Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][C:34]=1[C:42]([F:45])([F:44])[F:43]>>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[C:34]([C:42]([F:44])([F:43])[F:45])[CH:35]=2)=[O:41])=[CH:25][CH:24]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CN(CCOc1cccc2c1ccn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C

Procedure:
The title compound can be synthesized from [2-(1H-indol-4-yloxy)ethyl]-methylcarbamic acid tert-butyl ester, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)-phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1>C(#N)C>[CH:10]([O-:11])=[O:9].[F:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[CH:30][CH:31]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: Fc1ccc(OCCBr)cc1
Solvent: CC#N
Product: O=C(O[C@H]1C[N+]2(CCOc3ccc(F)cc3)CCC1CC2)C1(c2ccccc2)CCCCCC1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 48.6 %

Procedure:
A mixture of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (50 mg) and 1-(2-bromoethoxy)-4-fluorobenzene (50 mg) in acetonitrile (1 mL) was stirred at room temperature for 22 h. Purification by prep. HPLC using 5-98% MeCN/H2O containing 0.1% formic acid gave the title compound (19 mg) as a colourless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23]1([C:29](=[N:31]O)[NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:7]([C:8]1[O:10][N:31]=[C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(=NO)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Cc2nc(-c3ccccc3)no2)cc1
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To a solution of phenylacetic acid (2.04 g) in 50 mL of DMF was added carbonyldiimidazole (2.7 g). The mixture was stirred for 20 min and then benzene amidoxime (2.04 g) was added. The resulting mixture was stirred for 20 min at r.t. and 18 h at 75 ° C. After cooling, the reaction mixture was poured in to 50 mL of water and extracted with 2×50 mL of 1:1 hexane/EtOAc. The extract was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 1:5 EtOAc/hexane to give 2 g of the title compound as a yellow syrup.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([NH2:19])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17](=[S:29])[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=S
Yield: 105.6 %

Procedure:
To a solution of the compound 67 (9.50 g) in methylene chloride (133 mL) was added Lawesson's reagent (6.71 g) at 0° C. and the solution was stirred for 3 Hours. To the reaction solution was added an aqueous saturated sodium bicarbonate solution and ethyl acetate and then the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate:methanol=60:40:033:67:00:90:10) to give the title compound (5.30 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH3:15].[CH2:16]([OH:18])[CH3:17]>>[NH2:15][C:2]1[C:11]([O:18][CH2:16][CH3:17])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Reactant: N
Reactant: CCO
Product: CCOc1nc2cc(Cl)c(Cl)cc2nc1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 3.46 g of 2,3,6,7-tetrachloroquinoxaline in 200 ml of ethanol was saturated with ammonia at 0° C. and was then shaken overnight at 80° C. under pressure in a Cook Hydrogenator. The solution was evaporated to dryness and the residue was triturated with water to obtain a buff crystalline solid. The latter was chromatographed over silica gel and was eluted with a 1-1 ethyl acetate-petroleum ether (b.p.=60° to 80° C.) mixture to obtain 1.36 g of 2-amino-6,7-dichloro-3-ethoxy-quinoxaline melting at 191°-193° C.
Reaction SMILES: C[C:2]1[C:3]([NH2:15])=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].N1C=CC=C[CH:28]=1>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:15][C:3]1[CH:2]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:12]([O:14][CH3:28])=[O:13])(=[O:25])=[O:24]
Reactant: Cc1cc2ccccc2c(C(=O)O)c1N
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 133A (6.97 g, 34.7 mmol) in pyridine (70 mL) was treated with 2-fluorobenzenesulfonyl chloride (7.86 g, 40.4 mmol), stirred for 16 hours at ambient temperature, concentrated, diluted with 1M NaHSO4, and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product (6.04 g). MS (ESI(+)) m/e 360 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:48]=1.C(N(CC)CC)C>CN(C=O)C.CC(=O)OCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:48]=2)=[O:12])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.9 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (200 mg, 0.85 mmol), HATU (210 mg, 0.89 mmol) in DMF (5 mL) was added methyl 5-aminopicolinate hydrochloride (156 mg, 1.02 mmol) followed by triethylamine (226 mg, 2.24 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EA (10 mL) and washed with NaHCO3 (10 mL), NH4Cl (10 mL) and brine (10 mL) then dried over MgSO4 and concentrated to give 78 mg (25%) of methyl 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinate INT-14 which was used in the next step without purification. LCMS-ESI (m/z) calculated C17H15F3N2O4: 368; found 369 [M+H]+, tR=3.06 min (Method 1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[N:21]#[C:22][NH2:23].[OH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26].C(O)(C(F)(F)F)=O>C1COCC1>[OH:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24].[C:22](=[NH:21])([O:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)=[CH:12][CH:11]=1)[NH2:23]
Reactant: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 59.7 %

