Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[F:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[C:16]([F:18])[CH:17]=1>C1C=CC=CC=1.C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([CH:5]2[NH:4][C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[C:7](=[O:8])[CH2:6]2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CC1(C)C(=O)C=CNC1=O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)CC(c2cc(F)cc(F)c2)NC1=O

Procedure:
To a solution of 3,3-dimethylpyridine-2,4(1H,3H)-dione (978 mg, 7.03 mmol) [U.S. Pat. No. 2,525,231] in benzene (10 mL) was added 3,5-difluorophenylmagnesium bromide (50 mL of a 0.5 M solution in THF, 25 mmol) and the resulting mixture was heated to reflux for 1.5 h. The mixture was cooled, quenched with 1 N aqueous HCl (10 mL), made basic with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with H2O (50 mL), then brine (50 mL), and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 60:40, to give the title compound. MS: m/z=254 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:43]>>[ClH:43].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:20])[C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][CH:14]=4)[C:4]=23)[CH2:22]1
Reactant: ClCCl
Reactant: Cc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)cn1
Product: Cl
Reaction time: 1 h
Yield: 33 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(6-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (12 mg, 0.023 mmol) in DCM (3 mL) at room temperature was treated with TFA (1 mL). The reaction was stirred for 1 hour and then concentrated to dryness. The resulting residue was dissolved in a minimal amount of DCM and then added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamide hydrochloride (0.004 g, 33% yield) as a solid. 1H NMR (400 MHz, D2O) δ 9.02-8.99 (m, 1H), 8.65-8.61 (m, 1H), 8.23 (d, 1H), 7.80 (d, 1H), 7.40 (d, 1H), 3.52-3.46 (m, 1H), 3.36-3.26 (m, 1H), 3.25-3.17 (m 1H), 3.15-3.06 (m 2H), 2.67 (s, 3H), 1.84-1.76 (m, 1H), 1.71-1.61 (m, 1H), 1.46-1.31 (m, 2H); LCMS (APCI+) m/z 429, 431 (M+H)+, Retention time=2.25 minutes (Method 2).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[O:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:18][N:17]=[CH:16]1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[O:15]1[C:19]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH:6]4[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]4)=[CH:13][CH:12]=3)(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[CH:18][N:17]=[CH:16]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(-c4cnco4)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
The crude 4-(1-propyl-azetidin-3-yl)-phenylamine (40 mg, 0.21 mmol) was dissolved in CH2Cl2/pyridine 9:1 (10 ml) and 4-oxazol-5-yl-benzenesulfonyl chloride (51 mg, 0.21 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 95:5) to afford the title compound (30 mg, 36%) as a white amorphous solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)=[C:6]1[CH3:25])[CH2:2][CH2:3][CH3:4].[CH2:26]([N:28]([CH2:40][CH3:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:30]=1)[CH3:27]>>[CH2:36]([N:35]([CH2:38][CH3:39])[C:31]1[CH:30]=[C:29]([N:28]([CH2:26][CH3:27])[CH2:40][CH3:41])[CH:34]=[CH:33][C:32]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:20])[O:19]1)[CH3:37]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: CCCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c2ccccc21

Procedure:
In a manner similar to that described in part B above, 3.35 g (0.01 mole) of 2[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-benzoic acid and 2.42 g (0.011 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-n-butyl-2-methyl-3-indolyl)phthalide (Formula III: R°=R1 =R2 =R3 =Y1 =H; R=CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; R6 =(CH2)3CH3), as tan-colored crystals which melted at 78°-80° C. A toluene solution of the product spotted on silica gel developed an intense blue-black-colored image.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Se:10][C:9]=1[C:19]([O:21]CC)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Se:10][C:9]=1[C:19]([NH2:2])=[O:21])[CH3:5]
Reactant: CCOC(=O)c1[se]c(-c2ccccc2)cc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cc(-c2ccccc2)[se]c1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (160 mL) was added a solution of ethyl 3-[(dimethylamino)diazenyl]-5-phenylselenophene-2-carboxylate (1.2 g) in THF (25 mL) for 5 min and a catalytic amount of PEG-400 was added and stirred at rt for 48 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product as off-white solid, which was recrystallized from chloroform-hexane (270 mg, 31%), mp 222-224° C. IR (Neat) νmax 3346, 2927, 2850, 1645, 1594, 1221, 1113, 1019, 875, 850 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.25 (1H, s, —CONH2), 7.87 (1H, s, H-4), 7.57-7.60 (2H, m, Ar—H), 7.30-7.40 (3H, m, Ar—H), 6.18 (1H, br s, —CONH2), 3.58 (3H, s, —N—CH3), 3.19 (3H, s, —N—CH3); 13C NMR (100 MHz, DMSO-d6): δ 165.6, 152.1, 151.9, 136.1, 131.1, 128.9, 128.5, 126.2, 118.1, 43.7, 36.6; LC-MS (positive ion mode): m/z 343, 345 (M+Na)+.
Reaction SMILES: [S:1]1(=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.CN1CCN(C)C1=O.[Cl:19]C1C=CC=CC=1>>[Cl:19][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: Clc1ccccc1
Reactant: O=S1N=Cc2ccccc21
Solvent: CN1CCN(C)C1=O
Product: Clc1nsc2ccccc12
Yield: 92.7 %

