Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:75])([CH3:74])[CH3:73])=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:73])([CH3:74])[CH3:75])=[O:69])=[O:32])=[CH:34][CH:35]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)[C@@H](NC(=O)CN)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.006 g, 0.012 mmol) and NMM (0.007 ml, 0.064 mmol) in DMF (3 ml) at RT was added TBTU (0.005 g, 0.016 mmol). The reaction mixture was stirred for 60 min after which glycyl-3-methyl-D-valine (Method 10) (0.003 g, 0.016 mmol) was added. The mixture was stirred for 4 h before the solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: O[C:2]([CH3:11])([CH3:10])[CH2:3][C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1.C(N(S(F)(F)[F:18])CC)C.C([O-])(O)=O.[Na+]>ClCCl>[F:18][C:2]([CH3:11])([CH3:10])[CH2:3][C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)C[C@H]1COC(=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)C[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dichloromethane solution (100 mL) of the alcohol (47.8 g) from Step 3 was added to a −70° C. solution of (diethylamino)sulfur trifluoride (48.5 g) in dichloromethane (500 mL). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was then carefully added to a 0° C. mixture of saturated aqueous NaHCO3 (800 mL). The organic layer was separated and washed with saturated aqueous NaHCO3. The aqueous was further extracted with dichloromethane (100 mL) and the combined dichloromethane layers were dried and concentrated. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:5) followed by ethyl acetate to yield (4S)-4-(2-fluoro-2-methylpropyl)-1,3-oxazolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1c(F)cccc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
2-Bromo-6-fluoroaniline (8.2 g, 43.2 mmol) was dissolved in pyridine (10 mL) and treated with pivaloyl chloride (7.0 mL, 57.2 mmol). The reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and treated with ethyl acetate (50 mL). Mixture was washed 1 N hydrochloric acid (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with hexanes to give a solid which was filtered, washed with hexanes, and dried in vacuo. The title compound was obtained as white solid in 76% yield. 1H NMR (300 MHz, CDCl3): δ 7.39-7.31 (m, 1H), 7.14-7.03 (m, 2H), 6.98 (bs, 1H), 1.34 (s, 9H). Mass spec.: 274.1 (MH)+, 276.1 (MNa)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][C@H:32]3[CH2:36][O:35]C(C)(C)[O:33]3)[N:18]=[C:17]([CH3:39])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CCO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][C@H:32]([OH:33])[CH2:36][OH:35])[N:18]=[C:17]([CH3:39])[N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OC[C@H]1COC(C)(C)O1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OC[C@H](O)CO
Temperature: 50 °C

Procedure:
A solution of 1.85 g of (S)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-methylpyrimidin-4-yl]-benzenesulfonamide in EtOH (15 ml) was treated with 3 ml of conc. HCl and heated to 50° C. for 2 minutes. After evaporation, the residue was extracted with ether and yielded (R)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulfonamide as a foam.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH2:5][CH2:6][CH2:7][N:8]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>C1COCC1>[ClH:18].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27]([NH:2][C:3]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]=1)=[O:28]
Reactant: NC1=NCCCN1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC1=NCCCN1)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8.50 g (0.0625 mol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride, 10.0 g (0.12 mol) of 50% NaOH and 70 ml of THF was stirred for 0.5 hours at room temperature and then 10.0 g Na2SO4 was added. After stirring for an additional 0.5 hours, a solution of 9.4 g (0.050 mol) of 2,6-dichlorophenyl isocyanate in 50 ml of THF was added over a period of 1 hour. After stirring for 1 hour, the reaction mixture was filtered, the filtrate evaporated in vacuo and the residue dissolved in 25 ml of 10% HCl and 25 ml of H2O with warming. After filtration through a pad of diatomaceous earth, chilling in ice gave the crystalline hydrochloride which was recrystallized from MeOH-ether affording 12.40 g. This material was ground to a fine powder and dried to constant weight in vacuo (60° C., 5 mm Hg) to give 11.97 g (74%) of the title compound; m.p. 215°-217° C. dec., homogeneous by TLC [5×20 cm silica gel GF CHCl3 --MeOH-NH4OH (90:9:1)]. 1H-NMR (DMSO-d6) 1.85 [pentet, (poorly resolved)2H]; 3.35 (t, J=5 Hz, 4H); 7.2-7.7 (m, 3H); 9.16 (broad s, 2H) exchangeable; 10.02 (broad s, 1H) exchangeable, 11.19 (brS, 1H) exchangeable. IR(KBr) 3125, 1717, 1678, 1678 cm-1 ; UV max. (MeOH) 241 infl. (ε=11,200) and 220 nm infl. (ε=23,500).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][Mg]Br.O>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 500 mg, 1.62 mmol) was dissolved in anhydrous THF (10 mL) and cooled down to 0° C. Methylmagnesium bromide in toluene/THF (1.4 M, 1.27 mL) was slowly added and the RM was then warmed up to rt and stirred for 4 h. Water (2 mL) was added and the precipitate formed was filtered off. The filtrate was concentrated to give the title compound as a brown solid (tR 0.50 min (conditions 2), (MH+=325).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCCc1c(CCC(=O)OCC)cnn1Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(CCC(=O)O)cnn1Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-propyl-1H-pyrazol-4-yl]propionate (210 mg), 1N aqueous sodium hydroxide solution (1 ml), ethanol (1 ml), and tetrahydrofuran (1 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-propyl-1H-pyrazol-4-yl]propionic acid (170 mg, yield: 85%). This was recrystallized from ethyl acetate-hexane. Melting point: 158–159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:21](=[O:22])[NH:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: CCCc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2

