Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1C=CC=CC=1.N1C=CC=CC=1.C(O)(C)C>[C:1]1([O:7][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[CH2:9][Cl:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1ccccc1CCl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CC(C)O
Product: O=C(Oc1ccccc1)c1ccccc1CCl
Temperature: -20 °C
Reaction time: 4 h

Procedure:
The ester was prepared by Method C only, by dissolving 47 g (0.5 mole) of phenol in 60 ml of benzene in the apparatus used in the preparation of the para compound, adding 0.5 ml of absolute pyridine as catalyst, and then adding 95 g (0.5 mole) of undiluted o-chloromethylbenzoyl chloride drop by drop at 55° to 60° C. over a period of about 1 hour, the mixture being stirred for another 4 hours at the refluxing temperature to complete the reaction. The benzene was then distilled out of the clear, light red solution thus obtained. The viscous oily, clear, red residue obtained in a quantitative yield crystallized after standing for a while at -15° C. The crystal mass thus obtained was ground in a chilled mortar with about 100 ml of intensely cooled isopropanol; the undissolved portion was removed by suction filtering and washed with 100 ml of isopropanol chilled to -20° C. After drying, 87 g (70%) was obtained of a colorless crystallizate with a melting point of 39°-41° C. For the analysis, 15 g was dissolved at 35° C. in 125 ml of isopropanol and set aside to crystallize at -20° C. 12.7 g of colorless needles was obtained with a melting point of 39°-41° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methylacetophenone (2.02 mL, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 191-193° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 2.39 (s, 3H), 3.41 (m, 1H), 6.84 (s, 1H), 6.92 (m, 1H), 7.10 (m, 2H), 7.27 (m, 1H), 7.37 (m, 2H), 7.75 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH:20]=[O:21])=[CH:7]2.O.[CH2:23]1COCC1>>[OH:21][CH:20]([C:8]1[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:10](=[O:12])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH3:23]
Reactant: Cc1ccccc1-n1c(C=O)cc2cccc(C)c2c1=O
Reactant: C1CCOC1
Solvent: O
Product: Cc1ccccc1-n1c(C(C)O)cc2cccc(C)c2c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
8-Methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carbaldehyde 4101 (2.4 g, 8.6 mmol) was dissolved in anhydrous THF (280 mL) and cooled to −78° C. under a nitrogen atmosphere. Methyl MgBr (2 M, 5 mL, 10 mmol) was added slowly, and the resulting mixture was stirred at −78° C. for 2 h. H2O (5 mL) was added and then the solution was poured into ice-water (200 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue product was purified by flash column chromatography on silica gel (10-50% EA/PE) to afford the product, 3-(1-hydroxyethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one 4102 (1.8 g, 71% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6].O.N([O-])=O.[Na+].[N-:33]=[N+:34]=[N-].[Na+]>C(O)(=O)C.CCOC(C)=O>[N:1]([C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6])=[N+:33]=[N-:34]
Reactant: CCCN(c1cc(N)cc(C(=O)N[C@H](C)c2ccc(F)cc2)c1)S(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCN(c1cc(N=[N+]=[N-])cc(C(=O)N[C@H](C)c2ccc(F)cc2)c1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of 0.2 g (0.5 mmol) 3-amino-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide (Intermediate XXI) in 4 mL acetic acid was added 1 mL water followed by 0.038 g (0.55 mmol) sodium nitrite. After 2 minutes 0.035 g (0.055 mmol) sodium azide was added resulting in gas evolution. The reaction mixture was stirred for 30 minutes then diluted with 75 mL EtOAc, washed with 50 mL water, 50 mL 4M NaOH, 50 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica gel cartridge, 20-100% EtOAc/hexanes over 20 min) afforded 3-azido-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide. 1H NMR (CDCl3, 400 MHz) δ 7.45 (br t, J=1.47 Hz, 1H), 7.36 (m, 3H), 7.11 (t, J=2.01 Hz, 1H), 7.06 (m, 2H), 6.31 (br d, J=7.32 Hz, 1H), 5.28 (quint, J=7.14 Hz, 1H), 3.64 (t, J=7.15 Hz, 2H), 2.89 (s, 3H), 1.61 (d, J=6.96 Hz, 3H), 1.5 (m, 2H), 0.91 (t, J=7.33 Hz, 3H). LCMS [M+H]+=420.1
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[N:15]=[C:14]2[NH:16][C:17](=O)[N:18]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[C:19](=[NH:20])[C:13]2=[CH:12][N:11]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:9][C:10]1[N:15]=[C:14]2[N:16]([CH3:17])[C:1](=[O:4])[N:18]([C:21]3[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=3[Cl:27])[C:19](=[NH:20])[C:13]2=[CH:12][N:11]=1
Reactant: O=C([O-])[O-]
Reactant: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
484 mg of potassium carbonate and 456 mg of methyl iodide were added to a 5-mL N,N-dimethylformamide solution containing 1.00 g of the 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 1, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was added to ethyl acetate and a 0.5 N hydrochloric acid aqueous solution with stirring to separate the organic layer. After washing with saturated saline, the solution was dried with anhydrous sodium sulfate, and the solvent was distilled away. The crude product was solidified using chloroform-methanol-hexane, and 700 mg of a yellow solid was obtained as a subject compound.
Reaction SMILES: BrC1C=C2C(C(CC([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=O)=CN2)=CC=1.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41](=[O:47])[NH:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[C:35]2[CH2:48][C:49]([OH:51])=O>>[C:43]([NH:42][C:41]([C:36]1[NH:37][C:38]2[C:34]([C:35]=1[CH2:48][C:49]([NH:30][C:15]([NH2:14])=[N:16][CH2:17][C:18]1[CH:19]=[C:20]([Cl:29])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:22]([Cl:24])[CH:23]=1)=[O:51])=[CH:33][C:32]([Br:31])=[CH:40][CH:39]=2)=[O:47])([CH3:44])([CH3:46])[CH3:45]
Reactant: CC(C)(C)NC(=O)c1[nH]c2ccc(Br)cc2c1CC(=O)O
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CN=C(N)NC(=O)Cc2c(C(=O)NC(C)(C)C)[nH]c3ccc(Br)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetic acid (preparation I) in step 24 (A), the title compound was prepared. 1H-NMR (500 MHz, CD3OD) δ ppm 1.51 (s, 9 H) 2.20 (s, 3 H) 4.13 (s, 2 H) 4.54 (s, 2 H) 7.37 (m, 4 H) 7.84 (s, 1 H).
Reaction SMILES: C[CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1.[CH:16](N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:27]>CC(C)=O>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH:3]([CH3:16])[CH2:2][CH3:15])[C:26](=[O:27])[O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: CC(C)CNc1ccc2nc(S)sc2c1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CCC(C)N(C(=O)Oc1ccc(Cl)cc1)c1ccc2nc(S)sc2c1
Reaction time: 10 h
Yield: 23 %