Procedure:
Example 5 was repeated, except that 4 kg of 93% by weight pure benzisothiazolone and 90 g of 1,3-dimethylimidazolidinone in 5 l of chlorobenzene were phosgenated. To obtain the reaction product, 200 ml of high boiling paraffin oil were added prior to the vacuum distillation, and a Vigreux column of 20 cm in length was used. 3-Chlorobenzisothiazole of a purity of 99.4% by weight was obtained in a yield of 92.7% of theory.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[N:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C@@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=2)[CH:20]=[N:19][CH:18]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:21]3[CH:20]=[N:19][CH:18]=[N:17][CH:22]=3)=[CH:29][CH:28]=2)[CH3:31])[N:7]=1)([CH3:15])[CH3:14]
Reactant: C[C@H](N)c1ccc(Oc2cncnc2)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(Oc3cncnc3)cc2)n1
Temperature: 110 °C
Reaction time: 48 h
Yield: 9.9 %

Procedure:
To the solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (43 mg, 0.169 mmol) in NMP (0.7 mL) was added (S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethanamine (41 mg, 0.169 mmol) and DIEA (88 μL, 0.507 mmol). The brown reaction mixture was stirred at 110° C. for 2 days. The reaction mixture was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography [C-18] to provide (S)-4-isopropyl-3-(2-(((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (7 mg) as its trifluoroacetic acid salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([NH2:30])=[CH:27][CH:28]=2)[C:23]([CH3:31])=[C:22]1[CH3:32])[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([NH:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:19][CH3:20])[C:22]([CH3:32])=[C:23]3[CH3:31])=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CCn1c(C)c(C)c2cc(N)ccc21
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: CN(C)C=O
Solvent: O
Product: CCn1c(C)c(C)c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.8 %

Procedure:
To a solution of the compound obtained in Step 1 (510 mg, 2.07 mmol), 1-ethyl-2,3-dimethyl-1H-indol-5-amine (390 mg, 2.07 mmol) and DIEA (1.085 mL, 6.21 mmol) in DMF (8 mL) was added HATU (1181 mg, 3.11 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (533 mg, 1.280 mmol, 61.8%) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2)#[N:11].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:15]2)#[N:11]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C#N)ccc21
Yield: 98.5 %

Procedure:
tert-butyl bromoacetate (0.88 mL; 5.99 mmol) was added to a suspension of 5-cyanoindole (0.71 g; 4.99 mmol) and K2CO3 (1.38 g; 9.99 mmol) in CH3CN (20 mL) and the resulting mixture was stirred at reflux for 16 hours. Filtration and concentration in vacuo gave a light yellow oil which crystallized upon standing. The solid was triturated in a mixture of Et2O and hexane to give the title compound as an off-white solid (1.26 g, 98%). HPLC (Method A), Rt: 4.43 min (Purity: 96.8%). LC/MS (Method B): 256.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]([O-:12])(=[O:11])C.[Na+].C(Cl)Cl.[C]=O.[CH2:19](O)[CH3:20]>Cl[Pd]Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]([O:12][CH2:19][CH3:20])=[O:11])=[N:3][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: CCO
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)cn1
Temperature: 90 °C
Yield: 58 %

