Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:11][CH2:12][C:13]([F:17])([F:16])[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:42][S:43](Cl)(=[O:45])=[O:44].[NH4+].[Cl-]>ClCCl>[CH3:42][S:43]([O:15][CH2:14][C:13]([F:16])([F:17])[CH2:12][CH2:11][C@H:10]([N:18]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:24][CH:23]=1)(=[O:20])=[O:21])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])(=[O:45])=[O:44]
Reactant: CCCCCN([C@@H](CCC(F)(F)CO)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCCCN([C@@H](CCC(F)(F)COS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a stirred solution of the material from Step 7 (242 mg, 0.38 mmol) in dichloromethane (3.8 mL) at 0° C. were added N,N-diisopropylaethylamine (99 μL, 0.57 mmol) and methanesulfonyl chloride (33 μL, 0.417 mmol). The reaction mixture was stirred at room temperature overnight, poured into saturated aqueous NH4Cl and extracted with dichloromethane (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 167 mg of the title compound. LCMS (M+Na)=738.
Reaction SMILES: [CH3:1][CH:2]1[CH2:20][C:5]2[C:6]3[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:12][CH:11]=[CH:10][C:7]=3[S:8](=O)[C:4]=2[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:20][C:5]2[C:6]3[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:12][CH:11]=[CH:10][C:7]=3[S:8][C:4]=2[CH:3]=1
Reactant: CC1CC2=C(C1)S(=O)c1cccc(-c3ccccc3)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1=Cc2sc3cccc(-c4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 81.4 g of 2-methyl-8-phenyl-1,2-dihydrobenzo[b]cyclopenta[d]thiophenone (0.29 mol) (1a) in 800 ml of THF was admixed at 0° C. with 225 ml of a 1.0 molar solution of lithium aluminum hydride (0.23 mol) in diethyl ether. The mixture was stirred at room temperature for another 4 hours. 25 ml of water were then carefully added and the resulting suspension was filtered through a layer of Celite and dried over magnesium sulfate. After filtration, the solvent was removed and a brown vitreous solid was obtained. The solid was dissolved in 400 ml of toluene and, after addition of 2.0 g of p-toluenesulfonic acid, stirred at 70° C. for 2 hours. The cooled reaction mixture was washed with a saturated solution of sodium hydrogencarbonate and with water and dried over magnesium sulfate. After the desiccant had been separated off, the solvent was removed and the residue was chromatographed on silica gel (5% methylene chloride in hexane as eluant). This gave 39 g (52%) of (1b) as a light-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][CH3:12])[C:6]=2[CH:13]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[CH2:11]([N:7]1[C:6]2[CH:13]=[C:2]([C:21]3([OH:24])[CH2:22][CH2:23][C:18]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:19][CH2:20]3)[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[CH3:12]
Reactant: CCn1c(=O)oc2ccc(Br)cc21
Reactant: O=C1CCC2(CC1)OCCO2
Product: CCn1c(=O)oc2ccc(C3(O)CCC4(CC3)OCCO4)cc21

Procedure:
The title compound was prepared as a white solid from 5-bromo-3-ethyl-3H-benzooxazol-2-one (prepared by ethylation of 5-bromo-3H-benzooxazol-2-one) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:35](=[N:37]O)[NH2:36]>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:35]1[N:37]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:26][N:36]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1cc(F)ccc1F
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cc(F)ccc3F)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 45.7 (0.266 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 42.9 mg (34% of theory).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C@@H:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl.CCOC(C)=O.O>O1CCOCC1>[C:32]([O:31][C:30](=[O:36])[NH:29][C@H:26]1[CH2:27][CH2:28][C@@H:24]([C:22]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:2])=[O:3])[C:15]=4[N:16]=[CH:17][C:18]3=[N:20][N:21]=2)[CH2:25]1)([CH3:34])([CH3:35])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)n23)cc1
Temperature: 80 °C
Yield: 85.1 %

