Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([Cl:26])=[CH:11][C:12]([F:25])=[C:13]([N:15]3[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]3)[CH:14]=2)=[N:6][CH:7]=1.Cl.[N:28]([O-])=O.[Na+].[F:32][B-:33]([F:36])([F:35])[F:34].[Na+]>O>[F:32][B-:33]([F:36])([F:35])[F:34].[Cl:26][C:10]1[CH:11]=[C:12]([F:25])[C:13]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:22])[F:23])[C:17]([CH3:24])=[N:16]2)=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([N+:1]#[N:28])=[CH:7][N:6]=1
Reactant: O=N[O-]
Reactant: Cc1nn(-c2cc(Oc3ccc(N)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: Cc1nn(-c2cc(Oc3ccc([N+]#N)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
To a stirred mixture of 3.9 g (0.010 mole) of 1-[5-(5-aminopyridin-2-yloxy)-4-chloro-2-fluorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 10 mL of water was added 5.0 mL of concentrated hydrochloric acid. The mixture was cooled in an ice water bath, and a solution of 0.76 g (0.011 mole) of sodium nitrite in 1.4 mL of water was added portionwise. The resultant mixture was stirred at 0° C. for 30 minutes, and a solution of 1.5 g (0.014 mole) of sodium tetrafluoroborate in 5 mL of water was added portionwise. An additional 5 mL of water was added, and the reaction mixture was stirred at 0° C. for 45 minutes. The mixture was filtered, and the filter cake was rinsed with ice water followed by diethyl ether. The filter cake was dried under reduced pressure to yield 4.7 g of 2-[2-chloro-4 -fluoro-5-(4-difluoromethyl-4,5-dihydro -3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]pyridine-5-diazonium tetrafluoroborate.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:5]([C:14]([OH:16])=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2>C(O)(=O)C>[Br:1][C:7]1[CH:6]=[C:5]([C:14]([OH:16])=[O:15])[C:4]([OH:3])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2cccnc2c1O
Temperature: 50 °C
Yield: 87.9 %

Procedure:
Bromine (819.8 mg, 5.13 mmol) was added dropwise to a suspension of 8-hydroxyquinolin-7-carboxylic acid (970 mg, 5.13 mmol) in glacial acetic acid (24 mL). The reaction mixture was refluxed for 1 h, allowed to cool to 50° C. and poured onto ice water. The yellow solid formed was filtered on a Buckner funnel, washed with H2O and dried under vacuum, affording the title compound (1.20 g, 4.51 mmol) as a light brown solid that was used in the next step without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(N([CH2:24][CH3:25])CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>ClCCl>[CH2:30]([O:29][C:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:27]([O:29][CH2:30][C:25]4[CH:24]=[CH:33][CH:32]=[CH:31][CH:36]=4)=[O:28])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Solvent: ClCCl
Product: O=C(OCc1ccccc1)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a stirred solution of 3-hydroxymorphinan (5 mg, 0.015 mmol) and triethylamine (13 μL, 0.091 mmol) in dry dichloromethane (0.3 mL) was added benzyl chloroformate (5.2 μL, 0.036 mmol) at 0° C. The reaction mixture was stirred for 2 h at room temperature. After starting material disappeared on TLC, solvent was removed and column chromatography gave 6.3 mg (80%) of title compound: 1H NMR (300 MHz, CDCl3) δ7.3˜7.6 (10H, m); 7.0 (2H, m); 6.9 (1H, m); 5.3 (2H, s); 5.1 (2H, s); 4.3 (1H, dd); 3.9 (1H, m); 3.1 (1H, m); 2.7 (2H, d); 2.3 (1H, m); 1.0˜1.8 (10H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:5]=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:3]=1[NH:32][CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:74][O:75][CH2:76][CH2:77][NH2:78]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:5]=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[C:3]=1[NH:32][CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:78][CH2:77][CH2:76][O:75][CH3:74])=[O:40])=[CH:36][CH:35]=1
Reactant: COCCN
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccc(C(=O)O)cc2)c(NS(=O)(=O)CCC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccc(C(=O)NCCOC)cc2)c(NS(=O)(=O)CCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-{[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-6-(propane-1-sulfonylamino)-phenylamino]-methyl}-benzoic acid (200 mg), TBTU (300 mg), N,N-diisopropylethylamine (536 μl) and 2-methoxyethylamine (134 μl) in DMF (2 ml) was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and washed with aq. NaHCO3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([OH:30])=O)(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH3:67][N:68]([CH3:72])[CH2:69][CH2:70][NH2:71]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH:71][CH2:70][CH2:69][N:68]([CH3:72])[CH3:67])=[O:30])(=[O:23])=[O:24])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CN(C)CCN
Reactant: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)O)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)NCCN(C)C)c2)c1
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoic acid (0.20 g, 0.42 mmol) in dimethylformamide (4 mL) were added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.32 g, 0.83 mmol) and N-ethyldiisopropylamine (DIEA, 0.13 g, 1.04 mmol) at room temperature. The reaction was stirred for 15 min before N,N-dimethylethane-1,2-diamine (73 mg, 0.83 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL), 1.0 N aqueous hydrochloric acid (30 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford 3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]benzamide (0.20 g, 87%) as yellow solid. MS (EI) for C26H27ClN6O4S: 555.1 (MH+).
