Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:23][CH2:22][CH2:21][CH:17]([C:18]([NH2:20])=[O:19])[CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC#N>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:15]2[CH2:23][CH2:22][CH2:21][CH:17]([C:18]([NH2:20])=[O:19])[CH2:16]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)C1CCCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
Step 1): A solution of bromodiphenylmethane (48.2 g, 195 mmol) in DMSO (30 ml) was added dropwise to a solution of nipecotamide (25 g, 195 mmol) and K2CO3 (27 g, 195 mmol) in CH3CN (100 ml) and DMSO (50 ml) under stirring and cooling in an ice-bath for 1 hour. After the addition was complete, the mixture was stirred overnight at room temperature. The insoluble precipitates were filtered off and then the filtrate was evaporated. To the residue was added H2O and AcOEt, and agitated. The organic layer was washed with H2O, dried over MgSO4 and evaporated to give 1-diphenylmethylpiperidin-3-carboxamide, 33 g (57.5%): mp 86°-87° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[O:36][CH2:37][C@@H:38]2[CH2:40][C@H:39]2[C:41]([OH:43])=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[N+](=[CH2:54])=[N-]>CCOCC>[CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[O:36][CH2:37][C@@H:38]2[CH2:40][C@H:39]2[C:41]([O:43][CH3:54])=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)OC)c1

Procedure:
To a solution of (1R,2R)-2-{[3-({cyclopropyl[((3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl]amino}methyl)-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq., neutral form) from Example 2 was added a solution of diazomethane in ether until a faint yellow color persisted. The solvent was evaporated by a stream of nitrogen gas. The residue was purified by flash column chromatography (SiO2, 10% MeOH in DCM plus 1% aqueous NH4OH) afford the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:26][S:23]([O:15][CH2:14][C:10]1([CH2:9][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)[CH2:13][O:12][CH2:11]1)(=[O:25])=[O:24]
Reactant: O=[N+]([O-])c1cnn(CC2(CO)COC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(Cn2cc([N+](=O)[O-])cn2)COC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methanol (0.6 g, 2.8 mmol) was dissolved in DCM (16 ml) with triethylamine (0.778 mL, 5.6 mmol) and the reaction was cooled at 0° C. Mesyl chloride (0.415 g, 3.62 mmol) was added dropwise and the reaction was allowed to reach rt overnight. The mixture was diluted in DCM (25 mL), washed with water (20 mL) and the water re-extracted with DCM (20 mL). The combined organics were dried over Na2SO4, filtered and the solvent removed under vacuum. (3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methyl methanesulfonate was obtained as a yellowish oil (0.9 g, quantitative yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:29][C:30]2[C:31]([CH3:37])=[N:32][N:33]([CH3:36])[C:34]=2[CH3:35])[C:11]([NH:14][C:15]2[S:19][N:18]=[C:17]([C@H:20]3[C:24]([CH3:26])([CH3:25])[O:23]C(C)(C)[O:21]3)[N:16]=2)=[N:12][CH:13]=1.[ClH:38]>C(O)C>[ClH:38].[CH3:26][C:24]([OH:23])([CH3:25])[C@H:20]([C:17]1[N:16]=[C:15]([NH:14][C:11]2[C:10]([O:29][C:30]3[C:31]([CH3:37])=[N:32][N:33]([CH3:36])[C:34]=3[CH3:35])=[CH:9][C:8]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:13][N:12]=2)[S:19][N:18]=1)[OH:21]
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Agent: Cl
Solvent: CCO
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)C(C)(C)O)ns1
Temperature: 75 °C
Reaction time: 0.03 h
Yield: 89.6 %

Procedure:
A flask was charged with (S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)-1,2,4-thiadiazol-5-amine (0.233 g, 0.432 mmol), ethanol (10 mL), and 3M HCl (0.288 ml, 0.863 mmol). The reaction was heated to 75° C. for 1 hour and then concentrated in vacuo. Ether was added to the residue and the mixture was stirred for 2 minutes to precipitate the product. The mixture was decanted and the resulting solids were dried in vacuo to afford (S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (0.248 g, 0.387 mmol, 89.6% yield) as yellow solid. Mass Spectrum (apci) m/z=500.1 (M+H−HCl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:32]([C:29]3[CH:28]=[CH:27][C:26]([Br:25])=[CH:31][N:30]=3)=[O:33])[CH:18]=2)([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cccc(N)c2)(C(F)F)COC1
Reactant: O=C(O)c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)NC1=NC(c2cccc(NC(=O)c3ccc(Br)cn3)c2)(C(F)F)COC1

Procedure:
[5-(3-Amino-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester and 5-bromo-pyridine-2-carboxylic acid were coupled according the procedure described in example 51m). 1H-NMR (360 MHz, CDCl3): 9.92 (s, 1H, NH), 8.73 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.88 (m, 2H), 7.45 (m, 1H), 7.31 (m, 1H), 5.92 (t, 1H, CHF2), 4.84 (d, 1H), 4.65 (d, 1H), 4.31 (d, 1H), 3.96 (d, 1H), 1.52 (s, 9H); MS: 525 [(M+H)+].
