Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[S:9][C:10]([C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH2:28])=[CH:11][C:12]=1[S:13](=[O:26])(=[O:25])[N:14]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:15])([CH3:4])([CH3:3])[CH3:2].[C:38](#[N:41])[CH:39]=[CH2:40]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[S:9][C:10]2[CH:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:28][CH2:40][CH:39]([C:38]#[N:41])[C:11]=2[C:12]=1[S:13](=[O:25])(=[O:26])[N:14]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reactant: C=CC#N
Solvent: Cc1ccccc1C
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1c(NC(=O)OC(C)(C)C)sc2c1C(C#N)CCC2O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (5-[1-(t-butyldimethylsiloxy)vinyl]-3-{[2-(4-fluorophenyl)ethyl]methyl-sulfamoyl}-thiophene-2-yl)carbamic acid t-butyl ester (the compound of Preparation Example 113) (235 mg) and acrylonitrile (4 lpL) in xylene (1 mL) was irradiated with a 200 W microwave. After reacting at 100° C. to 150° C. for 30 minutes, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate) and (4-cyano-3-{[2-(4-fluorophenyl)ethyl]methylsulfamoyl}-7-t-butyl-dimethylsiloxy-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamic acid t-butyl ester (54 mg) was obtained as a mixture. In addition, the same reaction was carried out from the starting materials (293 mg), and the mixture (45 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][P:3]([O:6]C)[O:4][CH3:5].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][P:3](=[O:6])([O:4][CH3:5])[O:2][CH3:1])=[CH:12][CH:11]=1
Reactant: COP(OC)OC
Reactant: CSc1ccc(CCl)cc1
Product: COP(=O)(Cc1ccc(SC)cc1)OC
Temperature: 25 °C

Procedure:
First, dimethyl (4-methylthiobenzyl)phosphonate was synthesized, as follows: Trimethylphosphite (206 g, 1.66 mol) was stirred at reflux, and 245 g (1.42 mol) of 4-methylmercaptobenzyl chloride (prepared as described in Ulman, et al. U.S. Pat. No. 4,792,208, Example 1) was added dropwise over 30 min. The mixture was kept at reflux for 4 hours, and then cooled to room temperature. Dimethyl (4-methylthiobenzyl)phosphonate was obtained by fractional distillation at reduced pressure. The yield was 263 grams, which is 75% of theoretical.
Reaction SMILES: C[Si](C)(C)CCS([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH:9]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)=O.[F-].[Cs+].C(O)(=O)C>CN(C=O)C.C(OCC)(=O)C>[NH:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH:9]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N1C=CC(=O)CC1c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C=CNC(c2cccnc2)C1
Temperature: 90 °C
Yield: 94.4 %

