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[NH:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[S:12].Cl.C(=O)(O)[O-].[Na+]>CO>[OH:15][C:14]1[C:16]([CH:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[OH:9])=[CH:17][N:10]=[C:11]([SH:12])[N:13]=1
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: Cc1ccc(C=O)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(O)c2cnc(S)nc2O)cn1
Yield: 45.4 %

Procedure:
A mixture of 5 g (0.04 mol) of 2-methyl-5-formylpyridine, 5.29 g (0.04 mol) of 2-thiouracil and 50 ml of concentrated hydrochloric acid was heated overnight. The solution was neutralized with sodium bicarbonate. The organic material in the resulting precipitate was taken up in methanol which was then evaporated to give 4.53 g (45%) of 4-hydroxy-2-mercapto-5-[(6-methyl-3-pyridinyl)hydroxymethyl]pyrimidine [MS(m/e)250]. This compound (2 g) is treated with zinc-acetic acid as in Example 9 to give the same end product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[NH2:30])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=O)[CH3:32]>>[CH3:31][C:32]1[N:23]([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N:30]=1
Reactant: Nc1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2n1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 30 %

Procedure:
N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine (60 mg, 0.15 mmol) and acetic anhydride (˜1 mL) were stirred at reflux for 18 hours. The reaction mixture was quenched with ˜1 mL water, then basified with dilute sodium carbonate solution then extracted with DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume) to provide the title compound as a brown oil (19 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 6H), 1.97-2.10 (m, 5H), 2.23 (m, 2H), 2.54 (m, 4H), 2.62 (t, 2H), 3.40 (m, 2H), 3.82 (m, 2H), 4.00 (t, 2H), 4.07 (s, 2H), 6.80-6.88 (m, 4H), 7.00 (d, 1H), 8.30 (d, 1H), 8.92 (s, 1H). LRMS ESI+ m/z 435 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[O:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:41]4[CH2:42][CH2:43][CH:38]([N:35]5[CH2:36][CH2:37][O:32][CH2:33][CH2:34]5)[CH2:39][CH2:40]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CCC(N6CCOCC6)CC5)CC4=O)cc3)CC2)c(C)c1
Yield: 62.4 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and 4-morpholinopiperidine (44 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (85 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: Brc1ccc(I)cc1
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1ccc(Oc2ccc(Br)cc2)cc1C
Temperature: 120 °C
Yield: 42 %

Procedure:
A mixture of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (2.0 g, 10.3 mmol), 1-bromo-4-iodobenzene (8.74 g, 30.9 mmol), cesium carbonate (4.03 g, 12.4 mmol), copper (I) chloride (0.51 g, 5.15 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (0.47 g, 2.55 mmol) in 1-methyl-2-pyrrolidinone (20 mL) is heated to 120° C. for 1 hour under N2. The reaction is cooled and quenched with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 1.51 g (42%) of the title compound. Rf=0.35 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:3]=1.C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:3]=1)=[C:28]=[O:30]
Reactant: Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C=Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-(4-amino-pyridin-2-ylmethyl)-2H-phthalazin-1-one (21) (0.40 g, 1.48 mmol) in anhydrous DCM (160 mL) and triethylamine (0.46 mL, 4.09 mmol), was added a dropwise preformed solution of triphosgene (0.27 g, 0.93 mmol) in anhydrous DCM (30 mL). The reaction was stirred for 6 hrs at room temperature. The reaction mixture was then concentrated to dryness in vacuo yielding a grey solid. Single peak in LC-MS analysis, (yield taken to be quantitative) no purification performed. m/z (LC-MS, ESP), RT=3.79 mins, (M+MeOH) 329.0.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClC(Cl)C.C(N(CC)CC)C>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:22])=[O:21]
Reactant: OCCCC(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To an iced-cooled solution of 4,4-diphenyl-1-butanol (5.6 g) in dichloroethane (100 mL), 11 mL of triethylamine and 2.9 mL of methanesulfonyl chloride were added dropwise in the order mentioned. After 30 minutes of stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated to provide 7.5 g of the title compound. Yield 99%.
Reaction SMILES: [F:1][CH:2]1[N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:5]=2[NH:4][C:3]1=[O:32].C1(C)C=CC(S(N2C(C3C=CC=CC=3)C3C=C([N+]([O-])=O)C=CC=3NC(=O)C2)(=O)=O)=CC=1.C(OF)(F)(F)F>CN(C=O)C>[F:1][CH:2]1[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]2[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:5]=2[NH:4][C:3]1=[O:32]
Reactant: Cc1ccc(S(=O)(=O)N2C(F)C(=O)Nc3ccc([N+](=O)[O-])cc3C2c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)N2CC(=O)Nc3ccc([N+](=O)[O-])cc3C2c2ccccc2)cc1
Agent: FOC(F)(F)F
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1F
Reaction time: 1 h

Procedure:
2.35 g. of sublimed potassium tert.-butylate are added at 5° to a solution of 4.55 g. of 3-fluoro-4-p-toluenesulfonyl-5-phenyl-7-nitro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one, obtainable from 4-p-toluenesulfonyl-5-phenyl-7-nitro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one and CF3OF, in 50 ml. of DMF. After stirring for 1 hour, the temperature is allowed to rise to 20° and the mixture is stirred for 48 hours more. The mixture is poured onto ice and worked up in the customary manner to give 3-fluoro-5-phenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.