Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33].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:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH:18][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[C:23]([C:32]([F:33])([F:35])[F:34])[CH:24]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 50 °C
Reaction time: 120 h

Procedure:
A reaction vial was charged with (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (210 mg, 0.00071 mol), 2-(4-fluoro-3-(trifluoromethyl)phenyl)acetic acid (300 mg, 0.001 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (600 mg, 0.002 mol), N,N-diisopropylethylamine (600 μL, 0.003 mol) and was stirred at 50° C. for 5 days. the solvent was removed under reduced pressureunder reduced pressure and the residue was purified by flash chromatography to afford the product as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:2]3[N:3]=[CH:4][C:5]4[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:11]=4[N:12]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc2[nH]ccc2c1
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4[nH]ccc4c3)ncc21

Procedure:
The title compound was prepared using Buchwald reaction from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 5-aminoindole. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (m, 4 H) 1.69 (m, 2 H) 1.97 (m, 2 H) 3.3 (s, 3 H) 3.99 (t, J=14.3 Hz, 2 H) 4.75 (t, J=8.0 Hz, 1 H) 6.29 (br. s., 1 H) 7.18-7.41 (m, 3 H) 7.96 (s, 1 H) 8.18 (s, 1 H) 9.16 (s, 1 H) 10.91 (br. s., 1 H). [M+H] calc'd for C21H22F2N6O, 413; found 413.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CN(C=O)C>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: O=c1cc(COC2CCCCO2)occ1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCBr
Temperature: 92.5 °C
Yield: 91 %

Procedure:
The compound was prepared according to example 11 using 5-hydroxy-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one (3.5 g, 15.5 mmol) in 20 mL of DMF, Cs2CO3 (5.04 g, 15.5 mmol) and 1,5-dibromopentane (8.8 g, 36.7 mmol). The sealed tube was heated at 90-95° C. for 1 h 40. A white solid 1 was obtained (5.30 g, 91% yield).
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][C:10]2[C:18]([CH3:19])=[C:17]3[C:13]([C:14](=[O:20])[O:15][CH2:16]3)=[C:12]([O:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:11]=2[CH2:32]/[CH:33]=[C:34](\[CH3:41])/[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=CC=1>FC(F)(F)C(O)=O>[OH:8][CH2:9][C:10]1[C:18]([CH3:19])=[C:17]2[C:13]([C:14](=[O:20])[O:15][CH2:16]2)=[C:12]([O:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:11]=1[CH2:32]/[CH:33]=[C:34](\[CH3:41])/[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)CC/C(C)=C/Cc1c(COCc2ccc(OC)cc2)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC/C(C)=C/Cc1c(CO)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
Methyl (E) 6-(1,3-dihydro-6-(p-methoxybenzyloxymethyl)-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (0.5 g) is dissolved in trifluoroacetic acid (10 ml) at 0° C. After 30 minutes the solvent is removed under vacuum and the residue is chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6-(1,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [NH3:1].C([O:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]([O:14]C)=O)[N:11]=1)(=O)C>>[C:12]([C:10]1[N:11]=[C:7]([CH2:6][OH:5])[O:8][CH:9]=1)(=[O:14])[NH2:1]
Reactant: COC(=O)c1coc(COC(C)=O)n1
Reactant: N
Product: NC(=O)c1coc(CO)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 mL (352 mmol) of 28% aqueous ammonia are added to a round-bottomed flask containing 0.60 g (3.01 mmol) of methyl 2-acetoxymethyloxazole-4-carboxylate, prepared in step 5.1., and the reaction medium is then stirred at room temperature for 24 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[NH:12][CH:13]=[C:14]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:15](=[O:17])[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cu][C:28]#[N:29]>CN1C(=O)CCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][C:11]2[NH:12][CH:13]=[C:14]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:15](=[O:17])[N:16]=2)=[CH:3][C:2]=1[C:28]#[N:29]
Reactant: N#C[Cu]
Reactant: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(Br)c3)nc2=O)cn1
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(C#N)c3)nc2=O)cn1
Temperature: 200 °C
Yield: 30.6 %

