Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)CCC.CN(C=O)C.[OH-].[Na+]>[Cu]I.C(Cl)(Cl)Cl>[N+:11]([C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(-c2ccncc2)c2occc2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
7-Iodo-5-nitrobenzofuran (2.00 g, 0.00692 mol), 4-tributylstannylpyridine (2.80 g, 0.00761 mol), copper(I)iodide (132 mg, 0.692 mmol) and dichlorobis(triphenylphosphine) palladium(II) (49 mg, 0.0692 mmol) were added to a 50 mL test tube followed by DMF (20 mL). The mixture was heated at 100° C. overnight in a StemBlock. After cooling to room temperature, aqueous sodium hydroxide (2 M; 4 mL) was added and the solution was stirred for 15 min. Chloroform (20 mL) was added and the mixture was filtered through Celite. The aqueous layer was then extracted with chloroform (3×) and the combined organic phases were evaporated. The residue was then triturated with ether and the precipitate was dried in vacuo overnight to yield a light brown solid. Yield: 686 mg (41%); HLPC (System A) purity=99%, m/z=241 (M+H)+, 1H NMR (270 MHz, DMSO-d6) δ ppm 7.33 (d, J=2.23 Hz, 1H) 7.98 (m, 2H) 8.38 (d, J=2.23 Hz, 1H) 8.50 (d, J=2.47 Hz, 1H) 8.75 (d, J=2.23 Hz, 1H) 8.79 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:19]2[S:23][C:22]([C@@:24]3([OH:36])[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[C:26]([CH3:35])([CH3:34])[CH2:25]3)=[N:21][CH:20]=2)[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[OH:36][C@:24]1([C:22]2[S:23][C:19]([C:12]3[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=3)=[CH:20][N:21]=2)[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[C:26]([CH3:35])([CH3:34])[CH2:25]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO[Si](C)(C)C(C)(C)C)cc([N+](=O)[O-])c3)s2)CC1(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc([N+](=O)[O-])c3)s2)CC1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of the product of Step 3 (4.4 g, 8.23 mmol) in acetonitrile (20 mL) was added triethylamine trihydrofluoride (4 mL, 24.7 mmol). The mixture was stirred for 5 h at room temperature, then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2×), and the combined organics were dried over sodium sulfate, filtered, and concentrated to give methyl (1S,4R)-4-hydroxy-4-{5-[3-(hydroxymethyl)-5-nitrophenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylate (3.5 g, 7.9 mmol, 96% yield) as an orange-maroon oily foam. MS ESI: [M+H]+ m/z 421.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>>[C:15](=[O:16])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([CH3:13])[C:8]=1[O:12][C:15](=[O:16])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(C(C)(C)C)cc(O)c1O
Reactant: O=C(Cl)Oc1ccccc1
Product: Cc1cc(C(C)(C)C)cc(OC(=O)Oc2ccccc2)c1OC(=O)Oc1ccccc1
Yield: 75.2 %

Procedure:
Prepared from 5-tert-butyl-3-methylbenzene-1,2-diol and phenyl chloroformate; purified by recrystallization from ethanol to yield a while solid (75.2%); 1H NMR (500 MHz, CDCl3, ppm): δ 7.35-7.38 (m, 4H), 7.23-7.28 (m, 7H), 7.16-7.17 (m, 1H), 2.36 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [CH:1]1([C@@H:4]([N:7]2[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[C:8]2=[O:15])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[N:22]([C:9]1[C:8](=[O:15])[N:7]([C@H:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH3:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH2:21][CH2:20]2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Br)cc2c1NCC2
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-[(1S)-1-cyclopropylpropyl]-3,5-dichloro-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 126-127° C.; 1H NMR (300 MHz, CDCl3): δ 7.31 (d, J=1.9 Hz, 1 H), 7.24 (d, J=1.4 Hz, 1 H), 7.01 (s, 1H), 4.32 (t, J=7.9 Hz, 2 H), 4.08-4.02 (m, 1 H), 3.14 (t, J=8.1 Hz, 2 H), 1.94-1.78 (m, 2 H), 1.05-1.00 (m, 1 H), 0.94 (t, J=7.3 Hz, 3 H), 0.81-0.77 (m, 1 H), 0.54-0.48 (m, 2 H), 0.34-0.30 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBrCl2 (M+H)+: 442.0089; Found m/z 442.0093.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][C:4]1([F:7])[F:6].C([O-])([O-])=O.[K+].[K+].[Cl:14][C:15]1[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=1>CN(C=O)C>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:2][CH:3]2[CH2:5][C:4]2([F:7])[F:6])=[CH:17][N:16]=1
Reactant: FC1(F)CC1CBr
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC1(F)CC1COc1cnc(Cl)nc1
Temperature: 80 °C