Procedure:
Into a 50 ml round bottomed flask were added 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (100 mg, 0.42 mmol), acetone (10 ml), N,N-diisopropylethylamine (54.2 mg, 0.42 mmol) and 4-chlorophenyl chloroformate (78.8 mg, 0.42 mmol). The reaction mixture was stirred for 10 h, filtered, and the solid that was obtained was triturated with diethyl ether to afford 38 mg (48%) of the title compound. 1H NMR (DMSO-d6) δ=0.85 (d, 6H), 1.70 (m, 1H), 3.53 (br s, 2H), 7.12 (d, 2H), 7.31 (d, 1H), 7.41 (m, 3H), 7.79 (s, 1H); ESIMS: m/z 393 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of t-butyl 3-methoxy-4-nitrophenylacetate (0.144 g, 0.539 mmol) and 10% Pd on carbon (0.155 g) in ethyl acetate (8 mL) and methanol (2 mL) was stirred under H2 (40-60 psi) for 2 h. The mixture was filtered through Celite and the filtrate concentrated to afford t-butyl 4-amino-3-methoxyphenylacetate (0.123 g, 96%) as a light yellow oil: 1H NMR (CDCl3, 300 MHz, ppm) 6.70 (m, 3H), 4.04 (bs, 2H), 3.84 (s, 3H), 3.42 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>ClCCl.CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C1CCNCC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1.5 g, 5.8 mmol) was taken in dichloromethane (15 mL) and was cooled to 0° C. using an ice-bath; oxalyl chloride (0.61 mL, 6.9 mmol) was added drop-wise, catalytic amount (2 drop) of dimethyl formamide was added to the reaction mixture. After the addition, reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. To this residue, solution of Piperidine (0.68 mL, 6.9 mmol) in 4 mL DCM and DMAP (0.71 g, 5.8 mmol) was added under nitrogen at room temperature and reaction mass was stirred for 0.5 h at room temperature. The reaction mixture was quenched by ice water and extracted with Dichloromethane and purified by column chromatography to gives 0.8 g of desired compound as free base. The free base was converted into HCl salt by treatment with ethanolic HCl. Sodium hydride (0.8 g, 20 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.9 g, 12 mmol) in THF was added drop wise in react ion mixture. Then reaction mixture stirred at RT for 2 h. Reaction monitored by TLC. After completion of reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to give 1 g of desired compound then it was stirred with ethanolic HCl to give HCl salt of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@@H:8]([CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36])[S:32][CH:33]=1)[C:9](N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:10])(C)(C)C.[OH2:44].OO.O.[OH-].[Li+]>C1COCC1>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35]([NH:34][C:31]1[S:32][CH:33]=[C:29]([CH2:28][C@H:8]([CH2:7][C:6]([OH:5])=[O:43])[C:9]([OH:10])=[O:44])[N:30]=1)=[O:36]
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1)C(=O)O
Reaction time: 0.08 h

