Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc2c(-c3ccccc3)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(-c6ccccc6)cccc5s4)cc3CC[C@@H]12
Yield: 61.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-phenylbenzothiazole (113 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 110 mg (61%) of the title compound as an amorphous foam. FDMS: m/e=470. α[D]589 =+53.51 (c=0.66, chloroform).
Reaction SMILES: CN(C)CCN(C)C.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([Li])CCC.CON(C)[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C1CCCCC1>[SH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: Sc1ccccc1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: O=C(c1ccccc1)c1ccccc1S
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of N,N,N',N'-tetramethylethylene diamine (4.4 g, 0.038 mol) and thiophenol (2 g, 0.018 mol) in cyclohexane (40 mL) was added dropwise n-butyllithium (24 mL, 0.038 mol) at room temperature. The suspension was stirred under nitrogen for 16 hours, followed by the dropwise addition of N-methoxy-N-methylbenzamide (3.3 g, 0.019 mol). After stirring for 20 minutes, the reaction mixture was added to cold aqueous HCl (1N). The product was partitioned between ethyl acetate and the acidic solution. The layers were separated and the organic portion was washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The liquid obtained was purified using silica gel chromatography (75% hexane/25% ethyl acetate) to give 2.3 g of the title compound a as a viscous yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Reactant: OB(O)c1ccncc1
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: COCCOC
Product: O=C(Nc1cccnc1)c1cc(-c2ccncc2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-([(3,4-difluorophenyl)methyl]oxy)-N-3-pyridinylbenzamide (may be prepared as described in Example 60; 120 mg, 0.29 mmol), 4-pyridinylboronic acid (52.8 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium(0) (19.85 mg, 0.02 mmol), sodium carbonate (0.57 ml, 0.57 mmol) and 1,2-dimethoxyethane (3 ml). The mixture was sealed and heated to 120° C. for 1 hr under microwave conditions. The 1,2-dimethoxyethane was evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 23.5 mg.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cn(-c2cc(F)ccc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.4 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (50 g, 314 mmol), 4-methyl-1H-imidazole (25.7 g, 314 mmol) and potassium carbonate (100 g, 725 mmol) in dichloromethane (600 mL) was stirred at room temperature for 4 days. The mixture was washed with water then dried over magnesium sulfate. Solvent was removed under reduced pressure and the residue was recrystallized in ethyl acetate to provide product 1A as a yellow solid (35 g, 50% yield). EIMS 221.9 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[O:5]/[C:6](/C)=[CH:7]/[CH2:8]O)[CH3:3].[CH3:17][C:18](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:19].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.CCOCC>[CH3:16][CH:14]([Si:4]([CH:2]([CH3:1])[CH3:3])([CH:11]([CH3:12])[CH3:13])[O:5][CH2:6]/[C:7](/[CH3:8])=[CH:17]/[CH:18]=[O:19])[CH3:15]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: C/C(=C\CO)O[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(=C\C=O)CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a room temperature solution of (E)-3-[tris-(1-methylethyl)silyloxy]but-2-en-1-ol (crude from the previous step, assumed 17.6 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (9.7 g, 22.9 mmol). The resulting suspension was stirred for 60 minutes, until the reaction was judged to be complete by TLC. The reaction mixture was diluted with Et2O and a saturated aqueous solution of NaHCO3 containing Na2S2O3 was added. This mixture was stirred vigorously until both layers became clear. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5% Et2O/pentane) to afford the title compound as a colorless oil (3.69 g, 82% yield). IR (film) 2944, 2867, 1681, 1464, 1384, 1123 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.09 (d, 1H, J=8.3 Hz, CHO), 6.28 (dd, 1H, J=1.5, 8.4 Hz, CH), 4.28 (d, 2H, J=0.9 Hz, CH2OTIPS), 2.09 (d, 3H, J=0.6 Hz, CH3C), 1.1 to 1.0 (m, 21H, TIPSO); 13C NMR 75 MHz, CDCl3) δ 191.2, 161.6, 124.1, 67.0, 18.0, 14.1, 11.9; HRMS (EI+) exact mass calculated for [M]+(C14H28O2Si) requires m/z 256.1859, found m/z 256.1862.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C1COCC1>[CH3:29][S:30]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 57 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with methanesulfonyl chloride (0.012 mL, 0.15 mmol) and Et3N (0.021 mL, 0.15 mmol) in THF (3 mL) at 23° C. for 23 h. Obtained as a yellow solid (38 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.O>CN(C=O)C>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][CH2:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:41]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 36.6 %

