Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Na (370 mg, 16.12 mmol) was dissolved in MeOH (5 mL) and 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.61 mmol) was added to the sodium methoxide solution. The reaction mixture was stirred for 8 hours for 60° C. The reaction mixture was quenched with water and the organic solvent was removed under reduced pressure. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solvent to afford title compound (380 mg, 77% yield). 1H NMR (600 MHz, CDCl3) δ 10.51 (s, 1H), 8.74 (s, 1H), 7.36 (d, J=3.6 Hz, 1H), 6.90 (d, J=4.2 Hz, 1H), 5.72 (s, 2H), 4.48 (s, 3H), 3.60 (t, J=7.8 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 307 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:9][C:10]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[S:11])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].IC.[C:30](=O)([O-])[O-].[K+].[K+]>CC(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:9][C:10]([S:11][CH3:30])=[N:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: O=C([O-])[O-]
Reactant: COC(CNC(=S)NC(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1)OC
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(CN=C(NC(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1)SC)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
(a-3) A mixture of 22.3 parts of (+)-N-[(4-amino-3-nitrophenyl)phenylmethyl]-N'-(2,2-dimethoxyethyl)thiourea, 10.2 parts of iodomethane, 11.8 parts of potassium carbonate and 240 parts of 2-propanone was stirred over weekend at room temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the elunet was evaporated, yielding 23 parts (100%) of (+)-methyl N-[(4-amino-3-nitrophenyl)phenylmethyl]-N'-(2,2-dimethoxyethyl)carbamimidothioate as a residue (141).
Reaction SMILES: [CH2:1]([CH:4]1[N:8]([CH3:9])[S:7](=[O:11])(=[O:10])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3].[C:13]1([S:19][CH2:20]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:13]1([S:19][CH2:20][N:6]2[C:5](=[O:12])[CH:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH3:9])[S:7]2(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC1C(=O)NS(=O)(=O)N1C
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Yield: 57.7 %

Procedure:
A mixture of 4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9 g), phenylthiomethyl chloride (7.43 g) and tetrabutylammonium bromide (1 g) suspended in 200 ml of toluene was refluxed for 8 hours, cooled, and concentrated in vacuo. The residue was purified by flash chromatography (15%-20% ethyl acetate in hexane) to afford 8.5 g (88%) of 2-phenylthiomethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =methyl).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH:56]([CH3:58])[CH3:57])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH:56]([O:55][CH2:54][CH2:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:51][CH:50]=1)([CH3:58])[CH3:57]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CC(C)OCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 4-(2-isopropoxyethoxy)phenyl borate (153 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 12 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-isopropoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 111) (159 mg).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([C:28](OCC)=[O:29])[C:19]3[CH:24]=[N:23][N:22]([CH:25]([CH3:27])[CH3:26])[C:20]=3[N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:33][CH2:34][C:35]1[C:36](=[O:43])[NH:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CS(C)=O>[CH3:41][C:40]1[CH:39]=[C:38]([CH3:42])[NH:37][C:36](=[O:43])[C:35]=1[CH2:34][NH:33][C:28]([C:18]1[CH:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]2)[N:21]=[C:20]2[N:22]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:24][C:19]=12)=[O:29]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCOC(=O)c1cc(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c1cnn2C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
Aqueous NaOH (0.065 g, 1.634 mmol) was added to a solution of ethyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.34 g, 0.817 mmol) in EtOH (4 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The crude acid (0.3 g, 0.773 mmol) was then dissolved in DMSO (3 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.235 g, 1.546 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (0.603 g, 1.159 mmol) was added to it and stirring was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (0.2 g, 50.0%).
Reaction SMILES: [C:1]([O:6][C:7]1=[CH:8][C:9](=[O:16])[NH:10]/[C:11]/1=[CH:12]\[CH:13]([CH3:15])[CH3:14])(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.[Pd]>[C:1]([O:6][CH:7]1[CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:16])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OC1=CC(=O)N/C1=C\C(C)C
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCC(=O)OC1CC(=O)NC1CC(C)C