Reaction SMILES: [OH-].[Na+:2].O1CCCC1.CO.[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][O:23][C:24]1[CH:56]=[CH:55][C:27]([CH2:28][N:29]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:35]3[C:30]2=[CH:31][CH:32]=[CH:33][C:34]=3[O:42][CH2:43][C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50]CC)=[O:49])=[CH:46][CH:45]=2)=[CH:26][C:25]=1[O:57][CH3:58]>O>[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13][C:12]=1[CH2:22][O:23][C:24]1[CH:56]=[CH:55][C:27]([CH2:28][N:29]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:35]3[C:30]2=[CH:31][CH:32]=[CH:33][C:34]=3[O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([C:48]([O-:50])=[O:49])=[CH:53][CH:54]=2)=[CH:26][C:25]=1[O:57][CH3:58].[Na+:2]
Reactant: CCOC(=O)c1ccc(COc2cccc3c2c2ccccc2n3Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cn2c3ccccc3c3c(OCc4ccc(C(=O)[O-])cc4)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
1 mL of 5 N sodium hydroxide solution was added to tetrahydrofuran:methanol=1:1(20 mL) solution of 110 mg of ethyl 4-((9-(4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-3-methoxybenzyl)-9H-carbazole-5-yloxy)methyl)benzoate, and stirred at 70° C. for 1 hour. The reaction mixture was allowed to cool, and the water was added thereto. The crystalline precipitate was isolated by filtration, and washed with 2-propanol. The collected precipitate was dried under reduced pressure, and 107 mg of the subject compound was prepared as white crystal.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=2)O1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)aniline were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene as pale yellow powder. APCI-Mass m/Z 630/632 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1C=CC=CC=1>[CH2:12]([N:13]([CH2:15][CH2:7][CH2:8][CH3:9])[CH:14]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH2:2][CH2:1][CH3:4]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccnc1
Solvent: c1ccccc1
Product: CCCCN(C=CC(=O)c1cccnc1)CCCC

Procedure:
A mixture of 0.10 mole of 3-acetylpyridine and 0.10 mole of N,N-dimethylformamide dimethylacetal in 100 ml of benzene was refluxed for 12 hours. The solvent was removed, giving 3-dibutylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.FC(F)(F)S(O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([N:33]([CH3:44])[CH:34]3[CH2:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]3)=[N:31][N:32]=2)=[C:24]([O:45][CH3:46])[CH:23]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:46][O:45][C:24]1[CH:23]=[C:22]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[S:29][C:30]([N:33]([CH3:44])[CH:34]2[CH2:39][C:38]([CH3:40])([CH3:41])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]2)=[N:31][N:32]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
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: C1COCCO1
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177 mg, 0.849 mmol) and 3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl trifluoromethanesulfonate (332 mg, 0.653 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (38 mg, 0.033 mmol) followed by a solution of Na2CO3 (208 mg, 1.958 mmol) in water (1 mL). The resulting mixture was purged with nitrogen, sealed, and heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic phase was separated, dried over MgSO4, and filtered. To the filtrate was added SiliaMetS DMT (541 mg, 0.61 mmol/g, 0.33 mmols) and the resulting suspension stirred at room temperature for 18 hours. The SiliaMetS DMT was removed by vacuum filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to afford the crude product as a pale yellow solid. The crude material was recrystallized from MeOH (3 mL) to afford the title compound as a white solid (0.166 g, 57% yield). LC-MS: Rt 0.86 min; MS m/z 441.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.37 (d, J=1.52 Hz, 1H), 7.29 (dd, J=8.59, 1.52 Hz, 1H), 4.35 (tt, J=12.38, 3.28 Hz, 1H), 3.99 (s, 3H), 3.88 (s, 3H), 2.97 (s, 3H), 1.61 (dd, J=11.87, 3.28 Hz, 2H), 1.41 (t, J=12.13 Hz, 2H), 1.26 (s, 1H), 1.21 (s, 6H), 1.09 (s, 6H). LC-MS: Rt 1.60 min; MS m/z 440.4 [M+H]+ [Method B]. HR-MS: Rt 1.43 min; MS m/z 441.2419 [M+H]+ [Method C].