Procedure:
6-Chloro-5-propylindoline (D54) (57 mg, 0.3 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound as a white crystalline solid m.p. =218°-220° C.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6]>S(Cl)(Cl)=O>[Cl:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:1])=[O:6]
Reactant: COc1ccc(C(=O)O)c(Cl)n1
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)c(Cl)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
A mixture of 2-chloro-6-methoxy-nicotinic acid hydrochloride salt (360 g, 1925 mmol) in thionyl chloride (500 mL) was stirred at 80° C. for 5 h. The solvent was evaporated in vacuo to yield 2-chloro-6-methoxy-nicotinoyl chloride (340 g, 85%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:24]3[CH:25]=[N:26][C:27]([C:28]([NH2:30])=O)=[C:23]3[CH2:22][N:21]([CH3:31])[C:20](=[O:32])[C:19]=2[CH:33]=1.O>O1CCOCC1.N1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:24]3[CH:25]=[N:26][C:27]([C:28]#[N:30])=[C:23]3[CH2:22][N:21]([CH3:31])[C:20](=[O:32])[C:19]=2[CH:33]=1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2ccc(Cl)cc2C1=O
Solvent: O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1Cc2c(C#N)ncn2-c2ccc(Cl)cc2C1=O
Reaction time: 4 h
Yield: 88.2 %

Procedure:
1.85 ml (13.4 mmol) of trifluoroacetic anhydride were added dropwise at <8° to a suspension of 3.72 g (12.8 mmol) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in 17 ml of dioxan and 2 ml of pyridine. The beige solution obtained was stirred at 50°-60° for 4 hrs., cooled and treated with 80 ml of water. The white crystals were filtered off under suction and dried in a high vacuum. There were obtained 3.08 g (88%) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile as colourless crystals of m.p. 272°-275°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=2)=[C:18]([F:34])[CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:33]=[CH:32][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=3)=[C:18]([F:34])[CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)c(F)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)c(F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A solution of 228 mg (1.03 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 10 min. to a solution of 286 mg (1.03 mmol) 3-[4-(4-amino-2-fluoro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 5 ml THF and stirring continued overnight. The reaction mixture was evaporated and purified by chromatography on silica (dichloromethane/ethanol 97:3). The obtained material was stirred with dichloromethane. The precipitate was filtered and dried to yield 130 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][OH:28])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[O:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 g 2-Chloro-4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile were suspended in 50 ml dichloromethane and cooled in an ice bath. 0.39 ml methanesulfonylchloride and 0.89 ml triethylamine were added. The resulting mixture was stirred at 0° C. for one hour then washed with water and brine, dried over MgSO4. The solvent was removed in vacuo to obtain 1.0 g methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester as pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]([F:40])([F:39])[CH:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][CH2:31]O>ClCCl>[I:25][CH2:31][CH2:30][CH:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([F:40])([F:39])[F:27]
Reactant: OCCC(c1ccccc1)C(F)(F)F
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)C(CCI)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of triphenylphosphine (3.93 g) and imidazole (1.02 g) in dichloromethane (20 ml) under an argon atmosphere was added slowly iodine (3.81 g) and rac-4,4,4-trifluoro-3-phenyl-butan-1-ol (2.04 g, CAS 65948-16-5). The mixture was stirred for 2 hours at room temperature, then dichloromethane (50 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (50 ml) and hydrochloric acid (1N, 25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a light yellow liquid, (1.99 g, 63%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C=O)C>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCc2ccccc2Cl)c1
Reaction time: 0.08 h