Procedure:
The mixture of 2-[2-(3-bromo-4-fluorophenyl)ethyl]-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (300 mg, 0.716 mmol) and copper(I) cyanide (77 mg, 0.859 mmol) in NMP (2 mL) was heated with a microwave reactor at 200° C. for 2 h. Purification via Biotage then afforded the title compound (80 mg, 30.6% yield). LCMS: rt=2.21 min, [M+H+]=366
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23](O)[C:24]([OH:26])=[O:25])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[OH:9][C:4]1[C:5]([OH:6])=[CH:7][C:8]([CH:23]([C:24]([OH:26])=[O:25])[NH:22][C:20]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[C:16](=[O:17])[C:11]2=[O:10])=[O:21])=[C:2]([F:1])[CH:3]=1
Reactant: CCN1CCN(C(=O)NC(O)C(=O)O)C(=O)C1=O
Reactant: Oc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1CCN(C(=O)NC(C(=O)O)c2cc(O)c(O)cc2F)C(=O)C1=O
Reaction time: 8 h

Procedure:
4-Fluorocatechol (3.06 g., 24 mmole) was added to a suspension of N-(2,3-dioxo-4-ethylpiperazin-1-ylcarbonyl)-2-hydroxyglycine (3.89 g, 15 mmole) in glacial acetic acid (13.5 ml) and concentrated sulphuric acid (1.5 ml). The mixture was stirred overnight, diluted with water (50 ml), adjusted to pH6 with saturated sodium carbonate and washed with ethyl acetate (2×50 ml). The aqueous solution was acidified to pH 2.5 and extracted with ethyl acetate (5×40 ml). The combined extracts were dried and evaporated to give the crude product, 6.10 g, as a foam.
Reaction SMILES: N#N.Cl[C:4]1[N:9]=[N:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:12]([CH3:23])[CH2:11]2)=[C:6]([CH3:24])[C:5]=1[CH3:25].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F-].[Cs+]>O1CCOCC1>[CH3:24][C:6]1[C:5]([CH3:25])=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:9]=[N:8][C:7]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:12]([CH3:23])[CH2:11]1
Reactant: Cc1c(Cl)nnc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c1C
Reactant: OB(O)c1ccccc1
Agent: N#N
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)nnc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c1C
Temperature: 95 °C
Yield: 86.4 %

Procedure:
Treat a N2 degassed mixture of (S)-tert-butyl 4-(6-chloro-4,5-dimethylpyridazin-3-yl)-2-methylpiperazine-1-carboxylate (3.03 g, 8.87 mmol), phenylboronic acid (1.62 g, 13.3 mmol), and CsF (4.09 g, 26.9 mmol) in 1,4-dioxane (120 mL) with (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (1.08 g, 1.32 mmol). Heat the reaction mixture at 95° C. overnight. Cool the reaction, and partition between EtOAc and H2O. Wash the organic layer with brine, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 15 to 85% EtOAc in hexanes) to afford the title compound as a white solid (2.93 g, 86%). ES/MS m/z 383.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][N:11]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:20][CH:21]1[CH2:33][C:25]2[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=2[C:23](=[O:34])[CH2:22]1>>[C:1]([O:5][C:6](=[O:19])[N:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH:22]2[CH:21]([CH3:20])[CH2:33][C:25]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=3[C:23]2=[O:34])=[O:17])=[CH:12][N:11]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)C2C(=O)c3sc(NC(C)=O)nc3CC2C)cn1