Procedure:
A mixture of 2-bromo-5-fluoropyridine (5.00 g, 28.4 mmol), sodium acetate (9.33 g, 114 mmol), and 1-1′bis(diphenylphosphino)ferrocene]dichloropalladium(II):CH2Cl2 (0.464 g, 0.57 mmol) in ethanol (80 mL) in a Parr® high pressure stainless steel reactor vessel is placed under an atmosphere of 50 psi carbon monoxide and heated at 80-100° C. for 4 h. The vessel is cooled, volatiles removed in vacuo, and the residue partitioned between ethyl acetate and water. The ethyl acetate extract is washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give a dark solid. The residue is chromatographed on SiO2 (10% ethyl acetate/hexanes) to yield the title compound 2.8 g (58%) as a white solid that is recrystallized from hexanes to give white crystals: mp 61-63° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Br:14][C:15]1[N:19]2[CH:20]=[C:21]([Br:25])[N:22]=[C:23](Br)[C:18]2=[N:17][CH:16]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:14][C:15]1[N:19]2[CH:20]=[C:21]([Br:25])[N:22]=[C:23]([NH:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=3)[C:18]2=[N:17][CH:16]=1
Reactant: Brc1cn2c(Br)cnc2c(Br)n1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(CNc2nc(Br)cn3c(Br)cnc23)cc1
Temperature: 108 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
4-Aminomethyl-benzenesulfonamide hydrochloride (2.22 g, 10 mmol) was added to a solution of 3,6,8-Tribromo-imidazo[1,2-a]pyrazine (2.77 g, 10 mmol) and DIPEA (3.65 ml, 21 mmol) in iBuOH (20 mL). The reaction was stirred at 108° C. for 3 h then allowed to cool to room temperature. The precipitate formed was filtered and washed with diethyl ether to give 4-[(3,6-Dibromo-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide as a pale brown solid (3.5 g, 76% yield). LC-MS m/z 462 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
To a solution of 5-nitro-2-thiophenecarboxaldehyde (1.00 g, 6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in acetone, 8.12 ml, 65 mmol) at −20° C. After stirring for 1 H, 30 ml of isopropanol was added to the mixture. H2O was added to the mature and extracted with CH2Cl2. The extra was washed with water, brine, dried (Na2SO4), and concentrated to give 967 mg (90%) of yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].C([Li])(CC)C.[CH2:24]([CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[CH2:25][CH3:26].Cl>C1COCC1.CCCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:30]3([OH:33])[CH2:31][CH2:32][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]3)=[C:14]([F:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2cccc(F)c2)cc1F
Reactant: CCCC1CCC(=O)CC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCOc1ccc(-c2ccc(C3(O)CCC(CCC)CC3)c(F)c2)cc1F
Temperature: -60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 15.0 g (60.4 mmol) of the 3,3′-difluoro-4-propoxybiphenyl obtained in the first step of Example 1 in 85 ml of THF was added by drops 70 ml (1.04M, cyclohexane solution, corresponding to 72.5 mmol) of sec-butyllithium while being maintained at a temperature lower than −60° C. After finishing of the dropping, it was stirred at the same temperature for 1 hour. Subsequently, a solution of 11.0 g (78.5 mmol) of 4-propylcyclohexanone in 55 ml of THF was added by drops thereto while being maintained at a temperature of −60° C., stirred at the same temperature for 3 hours, and then further stirred at room temperature for 2 hours. After 200 ml of a diluted hydrochloric acid was added by drops to the reaction liquid, it was extracted with 200 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution twice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (eluent: heptane/ethyl acetate=8/2) to obtain 21.2 g of a crude 3,3′-difluoro-4′-(1-hydroxy-4-propylcyclohexyl)-4-propoxybiphenyl. (Yield: 90.6%)
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[C:27]2[N:26]=[CH:25][N:24]=[C:22]([NH2:23])[C:21]=2[N:20]=[CH:19]1.C[Si](Cl)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[NH4+]>N1C=CC=CC=1.O>[C:33]([NH:23][C:22]1[C:21]2[N:20]=[CH:19][N:18]([C:27]=2[N:26]=[CH:25][N:24]=1)[C@@H:11]1[O:12][C@H:13]([CH2:16][OH:17])[C@@H:14]([OH:15])[C@H:10]1[O:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[O:2][CH3:1])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CO[C@@H]1CCCC[C@H]1O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CO[C@@H]1CCCC[C@H]1O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2′-O-(trans-2-methoxy-cyclohexyl)adenosine (0.056 mol) in pyridine (100 mL) is evaporated under reduced pressure to dryness. The residue is redissolved in pyridine (560 mL) and cooled in an ice water bath. Trimethylsilyl chloride (36.4 mL, 0.291 mol) is added and the reaction is stirred at 5° C. for 30 minutes. Benzoyl chloride (33.6 mL, 0.291 mol) is added and the reaction is allowed to warm to 25° C. for 2 hours and then cooled to 5° C. The reaction is diluted with cold water (112 mL) and after stirring for 15 min, concentrated ammonium hydroxide (112 mL). After 30 min, the reaction is concentrated under reduced pressure (below 30° C.) followed by coevaporation with toluene (2×100 mL). The residue is dissolved in ethyl acetate-methanol (400 mL, 9:1) and the undesired silyl by-products are removed by filtration. The filtrate is concentrated under reduced pressure and purified by silica gel flash column chromatography (800 g, chloroform-methanol 9:1). Selected fractions are combined, concentrated under reduced pressure and dried at 25° C./0.2 mmHg for 2 h to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][CH:23]([CH3:39])[CH2:24][CH2:25][Si:26]1(C2C=CC=CC=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.Br[CH2:41][CH2:42][C:43]([F:46])([F:45])[F:44]>>[CH3:39][CH:23]([CH3:22])[CH2:24][CH2:25][Si@H:26]1[CH2:27][CH2:28][C@H:29]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[CH:12][CH:13]=3)=[CH:6][CH:7]=2)[CH2:30][CH2:31]1
Reactant: FC(F)(F)CCBr
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(-c3ccc(OCCC(F)(F)F)cc3)cc2)CC1