Procedure:
295 mg (1.72 mmol) 1-bromomethyl-2,2-difluorocyclopropane and 318 mg (2.30 mmol) K2CO3 are added to a mixture of 150 mg (1.15 mmol) 2-chloro-5-hydroxypyrimidine in 2 mL DMF. The mixture is stirred at 80° C. over night. Then the reaction mixture is quenched by the addition of water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.CN(C)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=1>[Cl-].[Zn+2].[Cl-].ClC1C=CC=CC=1>[CH2:8]([O:9][C:18]1[CH:19]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:22][C:23]=1[C:8]([C:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([OH:10])=[O:12])=[O:9])[CH:7]([CH3:6])[CH3:2]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CC(C)COc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O

Procedure:
In a manner similar to that of part A of Example 3 condensation of tetrachlorophthalic anhydride (1.92 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (1.64 g.) in contact with zinc chloride (1.35 g.) and with chlorobenzene (40-45 ml.) as diluent afforded 2-(2,4-bis(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (II: Y'2 = Y'4 = (CH3)2N, Z4 = Z'5 = Z'6 = Z7 = Cl) (m.p. 199°-201° C.).
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][C@@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@H:5]([C:38]2[CH:39]=[N:40][N:41](CC3C=CC(OC)=CC=3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]1([F:1])[CH2:7][C@@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2cc([C@@H]3CCC(F)(F)C[C@H]3Oc3cc(F)c(S(=O)(=O)N(Cc4ccc(OC)cc4OC)c4ccncn4)cc3C)cn2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@@H]1CC(F)(F)CC[C@H]1c1cn[nH]c1
Yield: 64.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 143g by using the 4-({(1R,2S)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (0.15 g, 0.20 mmol) prepared in Example 144b, triethylsilane (0.16 mL), trifluoroacetic acid (0.20 mL) and dichloromethane (2.0 mL), to yield the title compound (60 mg, 63%) as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)[C:8]([NH2:10])=[O:9])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[C:7]([CH2:6][CH2:5][N:4]([CH:2]([CH3:1])[CH3:3])[CH:23]([CH3:25])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:8]([NH2:10])=[O:9])(=[O:28])[CH3:27]
Reactant: CC(C)N(CCC(C(N)=O)(c1ccccc1)C1CCCCN1)C(C)C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCCCC1C(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1

Procedure:
acylating α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-piperidineacetamide with acetic anhydride to form 1-acetyl-α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-piperidineacetamide;
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:18]([NH:17][CH2:14][CH2:15][CH3:16])=[O:19])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CCCN=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 44.6 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and propyl isocyanate (76 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (92 mg, 44%). LC-MS (m/z) 308.2 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:15][NH:14][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][C:6]([S:9](=[O:11])(=[O:10])[NH2:12])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C

Procedure:
1 mmol of 4-Cyano-benzenesulfonamide are dissolved in a mixture of ethanol/water (7:3) and 5 eq of hydroxylamine hydrochloride and 2.5 eq. Na2CO3 added. The suspension is heated to 80° C. for 2 h. After evaporation of the solvent mixture the resulting material is extracted from ethylacetate/water. The product was not further characterized.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].CC1C=CC(S(O[CH2:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Temperature: 70 °C
Yield: 98.7 %