Procedure:
To 1.31 g (9.22 [mmol) of Orcinol monohydrate in 20 mL anhydrous DMF under a nitrogen atmosphere was add ed 220 mg (9.17 mmol) of NaH (100%). After 5 min, 1.3 mL (100 mmol) of 2-chlorobenzyl bromide was added. The reaction mixture was stirred for 2 h and then quenched with 1N HCl. The reaction mixture was extracted into ethyl acetate (200 mL). The organic phase was washed with H2O (4×100 mL), dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (ether/hexane (50:50 to 100:0) gave 656 mg of the title compound as a hardened oil. 1H-NMR (300 MHz, CDCl3) δ 7.54 (dd, 1H, J=3, 7 Hz), 7.39 (dd, 1H, J=3, 7 Hz), 7.2 -7.3 (m, 2H), 6.41 (s, 1H), 6.29-6:30 (m, 2H), 5.29 (s, 2H), and 2.28 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]([CH3:13])[C:8]([O:10]CC)=[O:9])[CH3:5])[CH3:2].[OH-].[K+:15].O.C(O)C>>[CH2:1]([O:3][CH:4]([O:6][CH:7]([CH3:13])[C:8]([O-:10])=[O:9])[CH3:5])[CH3:2].[K+:15]
Reactant: CCOC(=O)C(C)OC(C)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(C)OC(C)C(=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
To a 250 mL flask containing 38.0 g (0.20 moles) ethyl 2-[(1'-ethoxy)ethoxy]propanoate at 23° C. is added a solution of 14.8 g (0.264 moles) KOH, 30.0 g (1.667 moles) water and 10.0 g (0.217 moles) ethanol over a 30 minute period. Maintaining ±23° C., the solution is stirred for one hour, then extracted with 20 g hexane. The aqueous phase is then stripped of all solvent under vacuum. A constant weight of 43.7 g potassium 2-[(1'-ethoxy)ethoxy]propanoate is obtained as a yellowish viscous liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1.[CH:22](=O)[C:23]1[O:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(N(CC)CC)C>[O:27]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:22][NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc2cncc(Br)c12)N1CC[C@H](NCc2ccco2)C1
Temperature: 25 °C
Reaction time: 30 h
Yield: 27.3 %

Procedure:
A suspension of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride (172 mg) obtained in Example 1-1 in 1,2-dichloroethane (10 ml) was added with triethylamine (0.28 ml, Wako Pure Chemical Industries), and then with furfural (42 mg, Aldrich), and the mixture was stirred at room temperature for 30 minutes, then added with sodium triacetoxyborohydride (170 mg, Aldrich), and further stirred at room temperature for 30 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (15 ml), and the organic layer was separated. The aqueous layer was extracted 3 times with chloroform (10 ml for each time), and the combined organic layer was washed with saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound (52 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14]>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:4](=[O:5])[CH2:3][CH2:2][Cl:1]
Reactant: O=C(Cl)CCCl
Reactant: Oc1ccccc1Cl
Product: O=C(CCCl)Oc1ccccc1Cl
Temperature: 75 °C

Procedure:
3-chloropropionylchloride (14 ml) was added to 2-chlorophenol (18.18 g) and the mixture was stirred and heated at 60° C. for 1 hour, at 75° C. for 1 hour and left over the weekend at ambient temperature. The compound was purified by destillation in vacuo to give 19,7 g (b.p. 91-94° C. 0.08 mm Hg) of 3-chloro-propanoic acid 2-chlorophenyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH:13]([Mg]Br)=[CH2:14].C1COCC1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:10]2
Reactant: O=[N+]([O-])c1cc(Br)cc(F)c1F
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cc(Br)c2cc[nH]c2c1F
Temperature: -40 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
A solution (20 mL) of 5-Bromo-1,2-difluoro-3-nitrobenzene (1.19 g, 5.00 mmol) in THF was cooled to −50° C. To this, a 1 M vinylmagnesium bromide/THF solution (15 mL) was added dropwise. After the mixture was stirred at −40° C. for 4 hours, a saturated aqueous ammonium chloride solution was added thereto, and concentrated under reduced pressure. The reaction solution was diluted with ethyl acetate, and after washed with saturated brine, the resultant was dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane) to thus obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:26]I>ClCCl.C(Cl)(Cl)Cl>[Br:25][C:21]1[CH:20]=[C:19]([N:18]2[CH:2]([CH2:3][I:26])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])[CH:24]=[CH:23][CH:22]=1
Reactant: II
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.14 g, 0.35 mmol) (from Example 17, Step E, supra) in dichloromethane (20 mL) was added I2 (0.23 g, 1.75 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL) and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired 4-(3-bromo-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a pale yellow foam. (Yield 0.12 g, 66%).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[CH:10]=1)C1C=CC=CC=1.[CH:23]([C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)([CH3:25])[CH3:24]>>[OH:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11]([N:28]2[CH:29]=[CH:30][C:26]([CH:23]([CH3:25])[CH3:24])=[N:27]2)[CH:10]=1
Reactant: COc1ccc2c(OCc3ccccc3)cc(Cl)nc2c1C
Reactant: CC(C)c1cc[nH]n1
Product: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 155 °C
Yield: 95 %

Procedure:
A mixture of 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (16, 1.00 g, 3.19 mmol) and 3-isopropylpyrazole was heated at 155° C. for 12 h. Then, the reaction mixture was partitioned between AcOEt and water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (AcOEt/CH2Cl2, 1:1) to give 900 mg (95%) of the target product 17 as a yellowish powder: m/z=298 (M+H)+.