Procedure:
The general procedure of Example 17 was repeated using 4'-bromo-4-(t-butyldimethylsiloxy)biphenyl, 4-(3-methyl-n-butyl)-4-phenyl-4-silacyclohexanone, and 1-bromo-3,3,3-trifluoro-n-propane, thereby obtaining the intended compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20]Cl)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1c(NC(C)=O)c(OCCCl)c(OC)c2occc12
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: COc1c(NC(C)=O)c(OCCN2CCN(C)CC2)c(OC)c2occc12

Procedure:
A solution of 15.5 g (0.05 mole) of 5-acetamido 6-(2-chloro ethoxy) 4,7 dimethoxy benzofuran prepared in the preceding example and 15 g (0.15 mole) of N-methyl piperazine was brought to reflux for 8 hours in 100 ml of toluene. It was filtered and the filtrate evaporated under vacum the residue was taken up again in alcohol and hydrochloric alcohol was added. It was filtered and recrystallized in absolute alcohol.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([CH2:30][CH2:29][CH2:28][CH2:27]3)[C:19]2=[O:31])=[O:17])[CH2:10][CH2:9]1)[C:3]([O:5]C)=[O:4].OS(O)(=O)=O.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)(=O)C.O>[CH3:1][C:2]([CH3:32])([CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([CH2:30][CH2:29][CH2:28][CH2:27]3)[C:19]2=[O:31])=[O:17])[CH2:10][CH2:9]1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)CN1CCC(CNC(=O)N2C(=O)C3(CCCC3)c3ccccc32)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CN1CCC(CNC(=O)N2C(=O)C3(CCCC3)c3ccccc32)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 2,2-dimethyl-3-[4-({[(2′-oxospiro[cyclopentane-1,3′-indol]-1′(2′H)-yl)carbonyl]amino}methyl)piperidin-1-yl]propanoate (170 mg, 0.38 mmol, step 3 of Example 2) in acetic acid (2 mL), H2SO4 (113 mg) in water (2 mL) was added, and the mixture was refluxed for 36 h. The mixture was cooled to room temperature and solid NaHCO3 (500 mg) was added slowly. The resulting mixture was concentrated to give white solid. To the solid, CH2Cl2 (40 mL) was added and stirred for 10 min, dried over MgSO4. The solution was filtered and concentrated and then resulted yellow oil. The oil was chromatographed on a column of silica gel eluting with CH2Cl2/methanol (14:1) to give 130 mg (80%) of the title compound as white solid. Recrystallization from ethyl acetate/diethyl ether gave white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([N:19]([CH2:24][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:27][OH:28])[CH2:20][CH2:21][O:22][CH3:23])=[O:18])[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([N:19]([CH2:24][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21][O:22][CH3:23])=[O:18])[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COCCN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
0.526 g of methanesulfonyl chloride are added to a mixture of 1.8 g of the product obtained in step 4 and 0.46 g of triethylamine in 40 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 1 h and is then concentrated under vacuum. The residue is taken up with ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum to give 2 g of the expected product.