Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][C:27]1[CH:26]=[C:25](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)[CH:30]=[CH:29][N:28]=1
Reactant: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Reactant: Cc1cc(Br)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)ccn1
Yield: 29.3 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60.2 mg, 0.2 mmol) and 4-bromo-2-methylpyridine (34.4 mg, 0.2 mmol) in DMF (2 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a yellow solid (23 mg, 23%). NMR indicated 7% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.53 (d, J=6.4 Hz, 1H), 8.13-8.03 (m, 4H), 7.59 (d, J=16.4 Hz, 1H), 7.53 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 3.56 (t, J=8.0 Hz, 1H), 2.77 (s, 3H), 2.25 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.18 (dd, J=9.2 Hz, 4.8 Hz, 1H); MS ESI 393.2 [M+H]+, calcd for [C25H20N4O+H]+ 393.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][CH2:12][CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].[C:33]([C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br)#[N:34]>O>[C:33]([C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([NH:11][CH2:12][CH2:13][CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:10])=[CH:6][CH:7]=1)#[N:34]
Reactant: CC(Cc1ccc(O)cc1)NCCC(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Cc1ccc(OCc2ccccc2C#N)cc1)NCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of 10.0 g 1-(4-hydroxyphenyl)-2-(3,3-diphenylpropylamino)-propane, 50 ml of dimethylsulfoxide and 2.4 g of sodium hydroxide in 10 ml of water is stirred at 60° for a half hour, whereupon 5.9 g of 2-cyanobenzyl bromide are added and the whole is stirred at room temperature for 20 hours. The mixture is diluted with water, extracted with ethyl acetate & the extract dried and evaporated. The residue is dissolved in the minimum amount of isopropanol, the solution neutralized with isopropanolic oxalic acid and the crude precipitate chromatographed on silica gel, using chloroform eluate, followed by chloroform-methanol (1:1). The initial fraction yields the 1-[4-(2-cyanobenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane, showing I. R. bands at 2220 and 907 cm-1, and the second fraction the 1-[4-(2-carbamoylbenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane, showing I. R. bands at 1655 and 1450 cm-1. The latter amide is taken up in aqueous ammonia, the mixture extracted with ethyl acetate & the extract dried and acidified with ethereal hydrogen chloride, to yield the corresponding hydrochloride melting at about 100° with decomposition.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O-:9])[N:3]=[CH:2]1.[Na+].[Cl-].[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH3:16]>>[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: CCCC(C)C
Reactant: [O-]CCCc1c[nH]cn1
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)CCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1H-imidazol-4-yl)propanolate and 5 mmol of 4-methylpentane chloride are treated as described in Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22](=O)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:21]=[C:22]([CH3:23])[C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cn1
Reactant: CC(=O)CCl
Product: COC(=O)c1c(C)cn2cc(OCc3ccccc3)ccc12
Yield: 69 %

Procedure:
This compound is obtained according to the same procedure as the compound of Preparation III using the Tschitschibabin reaction, starting with 19 g of methyl 2-[5-(benzyloxy)pyridin-2-yl]acetate [according to Bull. Pol. Acad. Sci. Chem.; (1990), 38(1-12), 17-27] and chloroacetone. 15.01 g of an orange-coloured solid are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[CH:4][N:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH2:11]([O:10][CH2:9][O:8][C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:21][CH:20]=2)=[N:7][CH:6]=1)[CH3:12]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOCOc1cnc(Cl)nc1
Product: CCOCOc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Yield: 91 %

Procedure:
Suzuki coupling of chloropyrimidine 108 (see Example 2S) and 4-(trifluoromethoxy)phenylboronic acid as in Example 2S above for 2 h, followed by chromatography of the product on silica gel, eluting with 0-2% Et2O/petroleum ether (foreruns) and then with 2% Et2O/petroleum ether, gave 5-(ethoxymethoxy)-2-[4-(trifluoromethoxy)phenyl]pyrimidine (110) (91%) as a white solid: mp (petroleum ether) 41-43° C.; 1H NMR (CDCl3) δ 8.60 (s, 2H), 8.41 (dt, J=9.0, 2.4 Hz, 2H), 7.30 (br dd, J=9.0, 0.9 Hz, 2H), 5.31 (s, 2H), 3.77 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); HRESIMS calcd for C14H14F3N2O3 m/z [M+H]+ 315.0951. found 315.0944.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21]
Reactant: O=c1c2cc(Br)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 47.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2b (200 mg, 0.519 mmol), 6-mercaptopurine monohydrate (97 mg, 0.570 mmol), K2CO3 (79 mg, 0.572 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 123 mg of an off-white solid (47%), mp 212-242° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 13.07 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.24 (d, J=2.3 Hz, 1H); 8.06 (dd, J=2.3, 8.7 Hz, 1H); 7.76 (dd, J=1.9, 7.4 Hz, 1H); 7.70 (d, J=8.7 Hz, 1H); 7.66 (d, J=8.1 Hz, 1H); 7.51 (dd, J=2.1, 7.9 Hz, 1H); 7.46 (dd, J=1.9, 7.9 Hz, 1H); 4.47 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.7, 156.8, 153.6, 151.5, 146.1, 143.6, 138.5, 134.0, 132.1, 131.8, 131.5, 130.5, 130.2, 129.9, 128.9, 128.8, 122.2, 120.3, 32.0. MS (ES): m/z 499.0 (M+). Anal. calcd. for C20H12ClBrN6OS.0.2C2H6O.0.05KCl: C, 47.79; H, 2.59; N, 16.39; S, 6.25. Found: C, 47.56; H, 2.54; N, 16.25; S, 6.58.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:36]1[CH:37]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:33]=[C:34]([CH3:39])[N:35]=1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-Dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M209) (295 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (197 mg, 84%).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)=O>>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)c(C)s1
Yield: 94.7 %

