Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:17][NH2:18]>N1C=CC=CC=1>[N:17](=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:2]=1[OH:1])[NH2:18]
Reactant: NN
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Solvent: c1ccncc1
Solvent: O
Product: NN=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 2-hydroxy-4-morpholin-4-yl-benzaldehyde (0.135 g, 0.65 mmol) in pyridine (5 mL) was treated with hydrazine hydrate (33 mg, 0.65 mmol) and stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the product as a pale yellow solid (96 mg, 67%)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([C:10]#[N:11])[C:7]=2[CH:12]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].Cl>ClCCl.ClC(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([C:4]1[C:3]([OH:2])=[CH:12][C:7]2[C:8]([C:10]#[N:11])=[CH:9][C:6]=2[CH:5]=1)=[O:21]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccc2c(c1)C(C#N)=C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
While stirring at from 20° to 30°, 7.96 g of 5-methoxybenzocyclobutene-1-carbonitrile in 40 ml of dichloromethane are added dropwise to a suspension of 26.6 g of aluminium trichloride in 60 ml of dichloromethane. Stirring is carried out for 30 minutes at from 20° to 30° and then, over a period of 15 minutes, 20.95 g of 2,6-dichlorobenzoyl chloride are added dropwise thereto and the whole is stirred for 4 hours at room temperature and then poured into a mixture of 500 g of ice-water and 10 ml of concentrated hydrochloric acid. Stirring is then carried out for 30 minutes, 200 ml of trichloromethane are added, the whole is vigorously shaken and the organic phase is separated off, washed several times with semiconcentrated hydrochloric acid, dried over magnesium sulphate, concentrated to dryness by evaporation and recrystallised from dichloromethane/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile is obtained having a melting point of 174°-175°.
Reaction SMILES: Cl.O.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=3)[N:22]=2)[CH2:12][CH2:11]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Solvent: O
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccccc4Cl)CC3)nn12