Procedure:
30.0 g of (Z)-4-butyryloxy-5-isobutylidene-3-pyrrolin-2-one (produced according to Example 3) was dissolved in 300 ml of toluene, mixed with 3.0 g of palladium/activated carbon(5 percent of pf Pd) and hydrogenated for 24 hours in an autoclave at 2 MPa (20 bar). Then the catalyst was filtered off, the filtrate was concentrated by evaporation and the residue was recrystallized from hexane. The yield of the title compound was 23.50 g (77 percent of theory). The title compound had a melting point of 101.5° to 102.7° C. Other data concerning the title compound was:
Reaction SMILES: [NH:1]([C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[CH2:7][C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]([CH3:4])=[O:3].O.NN.[H][H]>[Pd]>[NH:1]([C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[CH2:7][C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[C:10]=2[N:9]=1)[C:2]([CH3:4])=[O:3]
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 2-(acetamino)phenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By methods well known in the art, 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 8-(2-acetaminobenzyl)-3-[2-(4-aminophenyl)ethyl]-1-propylxanthine.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([NH:61][CH2:62][C:63](O)=[O:64])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]>>[C:51]([NH:61][CH2:62][C:63]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:64])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:20][CH2:21][CH2:22][CH3:23])=[N:15][CH:16]=[C:17](I)[CH:18]=3)=[N:8][C:7]=12)[CH3:2].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].C(#N)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:3]1[N:4]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:20][CH2:21][CH2:22][CH3:23])=[N:15][CH:16]=[C:17]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[CH:18]=3)=[N:8][C:7]=12)[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCCOc1ncc(I)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Reaction time: 2 h

Procedure:
The product from stage e) (0.25 mmol) was suspended in triethylamine (2 ml) and trimethylsilylacetylene (0.39 mmol) and acetonitrile (2 ml to try and solubilise reactants). Pd(PPh3)2Cl2 (0.006 mmol) and cuprous iodide (0.006 mmol) were added and the reaction mixture stirred. After 1 h a further portion of trimethylsilylacetylene (0.19 mmol) was added and stirring continued for 2 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organics were washed with brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 99% dichloromethane/methanol) gave the title compound; 1H NMR (400MHz, MeOD): δ=0.25 (s, 9H), 1.05 (t, 3H), 1.31 (t, 3H), 1.44 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q, 2H), 4.33 (t, 2H), 4.52 (t, 2H), 4.54-4.80 (m, 2H), 5.18-5.25 (m, 1H), 8.32 (d, 1H), 8.74 (d, 1H); LRMS (TSP—positive ion) 569 (MNH4+), 452.0 (MH+); Anal. Found C, 60.82;H, 6.90; N, 15.15 Calcd for C28H38O4N6Si: C, 61.07;H, 6.95; N, 15.26.
Reaction SMILES: FC(F)(F)C(O)=O.N1([C:13]23[O:28][N:27]=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:14]2[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)CCCC1.C([O-])(O)=O.[Na+]>>[O:28]1[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:27]1
Reactant: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(=O)OC(C)(C)C)CC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc2c1CNCC2
Temperature: 0 °C