Procedure:
To a solution of 2-(4-(3-(trifluoromethyl)phenoxy)phenyl)ethanol (1.395 g, 4.94 mmol) and cyanamide (0.249 g, 5.93 mmol) in THF (15 mL) was added triflic acid (0.527 mL, 5.93 mmol) under argon. The mixture was heated at 55° C. for 3 h. The mixture was purified by a reverse phase biotage with TFA affording the title compound (1.4 g, 59.8% yield). LCMS: rt=1.23 min, [M+H+]=325
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:16])C>CC(C)=O>[CH:11]1[CH:10]=[CH:9][C:8]([O:7][C:1]2[C:2]([OH:16])=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=1.[CH:11]1[CH:10]=[CH:9][C:8]([O:7][C:1]2[CH:2]=[CH:3][C:4]([OH:16])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)OO
Solvent: CC(C)=O
Product: Oc1ccc(Oc2ccccc2)cc1
Product: Oc1ccccc1Oc1ccccc1

Procedure:
The procedure of Example 21 was repeated, except diphenyl ether was used in place of 4-methyl anisole and perisobutyric acid (used as 20% acetone solution) was used in place of peracetic acid. Consequently, the conversion of perisobutyric acid was 98.5%, the conversion of diphenyl ether was 8.28% and there were produced 4.15g of 2-hydroxydiphenyl ether and 2.04g of 4-hydroxydiphenyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N+:5]([O-])=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12
Reactant: [O-][n+]1c(SC2CCCC2)cc(Cl)c2c1CCC2
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: Clc1cc(SC2CCCC2)nc2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.160 g, 0.59 mmol) in methylene chloride (10 mL) was added phosphorous trichloride (0.1 mL, 0.89 mmol). The mixture stirred at rt for 2 h. After this time, the mixture was quenched with a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.137 g, 91%) as a clear oil. MW=253.79. 1H NMR (CDCl3, 500 MHz) δ 6.96 (s, 1H) 3.98-3.90 (m, 1H), 3.02 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.22-2.08 (m, 4H), 1.83-1.72 (m, 2H), 1.68-1.58 (4H); APCI MS m/z 254 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[NH:6][C:7](=[O:21])[N:8]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:12])[C:10]=2[N:11]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[S:4][C:5]2[N:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:46])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:7](=[O:21])[N:8]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:12])[C:10]=2[N:11]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1nc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1nc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A mixture of 2-ethyl-6-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.54 g), potassium carbonate (0.17 g) and acetonitrile (15 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and acetone (5 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.25 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[C:24]2[Cl:31].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([N:8]([CH3:9])[CH3:10])=[CH:6][C:5]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[C:24]3[Cl:31])=[CH:4][N:3]=1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CN(C)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)c1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl
Temperature: 25 °C
Yield: 71.2 %

Procedure:
(Some starting materials may be obtained from ECA International, Palatine, Ill.) To a microwave vial (5 mL), 2-chloro-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (0.110 g, 0.390 mmol), 6-bromo-4-chloroquinoline (0.102 g, 0.419 mmol), PdCl2 (dppf)-CH2Cl2 adduct (0.0183 g, 0.0224 mmol) and potassium carbonate (0.500 mL, 1.00 mmol) were added into 1,4-dioxane (3 mL). The mixture was degassed by bubbling nitrogen through for 10 min. The tube was irradiated with microwave at 100° C. for 10 min. The reaction was cooled to RT then partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: acetone in hexanes 0% -30%) to afford the title compound as a white solid (0.0884 g). m/z: calc'd for C16H13Cl2N3; 317.0, found: 318.1 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.97 (s, 6 H), 7.55-7.63 (m, 2 H), 7.98 (dd, J=8.8, 2.0 Hz, 1 H), 8.25 (d, J=8.8 Hz, 1 H), 8.38 (dd, J=5.3, 2.0 Hz, 2 H), 8.84 (d, J=4.7 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.[CH3:26][N:27]1[C:32](=[O:33])[CH:31]=[C:30]2[S:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:29]2=[CH:28]1>>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[CH:16]=[C:12]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[C:7]4[O:8][C:9]([C:36]5[C:29]6=[CH:28][N:27]([CH3:26])[C:32](=[O:33])[CH:31]=[C:30]6[S:34][CH:35]=5)=[CH:10][C:6]=34)[CH:13]=[N:14]2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: Cn1cc2c(B3OC(C)(C)C(C)(C)O3)csc2cc1=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5csc6cc(=O)n(C)cc56)cc34)cn2)CC1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-c]pyridin-6(5H)-one by a procedure analogous to Example 223, Step D. 1H NMR (400 MHz, CD3OD): δ 9.01 (s, 1 H), 8.29 (s, 1 H), 8.17 (s, 1 H), 8.03 (s, 1 H), 7.83 (s, 1 H), 7.75 (s, 1 H), 7.07 (s, 1 H), 4.69 (m, J=13.1 Hz, 1 H), 4.51-4.62 (m, 1 H), 4.11 (m, J=16.4 Hz, 1 H), 3.87 (s, 3 H), 3.33-3.42 (m, 1 H), 2.80-2.96 (m, 1 H), 2.16-2.30 (m, 5 H), 1.95-2.15 (m, 2 H); MS (ESI): 489.37 [M+H]+; HPLC tR=2.32 min (ZQ3, polar—4 min).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:32])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cc(F)cc(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.19 g, 1.07 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 0.19 g, 44%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH2:6]([O:5][CH2:4][CH2:3][CH2:2][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using benzyl 3-bromopropyl ether to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (94%): mp 37-38° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.33-7.23 (m, 6H), 7.14-7.12 (m, 1H), 7.02-6.94 (m, 2H), 6.47 (d, J=0.9 Hz, 1H), 6.18 (d, J=0.9 Hz, 1H), 4.70 (ABq, 2H), 4.47 (s, 1H), 4.18-4.08 (m, 4H), 3.96-3.78 (m, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.01 (d, J=6.6 Hz, 2H); MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:14][C:15]1[C:20](Br)=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2]>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: Brc1ccccc1Br
Reactant: Clc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccc(CCCCCCBr)cc1
Yield: 45 %

