Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:18]2[N:19]=[CH:20][C:21]([C:24]([O:26]CC)=[O:25])=[N:22][CH:23]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.O.CO>C1COCC1>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:18]2[N:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][CH:23]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: CCOC(=O)c1cnc(-c2cc(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cn1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(-c2cc(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.2 %

Procedure:
Ethyl 5-[(9aS)-2-(2,4-difluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl]-2-pyrazinecarboxylate (0.250 g, 0.555 mmol) was dissolved in THF (4 mL), H2O (1 mL) and MeOH (1 mL) and LiOH monohydrate (0.035 g, 0.832 mmol) was added. The reaction mixture was stirred at ambient temperature for 45 min and then acidified to pH 5. The organics were extracted with CH2Cl2 and then dried (Na2SO4), filtered and concentrated to a white solid (0.200 g, 0.473 mmol, 85% yield): 1H NMR (CD3OD, 400 MHz) δ 9.36 (s, 2H), 7.74 (s, 1H), 7.41–7.35 (m, 1H), 6.97–6.91 (m, 2H), 4.86–4.83 (m, 1H), 4.33 (s, 2H), 3.71–3.64 (m, 1H), 3.48–3.41 (m, 1H), 2.46–2.38 (m, 3H), 1.42–1.38 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:27]=1.[C:28]([Cu])#[N:29]>CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:13]2[S:12][C:11]3[C:5]4[CH:4]=[CH:3][C:2]([C:28]#[N:29])=[CH:27][C:6]=4[O:7][CH2:8][CH2:9][C:10]=3[CH:14]=2)=[N:16][CH:17]=[N:18]1
Reactant: Clc1ccccc1-n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCCc1cc(-c3ncnn3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 53, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazole was reacted with CuCN in DMF to give 325 as a colorless solid after purification by reverse phase HPLC. MS: (ESI+) 405.1
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.[NH2:19][C@H:20]([C:24]([N:26]([CH3:55])[C@H:27]([C:31]([N:33]1[CH2:54][CH2:53][CH2:52][C@H:34]1[C:35]([N:37]1[CH2:51][CH2:50][CH2:49][C@H:38]1[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].Cl.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH:19][C@H:20]([C:24]([N:26]([CH3:55])[C@H:27]([C:31]([N:33]1[CH2:54][CH2:53][CH2:52][C@H:34]1[C:35]([N:37]1[CH2:51][CH2:50][CH2:49][C@H:38]1[C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:5]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3.74 g Z-D-Pro-OH (15 mmol, BACHEM) and 8.25 g H-Val-MeVal-Pro-Pro-NHBn×HCl (15 mmol) were dissolved in 80 ml dry DMF. After cooling to 0° C., 2.4 g DEPCN (2.25 ml, 15 mmol) and 4.2 ml triethylamine (30 mmol) were added. The reaction mixture was stirred at 0° C. for several hours and room temperature overnight, then the DMF was evaporated under reduced pressure. The residue was diluted with ethyl acetate and thoroughly washed with dilute aqueous HCl (pH 2), water, dilute aqueous NaOH (pH 9–10), and water. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 9.2 g of the desired protected pentapeptide.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(pyrrolidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-pyrrolidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25](OC)[O:26]C)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
7.09(1H, borad s), 7.35 to 7.85 (4H, m) 10.49 (1H, s). (b 4) A mixture of a solution of dimethyl 2-methyl-4-(2- nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (10.68 g) in acetone (110 ml) and 6N hydrochloric acid (10 ml) was stirred at 25° C. for 3 hours, which was neutrallized with an aqueous sodium bicarbonate solution and acetone was distilled off under reduced pressure. The resultant reddish yellow oily precipitates were solidified, which were cracked finely, collected by filtration, washed with water and air dried over-night to give crude crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (9.33 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:1][C:2]1[NH:3][N:4]=[C:5]([S:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1
Reactant: ClCc1ccccc1
Reactant: Nc1n[nH]c(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(SCc2ccccc2)n[nH]1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
3-Amino-5-mercapto-1,2,4-triazole (40.36 g) was treated at room temperature with sodium hydroxide (13.9 g) in ethanol (450 ml), and benzyl chloride (44.3 g) was added. The mixture was stirred overnight, and was then filtered. The ethanol was evaporated off, and the residue was recrystallised from ethyl acetate to give 64.97 g of the desired product, mp 104° C.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][C@@H:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](C)[CH:30]=2)=[O:27])[C:9]1=[O:36])=[O:6])([CH3:4])([CH3:3])[CH3:2].[N+:37](C1C=C(N=C=O)C=CC=1)([O-:39])=[O:38]>>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][C@@H:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:37]([O-:39])=[O:38])[CH:30]=2)=[O:27])[C:9]1=[O:36])=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc([N+](=O)[O-])c2)N=C(c2ccccc2)c2ccccc21
Yield: 94 %

