Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@:17]([CH3:23])([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[C@](C)(N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)[C@@](C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2S)-2-amino-2,3-dimethyl-1-butanol (CAN 7533-40-6) as starting materials and isolated (21 mg, 73%) as colorless oil; MS (ESI, m/z): 327.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1.Cl.[CH:27](O)(C)C>>[OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19]([O:21][CH:22]([CH3:27])[CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Ethyl 4',5,7-trihydroxy-2-isoflavonecarboxylate (100 mg) was added to 10 ml of isopropanol saturated with HCl gas, and the mixture was heated at 70° C. with stirring for five hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent:chloroform), and the solid thus obtained was recrystallized from a chlorofor/methanol mixed solvent, giving 60 mg of isopropyl 4',5,7-trihydroxy-2-isoflavonecarboxylate.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([C:9]([O:11]CC)=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CCO.O>[CH:1]([C:4]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1noc(C(=O)O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
Ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate (10.42 mmol, 1.919 g) was dissolved in EtOH (20 ml). Sodium hydroxide pellets (12.50 mmol, 0.500 g) were dissolved in cold water (10 ml) and solution slowly added. The resulting solution was heated at 60° C. for 1.5 h. EtOH was removed under vacuum. The residue was diluted with tert-butyl methyl ether. The mixture was acidified under cold conditions by adding 2 N HCl solution. The mixture was stirred overnight and washed with DCM. Water phase was evaporated precipitating the product. 1.673 g of the title compound was obtained. 1H-NMR (400 MHz, D2O): δ 1.33 (d, 6H), 3.10-3.25 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:35])[CH3:34])[C:25]4[CH:26]=N[C:28](OC)=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:37]1(C2N3C(CC(=O)NC4C=CC=CC=43)=NN=2)CCCCC1.BrCC(N(C(C)C)C1C=CC=CC=1)=O>>[CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:34])[CH3:35])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:37][CH:26]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=C1Cc2nnc(C3CCCCC3)n2-c2ccccc2N1
Agent: CC(C)N(C(=O)CBr)c1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(C3CCCCC3)n2-c2ccccc21)c1ccccc1

Procedure:
Following the procedure described for Preparation 8(A), 1-cyclohexyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(B) (640 mg, 0.226 mmol) was alkylated with 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1 (A)) (580 mg, 0.226 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 4% MeOH in CH2Cl2) provided 668 mg of 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide. 1H NMR (CDCl3) δ 7.62-7.31 (m, 9), 4.93 (m, 1), 4.10 (d, 1), 3.91 (d, 1), 3.76 (d, 1), 3.45 (d, 1), 2.85 (m, 1), 2.19 (br. d, 1), 1.91 (m, 2), 1.69-1.11 (m, 7), 1.06 (m, 6): MS 458.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH:35][CH3:36]>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:35]([CH3:36])[CH3:34])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Reactant: CNC
Product: CN(C)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 91 step D from 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) and dimethylamine (2M solution in THF, 1 ml, 2 mmol). Pale yellow solid (85 mg, 71%). LC-MS (ESI): 417 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N:10]([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20].[CH2:22]([Cl:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-:29].[CH2:22]([N+:10]([CH3:9])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:20])[CH:16]=[CH:17][C:18]1=[O:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)CCCN1C(=O)C=CC1=O
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Product: C[N+](C)(CCCN1C(=O)C=CC1=O)Cc1ccccc1
Product: [Cl-]
Reaction time: 16 h

