Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[S:11](Cl)(Cl)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2=[N:9][S:11][N:10]=[C:4]2[CH:3]=1
Reactant: Nc1cc(F)c(Br)cc1N
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Fc1cc2nsnc2cc1Br
Yield: 76 %

Procedure:
4-Bromo-5-fluorobenzene-1,2-diamine (500 mg, 2.4 mmol) was dissolved in 20 mL chloroform, treated in portions with thionyl chloride (580 mg, 4.9 mmol) and heated to reflux for 20 h. After cooling the mixture was diluted with 60 mL ethyl acetate, washed with 15 mL water, 15 mL saturated NaCl, dried (Na2SO4) and concentrated under vacuum. The material was chromatographed on silica with a 0-30% ethyl acetate-hexane gradient to give the title compound as a white solid (425 mg, 76%): mp 79-82° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=6.7 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −102.91; EIMS m/z 232.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.Br[CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2>O1CCCC1>[CH3:10][O:9][C:6]1[C@H:7]([CH2:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[N:8]=[C:3]([O:2][CH3:1])[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: BrCc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
To a cooled solution (−70° C.) of (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (25.8 g, 140 mmol, 2 eq.) in tetrahydrofuran (200 mL) was added dropwise n-butyllithium (2.5 M, 64.4 mL, 161 mmol 2.3 eq.) and then stirred for 30 minutes. A solution of #210 (15.4 g, 70 mmol, 1 eq.) in tetrahydrofuran (150 mL) was added dropwise at −65° C. and then the solution was stirred for 2 hours at this temperature. The reaction was quenched by saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (Gradient: 10 to 16% ethyl acetate in petroleum ether) to afford #211 (7.3 g, 32%, over two steps) as yellow solid. LC-MS (Protocol Z): m/z 326.2[M+H+], retention time=0.88 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>CCCCO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cccc(Nc2cc(NCCO)ncn2)c1
Temperature: 200 °C
Yield: 84 %

Procedure:
100 mg of 6-chloro-N-(3-methoxyphenyl)pyrimidin-4-amine, 27 mg of ethanolamine and 119 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and to the evaporation residue obtained 5 mL of water were added. The mixture obtained was extracted with EtOAc, the phases were separated and the organic phase obtained was dried and subjected to evaporation. 2-(6-(3-Methoxyphenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][CH2:16][C:17](Cl)=[O:18].Cl>ClC(Cl)C>[Cl:15][CH2:16][C:17]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)=[O:18]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Temperature: 45 °C
Yield: 97.6 %

Procedure:
2-Oxindole (6.7 g) was added to a stirred suspension of 23 g of aluminum chloride in 30 mL of dichloroethane in an ice bath. Chloroacetyl chloride (11.3 g) was slowly added and hydrogen chloride gas was evolved. After ten minutes of stirring, the reaction was warmed to 40-50° C. for 1.5 hours. The mixture was cooled to room temperature and poured into ice water. The precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 10.3 g (98%) of 5-chloroacetyl-2-oxindole as an off-white solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][N:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=CC(C#C)=CN=1>>[C:1]1([S:7]([C:10]2[N:11]([CH3:16])[C:12]([C:18]#[CH:23])=[CH:13][N:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(I)cnc1S(=O)(=O)c1ccccc1
Reactant: C#Cc1ccc(Cl)nc1
Product: C#Cc1cnc(S(=O)(=O)c2ccccc2)n1C

Procedure:
2-benzenesulfonyl-5-ethynyl-1-methyl-1H-imidazole was prepared from 2-benzenesulfonyl-5-iodo-1-methyl-1H-imidazole in the same manner as 2-chloro-5-ethynyl pyridine (Example 1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCc1ccccc1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCc1ccccc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-(phenyl)ethylamine to provide yellow solid 3-nitro-4-[2-(phenyl)ethylamino]quinoline, the melting point of the crude product being 174°-180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[S:14][CH2:13][C:12]([C:18]([O:20]CC)=[O:19])=[CH:11]3)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[S:14][CH2:13][C:12]([C:18]([OH:20])=[O:19])=[CH:11]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CS3)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
To a solution of ethyl 6-(4-methylphenyl)-2H-thiochromene-3-carboxylate (2.12 g, 6.84 mmol) in tetrahydrofuran (20 ml) and acetonitrile (20 ml) was added dropwise 1N sodium hydroxide (7 ml), and the mixture was stirred at 60° C. for 2.5 hours. The solvent was evaporated, and the residue was dissolved in diethylether. The mixture was extracted with water. The organic layer was extracted with 0.5N sodium hydroxide, and both of the aqueous layers were made pH 3 with 6N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated to give 6-(4-methyl-phenyl)-2H-thiochromene-3-carboxylic acid (1.83 g, 95%) as yellow powder.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[F:36]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:40]1[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][C:35]([F:36])=[C:30]([F:29])[CH:31]=3)[CH2:42][CH2:41]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1F
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)c(F)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
700 mg (1.78 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 352 mg (1.78 mmol) of 1-(3,4-difluorophenyl)piperazine (Example 16A) and a spatula tip of silica gel are stirred in 20 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is then purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN(C)C=O.C(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:18])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(C(=O)Cl)s1