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COc1ccc(Br)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(OC)nc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-methoxypyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: C=C(CC(=O)OC)C(=O)O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 4-methoxy-2-methylene-4-oxobutanoic acid (1.44 g, 10.0 mmol) in MeOH (100 mL) was added 10% Pd on carbon (200 mg). The mixture was stirred under H2 at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give the product as a colorless oil (1.4 g, 96% yield). ESI MS: m/z 147.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 3.69 (s, 3H), 2.99-2.94 (m, 1H), 2.77 (d, J=8.0 Hz, 0.5H), 2.73 (d, J=8.4 Hz, 0.5H), 2.46 (d. J=5.6 Hz, 0.5H), 2.42 (d, J=6.4 Hz, 0.5H), 1.27 (d, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:13](/[CH:31]=[CH:32]/[CH2:33][O:34][CH3:35])=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2]>[Pd].CO>[CH3:35][O:34][CH2:33][CH2:32][CH2:31][C:13]1[C:14]([NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[CH:15][C:10]([NH:9][C:6]2[N:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[N:11][CH:12]=1
Reactant: COC/C=C/c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COCCCc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
A solution of (E)-tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (Synthesis 183-B) (0.035 g, 0.073 mmol), palladium on carbon (0.035 g) in methanol (2 mL) was stirred overnight under hydrogen (1 atm). The reaction mixture was filtered through celite and the solvent was removed in vacuo. The crude oproduct was used without further purification. TFA (0.2 mL) was added to a solution of the crude material dissolved in dichloromethane (2 mL) at room temperature. The reaction mixture was stirred for 20 min. Solvent was removed in vacuo and the mixture was purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude product was purified by preparative thin layer chromatography, eluting with methanol/dichloromethan/NH3 (9%/90%/1%), to give the title compound as a yellow solid (0.020 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:16])=[C:7]([O:13][CH2:14][CH3:15])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCl.CO>C1COCC1>[C:17]1([NH:23][C:24]([NH:1][C:2]2[CH:12]=[C:11]3[C:5]([C:6]([Cl:16])=[C:7]([O:13][CH2:14][CH3:15])[O:8][C:9]3=[O:10])=[CH:4][CH:3]=2)=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOc1oc(=O)c2cc(N)ccc2c1Cl
Reactant: S=C=Nc1ccccc1
Agent: CCl
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1oc(=O)c2cc(NC(=S)Nc3ccccc3)ccc2c1Cl
Yield: 55 %

Procedure:
This compound was prepared by reaction of 7-amino-4-chloro-3-ethoxyisocoumarin with phenyl isothiocyanate at r. t. in THF for 24 hrs. The product was obtained as yellow solid: yield 55%, m.p. 176°-177° C. (dec.); TLC, Rf =0.76 (CH3Cl:MeOH=9:1), MS m/e=374 (M+). Anal. Calcd. for C18H15N2O3ClS: C, 57.62; H, 4.00. Found: C, 57.77; H, 4.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: Cc1ccccc1C=CCC(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reactant: C=CC(=O)OC
Solvent: COCCOC
Solvent: CO
Product: Cc1ccccc1C=CCC(CCC(=O)O)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred soluton of 1-(p-chlorophenyl)-4-phenyl-7-(o-methylphenyl)-1,6-heptadien-3-one (15.47 g., 0.04 mole) in glyme (150 ml.), followed by addition of methyl acrylate (4.13 g., 0.048 mole) in glyme (25 ml.). After stirring for 24 hours, the solvent is removed in vacuo, and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent, the residue is heated on a steam bath with a solution of 20% sodium hydroxide (25 ml.) in methanol (300 ml.) for 20 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (30 ml.), and the yellowish solid that precipitates is filtered and air-dried; yield 12.85 g., m.p. 60°-80°C. (glass). Several recrystallizations from n-butyl chloride, followed by a final recrystallization and ethanol gives material with m.p. 163.5°-165°C. Anal. Calcd. for C29H27ClO3 : C, 75.89; H, 5.93; Found: C, 75.67; H, 5.76.