Procedure:
4-Bromo-3,5-dimethylphenol (400.0 g), 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (727.3 g) and potassium carbonate (357.6 g) were added to N,N-dimethylformamide (4000 mL), and the mixture was stirred. The mixture was heated to 70° C., stirred for 20 hr and cooled to 5° C. Water (2000 mL) was added dropwise at 10° C. or below, seed crystal was added, and water (4000 mL) was further added. The mixture was stirred at room temperature overnight and at 10° C. or below for 2 hr. The precipitated crystals were collected by filtration, washed with water (4000 mL) and dried to give the title compound (631.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH2:20][CH2:21][OH:22])=[C:11]([CH3:19])[NH:12]3)=[O:7])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.OP(O)(O)=O.C(OCC)C>CS(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH2:20][CH:21]=[O:22])=[C:11]([CH3:19])[NH:12]3)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(C)c(CCO)c2c1C(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc2[nH]c(C)c(CC=O)c2c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
To a mixture in dry DMSO (11.6 mL) of 2-(4-chlorobenzoyl-5-methoxy-2-methylindol-3-yl) ethanol (2.0 g, 5.8 mmol), prepared as in step 1, and dicyclohexylcarbodiimide (DCC) (1.6 g. 7.8 mmol) was added 1.0 M H3PO4 in DMSO (1.0 mL) and the reaction mixture was stirred at room temperature for 48 hours. Diethyl ether (100 mL) was added and the solid dicyclohexylurea byproduct was removed by filtration. The filtrate was washed with water, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was triturated with hexane/ether to give 1.9 g (95%) of (4-chlorobenzoyl-5-methoxy-2-methylindol-3-yl) acetaldehyde.
Reaction SMILES: [N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](Cl)=[O:28]>ClCCCl>[N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:27](=[O:28])[CH2:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Reactant: Cc1ccccc1CC(=O)Cl
Solvent: ClCCCl
Product: CCC(c1ccc(NC(=O)Cc2ccccc2C)c([N+](=O)[O-])c1)n1ccnc1
Temperature: 0 °C
Yield: 89.3 %

Procedure:
To a stirred and cooled (0° C.) solution of 7 parts of 4-[1-(1H-imidazol-1-yl)propyl]-2-nitrobenzenamine in 126 parts of 1,2-dichloroethane were added 9.6 parts of 2-methylbenzeneacetyl chloride. After stirring for 12 hours at room temperature, the reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated in vacuo. The oily residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The eluent of the desired fraction was evaporated, yielding 9.6 parts (89.3%) of N-[4-[1-(1H-imidazol-1-yl)propyl]-2-nitrophenyl]-2-methylbenzeneacetamide; mp. 122° C. (interm. 48).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(O)(=O)C>[F:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1F
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1F
Temperature: 0 °C

Procedure:
25 ml of acetic anhydride was added to a mixture of 11.1 g of 2-fluoroaniline and 25 ml of glacial acetic acid. The mixture was heated at reflux for 5 minutes, then diluted with ice water. The resulting mixture was filtered, and the solid was dried to give N-(2-fluorophenyl)acetamide (3A), as a white solid, m.p.: 76°-77° C.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C=O)C.O>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH2:14][Cl:13])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: ClCCCI
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of sesamol (2.00 g, 14.48 mmol) in DMF (15 mL) was slowly added over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.65 g of an 80% dispersion in mineral oil, 21.67 mmol) in DMF (10 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (3.55 g, 1 7.37 mmol), and the resulting brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to a residue that was dried briefly under high vacuum producing a brown oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([F:12])([F:11])[F:10])([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCN(Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 1.52 g of magnesium in 25 ml of THF is admixed dropwise over 20 minutes with a solution of 14.25 g of 1-bromo-2-(trifluoromethyl)benzene in 15 ml of THF and the mixture is heated at reflux for 30 minutes. After it has cooled on an ice bath, it is admixed slowly with a solution of 10 g of 1-benzyl-4-piperidinone in 30 ml of THF and left with stirring at AT for 3 hours. The reaction mixture is poured into saturated aqueous ammonium chloride solution and extracted with AcOEt, the combined organic phases are washed with water and dried over Na2SO4 and the solvents are evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (70/30; v/v) mixture. This gives 4.5 g of the expected product.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[C:11]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:4]([O:3][CH2:2][CH3:1])=[O:5])[O:12][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCCC12OCCO2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL) was added ethyleneglycol (10.1 g) and p-toluenesulfonic acid (2.8 g) at room temperature and the mixture was heated under reflux with Dean-Stark apparatus for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at −78° C. Further, ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyano-2-(1,4-dioxa-spiro[4,5]decan-6-yl)ethan-2-one (14.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH:26]1[C@H:32]2[N:33]([CH3:34])[C@H:29]([CH2:30][CH2:31]2)[CH2:28][CH2:27]1>>[C@@H:29]12[N:33]([CH3:34])[C@@H:32]([CH2:31][CH2:30]1)[CH:26]([NH:25][C:10]([C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=1)=[O:12])[CH2:27][CH2:28]2
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CN1[C@H]2CCC(N)[C@@H]1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN1[C@H]2CCC(NC(=O)c3n[nH]c4ccccc34)[C@@H]1CC2
Yield: 18 %