Procedure:
In the same manner as described in Example 1, a Grignard solution in a mixture containing 450 ml of toluene and 40 ml of tetrahydrofuran was prepared from 58.8 g (0.4 Mol) of 1,4-dichlorobenzene. A solution of 146.4 g (0.6 Mol) of commercially available 1,6-dibromobenzene in 100 ml of toluene and a catalytic amount of dilithium tetrachlorocuprate were added to this solution. The full mixture was refluxed for 7 hours. The precipitate was then filtered off, the filtrate was acidified, and the phases were separated. The organic phase was washed, dried and evaporated, and the residue was fractionated. About 50 g of 1-(6-bromohexyl)-4chlorobenzene (45 percent yield) were obtained at a pressure of 0.2 hPa and at 106° to 109° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.BrC1C=CC2N=C(N)SC=2C=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].BrC1C=CC2N=C(NC(=O)C)SC=2C=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:23](=[O:25])[CH3:24])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2cccc(Br)c2s1
Agent: CC(=O)Nc1nc2ccc(Br)cc2s1
Agent: CN(C)c1ccncc1
Agent: Nc1nc2ccc(Br)cc2s1
Solvent: ClCCl
Product: CC(=O)Nc1nc2cccc(Br)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
The mixture (1.02 g, 4.45 mmol) of 7-bromobenzo[d]thiazol-2-amine and 6-bromobenzo[d]thiazol-2-amine and DMAP (620.6 mg, 5.079 mmol) were suspended in DCM (40 mL) and acetic anhydride (0.46 mL, 4.9 mmol) was added. The reaction was stirred under nitrogen at RT for 2 hours and was then quenched with 1 N HCl (25 mL). The layers were separated, and the aqueous phase was extracted with DCM, and the organic extracts were washed with 1 N HCl, dried over sodium sulfate, filtered, and concentrated to provide the mixture (865 mg, 72% yield) of N-(7-bromobenzo[d]thiazol-2-yl)acetamide and N-(6-bromobenzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 271 (MH+, 79Br), 273 (MH+, 81Br). Calculated exact mass for C9H7BrN2S: 270 (79Br), 272 (81Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C[O-].[Na+]>CO.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([C:16]([O:18][CH3:19])=[O:17])([C:12]([O:14][CH3:15])=[O:13])[CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCC(C(=O)OC)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reaction time: 40 h
Yield: 84.7 %

Procedure:
To a solution of the nitro diester, Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.44 g, 1.62 mmol) and methyl acrylate (0.22 mL, 2.43 mmol) in absolute methanol (5 mL) was added a catalytic amount of sodium methoxide at 21° C. under argon. The reaction mixture was stirred for 40 h at the same temperature and then diluted with dichloromethane (50 mL). The resulting mixture was washed with water, brine and dried. The residue obtained upon evaporation of the solvents was purified on a silica gel (hexane:ethyl acetate, 8:1) to give Trimethyl 1-(2-fluoro-4-nitrophenyl)propane-1,1,3-tricarboxylate (85) (0.49 g, 85%): 1H NMR δ 8.04 (dd, 1H, J=8.7, 2.3 Hz), 7.95 (dd, 1H, J=10.9, 2.3 Hz), 7.57 (dd, 1H, J=8.7, 7.5 Hz), 3.81 (s, 6H), 3.62 (s, 3H), 2.64-2.69 (m, 2H), 2.35-2.40 (m, 2H).