Procedure:
A mixture of 1-(2-chlorophenyl)piperazine hydrate hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2-chlorophenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:14]=1)(=[O:29])=[O:28]
Reactant: O=C1CNC(=O)N1c1cccc(CCCCOCCCCCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCOCCCCc1cccc(N2C(=O)CNC2=O)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
3-(3-{4-[(6-Hydroxyhexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione (2.67 g) in CH2Cl2 (50 ml) and triethylamine (1.2 ml) was treated with methanesulfonyl chloride (1.22 ml) and the mixture was stirred at 20° C. for 1.5 h. The mixture was diluted with CH2Cl2 and washed with 2M HCl, NaHCO3, dried and purified by chromatography on Biotage (40 g) eluting with EtOAc-petroleum ether(1:1) and then with 2% MeOH—CH2Cl2 to give the title compound (1.186 g) ES+ve 427 (MH)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:19](S(C)(=O)=O)=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1.O>C1COCC1>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]3[N:20]4[CH2:21][CH2:22][CH2:23][N:24]([C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[C:19]4=[N:18][C:13]=3[CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(S(C)(=O)=O)nc2cnc3cc(Br)ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCn2c1nc1cnc3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
Under a nitrogen atmosphere, potassium tert-butoxide (6 mL of a 1 M solution in THF) was added to a solution of tert-butyl 3-(7-bromo-2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (2.3 g, 4.8 mmol) in THF (50 mL). The reaction was stirred overnight at room temperature, and an analysis by LC/MS indicated the presence of starting material. Additional potassium tert-butoxide solution (4 mL) was added, and the reaction was stirred for an additional 30 minutes at room temperature. The reaction was poured into water. A solid was present and was washed with water and dried for three days in a vacuum oven to provide 0.95 g of tert-butyl 3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[H][H]>O1CCCC1.[Pt]=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (44.6 g, 153 mmol) in 1.95 L tetrahydrofuran was added 9.0 gm platinum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 60 p.s.i. at ambient temperature for 24 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 32.6 gm (73.7%) of the title compound as a white solid. MS(m/e): 293(M+). EA calculated for C14H17N2Br: C, 57.32; H, 5.96; N, 9.69.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[N:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:31][N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1nccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])=[O:24])[NH:12][C@H:11]3[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:5]2=[CH:4][CH:3]=1.CC[N:43]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH4+].[Cl-]>>[C:29]([C:28]1[CH:27]=[C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:40])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])[CH:34]=[CH:33][CH:32]=1)(=[O:30])[NH2:43]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(C(N)=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 22, rac-3-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid (42 mg, 0.072 mmol) was reacted with EDCI (28 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), triethyamine (15 mg, 0.14 mmol), and NH4Cl (38 mg, 0.72 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (3-carbamoyl-phenyl)-amide as a light yellow solid (Yield, 25 mg, 60%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([O:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:25])C.[Li+].[OH-].Cl>C1COCC1.CO>[C:21]([C:17]1[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:26][CH2:27][CH3:28])[C:4]([OH:29])=[O:3])=[C:8]([CH3:25])[CH:9]=2)[N:16]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1C)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of [rac]-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-methyl-phenyl]-2-ethoxy-propionic acid ethyl ester (50 mg, 0.124 mmol) in THF/methanol 2/1 (0.75 ml) was added a 1 N aqueous LiOH solution (0.75 ml, 0.72 mmol). The reaction mixture was stirred for 2 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (44 mg, 0.117 mmol, 95%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C(#N)C>[CH2:28]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH2:8][CH:9]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CCNCC(C(=O)OCC)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)CC(C(=O)OCC)c1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of ethyl 3-[(3-ethoxy-3-oxopropyl)amino]-2-phenylpropanoate (1.0 g) and sodium carbonate (0.72 g) in acetonitrile (2 ml), benzyl bromide (0.64 g) was added, and the reaction mixture was stirred at 75° C. for 2 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure to obtain ethyl 3-[benzyl(3-ethoxy-3-oxopropyl)amino]-2-phenylpropanoate as colorless oil (1.20 g).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:3][CH2:2]1.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.[NH2:64][C@H:65]([C:75]([O:77][CH3:78])=[O:76])[CH2:66][CH2:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71].Cl>CN(C=O)C>[CH3:78][O:77][C:75](=[O:76])[C@@H:65]([NH:64][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[O:30])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=1)=[O:29])[CH2:66][CH2:67][C:68]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:74]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 1.50 g 5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 22 ml DMF were added 0.60 ml DIPEA, 1.38 g HATU and 923 mg H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using DCM/MeOH 97:3 as eluent. Yield: 2.0 g.
Reaction SMILES: CC1(C)N([Br:7])C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([O:32][CH3:33])[CH:26]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC1C=CC=CC=1>[Br:24][C:25]1[CH:26]=[C:27]([O:32][CH3:33])[CH:28]=[C:29]([CH2:31][Br:7])[CH:30]=1
Reactant: COc1cc(C)cc(Br)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1cc(Br)cc(CBr)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
5,5-Dimethyl-1,3-dibromohydantoin (13.1 g, 46 mmol) and azobisisobutyronitrile (1.50 g, 9.1 mmol) were simultaneously added at 80° C. to a solution of 1-bromo-3-methoxy-5-methylbenzene (17.0 g, 91 mmol) synthesized by a method of the document (J. Med. Chem. 2001, 44, 1866) in monochlorobenzene (500 mL), and the reaction mixture was stirred at 80° C. for 30 minutes. The reaction solution was cooled to room temperature and then poured into a 10% aqueous sodium thiosulfate solution (100 mL), and the mixture was stirred for 30 minutes. The mixture was separated into aqueous and organic layers. The aqueous layer was subjected to extraction with toluene (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure to obtain 1-bromo-3-(bromomethyl)-5-methoxybenzene. Without further purification, this compound was dissolved in triethyl phosphite (14.3 mL, 97 mmol) and toluene (50 mL), and the reaction mixture was heated under reflux for 7 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain the title compound (1-2-1) (20.8 g, 64%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:23]=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Reactant: ClCCCOc1cccc2[nH]ccc12
Product: OC1(c2cnc3ccccc3c2)CCN(CCCOc2cccc3[nH]ccc23)CC1
Yield: 52.5 %

Procedure:
Beginning with 0.253 gm (1.2 mMol) 3-chloropropyl indol-4-yl ether and 0.275 gm (1.2 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.253 gm (52%) of the title compound were recovered as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:21])(=O)=O)=CC=1.C([Li])CCC.C(NC(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([F:21])[S:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2ccsc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1cc2ccc(Br)cc2s1
Yield: 32.5 %

Procedure:
Using analogous reaction condition and reagents as described Example 20 for the preparation of I-20a, 6-bromo-benzo[b]thiophene (I-25c: 0.5 g, 2.347 mmol) in dry THF was reacted with N-fluorobenzenesulfonimide (1.33 g, 4.22 mmol), n-butyl lithium (1.76 ml, 3.52 mmol), diisopropyl amine (0.57 ml, 3.99 mmol) to afford crude product. Purification by column chromatography on silica gel (100% hexane) afforded 176 mg of the product (33% yield).
Reaction SMILES: [NH2:1]N.C[N:4](/[CH:6]=[C:7]1/[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]/1=O)C>C(O)C>[N:1]1[NH:4][CH:6]=[C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]=12
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1