Procedure:
To a solution of tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (9.30 g, 18.1 mmol, Preparation #A.1) in 1,4-dioxane (100 mL) was added TEA (10.0 mL, 72.3 mmol) and SOCl2 (2.11 mL, 28.9 mmol). The mixture was heated at about 80° C. for about 1.5 h. The reaction mixture was cooled to ambient temperature, EtOAc and water (200 mL each) were added, and the layers were separated. The aqueous solution was extracted with EtOAc (2×100 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 and brine (100 mL each). The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 25-100% EtOAc in DCM to give tert-Butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (7.65 g, 85%): LC/MS (Table 2, Method a) Rt=2.37 min; MS m/z: 497 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: CCC(NC(=O)Cc1cccc(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH3:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=[O:28]>>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH3:25])=[O:28])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: COc1cc(F)ccc1-c1[nH]c2c(C#N)cnn2c1NC1CCCC1
Reactant: CS(C)=O
Product: COc1cc(F)ccc1C(=O)/C(=N\C1CCCC1)n1ncc(C#N)c1N
Reaction time: 1440 h
Yield: 35 %

Procedure:
A light yellow solution of 3-(cyclopentylamino)-2-(4-fluoro-2-methoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (130 mg, 0.383 mmol) in DMSO (5 mL) was kept at RT in a 10 mL vial. The resulting light yellow solution was stored for 60 days. Then, the crude compound in DMSO was purified by using an HPLC column chromatography using acetonitrile and ammonium acetate as eluent. The desired peak was collected and the solvent was removed under vacuum to obtain 48 mg (35% yield) of (E)-5-Amino-1-(1-(cyclopentylimino)-2-(4-fluoro-2-methoxyphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.62 (br m, 4H), 1.62-1.78 (br, 4H), 3.67 (p, 1H), 3.70 (s, 3H), 7.01 (dt, 1H), 7.13 (dd, 1H), 7.66 (s, 1H), 7.99 (dd, 1H), 8.06 (brvs, 2H). LC/MS calcd. for C18H18FN5O2 (m/e) 355.371, obsd. 355.9 (M+H, ES+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl>[CH2:1]([N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:17](=[O:18])[CH2:16][Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)N(Cc1ccccc1)C(=O)CCl
Reaction time: 1 h

Procedure:
To a stirred and cooled mixture of 33 parts of N-benzyl-N-tert.-butylamine in 60 parts of sodium hydroxide solution 20% and 160 parts of 1,2-dichloroethane are added dropwise 34 parts of 2-chloroacetyl chloride at a temperature between -5° and -10° C. Upon completion, stirring is continued at the same temperature for one hour. The reaction mixture is allowed to reach room temperature and the organic layer is separated, washed with water, dried and evaporated, yielding 43 parts of N-benzyl-N-tert.-butyl-2-chloroacetamide as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]([N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:5]=[CH:6][CH:7]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A suspension of tert-butyl 1-(3-aminophenyl)-2-(tert-butyldimethylsilyloxy)ethyl(2-methoxyethyl)carbamate (0.5 g, 1.95 mmol) and 4-bromobenzenesulfonyl chloride (0.99 g) in chloroform (20 mL) was stirred under nitrogen at room temperature. N,N-Diisopropyl ethyl amine (1 mL) was added and the mixture was stirred for 16 hours at 60° C. The solution was diluted with EtOAc (50 mL), washed with water (2×20 mL), 1 M HCl (20 mL) and brine (20 mL) and dried over Na2SO4. Evaporation of the solvents gave a brown oil which was purified by column chromatography (30% EtOAc in hexane) to give the title compound as a light yellow oil (0.3 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C:26](=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([O:21][CH3:26])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 74 %