Procedure:
To a solution of Intermediate A (179 mg, 1.10 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 120 mg, 3.00 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 92b (958 mg, 1.10 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.5 h. The solution was cooled, water added, and the mixture extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-16% MeOH in DCM, to give the title compound as a brown gum (216 mg, 37%). LCMS (Method 3): Rt 3.08 min, m/z 536 [MH+].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]=1[O:15][CH3:16])[N:4]=[C:3]([CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[N:4]=3)[CH2:21][CH2:20]1)[CH:12]=[CH:11]2
Reactant: COc1cc2ccc(CCl)nc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2ccc(CN3CCN(Cc4ccc5cc(OC)c(OC)c(OC)c5n4)CC3)nc2c(OC)c1OC

Procedure:
2-Chloromethyl-6,7,8-trimethoxyquinoline (336 mg) and piperazine (54 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:21])[CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16])[CH3:11].N1C=CC=CC=1>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15]([CH3:16])=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:18]=1[CH3:19])=[O:21])[CH3:11]
Reactant: NNC1CCCCC1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(C2CCCCC2)c1C

Procedure:
Similar to Example 1, equimolar amounts of cyclohexyl hydrazine hydrochloride and 2-acetyl-3-oxobutyric Acid Ethyl Ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 66° C.-67° C.).
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:4]=1)#[N:13]
Reactant: N#Cc1cn(CCl)c2ccccc12
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cn(CC(C#N)(C#N)CCC(F)(F)F)c2ccccc12
Yield: 52.5 %

Procedure:
1.70 g of 1-(chloromethyl)-3-cyano-1H-indole and 1.45 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 27 ml of N,N-dimethylformamide. 2.49 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.48 g of [{3-cyano-1H-indole-1-yl}methyl] (3,3,3-trifluoropropyl) malononitrile (referred to as the compound of the present invention (39), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.[ClH:39]>CO.CCOCC>[ClH:39].[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (82 mg, 0.16 mmol) was treated with 1.25 M HCl in MeOH (5.0 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with Et2O, and the resulting solids were collected by filtration to provide the title compound (55 mg, 76%) as a yellow solid: 298-302° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 9.30 (br s, 1H), 9.15 (t, J=1.0 Hz, 1H), 8.42-8.34 (m, 2H), 8.13 (d, J=8.0 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.13 (dd, J=7.0, 2.0 Hz, 1H), 4.39 (s, 2H), 3.74 (s, 3H), 3.60-3.51 (m, 2H), 3.15 (t, J=6.0 Hz, 2H); ESI MS m/z 426 [M+H]+; HPLC (Method A) 98.8% (AUC), tR=13.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:13][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]2[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[CH:21]=1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: c1ccncc1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1cccnc1