Reaction SMILES: CC[CH:3]1[C:23]2(CC)[C:24]3=[N:25][C:4]1=[CH:5][C:6]1[NH:10][C:9]([CH:11]=[C:12]4[NH:39][C:15](=[CH:16][C:17]5[C:34](CC)=[C:33](CC)[C:19](=[C:20]3C=C2C(OCC)=O)[N:18]=5)[C:14](CC)=[C:13]4CC)=[C:8](CC)[C:7]=1CC>ClCCl>[C:6]12[CH:5]=[C:4]3[N:25]=[C:24]([CH:23]=[CH:3]3)[CH:20]=[C:19]3[NH:18][C:17]([CH:34]=[CH:33]3)=[CH:16][C:15]3=[N:39][C:12]([CH:13]=[CH:14]3)=[CH:11][C:9]([NH:10]1)=[CH:8][CH:7]=2
Reactant: CCOC(=O)C1=Cc2c3nc(cc4[nH]c(cc5[nH]c(cc6nc2C1(CC)C6CC)c(CC)c5CC)c(CC)c4CC)C(CC)=C3CC
Solvent: ClCCl
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
A 50 mg portion of Purpurin NT2 was dissolved in 20 ml dichloromethane, and the resulting solution was allowed to stand for a total of 16 hours in sunlight, in contact with air, and under ambient conditions (temperature about 22°). The dichloromethane was then removed by evaporation, leaving 50 mg porphyrin derivative (hereafter "Porphyrin NT2") which was found by nuclear magnetic resonance to have the formula of FIG. 7 of the attached drawings where R1 through R8 are ethyl, R10 through R12 are hydrogen, and R13 is CH2CH3. The production of Purpurin NT2 is described in Example 1 of PCT/US86/02824; it has the formula of FIG. 5 of the drawings of that application where R1 through R8 are ethyl, R9 is CO2CH2CH3, and R10 through R13 are hydrogen.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:31][CH2:32][C:33](Br)=[O:34].O>C(Cl)Cl>[C:1]([S:20][CH2:21][CH2:22][NH:23][C:33](=[O:34])[CH2:32][Br:31])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
2-(tritylsulfanyl)-1-ethaneamine (0.5 g, 1.6 mmol) was dissolved in methylene chloride (10 ml) and added with triethylamine (0.22 ml, 1.6 mmol). To the solution, bromoacetylbromide (0.14 ml, 1.6 mmol) in methylene chloride (1 ml) was added dropwise. The resulting solution was stirred at room temperature for 15 min and added with water (30 ml). The organic phase was washed with 1 M hydrogen chloride, water, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution in sequence. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a white solid of N1-(2(tritylsulfanyl)ethyl)-2-bromoacetamide (0.67 g, 1.51 mmol, 94.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:5]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:6])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(Cl)c1F
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1

Procedure:
Prepared according to Method A step B from 3-chloro-2-fluoro-N-methoxy-N-methylbenzamide (2.5 g, 11.5 mmol) and 4-methoxyphenylmagnesium bromide (25 mL, 0.5 M in THF) to give 0.3 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=2[C:12](O)=[O:13])[CH2:7]1.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH:6]1[CH2:7][N:8]([C:10]2[N:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=2[C:12]([NH:24][C:25]2([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)=[O:13])[CH2:9]1
Reactant: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(Cl)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cnc3N3CC(Oc4cccc(Cl)c4)C3)CC2)cc1
Yield: 56.3 %

Procedure:
The title compound (D188) (12 mg) was prepared according to the experimental procedure described in Description 169 starting from 2-(3-(3-chlorophenoxy)azetidin-1-yl)-5-fluoronicotinic acid (D133) (14 mg, 0.043 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (9.85 mg, 0.043 mmol).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:12]=3)[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.COCCOC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[NH:12][N:13]=[CH:14][N:15]=4)[CH:9]=3)[NH:4][N:3]=2)=[CH:45][CH:44]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 60 °C
Yield: 11.3 %

Procedure:
A mixture of 2-{3-bromo-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazolyl}perhydro-2H-pyran (300 mg, 0.508 mmol), 4-trifluoromethylphenylboronic acid (144 mg, 0.758 mmol, 1.49 equiv.), [1,1′-bis(diphenylphosphino)-ferrocene}dichloropalladium (II) complex with dichloromethane (Aldrich), 41.5 mg (0.0508 mmol, 0.100 equiv.), 2.53 mL of anhydrous DME, and powdered potassium phosphate (K3PO4, 535 mg, 2.52 mmol, 4.96 equiv.) were refluxed for 5 days. The reaction was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel using 30-40% EtOAc in hexanes. To the purified material was added 5.00 mL of MeOH, and 5.00 mL of 6.0 N aq. HCl. The mixture was heated at 60° C. for 24 h. The reaction mixture was filtered. The solid was further purified by silica gel chromatography using EtOAc affording the title compound (69.3 mg). Further purification by prep HPLC afforded the title compound (18.9 mg, 11.3% yield): 1H NMR (CDCl3/CD3OD) δ 8.74 (s, 1H), 8.41-7.97 (m, 4H), 7.78 (d, 2H), 7.66 (d, 1H); ES-MS (m/z) 330 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:13]=[O:14])=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:22]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]([OH:22])=[O:14])=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: C1COCCO1
Reactant: COC(=O)c1sc(C=O)cc1C(C)C
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C(=O)O)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 5-Formyl-3-isopropyl-thiophene-2-carboxylic acid methyl ester (0.51 g, 2.40 mmol) in dioxane (12 ml) was added 2-methyl-2-butene (3 ml) and a solution of Na2ClO2 (0.65 g, 7.21 mmol) and NaH2PO4 (0.79 g) in water (3 ml). The mixture was stirred at rt for 2 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (0.45 g, 82% yield).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[Br-:6].[K+].S(=O)(=O)(O)O.[Cl:13][CH2:14][CH:15](O)[CH3:16]>C1(C)C=CC=CC=1.O>[Br:6][CH2:2][C:3]([O:5][CH:15]([CH3:16])[CH2:14][Cl:13])=[O:4]
Reactant: CC(O)CCl
Reactant: [Br-]
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CCl)OC(=O)CBr

Procedure:
94.5g (1 mol) of chloroacetic acid and 154.7g of potassium bromide were put into a 1 liter four necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. To the mixture were added 100 ml of water as a reaction medium and stirred vigorously. Then 127.4g (1.3 mol) of c.-- sulfuric acid were added droppwise over the course of an hour at a constant rate. During that time, the temperature of the reaction mixture rose to about 50° C. After the droppwise addition, stirring was continued for an hour at 55° C. Then 94.5g (1 mol) of 1-chloro-2-propanol and 200g of toluene were added to the reaction mixture, and refluxed for an hour at 100° ~ 110° C in an oil bath. A receiver was attached to a reflux condenser and water was removed from the reaction mixture by azeotropic distillation with toluene. Then the resultant crystals of potassium hydrogen sulfate were filtered off from the reaction mixture to give a toluene solution of 1-chloro-2-propyl bromoacetate, which was sufficient to use industrially as it is. But if needed, toluene was removed from the filtrate followed by distillating the residue to give 201.2g (93.4% of theory) of 1-chloro-2-propyl bromoacetate of bp 76° ~ 77° C (2 mmHg) as a colorless and clear liquid. nD25 = 1.4780, D420 = 1.5933. 176.6g (99.8%) of potassium hydrogen sulfate was isolated.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16][C:17](=O)OC(C)(C)C)=[N:13][CH:12]=3)[CH:9]=2)[CH:4]=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl.[C:33](O)([C:35]([F:38])([F:37])[F:36])=O>CN(C=O)C.CCOC(C)=O.Cl>[NH2:1][C@@H:10]([CH2:9][C:8]1[CH:11]=[CH:12][C:33]([C:35]([F:38])([F:37])[F:36])=[CH:6][CH:7]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[N:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)=[CH:12][N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3cncnc3c2)s1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N[C@H](CNc1ncc(-c2ccc3cncnc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a stirred orange mixture of tert-butyl 5-(quinazolin-7-yl)thiazol-2-ylcarbamate (22 mg, 67 μmol) and Cs2CO3 (44 mg, 134 μmol) in DMF (1.0 mL), was slowly added a solution of