Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][N:7]=[C:6]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:5]=1.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[N:28]1([C:33]([O:10][C:9]2[C:4]([NH2:3])=[N:5][C:6]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:12]=3)=[N:7][CH:8]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)N1CCCC1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.5 mg (0.15 mmol) of sodium hydride were added to a suspension of 50.0 mg (0.15 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinol from example IV in 2 ml of THF at RT. After the mixture had been stirred at RT for 30 min, 21.8 mg (0.16 mmol) of 1-pyrrolidinecarbonyl chloride were added and the mixture was stirred at RT overnight. The product was purified by thin-layer chromotography (silica gel, CH2Cl2/MeOH 10:1).
Reaction SMILES: N[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][C:3]=1[C:9]#[N:10].N(OC(C)(C)C)=O.C(Br)(Br)[Br:19]>>[Br:19][C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][C:3]=1[C:9]#[N:10]
Reactant: Cc1nc(C#N)c(N)n1C
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: Cc1nc(C#N)c(Br)n1C
Yield: 42 %

Procedure:
A solution of 5-amino-1,2-dimethyl-1H-imidazole-4-carbonitrile (8.5 g, 62 mmol) in bromoform (51 mL) was cooled with an ice water bath, and tert-butyl nitrite (12.87 g, 124.8 mmol) was added dropwise. The reaction was heated on a steam bath for 30 minutes, allowed to cool, and then refrigerated. The solution was decanted to separate it from a precipitate, and then the solution was purified by column chromatography on silica gel (eluting with ethyl acetate) to provide 5.2 g (42%) of 5-bromo-1,2-dimethyl-1H-imidazole-4-carbonitrile as a bright orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[OH:14][C:15]1[C:16]([C:25]([NH:27][NH2:28])=[O:26])=[CH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[N:28][NH:27][C:25]([C:16]1[C:15]([OH:14])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=[O:26]
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1c(O)ccc2ccccc12
Product: O=C(NN=Cc1c(O)ccc2ccccc12)c1cc2ccccc2cc1O
Yield: 97 %

Procedure:
Following the general procedure of Example 1, condensation of 2-Hydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide gave a white solid (97%): mp >300° C.; 1H NMR d 12.70 (s, 1 H), 12.25 (br s, 1 H), 11.37 (br s, 1 H); 9.58 (s, 1 H), 8.52 (s, 1 H), 8.33 (d, 1 H, J=8.7 Hz), 7.94 (d, 2 H, J=8.7 Hz), 7.89 (d, 1 H, J=8.1 Hz), 7.78 (d, 1 H, J=8.4 Hz), 7.58 (t, 1 H, J=7.6 Hz), 7.52 (t, 1 H, J=7.5 Hz), 7.41 (m, 2 H), 7.37 (s, 1 H), 7.25 (d, 1 H, J=9.0 Hz); 13C NMR d 163.05, 158.12, 153.88, 147.57, 135.94, 132.90, 131.68, 130.62, 128.90, 128.68, 128.33, 127.79, 127.73, 126.81, 125.85, 123.86, 123.54, 120.98, 119.84, 118.87, 110.62, 108.61; HRMS Calcd for C22H16N2O3 :356.1161, found 356.1151; Anal. (C22H16N2O3) C, H, N.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.Cl>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2sc(C(=O)CCCCl)cc2C1
Agent: Cl
Product: CC(=O)N1CCc2sc(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)cc2C1
Yield: 34.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.8 g of 5-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 1.6 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.0 g of 5-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine as an oil, m.p. 235° C. as hydrochloride 1/2hydrate thereof.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Brc1ccccn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccccn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromopyridine (243 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (346 mg, 68%) as a brown solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(Sc2ccc(NS(C)(=O)=O)cc2)s1
Yield: 96.6 %

Procedure:
A solution of 2-acetamido-5-(4-aminophenylthio)thiazole (3.2 g) in pyridine (64 ml) was added methanesulfonyl chloride (1.52 g) at 5° C. with stirring. The reaction mixture was stirred for 3 hours at 5° C. and concentrated in vacuo to give solid. The solid was subject to column chromatography on silica gel (silica gel, 70-230 mesh; Merck: 200 g) and eluted with a mixture of chloroform and methanol (50:1) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the objective compound were combined and evaporated to dryness in vacuo to give 2-acetamido-5-(4-methanesulfonylaminophenylthio)thiazole (4.0 g, yield: 96.6%). mp: 236°-239° C.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(=O)[CH3:2].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1](=[N:12][OH:13])([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1ccccc1N
Temperature: 25 °C

