Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[CH2:9][CH2:8]2.CC1C=CC(N=[CH:23][C:24]2[C:25]([NH2:33])=[CH:26][C:27]3[O:31][CH2:30][O:29][C:28]=3[CH:32]=2)=CC=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]2[C:10]3=[N:33][C:25]4[CH:26]=[C:27]5[O:31][CH2:30][O:29][C:28]5=[CH:32][C:24]=4[CH:23]=[C:9]3[CH2:8][C:7]=2[CH:6]=1
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COCOc1ccc2c(c1)CCC2=O
Product: COCOc1ccc2c(c1)Cc1cc3cc4c(cc3nc1-2)OCO4
Yield: 15.8 %

Procedure:
Using the procedure of Example 1, 5-methoxymethoxyindan-1-one (327 mg, 1.7 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (432 mg, 1.7 mmol) to yields 8-methoxymethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (86.3 mg, 15% of theory).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:21]([O:30][CH2:31][CH2:32][OH:33])[N:20]=[C:19]([CH2:34][CH2:35][CH3:36])[N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:38]1[N:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>O1CCCC1.CC(N(C)C)=O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[C:21]([O:30][CH2:31][CH2:32][O:33][C:38]3[N:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=3)[N:20]=[C:19]([CH2:34][CH2:35][CH3:36])[N:18]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)([CH3:5])([CH3:6])[CH3:4]
Reactant: Clc1ncc(Br)cn1
Reactant: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCOc2ncc(Br)cn2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
To a suspension of sodium hydride (0.25 g) in tetrahydrofuran (5 ml) is added dropwise a solution of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]benzenesulfonamide (1.00 g) in dimethylacetamide (3 ml) and tetrahydrofuran (10 ml) at room temperature, and thereto is added 2-chloro-5-bromopyrimidine (0.56 g), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is acidified with ice-cold diluted hydrochloric acid, and extracted with ethyl acetate. The extract is washed, dried, and evaporated to remove the solvent. The resulting oily product is purified by silica gel column chromatography (solvent; chloroform), and crystallized from n-hexane to give 4-tert-butyl-N-[6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]benzenesulfonamide (1.21 g) as crystals.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:14]([N:16]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:17][C:18](=[O:45])[C@@H:19]([CH:24]([C:34](=[O:44])[NH:35][O:36]CC1C=CC=CC=1)[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@@H:12]([C:14]([N:16]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:17][C:18](=[O:45])[C@@H:19]([CH:24]([C:34](=[O:44])[NH:35][OH:36])[CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)N)C(CCCc1ccccc1)C(=O)NO
Yield: 87.8 %

Procedure:
A solution of 0.820 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-[(benzyloxy)carbamoyl]-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in 20 ml methanol was hydrogenated in the presence of 0.240 g of 5% palladium-on-carbon for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.480 g of 2′-(D-alanyl)-2(R)-[1(RS)-(hydroxycarbamoyl)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a colorless glass.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)(O)C(=O)O
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (101 mg, 97%), MS (ISP) m/z=517.4 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2-hydroxy-2-methyl-propionic acid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:13]=[C:12]2[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])C1C=CC=CC=1>[Pd].CCOC(C)=O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([Si:18]([CH:22]([CH3:23])[CH3:24])([CH:19]([CH3:20])[CH3:21])[CH:25]([CH3:27])[CH3:26])[CH:13]=[C:12]2[CH2:28][CH2:29][N:30]1[C:31](=[O:40])[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]1=[O:39]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(O)ccc21