Procedure:
A solution of hydrazine (3 mL) and tert-butyl(3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22 g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h. Solvent was removed under reduced pressure, and the residue was triturated with dichloromethane (160 mL) and ethyl acetate (15 mL). The resulting solid was filtered. The filtrate was concentrated and the resulting solid was triturated again and filtered. The combined solids were used without further purification. LC/MS: 210.1 (M+1).
Reaction SMILES: N#N.Cl[CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20]2[C:21]([C:26](N(OC)C)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1.CCOC(C)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20]2[C:21]([C:26]([CH:4]3[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]3)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1ncccc1CSc1cccc(Cl)c1
Reactant: CN1CCC(Cl)CC1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)c2ncccc2CSc2cccc(Cl)c2)CC1
Temperature: -40 °C
Reaction time: 1.25 h
Yield: 64 %

Procedure:
Anhydrous CeCl3 (1.1 g, 4.46 mmol) was placed in a 50 ml 2-necked flask and flamed out under vacuum. The vacuum was replaced with N2, and dry THF (20 ml) was added. The CeCl3/THF solution was stirred at room temperature for 16 hours and then cooled to -40° C., and the Mg-Grignard reagent from 4-chloro-1-methyl-piperidine (3 ml of an 0.8M stock solution in THF) was added. The resulting solution was stirred at -40° C. for 75 minutes, and then 3-[(3-chlorophenyl)thiomethyl]-N-methoxy-N-methyl-2-pyridinecarboxamide (345 mg, 1.07 mmol) was added dropwise. After 40 minutes, the mixture was poured into 5% HCI/EtOAc, stirred for 5 minutes, and then basified to pH ~8. The organic product was extracted with EtOAc (6×100 ml), the extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The product was chromatographed on silica and eluted with 5-10%MeOH/CH2Cl2 to afford [3-[(3-chlorophenyl)thiomethyl]-2-pyridinyl][1-methyl-4-piperidinyl]methanone (251 mg, 64%); HRMS, FAB, calcd. 361.1141; found. 361.1141.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Br[C:20]1[S:24][C:23]([C:25]#[N:26])=[N:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:25]([C:23]1[S:24][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:21][N:22]=1)#[N:26]
Reactant: N#Cc1nnc(Br)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Temperature: 60 °C
Yield: 84 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.35 g, 5.4 mmol, 1 eq.) and 5-bromo-1,3,4-thiadiazole-2-carbonitrile (1.54 g, 8.1 mmol, 1.5 eq.) in 50 ml ACN was added potassium carbonate (2.24 g, 16.2 mmol, 3 eq.). The reaction was heated at 60° C. for three hours. The reaction was quenched by water, acidified to pH=3 with 1N HCl and then extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography to give desired product as yellow oil (1.63 g, yield 84%). MS (ESI) m/z=718 [2M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[N:6]=[CH:5]1.Br[CH2:15][C:16]([O:18]CC)=[O:17].O>CN(C=O)C>[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: Cn1cnc2cc(O)ccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2cc(OCC(=O)O)ccc21
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
To a solution of NaH (204 mg, 8.49 mmol) in DMF (5 mL) was added 1-methyl-1H-benzo[d]imidazol-5-ol (420 mg, 2.83 mmol) at 28° C. After being stirred for 5 minutes, ethyl 2-bromoacetate (568 mg, 3.4 mmol) was added and the resulting mixture stirred for a further 16 h under the reaction was complete by TLC. The mixture was treated with water (50 mL) and extracted with ethyl acetate (2×20 mL). The water layer was treated with 2N HCl until pH 3 and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the product (160 mg, 24.1%) as white solid which was used in next step without further purification. LCMS (m/z): 207.1 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:51][C:50]([O:52][C:53]3[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=3[F:60])=[CH:49][C:48]2=[O:61])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:2][O:3][C:4](=[O:16])[CH:5]([N:15]1[CH2:51][C:50]([O:52][C:53]2[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=2[F:60])=[CH:49][C:48]1=[O:61])[CH2:6][C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Reactant: COC(=O)C(N)Cc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
In a flask was placed 2-amino-3-(2,6-dichloro-phenyl)-propionic acid methyl ester hydrochloride salt (313 mg, 1.10 mmol), acetonitrile (5 mL) and N,N-diisopropylethylamine (200 μL, 1.23 mmol). This mixture was stirred at 60° C. for 1 h and then cooled to 25° C. The mixture was then treated with N,N-diisopropylethylamine (200 μL, 1.23 mmol) and heated at 80° C. and a solution of 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 321 mg, 1.00 mmol) in acetonitrile (1 mL) was added slowly. The mixture was heated at 100° C. for 16 h and then placed in a sealed microwave tube and heated at 140° C. for 1 h in the microwave. The mixture was then concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 10% ethyl acetate/hexanes to 100% ethyl acetate) afforded 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (58 mg, 12%) as a gold oil: HR-ES-MS m/z calculated for C20H15NO4Cl2F2 [M+H]+ 442.0419, observed 442.0420.