Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=[O:13])[C:5]([CH3:20])=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30].[OH-].[Na+].O1CCOCC1.FC(F)(F)C(O)=O>O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([OH:14])=[O:13])[C:5]([CH3:20])=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
A mixture of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (0.40 g, 0.00084 mol, from Step 4), and 1.5 N NaOH (0.7 mL, 0.042 g, 0.001 mol) containing dioxane (0.5 mL) is stirred at 55° C. for 30 min. The resulting clear brown solution is cooled in an ice bath, diluted with water (3 mL), acidified with trifluoroacetic acid, and the product is purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=465) are combined and freeze-dried to afford the title compound (0.17 g, 44%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.6 Hz), 7.54 (m, 2H), 6.99 (m 2H), 5.56 (s, 2H), 2.15 (s, 3H), and 2.13 (s, 3H); ES-HRMS m/z 465.0256 (M+H calcd for C20H16N2O4F2Br requires 465.0256); 19F NMR (CD3OD/400 MHz) −111.89 (m) and −115.95 (m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>P(Cl)(Cl)(Cl)=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:17][C:16]([NH2:18])=[N:15][N:14]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)c1ccc2cnccc2c1
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2ccc3cnccc3c2)s1
Temperature: 80 °C

Procedure:
Commercially available isoquinoline-6-carboxylic acid (15.4 g, 89 mmol) and thiosemicarbazide (12.2 g, 133 mmol) were mixed in 150 ml phosphorus oxychloride. The mixture was heated at 80° C. for 60 hours. After removing the excess phosphorus oxychloride via rotatory evaporation at a reduced pressure, the remaining residue was mixed with ice water and the pH increased to pH 12 with KOH. After filtration and washing with water, a yellow amorphous solid 1a was obtained as the crude product (17 g, y (yield)=85%). It was used directly for next step. A pure sample of the product was obtained by subjecting the crude product to a silica gel column chromatography with a gradient of 1-5% 2M NH3 methanol solution in dichloromethane as the eluent. 1H NMR (400 MHz, DMSO-d6): δ 7.73 (s, 2H), 8.02 (d, J=6 Hz, 1H), 8.27 (m, 2H), 8.38 (s, 1H), 8.66 (d, J=6 Hz, 1H), 9.45 (s, 1H). MS (API-ES) m/z (%): 229 (100%, M++1).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[CH2:14][CH2:13][C:12]3[NH:11][C:10](=O)[CH2:9][CH2:8][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:15]2[CH2:14][CH2:13][C:12]3[NH:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2=C(CCc3c(Cl)cccc32)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cccc2c1CCC1=C2CCCN1