Procedure:
Combine 2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione and EtOAc (40 mL) and hydrogenated overnight with 1 g 5% Pd/C at atmospheric pressure. Filter through celite, concentrate to dryness, and chromatograph on silica gel eluting stepwise with a gradient 10% EtOAc in hexanes to 30% EtOAc in hexanes to give the title compound as a solid: FDMS 462 (M+1) Analysis for C27F24N2O3Si H2O: calcd: C, 69.55; H, 7.44; N, 6.01. Found: C, 69.44; H, 7.17; N, 6.00.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:25]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[N:10]=1)C1C=CC=CC=1.CO.C(O)(=O)C.O1CCCC1>[OH-].[OH-].[Pd+2]>[CH2:32]([N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:11]4[NH:10][C:9](=[O:8])[CH:14]=[CH:13][N:12]=4)=[CH:21][CH:20]=3)=[N:27][C:26]=2[CH2:28]1)[CH3:33]
Reactant: CCN1CCc2c(nc(-c3ccc(Nc4nccc(OCc5ccccc5)n4)cc3)nc2N2CCOC[C@@H]2C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCc2c(nc(-c3ccc(Nc4nccc(=O)[nH]4)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Step 3—Synthesis of compound xb: (S)-4-(benzyloxy)-N-(4-(7-ethyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyrimidin-2-amine (0.066 g, 0.12 mmol) was purged under nitrogen then added 20% Palladium hydroxide on carbon (2:8, Palladium hydroxide:carbon black, 0.101 g) followed by dry Methanol (3.6 mL, 89 mmol), Acetic acid (0.18 mL, 3.2 mmol) and dry Tetrahydrofuran (3.6 mL, 44 mmol) purged with hydrogen, heated at 40° C. and stirred overnight under an atmosphere of hydrogen. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated. chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.23 (d, J=8.7, 2H), 7.77 (t, J=9.4, 3H), 5.85 (d, J=5.9, 1H), 4.15 (d, J=6.5, 1H), 3.87 (d, J=10.8, 1H), 3.75-3.68 (m, 1H), 3.62 (dd, J=16.9, 7.9, 4H), 3.55-3.35 (m, 2H), 2.68 (s, 3H), 2.58-2.52 (m, 3H), 1.25 (d, J=6.6, 3H), 1.11 (t, J=7.1, 3H). LC/MS-m/z+448.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10](S)[CH:11]=2)[CH2:6]1)=[O:4].ClCC1SC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C.[Cl-].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>C(#N)C.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1Cc2ccc(S)cc2C1
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
Compound 1C (crude mixture from above, 830 mg) was dissolved in acetonitrile (80 mL) with the chloride 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.50 g, 1.71 mmol) and Cs2CO3 (2.37 g, 7.27 mmol) The reaction mixture was stirred at RT overnight. Ether (50 mL) and H2O were added and stirring was continued for another 5 min. The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined organics was dried over MgSO4 and concentrated to an oil. The crude product was purified by column chromatography eluted with EtOAc and hexanes to give the desired product as a thick yellow oil (0.48 g, 28% for 2 steps).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]4[NH:21][N:22]=[CH:23][C:18]4=[C:17]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:27]=[CH:28][CH:29]=4)[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.NC1C=C(C2N=C(NC3C=CC(N4CCN(C)CC4)=CC=3)N=C3N([CH:65]4[CH2:70][CH2:69][CH2:68][CH2:67][O:66]4)N=CC=23)C=CC=1.C(Cl)(=O)C=C>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:20]=[C:19]4[N:21]([CH:65]5[CH2:70][CH2:69][CH2:68][CH2:67][O:66]5)[N:22]=[CH:23][C:18]4=[C:17]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:27]=[CH:28][CH:29]=4)[N:16]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3nc(-c4cccc(N)c4)c4cnn(C5CCCCO5)c4n3)cc2)CC1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3[nH]ncc23)c1
Agent: C=CC(=O)Cl
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3c2cnn3C2CCCCO2)c1

Procedure:
As an example, N-(3-(6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide be prepared according to Route III. Beginning with 4-(3-aminophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine, acylation with acryloyl chloride provides N-(3-(6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide. Deprotection under mild acidic conditions yields N-(3-(6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:21]([NH2:22])=[CH:20][NH:19][N:18]=1>N1C=CC=CC=1>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:21]([NH:22][C:5](=[O:7])[CH3:6])=[CH:20][NH:19][N:18]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
Acetic anhydride (27 μl, 0.28 mmol) was added to a solution of 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol) in pyridine (5 ml) and the reaction mixture stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the residue purified by flash column chromatography [SiO2, EtOAc-petrol (1:2.5, 2:1)] to give N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide as a brown crystalline solid (29 mg, 48%). (LC/MS: Rt 1.70, [M+H]+ 241.64).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([N:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([N:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1
Product: O=C(NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=402.1, tR (minutes, Method D)=0.78
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1F
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F