Procedure:
The polymer prepared in Example XIII above (110 g) is dissolved in 1100 ml of N,N-dimethylformamide and 100 g of benzyl chloride is added rapidly with stirring. After standing about 16 hours, the mixture is heated 2 hours on a steam bath. The product is precipitated in acetone, washed twice with acetone and dried under vacuum. The solid is redissolved in methanol, reprecipitated in dioxane, washed with acetone, and vacuum-dried to yield about 130 g of off-white solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C@@H:33]1[CH2:38][CH:37]=[CH:36][CH2:35][C@H:34]1[C:39]([O:41][CH2:42][CH3:43])=[O:40].[C:44](O)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[C:44]([O:32][C@H:33]1[CH2:38][CH:37]=[CH:36][CH2:35][C@H:34]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CC=CC[C@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC=CC[C@@H]1OC(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
DEAD (2.06 g, 11.8 mmol) was added dropwise to a solution of triphenylphosphine (3.08 g, 11.8 mmol) in THF (35 ml) at 0° C. over a period of 5 min. Trans 1-Hydroxy-2-carboethoxycyclohex-4-ene 2a (1.00 g, 5.88 mmol in 5 ml THF) was then added slowly, the mixture was stirred for 5 min, and then benzoic acid (1.44 g, 11.8 mmol, in 5 ml THF) was added. The mixture was stirred at RT for 2 hours. Solvents were evaporated, an the residue purified by chromatography on silica gel (EtOAc:hexane 2:8 as eluant). The product was then distilled under vacuum to yield ethyl cis-2-benzoyloxy-cyclohex-4-enecarboxylate (4, 1.1 g, 71%).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Reactant: O=C(CBr)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2CCOCC2)cc1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate (prepared from 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (8.35 g, 20 mmol)) was dissolved in acetone (25 ml) and treated with a solution of 4-bromoacetyltetrahydropyran (G. H. Harnest and A. Burger, J. Amer. Chem. Soc., 1943, 65, 370) (4.4 g, 20 mmol). After 20 min., potassium carbonate (1.38 g, 10 mmol) was added and the mixture stirred again for a further 45 min. Excess ethyl acetate was then added and the organic solution washed with water, brine and dried over anhydrous MGSO4. Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate gave the title compound as a pale yellow foam (8.5 g; 76%); νmax (CHCl3) 3420, 1780, 1750, 1680 and 1615 cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)=O.[C:26](#[N:28])[CH3:27]>>[CH2:24]([C:5]1[CH:4]=[C:3](/[CH:1]=[CH:27]/[C:26]#[N:28])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[N:11]1[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)[CH3:25]
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reactant: CC#N
Product: CCc1cc(/C=C/C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with acetonitrile according to Method D12d according to afford 2-(2-ethyl-4-((1E)-2-cyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=CC=1.C1(=O)CCCC1>C1(C)C=CC=CC=1>[N:13]1[CH:12]=[CH:11][C:10]([C:4]2[S:3][C:2]3[NH:1][C:19]4([CH2:20][CH2:21][CH2:16][CH2:26]4)[NH:9][C:7](=[O:8])[C:6]=3[CH:5]=2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1cc(-c2ccncc2)sc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O=C1CCCC1
Product: O=C1NC2(CCCC2)Nc2sc(-c3ccncc3)cc21
Yield: 22.1 %

Procedure:
A mixture of 2-amino-5-(pyridin-4-yl)thiophene-3-carboxamide (300 mg, 1.29 mmol), p-toluenesulfonic acid (150 mg) and cyclopentan-1-one (10 mL) in toluene (30 mL) was heated to reflux for overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the crude title compound (90 mg), which was further purified by preparative TLC to give the title compound (55 mg, yield 15%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].C(N(CC)CC)C.[N:43]1[CH:48]=[CH:47][C:46]([C:49]2[NH:53][C:52]3[CH:54]=[CH:55][CH:56]=[C:57]([C:58]([Cl:60])=[O:59])[C:51]=3[N:50]=2)=[CH:45][CH:44]=1>ClCCl>[ClH:60].[ClH:60].[ClH:60].[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[NH:1][C:58]([C:57]1[C:51]2[N:50]=[C:49]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)[NH:53][C:52]=2[CH:54]=[CH:55][CH:56]=1)=[O:59])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Reactant: O=C(Cl)c1cccc2[nH]c(-c3ccncc3)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(-c3ccncc3)nc12
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(4-pyridyl)-1H-benzimidazole-4-carboxylic acid (155 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.056 ml) and N,N-dimethylformamide (2 drops) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to give 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride. To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (76.8 mg) and triethylamine (65 mg) in dichloromethane (5 ml) was added 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride in dichloromethane (2 ml) under ice bath cooling and stirred at ambient temperature for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography (methanol:chloroform=1:49). To the purified product was added water and 1N hydrochloric acid (0.51 ml). The solution was lyophilized to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]-phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylamino-benzamide trihydrochloride (120 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH:26]=4)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][O:31][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:19]=[C:18]([C:17]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:38]5[S:37][CH:41]=[CH:40][CH:39]=5)[CH:3]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:23]=[CH:22][N:21]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(N)c4)nn4ccccc34)n2)c1
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 37 %