Procedure:
1H-Indazole-3-carboxylic acid (9.73 g, 60 mmol), 1,1'-carbonyldiimidazole (9.74 g, 60 mmol), and 4-aminotropane (8.42 g, 60 mmol) were converted to the title compound by the procedure of Preparation 7, Step 2 to give 3.02 g. Yield: 18%. m.p. 222° C.-224° C. EA calculated for C16H20N4O: C, 67.58; H, 7.09; N, 19.70. Found: C, 67.65; H, 7.25; N, 19.75. MS(FD) M+284.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:25])[CH3:24])[CH2:12][C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([O:28][C:26](=[O:27])[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[N:13]1[CH2:14][CH2:15][C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:30]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2c(ccn2C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
5-[1-(2-Chlorophenyl)-7-ethoxycarbonyl-7-methyloctyl]-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) was dissolved in dichloromethane (5 mL) with stirring under an argon atmosphere. TFA (0.48 mL, 4.75 mmol) was added to the solution. After 1 hour, TLC showed the starting material was gone. The mixture was poured into ice cold water (50 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=1/9 to 1/3) to afford 8-(2-chlorophenyl)-2,2 dimethyl-8-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-octanoic acid ethyl ester (Compound Ir, 65 mg, 65.9% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.80 (s, 1H), 7.54 (d, 1H, J=7.5 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.26-7.16 (m, 2H), 6.60 (s, 1H), 5.94 (s, 1H), 4.17 (m, 1H), 4.08 (q, 2H, J=7.2 Hz), 3.75 (d, 1H, J=13.2 Hz), 3.35 (d, 1H, J=13.2 Hz), 2.83-2.57 (m, 4H), 2.01-1.56 (m, 4H), 1.45-1.40 (m, 2H), 1.21 (t, 3H, J=7.2 Hz), 1.24-1.11 (m, 4H), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.14, 140.07, 134.95, 129.43, 129.25, 127.82, 126.79, 125.12, 116.43, 115.93, 105.80, 63.89, 60.37, 48.79, 48.32, 42.37, 40.94, 33.34, 30.64, 25.55, 25.41, 25.08, 24.07, 14.56. HRMS (HR, DART-TOF): Calculated for C25H35ClN2O2 (M+H)+: 431.2460. found 431.2476.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]([OH:15])=O)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:57]1[C:65]2[C:60](=[C:61]([CH2:66][NH2:67])[CH:62]=[CH:63][CH:64]=2)[CH:59]=[N:58]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[NH:67][CH2:66][C:61]2[CH:62]=[CH:63][CH:64]=[C:65]3[C:60]=2[CH:59]=[N:58][NH:57]3)=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(C)C
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.5 %

Procedure:
To a solution of 3-Isopropyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (190 mg, 0.83 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.35 mL, 2.49 mmol), HBTU (0.38 g, 1.0 mmol), HOBT (0.14 mg, 1.0 mmol), and C-(1H-Indazol-4-yl)-methylamine (180 mg, 1.25 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-100% EtOAc in hexane to afford the desired product (0.1262 g, 42% yield).