the cyclic sulfamidate (38 mg, 100 μmol) in DMF (0.5 mL) at 50° C. The resulting light yellow mixture was stirred at 50° C. for 30 minutes. The mixture was then cooled to 0° C. and was then diluted with EtOAc and 1N HCl(aq) and the entire mixture was stirred at room temperature for 30 minutes. The layers were separated, the aqueous layer was extracted with EtOAc (5 mL×3), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue, which was taken up in a solution of DCM (1.5 mL), and TFA (1.5 mL) was slowly added. The overall solution was stirred at room temperature for 30 minutes and concentrated. The crude residue was dissolved in DCM and mixed with silica. The solvent was evaporated, and the residue was purified with flash column chromatography (pure DCM→10% MeOH in DCM) to obtain N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(quinazolin-7-yl)thiazol-2-amine (12 mg, 42%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=1[O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.C(=O)([O-])O.[Na+].[CH:26]1([C:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41]([O:43][CH3:44])=[O:42])=[CH:38][CH:39]=3)[NH:34][C:33]=2B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([C:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41]([O:43][CH3:44])=[O:42])=[CH:38][CH:39]=3)[NH:34][C:33]=2[C:2]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=2[O:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
Reactant: O=[N+]([O-])c1cccc(Br)c1OCCOC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOC3CCCCO3)[nH]c2c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a solution of 2-[2-(2-bromo-6-nitrophenoxy)ethoxy]tetrahydropyran (12.30 g, 35.6 mmol) in 1,2-dimethoxyethane (150 ml) and water (75 ml) was added sodium hydrogen carbonate (9.74 g, 117.0 mmol) and tetrakis(triphenylphosphine)palladium (4.52 g, 3.91 mmol) and the mixture was heated at 85° C. for 15 min. Methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (16.40 g, 35.6 mmol) was added in 6 divided portions to the reaction mixture at 30 min intervals, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3.5:1) to give methyl 3-cyclohexyl-2-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1H-indole-6-carboxylate (14.40 g, yield 77%).
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:2]=12.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:16][C:13](=[O:15])[CH3:14])[C:2]=12
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc2c1CCCCC2
Product: CC(=O)OC1CCCCc2cccnc21
Temperature: 90 °C

Procedure:
The N-oxide was dissolved in acetic anhydride (222 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated. Distillation (Kugelrohr, bpl 10-140° C. @ 1 Torr) of the resultant oil provided 53.26 g of acetic acid 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1>[CH3:19][N:20]([C:2]1[N:7]=[C:6]([N:17]2[CH:18]=[C:14]([CH3:13])[N:15]=[CH:16]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CNc1ccccc1
Solvent: C1COCCO1
Product: Cc1cn(-c2nc(N(C)c3ccccc3)nc(C)c2[N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4dichloro-6-methyl-5-nitropyrimidine (150 mg, 0.72 mmol) in dioxane (5 mL) at 80° C. was added 4-methylimidazole (60 mg, 0.72 mmol) and N-methylaniline (77 mg, 0.72 mmol). The solution was stirred overnight at 80° C., cooled, and directly chromatographed (1/1 hexane diethyl ether) to yield the title compound (t).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:31])([F:32])[F:30])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Methanesulphonyl chloride (2.65 g) was added dropwise to a solution of 6-[4-(3-hydroxypropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (6.7 g) and diisopropylethylamine (9.7 ml) in NMP (40 ml). The mixture was stirred at room temperature for 3 hours. After adding ice (100 g), solid product was collected by filtration, washed with cold ethanol (20 ml) to give 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy]propyl methanesulfonate (7.4 g).