Procedure:
To a solution of 1-(2-trimethylsilyl-ethanesulfonyl)-2,3-dihydro-1H-[2,3′]bipyridinyl-4-one (106.1 mg, 0.31 mmol) in DMF (0.5 mL) was added cesium fluoride (153.5 mg, 1.0 mmol) under Ar atmosphere. The mixture was heated at 90° C. for 2 hours, then cooled to room temperature. Acetic acid (0.062 mL, 1.085 mmol) was added, and the mixture was diluted with ethyl acetate and filtered. The filtrate was taken to dryness under reduced pressure. Purification of the residue by flash chromatography (dichloromethane/methanol 95:5) gave 2,3-dihydro-1H-[2,3′]bipyridinyl-4-one (51 mg, 93.5%).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:3]([CH2:4][CH2:5][CH2:6]1)[CH2:2]2.[Br-].CCO[CH2:16][CH3:17]>C1COCC1.[Cu]I>[C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([C:10]([OH:9])=[O:11])[CH2:2]1)(=[O:8])[C:17]1[CH:16]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: CCOCC
Reactant: O=C1OC(=O)C2CCCC1C2
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCC[C@@H](C(=O)c2ccccc2)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A stirred solution of 1,3-cyclohexanedicarboxylic anhydride (67 mg, 0.43 mmol) (prepared from 1,3-cyclohexanedicarboxylic acid as described in patent application US 2004010005) and copper(I) iodide (8 mg, 0.04 mmol) in dry THF (3 mL) was cooled to −70° C. and phenmagnesium bromide in THF (0.4 mL of 1 M, 0.40 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1 h and allowed to warm slowly to rt. After 2 h the mixture was poured into ether (75 mL) and extracted with satd aqueous NaHCO3 (2×30 mL). The combined aqueous extracts were acidified to pH 1 by cautious addition of concentrated HCl and back extracted with ether (2×50 mL). These ether extracts were combined, dried over Na2SO4 and evaporated under reduced pressure to afford cis-3-benzoylcyclohexane-1-carboxylic acid (78 mg, 77%) as an oil which solidified on standing. 1H NMR (CDCl3) δ 1.3-2.8 (9H), 3.32 (m, 1H), 7.45 (m, 2H), 7.55 (1=m, 1H), 7.92 (m, 2H). MS ESI+ve m/z 233 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.Cl.[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].[OH-].[Na+]>C1COCC1.CO>[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:29]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COCc1cccc(N)c1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-methoxymethyl-aniline-hydrochloride in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][C:24]([CH3:25])([CH3:26])[C:27]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:29])=[C:16]([CH:15]2[CH2:14][C:13](=[O:30])[NH:12][CH:11]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:40])[CH:21]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(F)c(F)c1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(F)c1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,3-difluoro-6-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) and CDI (16.2 mg, 0.1 mmol) in DMF (1 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (28.5 mg, 0.3 mmol) and NaH (10 mg, 60%, 0.25 mmol) in DMF (0.5 mL), which had been stirred for 2 h at room temperature. After the resulting mixture was stirred at room temperature for 2 h, it was poured into water and the aqueous solution was acidified to “PH” 1-2 by addition of concentrated hydrochloric acid. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by Prep-HPLC to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(NCc2ccc(Cl)cc2)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with 4-chlorobenzylamine (2.72 g, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-(4-chloro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester (2.98 g, 10.68 mmol, 55.6%), as a light yellow oil. LC-MS (ESI) calcd for C15H18ClNO2 279.10, found 280.1 [M+H+].
Reaction SMILES: O.[OH-].[Na+].[NH2:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:15])([F:14])[S:10](Cl)(=[O:12])=[O:11]>CC(C)=O>[F:8][C:9]([F:15])([F:14])[S:10]([NH:4][CH2:5][CH2:6][OH:7])(=[O:12])=[O:11]
Reactant: NCCO
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(NCCO)C(F)(F)F

Procedure:
In a mixed solvent prepared from 100 ml of water and 50 ml of acetone and containing 3.2 g of sodium hydroxide, 3.7 g of 2-aminoethanol was reacted with 12.5 g of trifluoromethanesulfonyl chloride at room temperature for 12 hours. The solvent was evaporated from the resultant reaction mixture by vacuum distillation. To the residue was added 50 ml of chloroform. The sodium chloride generated was removed by filtration. The resultant chloroform solution was distilled under vacuum to obtain 2-trifluoromethanesulfonamidoethanol. A 10 g portion was taken out of this reaction product and dissolved in 100 ml of acetone. Thereto was added dropwise 12.0 g of thionyl chloride over a period of 3 minutes. Subsequently, 10 ml of an aqueous solution containing 2.06 g of sodium hydroxide was added thereto dropwise to react the reactants at 55° C. for 12 hours. The solvent was removed from the resultant reaction mixture, and 100 ml of water was added to the residue. After this mixture was stirred, 100 ml of diethyl ether was added to conduct extraction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1C(C(O)=O)=C(C)N(C2C=CC(C(F)(F)F)=CN=2)[N:21]=1>>[NH2:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)c(C)c1C(=O)O
Reactant: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Product: Nc1ccc(C2(O)CCC3(CC2)OCCO3)nc1