Procedure:
A mixture of α(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid (0.5g.), methanol (5ml.) and concentrated sulphuric acid (4 drops) was heated under reflux for six hours. The mixture was then poured into water (10 ml.), and the resulting mixture was neutralised with sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 × 5 ml.) and the combined extracts were washed successively with sodium bicarbonate solution (5 ml.) and water (5 ml.), and then dried with sodium sulphate. The solvent was evaporated in vacuo and the residue crystallised from cyclohexane to give methyl α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionate m.p. 90°-92.5° C, in 74% yield.
Reaction SMILES: [F:1][C:2]([F:27])([C:23]([F:26])([F:25])[F:24])[C:3]([F:22])([F:21])[C:4]1([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[O-:28][C:29]#[N:30].[Na+].FC(F)(F)C([O-])=O.O>C(Cl)Cl>[F:17][C:12]([F:18])([C:13]([F:16])([F:15])[F:14])[C:11]([F:19])([F:20])[C:4]1([C:3]([F:21])([F:22])[C:2]([F:1])([F:27])[C:23]([F:24])([F:25])[F:26])[O:8][CH:7]([CH2:9][O:10][C:29](=[O:28])[NH2:30])[CH2:6][O:5]1
Reactant: OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Reactant: N#C[O-]
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Reaction time: 24 h

Procedure:
A solution of 44.0 grams (0.1 mol) of 2,2-bis(heptafluoropropyl)-4-hydroxymethyl-1,3-dioxolane prepared by the method disclosed in patent application Ser. No. 873,660 filed Nov. 3, 1969, in 250 ml methylene dichloride is treated with 13.0 grams of sodium cyanate while 22.8 grams trifluoroacetate acid is added dropwise. The reaction is carried out at 25°-35° C. for 24 hours. After the reaction is completed, a small amount of water is added to dissolve the salts and the methylene dichloride solution is separated and washed with water. Vacuum-stripping yields the desired product. The product, 2,2-bis(heptafluoropropyl)-4-carbamoyloxymethyl-1,3-dioxolane, is purified by crystallization from a mixture of benzene and hexane.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][CH:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:3]1([CH2:13][C:14]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A suspension of 2.96 g (0.062 mol) of NaH. oil (50%) was washed with THF to remove the oil, then suspended in 300 mL THF, and then treated with 20.0 g (0.056 mol) of di-t-butyl (1-naphthylmethyl)malonate. The solution was refluxed for 40 minutes, then cooled to room temperature. A solution of 6.8 mL (0.057 mol) of benzyl bromide in 40 mL THF was then added and the mixture heated at reflux for 15 minutes, then left stirring at room temperature overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed with 1N citric acid, saturated NaCl, saturated NaHCO3, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 25 g of a yellow oil. Chromatography on silica gel, eluting with hexane:EtOAc (90:10) gave 20.0 g (80% yield) of the product as a clear oil. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.CCOC(C)=O.CCCCCCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CO)cc3)cc12
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (783 mg, 3.03 mmol), 4-(hydroxymethyl)benzene boronic acid (460 mg, 3.03 mmol), 2N aqueous potassium carbonate (6.4 mL, 13 mmol) in toluene (9 mL) and EtOH (13 mL) was degassed with N2 for 5 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (247 mg, 0.30 mmol). The mixture was heated in a sealed tube to 120° C. and stirred for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 mL), then washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting brown foam was purified by flash chromatography (20-100% EtOAc/heptane) to afford a pale yellow solid. The solid was dissolved in 5:1 EtOAc/heptane (30 mL), and a colorless precipitate formed. The precipitate was collected by filtration, washed with heptane and dried under vacuum to afford the title compound (173 mg, 20% yield) as a colorless solid. MS (ES+) 286.0 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 9.92 (s, 1H) 8.07 (s, 1H) 8.25 (s, 1H) 7.64 (s, 1H) 7.44 (m, 4H) 4.70 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[S:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[S:9]1[CH2:10][CH:11]=[C:12]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(C2=CCSCC2)cn1
Temperature: 115 °C
Yield: 46.9 %

Procedure:
To a solution of 5-bromopyridin-2-amine (344 mg, 1.99 mmol) in DME (6 mL) was added 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.33 mmol), and sodium carbonate (1.99 mL, 3.98 mmol). The mixture was purged with nitrogen for 5 min, and followed by the addition of PdCl2(dppf)-CH2Cl2 (108 mg, 0.13 mmol). The resulting mixture was heated to 115° C. in an oil bath for 5 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried and was concentrated. The residue was purified by flash column chromatography on silica gel (ISCO) eluting with 0-90% ethyl acetate in heptane to give Fractions were combined and concentrated to give 5-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-2-amine (120 mg, 47%) as brown color solid. LCMS (m/z): 193 (MH+), 0.44 min.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[O:18]=[C:19]1[O:23][CH:22]([C:24](Cl)=[O:25])[CH2:21][CH2:20]1>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][C:24]([CH:22]1[CH2:21][CH2:20][C:19](=[O:18])[O:23]1)=[O:25]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=C1CCC(C(=O)Cl)O1
Product: O=C1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)O1