Procedure:
A-14 is prepared via general procedure A1 starting from (5-chlorocarbonyl-pyridin-2-yl)-ethyl-carbamic acid tert-butyl ester (A-09) (7.62 g, 26.8 mmol) and N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06) (5.00 g, 22.3 mmol). After evaporation of the solvent 8.62 g of A-14 are obtained which is used without further purification in the next step.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH2:5].[C:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:10]1([CH3:30])[CH3:29])(=[O:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:5][CH2:4][CH2:3][S:2][CH3:1])=[O:20])=[CH:16][CH:17]=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:10]1([CH3:30])[CH3:29])(=[O:8])[CH3:7]
Reactant: CSCCN
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCCNC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Condensation of 2-(methylthio)ethylamine (4.1 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 l) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH2:1](S)[CH2:2][SH:3].S1CCC1S[Sn:10]([S:21][CH:22]1[CH2:25][CH2:24][S:23]1)([S:16]C1CCS1)[S:11][CH:12]1[CH2:15][CH2:14][S:13]1>>[S:23]1[CH2:24][CH2:25][CH:22]1[S:21][Sn:10]1([S:11][CH:12]2[CH2:15][CH2:14][S:13]2)[CH2:1][CH2:2][S:3][S:16]1
Reactant: SCCS
Reactant: C1CC(S[Sn](SC2CCS2)(SC2CCS2)SC2CCS2)S1
Product: C1C[Sn](SC2CCS2)(SC2CCS2)SS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
18.84 g (0.2 mole) of 1,2-ethanedithiol was introduced into 107.9 g (0.2 mole) of tetrakis(thietanylthio)tin prepared in Reference Preparation Example 3, and the resulting mixture was stirred at room temperature (20 degrees centigrade) for 2 hours. In order to remove the by-produced 3-mercaptothietane, methanol was introduced, each time of introducing in an amount of 100 g, and the resulting solution was stirred and washed. In this way, a separation operation was repeatedly carried out 8 times by decantation to precipitate a white solid. The precipitated solid was collected by filtration and dried to obtain 70.6 g (Yield: 84%) of bis(thietanylthio)dithiastannolane as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[C:27]([F:44])=[C:28]([NH:32][S:33]([C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Yield: 114.5 %

Procedure:
To 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate (1.13 g, 1.694 mmol) in DCM (20 mL) was treated with TFA (20 mL) at rt for 30 min. The reaction mixture was concentrated and the residue was triturated with DCM and hexane to give (1.10 g, 95% yield) of the title compound of Step B. 1H NMR (400 MHz, DMSO-d6) d ppm 10.95 (br. s., 1H), 9.04 (br. s., 1H), 8.34 (d, J=5.5 Hz, 1H), 7.63-7.76 (m, 1H), 7.42-7.49 (m, 1H), 7.38 (t, J=6.1 Hz, 1H), 7.30-7.36 (m, 1H), 7.26 (t, J=9.2 Hz, 2H), 6.52 (d, J=5.4 Hz, 1H), 3.77 (d, J=4.8 Hz, 4H), 3.27 (br. s., 4H). m/z (ES+): 568 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[C:19]1([NH:25][CH:26]2[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=O)[CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C1C=CN=CC=1)C.ClCCl>[O:8]1[C:7]2[CH:2]=[CH:3][C:4]([CH2:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:31]([CH:28]3[CH2:29][CH2:30][CH:26]([NH:25][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:27]3)=[O:33])=[CH:5][C:6]=2[O:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)C1CCC(Nc2ccccc2)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)C1CCC(Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (17 mg), 3-phenylaminocyclopentanecarboxylic acid (15 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20 mg), and N,N-dimethyl-4-aminopyridine (12 mg) in 5 ml dichloromethane was stirred at room temperature overnight. After addition of water (5 mL), the mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography on silica (33% ethyl acetate in hexane) gave the product as a resin: MS (m+1)=423.3; H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 1.30 (m, 4H), 1.75 (m, 2H), 1.90 (m, 1H), 1.95 (m, 1H), 2.15 (m, 1H), 2.30 (m, 1H), 2.65 (m, 2H), 3.00 (m, 1H), 4.00 (m, 2H), 4.40 (m, 2H), 4.15 (m, 4H), 5.20 (s, 1H), 6.6-6.8 (m, 3H), 7.1-7.6 (m, 5H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[OH-:32].[Na+].[I-].[Na+]>O>[OH:32][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: [OH-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCO)CC3)c[nH]c12
Yield: 68 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (23.0 mg, 0.050 mmol), 50% NaOH in water (1 mL), and sodium iodide (5.0 mg) were reacted to give the title compound (15.0 mg, 68%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH2:17](Br)[CH:18]=[CH2:19].C([O-])([O-])=O.[Na+].[Na+]>CN1CCCC1=O.C(OC(=O)C)C>[CH2:19]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:11][CH:12]=1)[CH:18]=[CH2:17]
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A 500 ml round bottom flask, equipped with a reflux condenser and an oil bath with a magnetic stirrer was charged with 13.94 g of the above 4-(2-benzoxazolyl)-phenol, 9.7 g of allyl bromide and 17.5 g of anhydrous Na2CO3 in 300 ml of 1-methyl-2-pyrrolidone. A trace of KJ was added. After 5 h hour at 110° C. no starting material could be observed on tlc. The reaction mixture was diluted with ethylacetate and washed with 1n NaOH, water and NaCl solution, dried with Na2SO4, concentrated and recrystallised from hexene to yield 14.3 g (86%) of 2-(4-prop-2-enyloxy-phenyl)-benzoxazole. M.p. 95-96° C., UV (ethanol) 308 nm (26′184).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
0.59 g (2.41 mmol) of 2,4-Dichloro-3-nitroquinoline and 0.42 g (2.41 mmol) of N-(tert-butoxycarbonyl)-1,3-propanediamine were heated at 70° C. in 10 ml of triethylamine and stirred for 1.5 hours. Triethylamine was distilled off under reduced pressure. The resulting residue was dissolved in methylene chloride, washed with water, and dried (Na2SO4). After the solvent was distilled off under reduced pressure, the residue was triturated with methanol and filtered to obtain 0.61 g (1.60 mmol) of 4-[3-(tert-butoxycarbonylamino)propylamino]-2-chloro-3-nitroquinoline shown below as yellow crystals (mp: 159-161° C.). ##STR34## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3310, 1680, 1580. 1H-NMR (CDCl3) δ (ppm) : 1.50 (9H, s), 1.77 (2H, m), 3.27 (2H, q, J=6.1 Hz), 3.36 (2H, q, J=6.0 Hz), 4.82 (1 H, br), 7.37 (1H, br), 7.55 (1H, t, J=7.8 Hz), 7.72 (1H, t, J=7.7 Hz), 7.89 (1H, d, J=8.2 Hz), 8.27 (1H, d, J=8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)ccc1Cl
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 2-chloro-5-methylbenzoate (3.0 g, 16.2 mmol), N-bromosuccinimide (3.0 g, 17.0 mmol), and benzoyl peroxide (catalytic) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux overnight. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (2×100 mL). The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 5-(bromomethyl)-2-chlorobenzoate (4.06 g, 95% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[N:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[N:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[C:5]2[N:6]([C:8]([C:11]([NH:59][C:56]3[CH:57]=[CH:58][N:53]=[CH:54][CH:55]=3)=[O:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Reactant: Nc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Yield: 38.8 %