Procedure:
4.0 g of 7-chloro-1,2,5,6-tetrahydrobenzo[f]quinolin-3(4H)-one were added portionwise within 35 minutes at between 20° and 25° to a suspension, stirred under nitrogen, of 1.30 g of lithium aluminum hydride in 60 ml of dry tetrahydrofuran. The reaction mixture was subsequently heated to boiling under reflux for 150 minutes, then cooled and thereupon treated at between 0° and 10° with 4.2 ml of 6.5N sodium hydroxide solution. The resulting suspension was filtered, whereupon the filter residue was rinsed with 5×20 ml of tetrahydrofuran each time and the filtrate was evaporated in vacuo. The thus-obtained crude 7-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline was taken up in 10 ml of pyridine and 9.0 ml of acetic anhydride. The reaction mixture was left to stand at room temperature for 20 hours, evaporated, the residue remaining behind was taken up twice in 50 ml of dry toluene and the solutions obtained were evaporated to dryness. The residue was dissolved in methylene chloride and chromatographed on 70 g of silica gel (particle size 0.04-0.063 mm). The 4-acetyl-7-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline, eluted with chloroform, exhibits a melting point of 89°-90° after recrystallization from isopropyl ether.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9](=[O:18])[C:8]1=[O:19]>>[CH3:17][N:10]1[C:11]2[C:16](=[CH:15][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=2)[N:7]([CH3:6])[C:8](=[O:19])[C:9]1=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1c(=O)c(=O)n(C)c2ccccc21
Product: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (3 mL) was heated to 65° C. and 1,4-dimethylquinoxaline-2,3(1H,4H)-dione (example 6-3b, 1 g, 5.5 mmol) was added in portions over 0.5 hour. The reaction mixture was stirred for 4 hours then cooled to ambient temperature and poured slowly onto ice. The resulting precipitate was filtered and washed with water to give 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.50 (s, 6H), 7.25 (m, 2H), 7.38 (m, 4H).
Reaction SMILES: Cl[CH:2]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:18][CH3:19])[C:8]([O:16][CH3:17])=[N:9]2)[CH3:3].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:13]1[C:4]([CH:2]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH3:3])=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:15])[N:9]=[C:8]([O:16][CH3:17])[C:7]([O:18][CH3:19])=[N:6]2
Reactant: c1c[nH]cn1
Reactant: COc1nc2cc(Cl)c(Cl)c(C(C)Cl)c2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc2cc(Cl)c(Cl)c(C(C)n3ccnc3)c2nc1OC
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 5-(1-chloroethyl)-6,7dichloro-2,3-dimethoxyquinoxaline (95 mg, 0.295 mmol), imidazole (22 mg, 0.325 mmol), anhydrous potassium carbonate (45 mg, 0.325 mmol) in dry dimethylformamide (10 mL) was heated under nitrogen at 100° C. for 6 hours, cooled, and partitioned between brine and three portions of ethyl acetate. The combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution with dichloromethane:mehanol) to give 6,7dichloro-2,3-dimethoxy-5-(1-imidazol-1-ylethyl)quinoxaline (60 mg, 58%); as a yellow solid.
Reaction SMILES: C(N1CCOCC1)C.[NH:9]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:10]([C:15]([OH:17])=O)[C@H:11]([CH2:13][CH3:14])[CH3:12].[NH2:28][C@H:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[NH:9]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:10]([C:15]([NH:28][C@H:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:17])[C@H:11]([CH2:13][CH3:14])[CH3:12]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
1.3 ml of N-ethylmorpholine are added to the solution of 2.65 g of Z-Ile-OH, 2.58 g of H-Phe-OBut and 1.35 g of HOBt in 30 ml of dimethylformamide and 2.2 g of DCC are added to 0° C. The mixture is allowed to stand for 1 hour at 0° C. and overnight at room temperature. On the following day the precipitate is filtered off and the filtrate is concentrated. The residue is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking with 20 ml of saturated NaHCO3 solution, 20 ml of K2SO4 /KHSO4 solution and 20 ml of NaHCO3 solution and is dried over Na2SO4 and concentrated. The product crystallizes from petroleum ether. Yield 3.7 g, melting point 122°-125°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)CC)(=O)[CH2:19][CH3:20].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH2:19][CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Intermediate 1 (2.0 g, 6.86 mmoles) was taken in a RB flask and to this triethylamine (16 ml) and propionic anhydride (2.80 g, 21.50 mmoles) were added and the mixture was refluxed for 22 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.78 g, 31% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.10(d, J=2.4Hz, 1H), 7.97(dd, J=8.9, 2.4 Hz, 1H), 7.68(d, J=8.9Hz, 1H), 7.46(m, 3H), 7.27(d, J=6.9Hz, 2H), 2.55(q, J=7.5Hz, 2H), 1.19(t, J=7.5Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:7]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:6]([CH3:41])[N+:5]=1[O-])([CH3:3])[CH3:2].[C:43]([O:46]C(=O)C)(=[O:45])[CH3:44]>>[C:43]([O:46][CH2:41][C:6]1[C:7]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:9]([CH2:10][O:11][Si:12]([C:25]([CH3:26])([CH3:28])[CH3:27])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCc1c(-c2ccc(F)cc2)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(C)C)[n+]([O-])c1C
Product: CCCCCc1c(COC(C)=O)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
A mixture of the intermediate obtained in Example 199, Step B (4.8 g, 7.97 mmol) and acetic anhydride (20 mL) was heated to 100° C. for 20 min. The mixture was poured onto ice and the aqueous phase extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution (3×50 mL), and saturated aqueous sodium chloride solution (3×50 mL). Silica gel chromatography provided a yellow oil (4.4 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.40 (m, 6H), 7.31 (m, 4H), 7.06 (m, 4H), 5.29 (s, 2H), 4.26 (s, 2H), 3.14 (sept, 6.8 Hz, 1H), 2.2 (m, 2H), 2.18 (s, 3H), 1.2 (m, 2H), 1.16 (d, 6.6 Hz, 6H), 1.05 (m, 4H), 0.99 (s, 9H), 0.77 (t, 6.8 Hz, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:7]([C:9]2[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=2[Cl:15])=O)[CH2:6][CH2:5]1>C1COCC1>[Cl:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[NH:2][N:3]=[C:7]([CH:4]3[CH2:6][CH2:5]3)[C:9]=12
Reactant: O=C(c1c(Cl)ncnc1Cl)C1CC1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]nc(C3CC3)c12
Reaction time: 4 h