Procedure:
The protected amido acid, 4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butanoic acid tert-butyl ester: A solution of the product of section (f) of this example (57.5 mg, 0.10 mmol) in THF (1.5 mL) and H2O (0.5 mL) was cooled to 0°. A 30% aqueous solution of H2O2 (91.3 μL, 0.80 mmol of H2O2) and lithium hydroxide monohydrate (8.5 mg, 0.20 mmol) were added serially to the cooled solution. The mixture was stirred at 0° for 5 min and then at room temperature for 2.5 h. Excess H2O2 was quenched by the addition of a 1.5M aqueous solution of Na2SO3 (as judged by a KI stick indicator). The resulting mixture was diluted with H2O and washed with CH2Cl2 (3×). The aqueous layer was rendered acidic with 1N aqueous HCl and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to dryness to yield the desired monoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of 2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}-methyl}butanedioic acid. The monoprotected dicarboxylic acid was used for the following coupling step without purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](CCN)=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCN)cc1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=S)Nc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(4-methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.1 g (67%) of the titled product as a white solid:
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[C:3]([F:13])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCCI
Reactant: O=C1COc2ccc(F)c(F)c2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2ccc(F)c(F)c2N1CCCCl
Yield: 72 %

Procedure:
5,6-Difluoro-4H-benzo[1,4]oxazin-3-one (0.13 g, 0.69 mmol), Cs2CO3 (0.45 g, 1.4 mmol), and 1-chloro-3-iodopropane (0.15 g, 0.76 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.13 g, 75%). Rf=0.60 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 6.88-6.74 (m, 2H), 4.52 (s, 2H), 4.19-4.14 (m, 2H), 3.58 (t, J=6.4 Hz, 2H), 2.22-2.14 (m, 2H); 13C NMR (CDCl3) δ 165.1, 147.5 (dd, J=242.5 Hz, J=12.7 Hz), 143.8 (t, J=3.0 Hz), 140.7 (dd, J=249.8 Hz, J=17.3 Hz), 119.8 (d, J=4.6 Hz), 111.9 (dd, J=7.4 Hz, J=3.9 Hz), 111.2 (d, J=18.8 Hz), 68.4, 42.4 (d, J=9.7 Hz), 42.1, 31.1 (d, J=3.5 Hz).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]2=[N:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH:16]([Mg]Cl)([CH3:18])[CH3:17].[Cu](C#N)C#N.C(Br)C=C>C1COCC1.[Cl-].[Na+].O>[Cl:11][C:10]1[C:5]2[N:6]([C:2]([CH2:18][CH:16]=[CH2:17])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)c1nc2c(Cl)nccn2c1Br
Reactant: CC(C)[Mg]Cl
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C=CCBr
Product: C=CCc1c(C(=O)OC)nc2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
To a suspension of methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (250 mg, 0.861 mmol) in THF (8.6 mL) cooled to −40 C was added isopropylmagnesium chloride (0.99 mL, 1.29 mmol) dropwise. After 1 h stirring, copper cyanide (7.7 mg, 0.09 mmol) and allyl bromide (0.15 mL, 1.7 mmol) were added and the mixture was warmed to r.t. After 1 h, the reaction was poured into brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified on silica (gradient elution, 0-80% EtOAc/hexanes) to yield the title product (48 mg). HRMS (ESI) calc (M+H)+=252.0534. found 252.0539.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)[CH:18]=2)[C:13]([Cl:28])=[CH:12][N:11]=1>CN1C(=O)CCC1>[Cl:28][C:13]1[C:14]2[C:19](=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([NH:7][C:6]([NH2:8])=[NH:5])=[N:11][CH:12]=1
Reactant: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 84848.5 %