Procedure:
The resolved aminobenzodiazepine of Example 26 was treated with m-nitrophenyl isocyanate as described in Example 45 to provide a colourless oil (490 mg, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].N12CCCN=C1CC[CH2:31][CH2:30][CH2:29]2.C(Br)C=C>C(O)C>[CH2:31]([O:26][C:20]1[CH:19]=[C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][CH2:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH:30]=[CH2:29]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Solvent: C=CCBr
Solvent: CCO
Product: C=CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC
Reaction time: 3 h

Procedure:
A 0.3 g quantity of 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101 was suspended in 10 ml of ethanol, 0.37 g of 1,8-diazabicyclo[5,4,0]undec-7-ene and 0.14 ml of allyl bromide were added thereto, and stirring was conducted for 3 hours while heating and refluxing. After distilling off ethanol under reduced pressure, water was added, ethyl acetate extraction was performed, followed by drying over anhydrous magnesium sulfate and distilling the solvent off. The residue was subjected to silica gel column purification (n-hexane:ethyl acetate=3:1), thereby yielding 0.2 g of white powdery 3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21]C(=O)OCC)[NH:6]2.[NH2:27][C:28]([CH3:33])([CH2:31][OH:32])[CH2:29][OH:30]>>[NH2:21][C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([NH:27][C:28]([CH3:33])([CH2:31][OH:32])[CH2:29][OH:30])[N:10]=[C:9]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20])[N:8]=2
Reactant: CC(N)(CO)CO
Reactant: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Product: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(N)nc12

Procedure:
The titled compound was prepared from the product of example 5, step (e) (50 mg) and 2-amino-2-methyl-1,3-propanediol (70 mg) using the method of example 5, step (f) and purified by preparative HPLC to yield a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=2[I:30])[C:15]([NH:17][CH:18]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:16])=[O:8])[CH2:4][O:3]1.[C:39]([O:42][CH2:43][CH2:44]Br)(=[O:41])[CH3:40]>>[C:39]([O:42][CH2:43][CH2:44][N:9]([C:10]1[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=1[I:30])[C:15]([NH:17][CH:18]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:38])([CH3:1])[O:6]1)=[O:8])(=[O:41])[CH3:40]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Yield: 83 %

Procedure:
The alkylation of 5-(2,2-dimethyl-1,3-dioxolane-4-carboxamido)-3-acetoxymethyl-N-(1,3-diacetoxyprop-2-yl)-2,4,6-triiodobenzamide with 2-bromoethyl acetate was performed according to the procedure of Example 30a. The crude product was isolated in 83% yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.C#N.COC(=O)[O-].C[N+:19]([CH3:22])(C)C>>[O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:22]([C:4]1([CH3:10])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1)#[N:19]
Reactant: C[N+](C)(C)C
Agent: C#N
Agent: COC(=O)[O-]
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CC(=O)CC(C)(C#N)C1

Procedure:
To 622 g (4.5 mol) of isophorone there are added, at 120° C. over a period of 120min, a mixture of 207.3 g (1.5mol) of isophorone and 81 g (3.0 mol) of HCN in the presence of 5.2 g (0.02 mol) of a 50% strength aqueous tetramethylammonium methylcarbonate solution. 10 min after the end of the metering operation the HCN concentration is only 140 ppm. Following neutralization with 4 g of H3PO4 the mixture is distilled. Following a first runoff of 3 g, there are obtained 422.6 g of isophorone and 476.7 g of 3-cyano-3,5,5-trimethylcyclohexanone. This is equivalent to a yield of 96.2% based on HCN used and 98% based on isophorone converted.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2Cl)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 26.7 g of ethyl 2-aminothiazol-4-ylglyoxylate, 23 g of o-chlorophenyl isocyanate and 300 ml of dimethylformamide. The resulting product was a white powder having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[Li+]>>[Br:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Br)c(C)[nH]3)[C@H](OC)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Product: CO[C@@H]1CN(c2nc(C)c(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Br)c(C)[nH]1
Yield: 61.5 %

Procedure:
The same operation as in Example (1i) was performed using ethyl cis(±)-2-(4-{[(4-bromo-5-methyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (31d) (0.19 g, 0.39 mmol) and 2 N lithium hydroxide (4 mL), to obtain 0.11 g of the title compound as a white solid (61%).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[N+]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])([O-])=O>>[N+:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]=1[C:12]#[N:13])([O-:20])=[O:19]
Reactant: CCC(O)CC
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCC(CC)Oc1cccc([N+](=O)[O-])c1C#N
Yield: 86.5 %

Procedure:
Prepared as in Example 111c from pentan-3-ol and 2,6-dinitrobenzonitrile in 86.5% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (t, J=7.6 Hz, 6H), 1.70 (m, 4H), 4.62 (m, 1H), 7.78 (dd, J=7.2, 2.4 Hz, 1H), 7.88 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:10]([O-:13])(=[S:12])[CH3:11].[K+]>CC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][S:12][C:10](=[O:13])[CH3:11]
Reactant: BrCc1ccccc1Br
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCc1ccccc1Br