Procedure:
8-(5-Bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.0 g) described in Reference Example 76 (1) was used in place of 1-(5-bromopyridin-2-yl)-c-4-(tert-butyldimethylsilanyloxy)-r-1-cyclohexanecarbonitrile in Reference Example 144 (2) and (3), and reacted and treated in a similar manner to give the titled compound (1.28 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2].Br[CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][CH2:22][S:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:14][CH2:13]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: CCc1[nH]c2cc(F)ccc2c1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1[nH]c2cc(F)ccc2c1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-ethyl-6-fluoro-3-piperidin-4-yl-1H-indole (0.9 g), 1-(3-Bromo-propylsulfanyl)-4-fluoro-benzene (1.0 g), potassium iodide (20 mg) and potassium carbonate (0.7 g) in DMF (10 ml) is heated at 100° C. for 3 h, and allowed to cool to rt overnight. Ethyl acetate (50 ml) and water (25 ml) are added and the organic phase is washed with water, dried and concentrated in vacuo. The crude product is purified by flash chromatography (95:5 CH2Cl2:MeOH) and its hydrochloride salt is prepared by reaction in acetone with the appropriate amount of ethereal HCl giving, after recrystallisation from ether, 1.1 g pure product (70%) as white crystals.
Reaction SMILES: Cl[C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na+].[SH-:11]>C(O)C>[SH:11][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [SH-]
Reactant: O=c1cccccc1Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1cccccc1S
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-2,4,6-cycloheptatrien-1-one [2.82 g, described by T. Nozoe et al., Proc. Japan Acad., 28, 483 (1952)] in ethanol (20 ml) is added dropwise to a suspension, cooled to -70° C., of sodium sulfhydrate (2.2 g) in ethanol (20 ml). The mixture is stirred at -70° C. for two hours, allowed to warm to room temperature and stirred at room temperature for one hour. The mixture is filtered and the filtrate is evaporated. The residue is suspended in water, the mixture is acidified to pH2 with 10% hydrochloric acid and extracted with ethyl acetate. The organic extract is dried and evaporated. The residue is dissolved in benzene and subjected to chromatography on silica gel. The eluates are evaporated to give the title compound, mp 55° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cn1

Procedure:
A solution containing 10 g methyl 5-nitropicolinate in 400 ml ethyl acetate is stirred under hydrogen in the presence of 1 g platinum oxide at room temperature and atmospheric pressure. When no further hydrogen uptake occurs, the catalyst is removed by filtration, the filtrate concentrated, and the product collected. This is recrystallized from ethyl acetate to give analytically pure methyl 5-aminopicolinate, mp 147°-150.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]([CH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])(C)(C)C.Cl.O>ClCCl.C(#N)C>[NH2:14][C:15]([CH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C)(c1ccccc1)C1CCC(O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(N)(c1ccccc1)C1CCC(O)CC1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (8 mL) was added to a solution of [1-(4-hydroxy-cyclohexyl)-1-phenyl-ethyl]-carbamic acid tert-butyl ester (29) in dichloromethane (75 mL) from the previous stage. After stirring for 4 hours the reaction mixture was worked up by adding 2M aqueous hydrochloric acid (39 mL), followed by evaporation. Freeze drying overnight gave a pale brown semi-solid residue. This was treated with a mixture of water and acetonitrile. After freeze drying again 1.24 g of crude product as the hydrochloride was obtained which was used in the next stage without further purification. Rt=0.58 min (Method 5). Detected mass: 185.15 (M—NH3—H2O+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:16]=2)[N:13]=1
Reactant: BrC1CCCCC1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1n(C2CCCCC2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 75 °C
Reaction time: 17 h
Yield: 34.1 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (36 mg, 0.1 mmol), bromocyclohexane (40 μL, 0.3 mmol) and solid K2CO3 (42 mg, 0.3 mmol) in anhydrous DMF (1 mL) was stirred at 75° C. for 17 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional bromocyclohexane (50 μL, 0.375 mmol) was added, the reaction was allowed to continue at 75° C. for 24 h more. After cooling to room temperature, the reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The separated EtOAc layer was washed with saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow glassy product, which was lyophilized in acetonitrile to afford 15 mg (34%) of the title compound as a yellow powder. LC/MS (method A): retention time=4.06 min, (M+H)+=439. 1H NMR (CDCl3, 400 MHz): δ 7.18-7.50 (m, 5H), 7.19 (d,J=8.8 Hz, 2H), 7.03 (d,J=8.8 Hz, 2H), 4.47 (m, 1H), 1.26-2.04 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O>>[CH:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4)ncnc32)CC1