Procedure:
In substantially the same manner as in Example 8 (1), 15 g of 2-amino-2',5-dichlorobenzophenone was allowed to react with 5-oxotetrahydrofuran-2-carbonyl chloride to afford 18.1 g of 2',5-dichloro-2-(5-oxotetrahydrofuran-2-carbonyl) aminobenzophenone, m.p. 170° C.-173° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Fc1ccc2[nH]cc(CCCCCl)c2c1
Product: Fc1ccc2[nH]cc(CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)c2c1

Procedure:
from 1-(2,3-dichlorophenyl)piperazine and 3-(4-chlorobutyl)-5-fluoro-1H-indole. Mp 147–148° C. 1H NMR (DMSO-d6): 1.45–1.55 (m, 2H); 1.60–1.70 (m, 2H); 2.35 (t, 2H); 2.50 (b s, 4H); 2.65 (t, 2H); 2.95 (b s, 4H); 6.85–6.95 (m, 1H); 7.10–7.15 (m, 1H); 7.20 (s, 1H); 7.25–7.35 (m, 4H); 10.85 (b s, 1H). Ms m/z: 420 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:34])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=1)[CH:9]=[CH:8][C:7]=2[CH3:33])#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:33][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=2)=[C:11]2[C:6]=1[NH:5][C:4](=[O:34])[C:3]([C:1]1[NH:37][N:36]=[N:35][N:2]=1)=[CH:12]2
Reactant: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2cc(C#N)c(=O)[nH]c12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2cc(-c3nnn[nH]3)c(=O)[nH]c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A liquid mixture of 0.822 g (1.84 mmol) of the 3-cyano-8-methyl-5-[3-(2-quinolinylmethoxy)benzyloxy]-1,2-dihydroquinolin-2-one obtained in Example 3, 0.359 g (5.52 mmol) of NaN3, 0.295 g (5.52 mmol) of NH4Cl and 20 ml of DMF was stirred at a bath temperature of 120° C. for 8 hours. The solvent was distilled off and the residue was dissolved in a large amount of a CHCl3 --MeOH mixed solvent. The solution was washed with water and then dried over MgSO4. The solvent was distilled off, whereby 0.519 g of the title compound was obtained as pale yellow powder (yield: 57.5%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.CN([CH:11]=[O:12])C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH:11]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH3:1])=[O:12]
Reactant: Cc1cscc1C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1csc(C=O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 3,4-dimethylthiophene trimer (3.7 g, 11 mmol) in 20 mL of a DMF: CHCl3 (1:1, v:v) solvent mixture, was added 20 mL of a solution of DMF and POCl3 (4:1, v:v). The DMF:POCl3 mixture was added cautiously, dropwise at 0° C. Following the addition, the reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was then poured into ice water and neutralized with 25% NaOH solution to pH˜8. The aqueous mixture was extracted with dichloromethane. Upon solvent removal the residue was subjected to purification by column chromatography using silica gel and a dichloromethane-petroleum ether (1:3) mixed solvent as the eluting solution to yield pure product 2-formyl-3,4-dimethylthiophen trimer 2.2 g (Yield: 55%) 1H NMR (CDCl3) δ 10.09 (1H, s, CHO), 7.00 (1H, s, aromatic H), 2.54 (3H, s, CH3), 2.23 (3H, s, CH3), 2.16 (3H, s, CH3), 2.13 (3H, s, CH3), 2.11 (6H, s, CH3), and the corresponding trimer dialdehyde 1.57 g (Yield: 37%) 1H NMR (CDCl3) δ 10.09 (2H, s, CHO), 2.54 (6H, s, CH3), 2.15 (12H, m, CH3).