Procedure:
Add hydrazine hydrate (2.67 g, 53.4 mmol) slowly to cyclopropyl-(4,6-dichloro pyrimidin-5-yl)-methanone (9.66 g, 44.5 mmol) dissolved in 300 mL THF at room temperature and stir for 4 hours. Upon completion, partition the reaction mixture between water and ethyl acetate, collect the organic layer, wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate under vacuum. Purify the resultant title compound by passing through a short silica gel (60-120 mesh) pad using Chloroform/methanol (97:3) as eluent.
Reaction SMILES: O[C:2]1[C:7]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].C(OC(=O)C)(=O)C>>[CH3:20][CH:16]1[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:2]=2[O:18][C:17]1=[O:19]
Reactant: Cc1ccccc1Sc1cccc(C(C)C(=O)O)c1O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1Sc1cccc2c1OC(=O)C2C
Yield: 74.7 %

Procedure:
A mixture of 2-[2-hydroxy-3-(o-tolylthio)phenyl]propionic acid (2.0 g) and acetic anhydride (5 ml) was refluxed under heating and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, benzene) to give 3-methyl-7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one (1.4 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[CH3:19][N:17]([CH3:18])[C:15]([NH:14][CH:11]([CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1)[CH2:12][CH3:13])=[O:16]
Reactant: CCC(NC(=O)N(C)C)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCC(NC(=O)N(C)C)C1CCC(=O)CC1

Procedure:
A solution of 1-(1-1,4-dioxaspiro[4.5]decan-8-ylpropyl)-3,3-dimethylurea (as prepared in the previous step, 36 mg, 0.13 mmol, 1.00 equiv) in CH3CN (5 mL) and HCl (2M, 1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[N:29]=[CH:28]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)C=NC(=O)O1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)cc2)CC1
Yield: 28.3 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 97 and 5,5-dimethyloxazolin-2-one (138 mg) described in Preparation Example 43, the title compound (123 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH3:9].[C:11]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:23][CH2:22]1)=[O:19].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:29](=[O:30])[CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:18](=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:22][CH2:23]1
Reactant: CNCCCC(=O)OC
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 127.4 %

Procedure:
To a stirred mixture of 4-methylaminobutyric acid methyl ester hydrochloride (546 mg, 3.26 mmol) and 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (1.20 g, 3.26 mmol) in DCM (15 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.36 g, 3.58 mmol) followed by N,N-diisopropylethylamine (1.42 mL, 8.15 mmol). LC-MS (Method 2-90) showed product was present (Rt 3.11 min; m/z 482.4 [M+H]+). Water and DCM were added and the layers were separated. The organic layer was washed with water (2×) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.0 g, 100% yield) as a light yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH3:26][O:27][CH2:28]Cl>C(OCC)C.O.C1COCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26][O:27][CH3:28])[CH2:23][CH2:24][CH3:25]
Reactant: COCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)COC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of diisopropylamine (9.4 mL) and THF (150 mL) was added n-butyl lithium (2.4M n-hexane solution, 25 mL) by drops at −78° C., which was stirred for 30 minutes at the same temperature. Tributyltin hydride (16 mL) was added dropwise to the reaction mixture at the same temperature, after which the reaction mixture was stirred for 30 minutes under ice cooling. The reaction solution was cooled to −78° C., then chloromethyl methyl ether (4.6 mL) was added dropwise thereto, and then which was gradually warmed to room temperature. Water (100 mL) and diethyl ether (300 mL) were added to the reaction solution, and the organic layer was washed with saturated brine, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=30:1) to obtain the titled compound (18 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:20])[CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[O:20][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OC)c([N+](=O)[O-])c(OCc2ccccc2)c1
Yield: 84.7 %