Procedure:
4-(4-Phenoxy-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester was prepared according to General Procedure D by the reaction of 4-(4-phenoxy-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (from Step 1) with trifluoroacetic acid, followed by reaction of the resulting amine with isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.2 Hz), 1.94-2.03 (m, 4H), 3.00-3.12 (m, 2H), 4.08-4.15 (m, 2H), 4.78-4.82 (m, 1H), 5.00-5.02 (m, 1H), 7.32-7.38 (m, 3H), 7.49-7.53 (m, 2H), 8.11 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=382.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(N2CCOCC2)c2ncc(-c3cncnc3)cc2n1
Temperature: 95 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-pyrido[3,2-d]pyrimidine (120 mg, 0.0003647 mol), pyrimidine-5-boronic acid (40.4 mg, 0.0003282 mol), sodium carbonate (57.9 mg, 0.0005471 mol), DMF (5 mL) and water (3 mL) were added and the reaction vessel degassed with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (15 mg, 0.0003 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 0-1.5% MeOH in chloroform) to yield the desired product [55 mg, 43%]. 1H NMR (300 MHz, CDCl3): δ 9.35 (s, 1H), 9.08 (s, 2H), 8.91 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.7 Hz, 1H), 3.89-3.92 (m, 8H); LC-MS (ESI): Calculated mass: 328.1; Observed mass: 329.1 [M+H]+ (RT: 0.56 min).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][CH2:4][C:5]1([C:9]([O:11]CC)=[O:10])[CH2:8][CH2:7][CH2:6]1.O.[OH-].[Na+]>C(O)C.C1COCC1>[F:1][CH:2]([F:14])[O:3][CH2:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)C1(COC(F)F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)C1(COC(F)F)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
To a stirred solution of Intermediate 223A (0.263 g, 1.263 mmol) in ethanol (3.5 mL), THF (3.5 mL), and water (3 mL) was added NaOH (0.152 g, 3.79 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue dissolved in water and extracted with ethyl acetate (3×15 mL) The aqueous layer was then acidified to pH 2-3 using a 1.5 N aqueous solution of HCl and extracted with EtOAc (3×15 mL). The combined organic layer was washed with water, dried over Na2SO4 and concentrated to afford Intermediate 223B as a brown oil (0.08 g, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (s, 1H), 6.97-6.40 (m, 1H), 4.15-3.90 (m, 2H), 2.38-2.09 (m, 2H), 2.01-1.51 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[C:10]1=[O:27].C(=O)([O-])[O-].[K+].[K+].C(NCC)C>CN(C=O)C>[CH2:8]([N:9]([CH2:10][CH3:11])[CH2:2][C:3]([OH:5])=[O:4])[CH3:7].[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[C:10]1=[O:27]
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Agent: [K+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)CC(=O)O

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione bromoacetate (409 mg) was dissolved in DMF (10 mL). Potassium carbonate powder (800 mg) was added. Diethylamine solution (0.4 mL) was added dropwise while stirring. The reaction mixture was stirred for 24 hrs at room temperature. The solvent and the residual diethylamine were removed by rotary evaporation in vacuo. The resultant solid mixture was subjected to silica gel column chromatography (eluted with acetic ether: petroleum ether=2:1) and then a white solid (128 mg) was obtained. 1H NMR (CDCl3, ppm) δ 7.87-7.90 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.04 (m, 1H), 4.28-4.33 (m, 2H), 4.08-4.16 (m, 2H), 3.30 (s, 2H), 2.97-3.02 (m, 1H), 2.76-2.85 (m, 2H), 2.61-2.68 (m, 4H), 2.10-2.14 (m, 1H), 1.02-1.06 (m, 6H). MS (m/e): 416 (M+H+).