Reaction SMILES: [N+:1]([O-:16])([O:3][C@@H:4]([C@H:6]([O:12][N+:13]([O-:15])=[O:14])[CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH3:5])=[O:2].Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[C:18](=[O:19])([O:20][CH:21]([Cl:23])[CH3:22])[O:10][CH2:9][CH2:8][CH:7]([CH3:11])[C@@H:6]([O:12][N+:13]([O-:15])=[O:14])[C@H:4]([O:3][N+:1]([O-:16])=[O:2])[CH3:5]
Reactant: CC(CCO)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,3R)-6-hydroxy-4-methylhexane-2,3-diyl dinitrate (Intermediate 2, 0.78 g, 3.26 mmol) in CH2Cl2 (15 mL) cooled at 0° C., 1-chloroethyl chloroformate (0.355 mL, 3.26 mmol) was added. Then a solution of Pyridine (0.263 mL, 3.26 mmol) was added dropwise. The solution was stirred at room temperature overnight. Then it was diluted with CH2Cl2 (25 mL) and washed with HCl 1 N (2×15 mL), a saturated solution of NaHCO3 (15 mL) and brine. The organic layer was dried over Na2SO4 and concentrated affording the title compound as colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30](Cl)[C:31](OCC)=[O:32])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:38][C:39]([NH2:41])=[S:40].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:40][C:39](=[NH:38])[NH:41][C:31]3=[O:32])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCCC2(C)CCc3c(C)c(OC(C)=O)c(OC)c(OC)c3O2)cc1
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Product: COc1c(OC(C)=O)c(C)c2c(c1OC)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2

Procedure:
The procedure described in Example 1(a) was repeated, except that 558 mg of ethyl 3-{4-[2-(6-acetoxy-7,8-dimethoxy-2,5-dimethylchroman-2-yl)ethoxy]phenyl}-2-chloropropionate, 100 mg of thiourea and 12 ml of sulfolane were heated at 110°-115° C. for 3.5 hours. The product was subsequently treated as described in Example 1(a), except that the crude product, in the form of an oil, was purified by column chromatography through silica gel, eluted with a 20:1 by volume mixture of ethyl acetate and methanol, to give the title compound, softening at 103°-110° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=[C:8]([N+:13]([O-])=O)[C:9]=1[S:10][C:11]#[N:12])([O-:3])=[O:2].N>C(O)(=O)C.O.[Fe]>[N+:1]([C:4]1[C:9]2[S:10][C:11]([NH2:12])=[N:13][C:8]=2[CH:7]=[C:6]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: N#CSc1c([N+](=O)[O-])cc(-c2cccnc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2cc(-c3cccnc3)cc([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
A solution of 3-(3,5-Dinitro-4-thiocyanato-phenyl)-pyridine (0.66 g, 2.19 mmol) in glacial acetic acid (15 ml) was treated with iron powder (0.61 g, 11.0 mmol) and stirred at ambient temperature for 16 h. The resultant mixture was diluted with water (200 ml) and made alkaline by the addition of concentrated ammonia solution. The solid material was collected by filtration and washed with water followed by ethyl acetate. The filtered solid was then extracted with boiling ethanol (3×200 ml) which was removed in vacuo to give 7-Nitro-5-pyridin-3-yl-benzothiazol-2-ylamine as a pale yellow solid (0.57 g, 95%).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[C:6](=[O:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:9]([C:7]2[C:6](=[O:12])[N:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4](=[O:20])[N:3]([CH2:1][CH3:2])[CH:8]=2)=[O:11])=[CH:38][CH:37]=1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Product: CCn1cc(C(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 4-(6,7-dimethoxy-quinazolin-4-yloxy)-phenylamine by the procedure for example 134. mp=238-241° C.; LCMS m/z=558 (M+H); 1H NMR (CDCl3): δ 10.82 (s, 1H), 8.63 (d, 2H J=6.5 Hz), 7.76 (d, 2H, J=9.0 Hz), 7.55 (s, 1H), 7.32 (s, 1H), 7.23 (d, 2H, J=8.9 Hz), 4.07 (s, 7H), 4.03 (q, 3H, J=7.2 Hz), 1.59 (s, 1H), 1.49 (s, 1H), 1.46 (t, 3H, 7.2 Hz), 1.20 (t, 1H, J=7.0 Hz), 1.03 (t, 1H, J=7.3 Hz).