Procedure:
In DMF (10 ml), 3-benzyloxy-5-methoxy-4-nitrophenol (1.43 g, 5.20 mmol), potassium carbonate (1.08 g, 7.79 mmol) and methyl bromoacetate (591 μl, 6.24 mmol) were stirred at room temperature for 2 days. The reaction mixture was poured in water (200 ml), followed by extraction with ether (200 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (20:1) eluate fractions, the title compound (1.53 g, 85%) was obtained as a yellow crystalline solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:29][C:30]([NH2:32])=[NH:31])=[N:5][CH:4]=1.Cl.NC(N)=N.[C:38](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)[C@@H](C1C=CC=CC=1)C)([CH3:41])([CH3:40])[CH3:39]>COCCOC>[C:38]([O:19][C:18](=[O:20])[CH2:17][N:16]([S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:11][CH:10]=1)(=[O:14])=[O:15])[C@@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: C[C@H](c1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: COCCOC
Product: C[C@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 57.5 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1R)-1-phenylethyl]glycine hydrochloride ##STR28## NaH (30 mg, 80% dispersion by wt in mineral oil, 1.01 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (154 mg, 1.61 mmol) in DME (6.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-[(1R)-1-phenylethyl]glycine t-butyl ester (200 mg, 0.40 mmol) in DME (3.0 mL) was added and the mixture heated at 95° C. for 5 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using pentane-EtOAc (50:50 to 33:66) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1R)-1-phenylethyl]glycine t-butyl ester (125 mg, 0.23 mmol) as pale yellow foam after repeated evaporation from CH2Cl2.
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][C:10]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:11][CH:12]=[C:5]2[C:4]1=[O:24].[Na].[SH:26][C:27]1[N:31](C2C=CC=CC=2)[N:30]=[N:29][N:28]=1>O1CCCC1>[C:5]1([CH:2]([S:26][C:27]2[NH:31][N:30]=[N:29][N:28]=2)[N:3]2[C:7](=[O:8])[C:6]3=[CH:9][C:10]([NH:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])=[CH:11][CH:12]=[C:5]3[C:4]2=[O:24])[CH:6]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3c(c2)C(=O)N(CBr)C3=O)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3c(c2)C(=O)N(C(Sc2nnn[nH]2)c2ccccc2)C3=O)cc1
Reaction time: 2 h
Yield: 191.4 %

Procedure:
N-Bromomethyl-4-(p-toluenesulfonamido)phthalimide (13 g) was dissolved in tetrahydrofuran (200 ml) and thereto a tetrahydrofuran solution (100 ml) of the sodium salt of 5-mercapto-1-phenyltetrazole (6 g) was slowly added at room temperature. The reaction mixture was allowed to stand at room temperature for 2 hours. Thereafter, the reaction mixture was poured into ice-cold water, and the crystals precipitated were recovered by filtration to obtain a crude product. The thus obtained crude product was recrystallized from an ethyl acetate/methanol mixed solvent to yield 15.4 g of N-(1-phenyl-5-tetrazolylthiomethyl)-4-(p-toluenesulfonamido)phthalimide. Melting Point: 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21].[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:18][CH:19]=[C:20]([CH3:21])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Reactant: COC(CC(C)=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 75.5 %

Procedure:
To a solution of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.7 g) in ethanol (50 ml) and toluene (150 ml) were added acetylacetoaldehyde-dimethylacetal (4.0 g) and 85% potassium hydroxide (0.67 g), and the mixture was refluxed. With intervals of 30 minutes, 85% potassium hydroxide (0.14 g) was added 3 times to the mixture. Then, the mixture was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was subjected to silica gel column chromatography (EtOAc/hexane) to give crystals of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.5 g).
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].[N:7]1[C:20]2[C:11](=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=[CH:9][CH:8]=1>>[OH:5][C:4]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[C:20]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[N:7]3)[N:18]=1)([CH3:6])[CH:1]([CH3:3])[CH3:2]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CC(=O)C(C)C
Product: CC(C)C(C)(O)c1ccc2ccc3cccnc3c2n1

Procedure:
The process of claim 1 wherein methyl isopropyl ketone is coupled with 1,10-phenanthroline to provide 2-[(1-hydroxy-1,2-dimethylpropyl)]-1,10-phenanthroline.