Procedure:
A stirred suspension of guanidine carbonate (720 g, 4.0 mol) in NMP (5 L) was heated to 130° C. under N2 for 1 hour. The suspension was cooled to room temperature and 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (1.0 kg, 3.3 mmol) was added as a solid. The mixture was heated at 130° C. for 4 hours, cooled to room temperature, filtered through a pad of clarcel. Water (6.7 L) was added to the filtrate. The resultant slurry was cooled to 5° C., stirred for 1 hour and the solid collected by filtration. The solid was washed with a mixture of NMP:water (1:1, 4 L) and water (4 L) and dried in vacuo at 50° C. to give (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidine (900 g, 2.8 mol, 85%) as a green solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:14][OH:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CN.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>C1COCC1>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:1][C:2]1([CH2:14][OH:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[O:22]
Reactant: COc1ccc2c(c1)CCCC2(N)CO
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring mixture of 2.0 g (0.00965 mol) of the product of Step C, 976 mg (0.00965 mol) of methylamine in 30 mL of THF at 0° C. was added dropwise a solution of 2,6-difluorobenzoylchloride in 15 mL of THF. The reaction mixture was stirred at ambient temperature for 30 minutes. The precipitated triethylamine hydrochloride was filtered off and the filtrate concentrated. It was purified by passing through a silica gel column eluting with EtOAc:Hexane (2:3) to afford a white solid: mp 174°-175° C. 1H NMR (CDCl3) d 7.30 (m, 2H), 6.90 (t, 2H), 6.85 (dd, 1H), 6.60 (d, 1H), 6.35 (broad s, 1H), 4.80 (dd, 1H), 4.20 (dd, 1H), 3.77 (s, 3H), 3.75 (d, 2H), 2.80 (m, 2H), 2.30 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]2[CH2:20][O:21][CH3:22].CI.[C:30](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:30])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]2[CH2:20][O:21][CH3:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2c(Cl)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of ethyl 4-chloro-1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.14 g), methyl iodide (0.33 ml), potassium carbonate (0.37 g) and N,N-dimethylformamide (10 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried to give the title compound (1.10 g, yield 93%) as colorless crystals. melting point 137-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[OH2:13]>OO.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([OH:13])[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O
Agent: OO
Solvent: CCO
Product: COc1ccc(Cl)cc1O

Procedure:
A solution of 5-chloro-2-methoxy benzeneboronic acid (1.9 g, 10 mmol) in hydrogen peroxide (2.04 ml, 30% solution) and ethanol 40 ml was refluxed for 30 min. Water was added and the product was extracted with two portions of ethylacetate. Drying over magnesium sulfate and evaporation of the solvent gave the product as an oil. Yield 1.05 g, 65%.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][N:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH:33]=[CH2:34]>>[CH2:32]([N:35]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][N:24]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[C:17]=1[CH3:25])[CH:33]=[CH2:34]
Reactant: C=CCNC1CCCCC1
Reactant: Cc1c(C(=O)O)ccnc1N1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Product: C=CCN(C(=O)c1ccnc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1C)C1CCCCC1
Yield: 68.1 %

Procedure:
Step (d) of Example 107 was repeated, except that the compound (50 mg) prepared in step (c) of Example 109 and allylcyclohexylamine (34 mg) were used as the starting compounds. Thus, the title compound (44 mg) was obtained.