Procedure:
2-Acetylaniline, 33.8 gm, was added slowly to 300 ml of ethanol containing 18.3 gm of hydroxylamine hydrochloride and 27.7 gm sodium carbonate. After addition of the entire amount of 2-acetylaniline, the system was refluxed for 16 hours and then cooled to room temperature. After cooling, the ethanol was removed by stripping. Water was then added to the residue to give a precipitate. The precipitate was filtered and dried to give a pale yellow solid, m.p. 55°-60° C.
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]([CH3:5])[CH3:4].[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11]>CCOCC>[CH3:4][CH:3]([CH3:5])[CH2:2][CH:10]([OH:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[F:7]
Reactant: CC(C)CBr
Reactant: O=Cc1ccccc1F
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CC(O)c1ccccc1F
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
In a 3 necked round bottom flask (100 ml), equipped with a dropping funnel reflux condenser and thermometer pocket, placed magnesium turnings (1.45 gm 0.0604 mole) and flame dried the apparatus. Dry diethyl ether (15 ml.) was added to Mg. Turning, Isobutyl bromide (6.57 ml, 8.28 gm, 0.0645 mole) was taken in 5 ml of dry ether and added drop wise to the Mg turnings. As soon as ether starts boiling (in a few minutes) the reaction was cooled using ice-salt and continued the addition of isobutyl bromide. After complete addition of isobutyl bromide continued for another 20 minutes. o-Fluro benzaldehyde (4.25 ml, 5.0 gm, 0.0403 mole) in 10 ml of ether was added drop wise at −10° C. (around ½ hr). After the completion of addition of fluoro benzaldehyde continued the stirring for 1 hr and the reaction was quenched with ice-cooled saturated ammonium chloride solution (30 ml), the solid separated is filtered off, the filtrate is extracted with ethyl acetate (20×1, 10×2 ml) dried over sodium sulphate and concentrated to yield 6.54 gm of crude product (GC showed area of 85% purity). The crude product on vacuum distillation gave 3.93 gm (54.2%) of pure 3-methyl-1-(2-fluoro phenyl)butylalcohol (12) and impure product ˜2.87 gm containing 3-methyl-1-(2-fluoro phenyl)butylalcohol (12) 60% and byproduct (o-fluoro benzylalcohol) 40%. 1HNMR CDCl3 (spectrum 11): 0.96(d, 6H), 1.55(m, 1H), 1.75(m, 2H), 1.95 (bs, 1H), 5.05(m, 1H), 7.0(m, 1H), 7.20(m, 2H), 7.45(m, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:9][CH:8]=2)[C:4](=[O:12])[O:5]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C1OC(=O)c2c(O)cccc21
Product: CN(C(=O)Oc1cccc2c1C(=O)OC2=O)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxy-isobenzofuran-1,3-dione and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (50%, white solid). HPLC-MS: m/z=298.1 (M+1); Rt: 2.58 min, purity: 85%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH3:25]I>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:25]
Reactant: CI
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(C)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Yield: 96 %

Procedure:
In the same manner as described in Example 9, 0.30 g (0.860 mmol) of the product of Example 62 was alkylated with methyl iodide to give 0.30 g (96%) of the desired product as a white solid. Electrospray Mass Spec: 364 (M+H).
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>O>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=Cc1ccccc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 2.22 g. of trans-cinnamic acid, 2.43 g, of 1,1'-carbonyldiimidazole and 50 ml. of tetrahydrofuran was stirred for 2 hours, then 1.7 ml. of 1H-imidazole-1-propanamine was added. The reaction mixture was stirred for 18 hours, then 5 ml. of water was added, the mixture was heated for 30 minutes and then concentrated. Methylene chloride and 10 ml. of 1N sodium hydroxide were added and then layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated, giving the desired product as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(O)C>[CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: COC(=NC(C)C)NC(C)C
Reactant: CC1(C)[C@H](/C=C2\CCSC2=O)[C@H]1C(=O)O
Solvent: CCO
Product: COC(=O)[C@@H]1[C@@H](/C=C2\CCSC2=O)C1(C)C
Yield: 18.8 %

Procedure:
Using the procedure of Example 17, 4 g of (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-carboxylic acid and 3.5 g of methyl N,N'-diisopropylcarbamimidate were reacted to obtain 0.8 g of methyl (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+63.5°±1.5° (c=1.1% in ethanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl.Cl[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1
Reactant: ClCCc1ccccn1
Reactant: O=C1CNCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CCc2ccccn2)CCN1
Yield: 33.2 %