Procedure:
In a similar apparatus to Example 1, 15.7 g (0.1 mole) of 2,4-dimethylthiazole-5-carboxylic acid were suspended in 100 ml of toluene, followed by the addition of 0.1 g of N,N-dimethylformamide. Under heating and reflux, phosgene was blown at a rate of 1.3 l/hr for 5 hours (0.29 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 17.2 g of 2,4-dimethylthiazole-5-carboxylic acid chloride. Its purity and yield were 97.5% and 98.0%, respectively.
Reaction SMILES: [C:1](=[O:14])([O-])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=C(C#CCC)C=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCCCCC>C(OCC)(=O)C>[CH2:3]([O:2][C:1]([N:19]1[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]1)=[O:14])[CH2:8][C:7]#[CH:6]
Reactant: OC1CCNCC1
Reactant: CCC#Cc1cccc(OC(=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CCCOC(=O)N1CCC(O)CC1
Yield: 101.7 %

Procedure:
10.0 g of 3-butynylphenyl carbonate and 5.8 g of 4-hydroxypiperidine were heated in a solvent-free condition at 100° C. of 30 minutes. After completion of the reaction, silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1-1:2) was used for purification to obtain 10.6 g of the intended compound.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].O.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[CH2:14]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.6 %

Procedure:
To a solution of 2-mercaptobenzimidazole (4.95 g, 33 mmol) in methanol (150 mL) and 2N NaOH/H2O (50 mmol) was added octyl bromide (7.16 g, 33 mmol). The solution was stirred at ambient temperature for 72 hours, during which a suspension formed which was filtered and the solid residue dissolved in CH2Cl2, washed with saturated NaHCO3, and dried over Na2SO4. Evaporation of the solvent gave the title compound as a white solid (6.2 g, 72%). m.p. 110°-113° C. NMR CDCl3)δ7.4(m, 4H), 3.22(t, J=8 Hz, 2H), 1.20(br, 15H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:8](=[O:27])[C:7]3=[CH:28][N:29]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:5]([C:6]=23)=[N:4][CH:3]=1.[OH-:40].[Na+]>CO.C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[C@H:12]([NH:9][CH2:10][C:11]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[N:29]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:32])=[O:31])[CH:28]=[C:7]([C:8]([OH:40])=[O:27])[C:6]=12)[C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OCc2ccccc2)C(C)(C)C)C3=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OCc4ccccc4)C(C)(C)C)c(Cl)cnc32)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
Crude (R)-benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate was dissolved in MeOH/THF (50%, 5 mL). Aqueous NaOH (1N, 2 mL) was added. The reaction mixture was stirred at 50° C. for 16 h and was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (34 mg, 38.9% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 1.22-1.32 (m, 9 H) 4.92 (br. s., 1 H) 5.18 (d, J=18.95 Hz, 1 H) 5.33 (d, J=18.95 Hz, 1 H) 7.88 (s, 1 H) 8.29 (s, 1 H). [M+H] calc'd for C15H16ClN3O3, 322; found, 322.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[C:30]([CH3:31])=[CH:29][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([CH3:32])[CH:15]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[C:30]([CH3:31])=[CH:29][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:28])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([CH3:32])[CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(N)cc1C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(NS(=O)(=O)c2ccc(OC)cc2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A solution of 2.2 g (12.5 mmol) of para-methoxybenzenesulfonyl chloride in 10 mL of tetrahydrofuran is added over 10 minutes at 0° C. to a solution of 3.5 g (12.5 mmol) of 5-(4-amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester as the free base (Example 2) and 2.5 g (2×12.5 mmol) of triethylamine in 40 mL of tetrahydrofuran. The ice bath is removed and the solution is permitted to stir at ambient temperature for 24 hours. The triethylammonium chloride is removed by filtration, the solvent is removed; the residue is taken up in diethyl ether, and the solution washed with 2×25 mL of 2N hydrochloric acid solution, brine, dried (magnesium sulfate), and evaporated leaving 5.0 g of a colored oil which crystallizes on standing. Recrystallization from 35 mL of isopropyl ether in the presence of charcoal affords 3.3 g of the title compound as off-white crystals; mp 90°-92° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:18])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Cc1ccccc1O
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Cc1ccccc1Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methyl-phenol to give (1H-pyrazol-3-yl)-(1-o-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:25])=O>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([Cl:25])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)Cl

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I) is dissolved in THF and stirred at 20-25°. Oxalyl chloride (1 equivalent) is added and the mixture stirred for about 15 min to give t-butyl-(1S)-2-chloro-1-[3,5-difluorobenzyl]-2-oxoethylcarbamate (XI). The mixture is cooled to <0° and LiCHICl (greater than 2 equivalents) is added. The mixture is stirred until the reaction is complete. The reaction is quenched with water and the product is extracted into ethyl acetate. The combined organic phases are washed with saline, dried over sodium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C@@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(#N)C.CCOCC>[NH2:12][C:10]([C@@H:9]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15])[CH2:13][CH3:14])=[O:11]
Reactant: O=C(Cl)CCCCl
Reactant: CC[C@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC[C@H](NC(=O)CCCCl)C(N)=O
Temperature: 0 °C
Yield: 78.7 %