Procedure:
176 mg (0.712 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-3′,4′-dichloroacetophenone (0.854 mmol; 330 mg) in a manner similar to Example 22, step (a) to afford 270 mg (91% yield) of methyl 4-[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH:19][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(OC)c(NC(=O)c2cc(C(N)=O)ccc2OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,5-dimethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: COc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, white solid (80 mg, 94%), MS (ISP) m/z=341.3 [(M+H)+], mp 264° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: OCc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
4-chloropyridine-N-oxide (4.4 g) was dissolved in methylene chloride (68 ml), trimethyloxonium tetrafluoroborate (5.0 g) was added to the mixture, and the mixture was stirred for 90 minutes at room temperature. The solvent was removed under reduced pressure, the obtained residue was dissolved in methanol, and an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added thereto under heat reflux. An aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was further added to the mixture after 30 minutes, the mixture was stirred for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-chloro-2-pyridinyl)methanol (3.0 g).
Reaction SMILES: C([O:4][C@H:5]([C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[C:18](OC(CC(N1CCOCC1)=O)C(O)=O)(=O)C.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[CH3:18][O:9][C:7](=[O:8])[CH2:6][C@H:5]([OH:4])[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(=O)OC(CC(=O)N1CCOCC1)C(=O)O
Reactant: CC(=O)O[C@@H](CC(=O)O)C(=O)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of (S)-3-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid and 2-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (11 g, 44.8 mmol) in dry methanol (30 mL) HCl in dioxane (4M, 7.3 ml, 29.16 mmol) was added and stirred at room temperature for 5 hrs. The reaction mixture was neutralized with solid NaHCO3, filtered through a mixture of Celite/Na2SO4 (1:1) and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave (S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (6 g).
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([CH:8](O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2].CC1C=CC=C(C)N=1.S(Cl)([Cl:34])=O>O1CCCC1>[CH2:1]([S:3][CH:4]1[N:7]([CH:8]([Cl:34])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6.8 g. of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-hydroxyacetate in 200 ml. of tetrahydrofuran at 0°-5° C. was added 2.98 ml. of 2,6-dimethylpyridine. This was followed by dropwise addition of a solution of 1.73 ml. of thionyl chloride in 20 ml. of tetrahydrofuran, over a 5-minute period. Stirring was continued at 0°-5° C. for 15 minutes, and then the reaction mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was dissolved in 200 ml. of dichloromethane. The resulting solution was washed successively with dilute hydrochloric acid and water, and dried with anhydrous sodium sulfate. Evaporation in vacuo gave the title compound as a yellow, viscous liquid (yield: 7.12 g). The IR spectrum (CHCl3) of the product showed an absorption at 5.63 microns. The NMR spectrum (CDCl3) of the product showed absorptions at 1.3 (t, 3H); 2.47-3.7 (m, 4 H); 4.9-5.3 (m, 1H); 5.4 (s, 4H); 6.06 and 6.18 (ss, 1H); 7.58 (d, 2H); and 8.22 (d, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([F:14])=[CH:4][N:3]=1.O[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]3)[C:5]([F:14])=[CH:4][N:3]=1
Reactant: CN(CCCO)c1nc(Cl)ncc1F
Reactant: COC(=O)Cn1ccc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(Cl)ncc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-1-propanol (Example 83, 0.60 g, 2.73 mmol) and methyl (5-hydroxy-1H-indol-1-yl)acetate (Example 9, 0.37 g, 1.82 mmol) in dichloromethane (9 mL) was added triphenylphosphine (0.70 g, 2.73 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.72 g, 2.73 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h. The desired product (0.42 g, 56%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 7.85 (d, 1H), 7.15-7.07 (m, 3H), 6.88-6.83 (m, 1H), 6.47-6.46 (m, 1H), 4.85 (s, 2H), 4.07 (t, 2H), 3.84 (t, 2H), 3.76 (s, 3H), 3.26 (d, 3H), 2.20-2.13 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-])=O)[CH:8]=2)[N:3]=1.[H][H]>[Pd]>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:11]([CH3:12])=[N:10]2
Reactant: [H][H]
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2nc1C
Agent: [Pd]
Product: Cc1nc2ccc(N)cc2nc1C