Procedure:
Trifluoroacetic acid (6.67 ml, 89.9 mmol) was added to a solution of 5-tert-Butyl 3-ethyl 7a-(pyrrolidin-1-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5-c]pyridine-3,5(6H)-dicarboxylate (5.5 g, 14.98 mmol) in MC (100 ml) at 0° C. and the mixture was stirred under reflux for 16 hours. Thereafter, the mixture was cooled to 0° C. and NaHCO3 solution was added. The phases were separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The crude product obtained was employed directly in the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([OH:20])=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:49][CH:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1)(=O)=O.O>CN(C=O)C>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([O:20][CH2:49][CH:50]4[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:57])[CH2:52][CH2:51]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COc1c(O)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
To a solution of 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-ol (207 mg, 0.42 mmol) in DMF (2 mL) was added cesium carbonate (274 mg, 0.84 mmol) and tert-butyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (135 mg, 0.46 mmol). The mixture was heated to 90° C. and stirred for 1.5 h. After cooling to rt, water was added and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (gradient: 25% ethyl acetate in hexanes to 30% ethyl acetate in hexanes) to provide 1,1-dimethylethyl 4-{[(3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-yl)oxy]methyl}piperidine-1-carboxylate (214 mg, 0.31 mmol, 73% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.51-7.34 (m, 7H), 6.98 (d, 1H), 6.83 (d, 1H), 5.16 (s, 2H), 4.22 (br m, 2H), 3.98 (d, 2H), 3.91 (s, 3H), 2.89 (s, 3H), 2.80 (br m, 2H), 2.37 (s, 3H), 2.12 (m, 1H), 1.93-1.88 (m, 2H), 1.85 (s, 9H), 1.48 (s, 9H), 1.39-1.35 (m, 2H); MS (I) for C41H49FN4O5: 697 (MH+).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(OC(Cl)(Cl)Cl)[O:17][C:18]([Cl:21])(Cl)Cl.Cl>C(Cl)Cl>[CH2:9]([N:8]([CH3:7])[C:18]([Cl:21])=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At −78° C. pyridine (1.25 mL, 15.5 mmol) followed by methyl benzylamine (2.0 mL, 15.5. mmol) are added to a solution of bis(trichloromethyl) carbonate (1.55 g, 5.2 mmol) in CH2Cl2 (20 mL). The reaction mixture is allowed to warm to RT and stirred for another 1.5 h. For workup 1N HCl is added to the yellow suspension and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the combined organic exctracts, filtration and evaporation of the solvent affords the title compound. MS (LC-MS): [M+H]+=184.1. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 3.84 min.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1.[I-].[Na+]>COCCOC>[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][N:30]1[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCc2ccccc2C1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 173.0 mg (0.44 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 586.0 mg (4.4 mmol) of 1,2,3,4-tetrahydroisoquinoline and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME was heated at 135° C. for 16 hr. The work up gave 109.3 mg (50.6%) of the product as a yellow solid, m.p. 170-173° C., mass (electrospray, m/e): M+H 491.0
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[C:3]=1[N+:15]([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)(=O)C.Cl>[NH2:15][C:3]1[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1onc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of 47 g (0.20 mole)(5-methyl-4-nitroisoxazol-3-yl)phenylmethanone of Example Ia in 600 ml glacial acetic acid was added to a mixture of 360 g (1.60 moles) SnCl2.2H2O in one liter of concentrated hydrochloric acid and 200 ml acetic acid at room temperature. After stirring at room temperature overnight (about 16 hours), the reaction mixture was poured carefully into a well stirred mixture of 2400 g of 50% sodium hydroxide and 6500 ml ice with ice bath cooling. The resulting solids were collected by filtration, washed with water and partitioned between 600 ml 5% sodium hydroxide and 2 liters of 1:1 dichloromethane:diethyl ether. The aqueous was extracted thrice with diethyl ether and the organic extract was dried (magnesium sulfate). Concentration gave 26.3 g (65%) of an oil. Chromatography on high pressure liquid chromatograph (HPLC) using dicloromethane as an eluent of 4.0 g of this oil yielded 2.7 g (44%) of an oil that solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][SH:9].[CH3:10][S:11]SC>[H-].[Na+]>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][S:9][S:11][CH3:10]
Reactant: CSSC
Reactant: Cc1ncsc1CCS
Agent: [H-]
Agent: [Na+]
Product: CSSCCc1scnc1C
Yield: 60.4 %

Procedure:
A mixture of 8.26 g (0.052 mol) of 2-(4-methyl-5-thiazolyl)-ethyl-mercaptan and 33.07 g (0.208 mol) of dimethyldisulphide is treated with 50 mg of sodium hydride (50% dispersion in oil) and the mixture is heated to reflux for 4 hours. The mixture is then left to cool, filtered over 10 g of aluminium oxide (activity I, neutral), which is back-washed with ether, and concentrated in a vacuum. The resulting crude product (9.5 g) is distilled through a Hempel column under a high vacuum, there being obtained 6.45 g of [2-(4-methyl-5-thiazolyl)ethyl]-methyl-disulphide.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]=[N:16][CH:17]([C:20](=[O:22])[CH3:21])[C:18]#[N:19]>C(Cl)(Cl)Cl>[Br:1][CH2:21][C:20](=[O:22])[CH:17]([N:16]=[N:15][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([C:10]([F:12])([F:13])[F:11])=[CH:7][C:6]=1[Cl:14])[C:18]#[N:19]
Reactant: CC(=O)C(C#N)N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: N#CC(N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=O)CBr
Temperature: 50 °C

Procedure:
A solution of bromine (2.2 ml) in chloroform (20 ml) was added dropwise to a stirred solution of 2-(2,6-dichloro-4-trifluoromethylphenylazo)-3-oxobutanenitrile (13.0g) in chloroform (20 ml) maintained at 50° C. The solution was then refluxed for 20 minutes, cooled, washed with water (4×50 ml), dried over magnesium sulfate, filtered and evaporated to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenylazo)-3-oxobutanenitrile (16.0g) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][CH:19](OC)[O:20]C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][CH:19]=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(CCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)OC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(=O)N(CCCC=O)CC1
Yield: 32.9 %

Procedure:
A solution of 4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3 g, 9.08 mmole) in glacial acetic acid containing 0.5 mL water (10 mL) was stirred at room temperature for 24 hours. The solution was concentrated at 35° C. under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The organic phase was dried (magnesium sulfate), concentrated, and the residue recrystallized from diethyl ether/hexane to give 5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.85 g,), m.p. 86-87° C.