Procedure:
345.6 g (2.5 moles) of ground potassium carbonate are mixed with 138.5 g (1 mole) of (S)-2-amino-butanamide hydrochloride in 2.5 liters of acetonitrile. The reaction mixture is cooled to 0° C. and a solution of 129.2 g (1.2 mole) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 1.2 liter of anhydrous ether for 30 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 225 ml of ether and dried in vacuo to obtain 162.7 g of (S)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([S:4]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Cyclopropyl sulfonyl chloride (2 g, 14.2 mmol) was added drop-wise at 0° C. to a solution of Benzyl alcohol (2.1 g, 28.4 mmol) and Pyridine (2.35 g, 29.8 mmol) in DCM (20 mL) and continued stirring at 25° C. for 16 h. The reaction mixture was diluted with DCM (100 mL), washed with 1N aq.HCl solution followed by water and brine; Organic layer collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the Benzyl cyclopropanesulfonate. 1H NMR (300 MHz, CD3OD) δ ppm 4.3-4.1 (2H, t), 2.7-2.6 (1H, m), 1.8-1.6 (2H, m), 1.6-1.4 (2H, m), 1.2-1.1 (4H, m), 1.0-0.9 (3H, t).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: CSc1ccccc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (550 mg, 2.22 mmol) and 2-(methylthio)phenylboronic acid to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline. Mass Spectrum (ESI) m/e=336.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:18]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1)[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:39]O.Cl.O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:18]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[C:19]1[CH:20]=[CH:21][C:22]([OH:39])=[CH:23][CH:24]=1)[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: OO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4.0 g (7.50 mmol) of material from Step A above in 75 mL of tetrahydrofuran at 0° C. was added 1.25 mL of an aqueous solution of 30% hydrogen peroxide. After 1 h, the solution was allowed to warm up to ambient temperature and stirring continued for 2 h. The reaction mixture was acidified with 1N hydrochloric acid to pH 4. Additional water was added, and the aqueous layer was extracted with ethyl acetate (three times). The combined organic extracts were washed with saturated brine, dried (magnesium sulfate) and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (silica gel, methanol/ethyl acetate) to afford the title compound. LC-MS 424.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[CH2:12][CH2:11][CH2:10][O:9][C:6]2=[N:7][CH:8]=1.[Br:13]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[Br:13][C:8]1[N:7]=[C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]2=[N:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cnc2c(n1)CCCO2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc2c(nc1Br)OCCC2
Temperature: 60 °C

Procedure:
To a solution of 2-methoxy-6,7-dihydro-8H-pyrano[2,3-b]pyrazine (J. Chem. Soc. Perkin Trans. I 1988, 2585-2593; 3.16 g, 19.0 mmol) in N,N-dimethylformamide (95 mL) was added N-bromosuccinimide (5.08 g, 28.5 mmol) at room temperature, and then heated at 60° C. for 5 h. After being cooled to ambient temperature, the reaction mixture was diluted ethyl acetate, washed with 2% aqueous sodium sulfite, water, and saturated brine. The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 3-bromo-2-methoxy-7,8-dihydro-6H-pyrano[2,3-b]pyrazine. MS (APCI): m/z 247 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH3:25])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 2-methylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.62 minutes; C21H20Cl2N4O2 (431.32); mass spectrum: (M+H)+=431.2.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[C:6]([O:10][C:11](=[O:34])[CH2:12][N:13]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:26])=[CH:20][N:21]=[C:22]2Cl)=[CH:17][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]>CC(O)(C)C>[C:6]([O:10][C:11](=[O:34])[CH2:12][N:13]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:26])=[CH:20][N:21]=[C:22]2[NH:4][C:3]([NH2:5])=[NH:2])=[CH:17][CH:16]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)N
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 50 °C
Yield: 11.1 %

Procedure:
N-Benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)methyl]glycine bistrifluoroacetate ##STR76## NaH (48.6 mg, 80% dispersion in mineral oil, 1.62 mmol) was added to t-BuOH (5 mL) and heated to 50° C. for 15 min. Guanidine hydrocloride (155 mg, 1.62 mmol) was added and heated at 50° C. for an additional 20 min. N-Benzyl-N-[(1,4-dichloro-7-isoquinolinyl)methyl]glycine t-butyl ester (40 mg, 0.09 mmol) added and the mixture was then heated at 95° C. for 20 h. The cooled mixture was evaporated in vacuo and the residue purified by column chromatography on silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5), followed by trituration with hexane and crystallisation with i-Pr2O, to give N-benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)methyl]glycine t-butyl ester (5 mg, 0.01 mmol) as a white solid.