Procedure:
This salt is stirred under nitrogen and anhydrous conditions for 1 hour with 6.5 ml of pyridine and 1.5 g of [o-(2,6-dichloro-anilino)-phenyl]-acetic acid at 20°-30°C and the mixture is then evaporated in vacuo at a maximum temperature of 40°C. The residue is dissolved in 50 ml of ether and while cooling with ice, washed with saturated potassium hydrogen carbonate solution, 1 N-hydrochloric acid, and with ice water. The bulk of the [o-(2,6-dichloro-anilino)-phenyl]-acetic acid-3-pyridyl ester remains in the ether layer and, after this latter has been dried with magnesium sulphate and evaporated in vacuo, is obtained therefrom as a pale brown oil which crystallises on trituration. The new ester contains as impurity 1-(2,6-dichloro-phenyl)-2-hydroxy-indole from which it can be separated by being dissolved in ether/petroleum ether 1:1 and filtered through a silica gel column. The [o-(2,6-dichloro-anilino)-phenyl]-acetic acid-3-pyridyl ester is obtained from the filtered ether/petroleum ether solution (evaporation in vacuo) in the form of colourless crystals which, after precipitation with petroleum ether from an ethereal solution, melt at 84°-86°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:9]=2)[C:5]([CH3:15])([CH3:14])[CH2:6]1)(=[O:13])[CH3:12]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CC(C)(C)c2cc(Br)ccc21
Product: CC(=O)N1CC(C)(C)c2cc(Br)c(S(=O)(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(5-Bromo-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (2.0 g, 7.5 mmol) was slowly added to chlorosulfonic acid (20 mL) and the resulting solution was stirred at room temperature for 3 days. The mixture was then carefully poured over ice and the resulting solid filtered, washed with water and dried in vacuo to give the title compound (2.7 g) as a pale brown solid. 1H NMR (Acetone-d6): 9.02 (1H, s), 7.89 (1H, s), 4.11 (2H, s), 2.26 (3H, s), 1.49 (6H, s).
Reaction SMILES: [OH:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].[Na]>ClCCl.CN(C)C1C=CN=CC=1>[C:38]([O:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4])(=[O:40])[CH3:39]
Reactant: Cc1cc(C)cc(Cc2c(C(C)C)c(=O)[nH]c(=O)n2COCCCN(O)C(N)=O)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON(CCCOCn1c(Cc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O)C(N)=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 1-(3-N1-hydroxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil obtained in the above Example 1-C (85 mg, 0.2 mmol) in dichloromethane (3.5 ml), was added DMAP (4-dimethylaminopyridine) (5 mg, 0.04 mmol), triethylamine (45 μl, 0.3 mmol) and acetic anhydride (25 μl, 0.24 mmol) and the mixture was stirred for 3 hours at 20° C. Then, it was added thereto dichloromethane (5 ml) and an aqueous saturated sodium hydrogenocarbonate solution (5 ml). The reaction medium was then extracted with dichloromethane (50 ml) and the organic phase was washed with water (10 ml) and then with a saturated sodium chloride solution (10 ml) and dried (sodium sulfate). The organic phase was then concentrated and subjected to a flash column chromatography on silica gel (dichloromethane/methanol 9:1) to give 70 mg (75%) of the desired 1-(3-N1-acetoxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil in the form of a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(C(=O)O)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 80.4 %

Procedure:
To a solution of methyl 6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.05 g, 11 mmol) in methanol (30 mL) was added an aqueous solution (10 mL) of lithium hydroxide monohydrate (1.38 g, 33 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, and, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (3.94 g, 80.5%) as crystals.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.P(Cl)(Cl)(Cl)=O.O.CN([CH:19]=[O:20])C>>[N:1]1[CH:2]=[C:3]([CH:19]=[O:20])[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12
Reactant: CN(C)C=O
Reactant: c1cn2ccnc2cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Imidazo[1,2-a]-pyrazine (0.30 g, 2.5 mmol) was dissolved in anhydrous DMF (10.0 mL) and added to a preformed solution of phosphorous oxychloride (0.26 mL, 2.8 mmol) in anhydrous DMF (10.0 mL). The solution was allowed to stir 72 h under nitrogen at RT. The solution was then poured into water (100 mL) and residual organics extracted with diethyl ether (3×30 mL). The remaining aqueous portion was concentrated to dryness under a nitrogen stream to yield the title compound (0.050 g). MS (ESI+) for m/z 148 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of Compound 45 (1.0 g, 3.2 mmol) in dichloromethane was added slowly to a stirred solution of piperazin (826 mg g, 9.59 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water sonicated briefly and filtered. The solid was dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.1 g (96%) yellow solids. M.P. 162° C. 1H NMR (DMSO-d6): δ 2.70 (s, 1H), 2.94 (m, 4H), 3.53 (m, 4H), 5.47 (s, 2H), 7.19–7.25 (m, 3H), 7.42 (m, 2H), 7.51 (dd, J=4.3, 9.3 Hz, 1H), 7.54 (td, J=2.4, 8.0 Hz, 1H), 7.58 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 363 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1coc2c1C(=O)CC(c1ccc(Br)cc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1ccc(Br)cc1)C2
Yield: 63.9 %

Procedure:
A mixture of 3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.049 ml), water (0.049 ml) and ethanol (30 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 35) (0.25 g) as colorless crystals.