Procedure:
The title compound was prepared 4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine and 2-thiopheneacetyl chloride using the acylation conditions described in Example 36, Step H to generate, after HPLC purification, the desired product as a TFA salt in 37% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 9.62 (s, 1H), 8.85 (d, J=6.8 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.27 (d, J=5.5 Hz, 2H), 7.61 (s, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.30-7.39 (m, 3H), 7.19 (t, J=8.0 Hz, 2H), 7.13 (t, J=6.9 Hz, 2H), 6.96-6.98 (m, 1H), 6.60 (d, J=6.1 Hz, 1H), 6.55 (d, J=5.3 Hz, 1H), 4.25-4.26 (m, 2H), 3.99 (s, 2H), 3.50 (m, 2H), 2.85 (s, 6H). ES-LC/MS m/z=608 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[NH:9][CH2:10][C:5]=2[S:4][CH:3]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1C=CC=CC=1>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: ClC1=Nc2c(Br)csc2CN1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: c1ccccc1
Product: Clc1ncc2scc(Br)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
7-Bromo-2-chloro-3,4-dihydrothieno[3,2-d]pyrimidine (750 mg, 3.0 mmol) and chloranil (740 mg, 3.0 mmol) were dissolved in benzene (30 mL) and stirred for 3 hours under reflux. The reaction mixture was cooled to room temperature and diluted with benzene (30 mL). The mixture solution was washed with 0.5 N sodium hydroxide (30 mL) solution and water. The organic layer was dried with magnesium sulfate and then concentrated. Purification of the resultant compound by chromatography (10% ethyl acetate/hexane) yielded the target compound (630 mg, 85% yield) as white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:22][CH2:21][CH2:20][C:19]([OH:23])=[C:18]([C:24]#[N:25])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2.[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27]>COCCOC>[Br:1][C:2]1[C:3]2[O:22][CH2:21][CH2:20][C:19](=[O:23])[C:18]([CH2:27][CH2:26][C:28](=[O:29])[CH3:30])([C:24]#[N:25])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2
Reactant: N#CC1=C(O)CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Reactant: C=CC(C)=O
Solvent: COCCOC
Product: CC(=O)CCC1(C#N)C(=O)CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Reaction time: 47 h

Procedure:
TEA (0.300 mL, 2.152 mmol) was added to a slurry of 10-bromo-1-(4-fluorophenyl)-6-hydroxy-7,8-dihydro-1H-oxepino[3,2-f]indazole-5-carbonitrile (102, R1=4-Fluorophenyl) (3.15 g, 7.87 mmol) in DME (40.0 mL) under a nitrogen atmosphere. Methyl vinyl ketone (1.30 mL, 15.8 mmol) was added dropwise. After about 47 h, the volatiles were removed under reduced pressure to afford 10-bromo-1-(4-fluorophenyl)-6-oxo-5-(3-oxobutyl)-5,6,7,8-tetrahydro-1H-oxepino[3,2-f]indazole-5-carbonitrile as a tan foam. LC/MS, method 3, Rt=2.33 min, MS m/z 470 and 472 (M+H)+. The material was dissolved in toluene (80 mL) in a 250 mL round bottom with Dean-Stark trap and reflux condenser attached under a nitrogen atmosphere. Toluene-4-sulfonic acid hydrate (0.599 g, 3.15 mmol) was added. After about 3 h at reflux, the mixture was allowed to cool to rt. Sat. aq. NaHCO3 (100 mL) was added.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([CH3:18])[CH:7]=[CH:6][C:5]=2[N:4]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([CH3:18])[CH:7]=[CH:6][C:5]=2[N:4]1[S:19]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(C)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCC1c2cc(F)ccc2-c2cc(C)ccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 60.7 %