Procedure:
o-Fluorobenzoic acid is reacted with chlorosulfonic acid by the method of Example 1 to form 2-fluoro-5-chlorosulfonylbenzoic acid. This is reacted with 3,5-dimethylpiperidine by the method of Example 1 to form 2-fluoro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid. This product (0.0015 mole) is heated to 60° C. with diethylamine (10 ml.) and ethanol (3.0 ml.) to form a clear solution, and the reaction mixture is then heated at reflux temperature for 24 hours. The resulting brown solid is filtered off, dissolved in 1N NaOH, washed twice with ether, and the product precipitated by the addition of concentrated HCl. Recrystallization from diethyl ether replaced by isopropyl ether yields the product, m.p. 139.5°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[CH:9][N:8]=1)[NH2:5].Cl[C:19]([O:21][CH:22]1[CH:29]2[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:31][CH:23]1[CH2:24]3)[CH2:28]2)=[O:20].C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[CH:9][N:8]=1)[NH:5][C:19]([O:21][CH:22]1[CH:23]2[CH2:31][CH:27]3[CH2:26][CH:25]([CH2:30][CH:29]1[CH2:28]3)[CH2:24]2)=[O:20]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)[C@@](C)(N)Cc1ncc2ccccn12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@](C)(Cc1ncc2ccccn12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 2 h

Procedure:
To a stirred solution of the crude compound of Step 3 (0.83 g, 3.56 mmol) in dry THF (10 mL) was added a solution of 2-adamantyl chloroformate (0.80g, 3.7 mmol) in dry THF (3 mL) followed by a solution of triethylamine (0.38 g, 3.8 mmol) in dry THF (5 mL) dropwise. After 2 hours stirring, thereaction mixture was filtered, and the solvent removed in vacuo to give theproduct (1.2 g, 82%) as a colorless amorphous solid, which was used withoutfurther purification; IR (KBr) 1737 and 1699 cm-1.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1)([O-:3])=[O:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([Cl:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:20]([C:25]3[CH:26]=[C:27]([Cl:33])[C:28]([Cl:32])=[C:29]([Cl:31])[CH:30]=3)[C:21]([F:23])([F:22])[F:24])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=Cc1ccc(-n2cnc([N+](=O)[O-])n2)c(C#N)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc([N+](=O)[O-])n1
Temperature: 180 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2-dichlorobenzene (10 mL), were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (2.5 g, 7.5 mmol), CuCl (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh, 25-30% EtOAc in Pet ether) afforded the title compound as a off white solid (0.9 g, 50%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J=16.0 Hz, 1H), 6.56 (dd, J=16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 436.11 ([M−2H]−).
Reaction SMILES: [NH2:1][C:2]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[C:3]([F:9])[C:4]([O:6]CC)=O.[Cl:17][C:18]1[C:23]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]([N:28]=[C:29]=[O:30])=[C:20]([F:31])[CH:19]=1>>[Cl:17][C:18]1[C:23]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:22][C:21]([N:28]2[C:4](=[O:6])[C:3]([F:9])=[C:2]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[NH:1][C:29]2=[O:30])=[C:20]([F:31])[CH:19]=1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)C(F)=C(N)C(F)(F)C(F)(F)F
Product: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using ethyl 3-amino-2,4,4,5,5,5-hexafluoro-2-pentenoate and 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione, m.p. 160°-162° C.;
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C@H:4]([C:6]([OH:8])=O)[CH3:5].[C-:9]1([CH:14]=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[CH-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[Fe+2:21].[NH2:22][C@H](C([O-])=O)C>CCCCC.C(O)C>[NH2:3][C@H:4]([C:6](=[NH:22])[O-:8])[CH3:5].[Na+:2].[C-:9]1([CH:14]=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[CH-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[Fe+2:21]
Reactant: C[C@H](N)C(=O)[O-]
Reactant: C[C@H](N)C(=O)O
Agent: [Fe+2]
Agent: O=C[c-]1cccc1
Agent: [Na+]
Solvent: CCO
Solvent: CCCCC
Product: C[C@H](N)C(=N)[O-]
Temperature: 25 °C
Yield: 950 %