Procedure:
A solution of 6-chloro-8-((4-methoxybenzyl)(5-methylpyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (0.07 g, 0.165 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.047 g, 0.248 mmol), 1-hydroxybenzotriazole (0.033 g, 0.248 mmol), TEA (0.069 mL, 0.495 mmol) and pyridin-4-amine (0.023 g, 0.248 mmol) in acetonitrile (2 mL) was heated to 80° C. for 16 hours. The solution was quenched with EA/water. The organic layer was washed with sat NaHCO3 and sat NaCl. The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to give the crude product mixture. The crude product was purified by ISCO (5% EtOAC/DCM; 12 g column), followed by ISCO (5% MeOH/DCM; 12 g column) to afford the title compound (32 mg). [M+H]=500.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[O:14][C:11]2[CH:12]=[C:13]3[C:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=2)=[CH:25][CH:24]=1
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccc(Cl)cc3)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF; 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-chlorophenyl isocyanate (411 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 32 hours under N2 atmosphere at RT (35° C.). The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to afford 10f as solid. Yield: 520 mg, 71.42%.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([S:8][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Br:11])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cncc(SCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Benzyl mercaptan (1 g, 7.35 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.294 g, 7.35 mmol) was added, the ice bath was removed, and the reaction stirred for 15 minutes. 3,5-Dibromopyridine (1.74 g, 7.35 mmol) was added and the reaction was heated to 130° C. After heating for 1 hour the reaction was cooled then diluted with EtOAc and hexanes (1:1) and washed with 4× H2O and brine, with back-extraction. The combined organics were dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel (0-40% EtOAc in hexanes) to yield the title compound.