Procedure:
To a solution of 2-bromo-benzyl bromide (1 ml, Aldrich 187070) in acetone was added potassium thioacetate (0.9 g, Aldrich 241776) and the mixture refluxed for 2 hr. The reaction mixture was purified on a plug of silica eluting through with further acetone to give thioacetic acid S-(2-bromo-benzyl) ester (1.57 g) 1H-NMR (400 MHz, CDCl3): 2.34 (3H, s), 4.24 (2H, s), 7.09-7.14 (1H, dt), 7.23-7.27 (1H, dt), 7.44-7.46 (1H, dd), 7.54-7.56 (1H, dd).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([F:16])[CH:8]=1.C(#N)C.O>O1CCCC1.C(OCC)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH:1]2[CH2:3][CH2:2]2)([OH:15])[CH3:14])=[C:9]([F:16])[CH:8]=1
Reactant: CC(=O)c1ccc(Cl)cc1F
Reactant: Br[Mg]C1CC1
Solvent: CCOCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Cl)cc1F)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
114.6 ml (57.31 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were taken up at 0° C. in 23 ml of diethyl ether, and 4.95 g (28.65 mmol) of 4′-chloro-2′-fluoroacetophenone dissolved in 5 ml of diethyl ether were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, and the reaction solution was mixed with acetonitrile, water and a little kieselguhr, and the mixture was filtered through kieselguhr. The phases of the filtrate were separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to result in 4.30 g (70% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[CH3:29][S:30][CH2:31][CH2:32][NH2:33]>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:33][CH2:32][CH2:31][S:30][CH3:29])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CSCCN
Solvent: CO
Solvent: ClCCl
Product: CSCCNC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Yield: 50.3 %

Procedure:
The title compound was prepared by the procedure of Example 14, step (e) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 120 mg, 0.317 mmol) and 2-methylsulfanyl-ethylamine (69.0 μL, 0.951 mmol). Silica gel chromatography (1-4% MeOH/DCM) afforded the title compound (72 mg, 50%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.26 (d, 1H, J=8.6 Hz), 7.94 (s, 1H), 7.39 (dd, 1H, J=8.6, 2.3 Hz), 7.32 (d, 1H, J=2.3 Hz), 5.75 (m, 1H), 2.51-2.61 (m, 4H), 2.29-2.36 (m, 2H), 2.05-2.12 (m, 2H), 1.91 (s, 3H), 1.60 (t, 2H, J=6.3 Hz), 1.54 (s, 6H), 1.09 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C25H33N5OS, 450.4 (M−H). found 450.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:19]([CH:22]=1)[C:20]#[N:21]>>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH2:25][CH2:24]2)=[C:19]([C:20]#[N:21])[CH:22]=1)=[O:9]
Reactant: O=C(O)c1sc2ccccc2c1Cl
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: N#Cc1cc(NC(=O)c2sc3ccccc3c2Cl)ccc1N1CCC(N2CCOCC2)CC1
Yield: 52.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 3-chlorobenzo[b]thiophene-2-carboxylic acid (1.1 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.5 g), the title compound (1.3 g) was obtained. melting point: 227-228° C.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH:4]1[CH2:15][N:14]2[C:6]([C:7]3[NH:8][C:9]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:10][C:11]=3[N:12]([CH2:17][CH2:18][CH3:19])[C:13]2=[O:16])=[N:5]1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CS(C)=O>[ClH:2].[ClH:1].[CH:20]1([C:9]2[NH:8][C:7]3[C:6]4=[N:5][CH:4]([CH2:3][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:15][N:14]4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:10]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: CCCN1C(=O)N2CC(CCl)N=C2c2[nH]c(C3CCCC3)nc21
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCN1C(=O)N2CC(CN3CCCCC3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 80 °C
Yield: 48.4 %

Procedure:
Compound 26 (49 mg, 0.14 mmol) obtained in Example 26 was dissolved in dimethyl sulfoxide (5 mL), to the solution was added piperidine (100 μL, 1.01 mmol, 7.2 equivalents), and the mixture was stirred with heating at 80° C. for 3.5 hours. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5), to the product was added a 4 mol/L solution of hydrogen chloride in ethyl acetate, then the mixture was concentrated. The residue was crystallized from acetone to obtain the title compound (31 mg, 48%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5]Br.[CH3:8][Si:9]([CH3:39])([CH3:38])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:37]=[CH:36][C:22]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](CCO)[N:28]=[CH:27]4)=[CH:21][CH:20]=2)=[CH:17][CH:16]=[N:15]1>>[CH3:38][Si:9]([CH3:39])([CH3:8])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([O:23][C:24]3[CH:32]=[CH:31][C:30]4[C:26](=[CH:27][N:28]([CH2:5][CH2:4][CH2:3][OH:2])[N:29]=4)[CH:25]=3)=[CH:36][CH:37]=2)=[CH:17][CH:16]=[N:15]1
Reactant: COC(=O)CCBr
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3c(cnn3CCO)c2)cc1
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nn(CCCO)cc3c2)cc1

Procedure:
The titled compound AB is synthesized from intermediate Y-1 and 3-bromo-propionic acid methyl ester according to the procedure described for the synthesis of intermediate Y.