Procedure:
Aqueous sodium hydroxide (11.2 mmol in 11 ml of water) was added to L-alanine (1.0 g, 11.22 mmol) and stirred for several minutes at room temperature. The solvent was removed in vacuo and the residue dried at 60° C. under high vacuum overnight. 4 Å molecular sieves, ferrocenecarboxaldehyde (11.78 mmol, 2.52 g) and absolute ethanol (50 ml) were added to the alaninate and stirred for 5 hours; the course of the reaction can be followed by IR. The molecular sieves were separated by filtration, the filtrate concentrated on a vacuum line and a red solid was obtained. Pentane (50 ml) was added and the mixture was stirred until a suspension was formed. This was filtered through a sinter and the residue was washed with pentane and dried under vacuum to give the title compound as a yellow-orange solid (3.28 g, 950%); νmax (KBr disc) 1641 s (C=N) and 1591 (CO2-) cm-1. The imine rapidly undergoes hydrolysis on silica or in the presence of water.
Reaction SMILES: C(=O)C1C=CC(OC)=C(OC)C=1.FC1C=CC=CC=1C=O.[C-]#N.[K+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]([CH:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])O)=[O:36])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.[NH:62]1[CH2:68][CH2:67][CH2:66][CH2:65][NH:64][C:63]1=[S:69].[ClH:70]>CC(C)=O.C(O)C>[ClH:70].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2([OH:36])[N:64]3[CH2:65][CH2:66][CH2:67][CH2:68][N:62]=[C:63]3[S:69][CH:37]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(C(=O)C(O)c2ccccc2F)cc1OC
Reactant: S=C1NCCCCN1
Agent: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc(C2(O)C(c3ccccc3F)SC3=NCCCCN32)cc1OC
Reaction time: 72 h

Procedure:
A mixture consisting of 16.6 g. of veratraldehyde, 12.5 g. of o-fluorobenzaldehyde, 8 g. of potassium cyanide, and 100 ml of 65% ethanol is reacted as described in Example 20, yielding 12.5 g. of 3,4-dimethoxy-2'-fluorobenzoin, m.p. 126°-128° C. A 5.8 g. portion of the benzoin derivative is converted to its methanesulfonate ester by the procedure of Example 20, giving 6.7 g. of the ester melting at 111°-113° C. 2.58 g. of the methanesulfonate ester, 0.91 g. of hexahydro-2H-1,3-diazepin-2-thione, and 55 ml. of acetone are mixed and left at room temperature for three days. 7 ml. of 2 N ethanolic hydrogen chloride are added, yielding 2.2 g. of the title compound, melting at 192°-194° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21](O)=[O:22])=[CH:12]2)[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:48][CH2:49][CH2:50][NH2:51].C(N(CC)CC)C>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21]([NH:51][CH2:50][CH2:49][F:48])=[O:22])=[CH:12]2)[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3cc(F)c(C)nc3C)c2c1
Reactant: NCCF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cnc2c(C(=O)NCCF)cn(Cc3cc(F)c(C)nc3C)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
See FIG. 23(a). In a 25 mL thermal vial was charged with 1-((5-fluoro-2,6-dimethylpyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.32 mmol) and HATU (146 mg, 0.38 mmol) were taken in NMP (4 mL) and stirred for 10 min at rt. Then 2-fluoroethanamine (20.13 mg, 0.32 mmol) and Triethyl amine (133 mL, 0.96 mmol) were added and stirred for 1 h at rt. The LCMS showed completion of the reaction. The reaction mixture was poured into water and extracted with chloroform. The organic layer was dried and concentrated and crude was submitted to reverse phase purification. The pure fractions were concentrated to get 1-((5-fluoro-2,6-dimethylpyridin-3-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (75 mg, 65.6%) as a solid. ES+MS m/z: 359 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.37 (d, J=2.64 Hz, 3 H ) 2.42 (s, 6 H ) 3.66 (d, J=5.46 Hz, 1 H ) 3.75 (d, J=5.27 Hz, 1 H ) 4.49 (t, J=4.90 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 5.52 (s, 2 H ) 6.85 (d, J=10.17 Hz, 1 H ) 7.86 (s, 1 H ) 8.15 (s, 1 H ) 8.34-8.46 (m, 1 H ) 8.89 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][N:14](C(OCC)=O)[CH2:15][CH2:16][C:3]=12.[ClH:22].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:22].[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(Cl)c2CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1c2c(nc3ccccc13)CCNCC2

Procedure:
11-Chloro-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline dihydrochloride was prepared by hydrolysis of 11-chloro-3-phenoxycarboxyl-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline or 11-chloro-3-ethoxycarbonyl-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline with concentrated hydrochloric acid. Yield of the dihydrochloride: 69% of theory; m.p. 261° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18]O>>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9]2(=[O:10])[O:11][CH2:18][CH2:17][CH2:16][CH2:15][O:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: OCCCCO
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCCO2)cc1

Procedure:
With 4-nitrobenzylphosphonic acid and 1,4-butanediol, the same procedure as in Reference Example 11 was followed, to yield 2-(4-nitrobenzyl)-1,3,2-dioxaphosphepane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless needles having a melting point of 136° to 137° C.