Procedure:
The title compound was prepared from 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-methyl-5,6-dihydrophenanthridine (0.24 g, 0.58 mmol), cyclohexene (2.1 mL, 21 mmol), and 1 M boron tribromide in dichloromethane (7.0 mL, 7.0 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4), followed by re-crystallization from a mixture of ethyl acetate-hexane (2×), to afford 4-[(6-ethyl-8-fluoro-2-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.14 g, 59%), m.p. 197-200° C.;
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: COc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(OC)cc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2-fluoro-5-methoxynitrobenzene and dimethyl sulfoxide, ethyl 2-(4-methoxy-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([CH:9]([F:20])[CH2:10][CH2:11][O:12]CC2C=CC=CC=2)[CH:7]=[CH2:8])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.C[Si](I)(C)C>ClCCl>[C:4]1(=[O:21])[N:5]([CH:6]([CH:9]([F:20])[CH2:10][CH2:11][OH:12])[CH:7]=[CH2:8])[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]12
Reactant: C=CC(C(F)CCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: C=CC(C(F)CCO)N1C(=O)c2ccccc2C1=O

Procedure:
Compound 18 prepared above (20.0 g, 56 mmoles) is dissolved in dry dichloromethane (Baker Blue Label) and treated with trimethylsilyliodide (11.2 g, 56 mmoles) overnight under nitrogen. The mixture is washed with NaHCO3, then with water, dried, and evaporated. The oil obtained, 19, is purified by filtration over silica, washing first with pet. ether (3 L), then with ethyl acetate: 15 g (about quantitative).
Reaction SMILES: N[C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].[CH2:21]=O.[C:23]([BH3-])#[N:24].[Na+]>CCOCC.C(O)(=O)C.C(#N)C>[CH3:21][N:24]([CH3:23])[C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: C=O
Reactant: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N(C)C
Reaction time: 2 h

Procedure:
A stirred solution of 4.6 gms. (0.0165 mole) of methyl 2-amino-3-benzoylphenylacetate and 13.2 ml. (0.165 mole) of 37% formaldehyde in 66 ml. of acetonitrile was treated wih 3.14 gms. (0.0495 mole) of sodium cyanoborohydride. Glacial acetic acid (1.65 ml.) was added over a ten minute period and stirring contained for 2.0 hrs. at room temperature. An additional 1.65 L ml. of glacial acetic acid was added and the mixture stirred over a weekend (co. 65 hours). The mixture was diluted with ether and the ether solution was successively washed with 3N potassium hydroxide solution, water, dried over sodium sulfate and concentrated under vacuum to give approximately 1.0 g. (18%) of a yellow oil. A portion of the oil was molecularly distilled for an analytical sample.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27](=[O:28])[CH2:26][CH2:25][C:24]2=[O:29])[CH2:19][CH2:18]1>C(O)CC(C)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:24](=[O:29])[CH2:25][CH2:26][C:27]3=[O:28])[CH2:19][CH2:18]2)[N:3]=1
Reactant: O=C1CCC(=O)N1C1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCC(N4C(=O)CCC4=O)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The mixture of 215 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 192.3 g of 1-(4-piperidinyl)-pyrrolidine-2,5-dione and 5,600 ml of isoamyl alcohol is stirred and refluxed for 22 hours. It is cooled to 20°, filtered and the residue washed once with 250 ml of cold ethanol and twice with 250 ml of diethyl ether each. The solids are suspended in 6000 ml of ethanol and 300 ml of water, the suspension heated to reflux, immediately cooled to 20° and filtered. The residue is washed with 300 ml of cold ethanol and 200 ml of diethyl ether, to yield the 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]-pyrrolidin-2,5-dione hydrochloride melting at 237° with decomposition.