Procedure:
Piperazinone (2.2 g, 22 mmol), 2-(2-chloroethyl)pyridine hydrochloride (3.9 g, 22 mmol) and i-Pr2NEt (5.67 g, 7.6 mL, 44 mmol) were heated at reflux for 16 h. The mixture was concentrated, and the residue was purified by column chromatography (80 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (1.5 g, 33%) as a yellow solid; ESI MS m/z 206 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[N:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.[OH:26]S(O)(=O)=O.O>C(O)(C)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:4]([C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[N:6][C:7]3[C:12]2=[N:11][CH:10]=[N:9][C:8]=3[OH:26])=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccccc1Cl
Solvent: O
Solvent: CC(C)O
Product: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a suspension of 2-chloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-benzamide I-(4A-7)a (1.00 g, 2.54 mmol) in isopropanol (20 ml) was added neat H2SO4 (410 μl, 7.4 mmol) at room temperature. The reaction was refluxed for 8 hours followed by cooling to room temperature and stirring for 16 hr. To the heterogeneous solution was added 20 ml of water to promote further product precipitation. After stirring for 1 an additional hour at room temperature, the solid was collected on a sintered glass funnel, rinsing with water followed by hexanes. The product was further dried under reduced pressure to give I-(4A-7)b as a colorless solid (0.72 g, 80%): 1H NMR: (400 MHz, DMSO-d6): δ 12.57 (s, 1H), 8.08 (d, J=4.1 Hz, 1 H), 7.66 (dd, J=7.4, 1.2 Hz, 1H), 7.51–7.41 (m, 5H), 7.33–7.29 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH3:21][O:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1
Reactant: COCCO
Reactant: CCOC(=O)C1=C(Nc2ccc(O)cc2C)OCC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=C(Nc2ccc(OCCOC)cc2C)OCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step, 2-methoxyethanol (0.051 mL, 0.65 mmol) and triphenylphosphine (0.19 g, 0.72 mmol) in dichloromethane (2.0 mL) that cooled with ice bath, 2.2M diethyl azodicarboxylate (40% in toluene, 0.33 mL, 0.73 mmol) was added dropwise then the mixture was stirred at ambient temperature for 24 h. The reaction mixture was diluted with water, and extracted with chloroform. The organic layer was washed with 1M sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated to afford ethyl 2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.30 g, crude material).
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: NCCO
Reactant: O=C1COCC(=O)O1
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 2-aminoethanol to produce [2-(2-hydroxyethylamino)-2-oxoethoxy]acetic acid, (b) heating to cyclixe the latter to obtain 4-(2-hyroxyethyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 2-(3,5-dioxomorpholino)ethyl methanesulfonate and (d) reacting the mesylate with piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[F:28])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4ccccc4F)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2-fluorobenzoyl chloride gave the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][CH3:23])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[CH:18]([CH2:22][CH3:23])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1nccnc1Cl
Reactant: CCC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1CN(Cc2ccccc2)CCN1c1nccnc1Cl
Temperature: 100 °C
Reaction time: 96 h
Yield: 70.1 %

Procedure:
A mixture of 2,3-dichloropyrazine (3.9 g, 27 mmol), 1-benzyl-3-ethylpiperazine (4.6 g, 22.5 mmol; from Step 1) and K2CO3 (6.2 g, 45 mmol) in DMF (10 mL) was stirred at 100° C. for 4 days. The solvent from the filtered reaction mixture was evaporated off and the residue was purified by column chromatography on silica using heptane/EtOAc (90:10) as eluent to yield 5.0 g (71%) of the title compound as a light yellow oil. HRMS m/z calcd for C17H21ClN4 (M)+ 316.1455, found 316.1448.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C1COCC1.[Li]C(C)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]([OH:31])[C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cocn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: B
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ncco2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of oxazole (420 mg, 6.08 mmol) in THF (15 mL) was added BH3-THF (1.0M in THF, 6.69 mL, 6.69 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to −78° C., t-BuLi (1.7M, 4.29 mL, 7.30 mmol) was introduced to the mixture and stirred at this temperature for 30 min. 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 6.08 mmol) was added dropwise and the mixture was stirred at −78° C. for 3 hours. Work-up and purification gave 4-(hydroxy-oxazol-2-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a white foam (1.227 g, 71%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][N:25]([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:26][N:25]([CH3:27])[CH2:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CN(C)CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N2CCCCC2CN(C)C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 34.2 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (88.3 mg, 0.36 mmol) and N-(2-piperidylmethyl)-dimethylamine (Salor Chemical Company) (0.25 g, 1.72 mmol) was added a solution of K2CO3 (0.25 g, 1.60 mmol) in H2O (2.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 ML) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution was washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) to give 43 mg (34%) of the title compound as a yellow oil. MS m/z: 350 (M+1), 305, 214. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (m, 6), 2.29 (s, 6), 2.40 (s, 3), 2.81 (m, 2), 3.03 (br t, 1, J=11.8), 4.53-4.63 (m, 2), 6.75 (s, 1), 7.37 (m, 1), 7.50 (t, 2, J=7.5), 7.81 (d, 2, J=7.8), 12.47 (s, 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>C(O)CCC>[F:11][CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCC(F)COc1ccc(C(C)=O)cc1
Temperature: 0 °C
Yield: 42 %

Procedure:
Then, 6.3 g of p-hydroxyacetophenone and 12.7 g of 2-fluorooctyl-p-toluenesulfonate were dissolved in 35 ml of butanol. To the solution, a solution of 3.1 g of potassium hydroxide in 40 ml of butanol was added dropwise, followed by heat-refluxing for 6 hours. After the reaction, the reaction mixture was poured into 200 ml of ice water and extracted with isopropyl ether. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to precipitate a crystal. The crystal was purified by silica gel column chromatography to obtain 4.7 g of p-(2-fluorooctyloxy)acetophenone.