Procedure:
A near solution of 2,3-dimethyl-6-nitroquinoxaline (62.9 g, 0.31 mole) in 1 L of absolute alcohol (Mallinkrodt) was hydrogenated in Parr apparatus using 5% Palladium on carbon 50% wet catalyst (Englehard). Hydrogen uptake (100% of theory) in 2 hours was noted. After the reduction stopped the catalyst was removed by filtration and the filtrate remaining concentrated to dryness in vacuo. The residue remaining was used without further purification as an intermediate in part C. Yield 52 g (96%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[N:9]=1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([NH:13][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[F:24])(=[O:33])=[O:32])[CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccncn2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3F)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 223, Step A using 3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.213 mmol) and 2-fluorobenzenesulfonyl chloride (0.124 mg, 0.639 mmol), the title compound was obtained as an off white solid (60 mg, 57% yield). MS (ESI): 488 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([C:13]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1nnn[nH]1
Reactant: COc1cc2ccccc2cc1C(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1cc2ccccc2cc1C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 8.2 g. of 3-methoxy-2-naphthoic acid, 5.2 g. of aminotetrazole, and 80 ml. of pyridine was added dropwise 6.4 ml. of thionyl chloride, maintaining the temperature below 70° C. After stirring for one hour, the mixture was cooled to 25° C. and evaporated to dryness. The residue was washed with dilute hydrochloric acid, then recrystallized from N,N-dimethylformamide, then dissolved in base, filtered, reprecipitated with dilute acid, filtered, washed with methanol, then recrystallized again from N,N-dimethylformamide to provide 3-methoxy-N-(tetrazol-5-yl)naphthalene-2-carboxamide (a type IV compound), m.p. 280°-283° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]([C:13](=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25]([O:27]C(C)(C)C)=[O:26])=[O:19])[CH:10]=[CH:11][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:25]([C:21]1[N:20]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([N:9]2[CH:10]=[CH:11][CH:12]=[C:8]2[C:6]([OH:7])=[O:5])=[O:32])[CH:24]=[CH:23][CH:22]=1)([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)c1cccn1C(=O)CCCCC(=O)n1cccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccn1C(=O)CCCCC(=O)n1cccc1C(=O)O
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a stirred solution of 55 mg (0.12 mmol) 1-[6-(2-tert-butoxycarbonyl-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylic acid tert-butyl ester in 8 ml dichloromethane at 0° C. was added dropwise 0.15 ml (1.97 mmol) trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded 39 mg (95%) of the title compound as an off-white crystalline solid. MS m/e (%): 350 (M+NH4+, 100).
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=O)[CH2:3]1.[CH3:13][CH:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:15]([C:17]1[CH:18]=C(O)C=[C:21]([CH:23]=1)[OH:22])[CH3:16]>C(O)C>[OH:22][C:21]1[C:11]2[C:4]3[CH2:3][CH:2]([CH3:1])[S:6][C:5]=3[C:7](=[O:8])[O:9][C:10]=2[CH:18]=[C:17]([CH:15]([CH:14]([CH3:13])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:16])[CH:23]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CCOC(=O)C1SC(C)CC1=O
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SC(C)C3
Reaction time: 72 h

Procedure:
To 45 ml. of ethanol was added 8.8 g. of crude ethyl 5-methyl-3-oxo-tetrahydrothiophene-2-carboxylate and 5 g. of 5-(3-methyl-2-octyl) resorcinol. The mixture was cooled in ice and hydrogen chloride was bubbled in for onehalf hour. The mixture was stoppered and let stand at room temperature for 3 days. The reaction mixture was concentrated and dissolved in ether. The ether solution was extracted twice with water and once with aqueous sodium bicarbonate solution. The solution was dried over magnesium sulfate and concentrated. The product was crystallized from acetonitrile to give 4.65 g., m.p. 146°-149°C.
Reaction SMILES: C([S:11][CH:12]1[N:15]([C:16](=[C:30]([OH:33])[CH2:31][Br:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:34])[CH:13]1[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(OCC1C=CC=CC=1)=O.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[SH:11][CH:12]1[N:15]([C:16](=[C:30]([OH:33])[CH2:31][Br:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:34])[CH:13]1[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1SC(=O)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of p-nitrobenzyl α-[4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (480 mg) in methylene chloride (5 ml) containing 20% of nitromethane is added a solution of aluminum chloride (270 mg) in methylene chloride containing 20% of nitromethane (4 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into diluted hydrochloric acid, and is extracted with methylene chloride. The extract solution is washed water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (376 mg). Yield: 99.5%.