Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:2].[Br:11]Br>>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[C:4]([CH:7]=1)[C:5]#[N:6]
Reactant: CCc1ccccc1C#N
Reactant: BrBr
Product: CCc1ccc(Br)cc1C#N

Procedure:
9.74 ml of 2-ethylbenzonitrile are added dropwise to 100 g of Na-X zeolite (Linde 13X, STREM) with vigorous stirring. After the exothermic reaction, 5.6 ml of bromine are added dropwise at 55° C., add vigorous stirring of the mixture is continued. The temperature is kept at 45-50° C., by means of an ice bath. After the addition is complete, the ice bath is removed, and the mixture is stirred at 50° C. for 20 hours. 300 ml of methanol are added to the reaction mixture while stirring and the suspension is clarified by filtration through Hyflow. The filtrate is evaporated and the residue is partitioned between 100 ml of ethyl acetate and 50 ml of saturated sodium bicarbonate solution. The organic phase is dried with sodium sulphate, filtered and evaporated. The title compound is obtained as a beige crystalline solid from the residue by flash chromatography. Rt=4.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=O.CC(C)([O-])C.[K+].[C:29]([O:37]C)(=[O:36])[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].Cl>O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][C:29]([OH:37])=[O:36])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COC(=O)CCC(=O)OC
Reactant: COc1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(CC(=O)O)=C(c1ccc(C(C)(C)C)cc1)c1ccc(OC)c(OC)c1
Temperature: 90 °C

Procedure:
To a 2 L four-neck flask with overhead stirring was added the product from Step 1 (101 g), toluene (1.5 L) and potassium t-butoxide (50 g). Dimethyl succinate (60 mL) was added to the flask through addition funnel over 30 minutes. The reaction mixture was heated to 90° C. for 3 hours. The slurry was cooled and poured into ice water (1 L). The bottom water layer was acidified by hydrochloric acid (12N, 100 mL). The resulting slurry was extracted with ethyl acetate (1 L) and the top layer was washed with water and dried over sodium sulfate. The final solution was condensed to oily residue and the residue was dried in vacuum oven at 60° C. for 8 hours to afford 147 g of waxy solid, 4-(3,4-dimethoxyphenyl)-4-(4-t-butylphenyl)-3-methoxycarbonyl-3-butenoic acid. The product was used as is in next step without further purification.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[S:19])[NH2:18])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:20][CH2:21][C:22]([CH2:24]Cl)=O>C(O)C>[Cl:20][CH2:21][C:22]1[N:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:12][CH:13]=2)[S:19][CH:24]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(Cn2cnc3ccccc32)cc1
Solvent: CCO
Product: ClCc1csc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Temperature: 25 °C
Yield: 60 %

Procedure:
A stirred solution of 4-(1H-benzimidazol-1-ylmethyl)benzenecarbo-thioamide (0.50 g, 1.87 mmol) in ethanol was treated with 1,3-dichloroacetone (0.235 g, 1.85 mmol), heated at reflux temperature for 3 h, allowed to cool to room temperature and filtered. The filtercake was washed with cold ethanol and dried under vacuum to afford the title compound in 60% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, CDCl3): 4.85 (s, 2H), 5.67 (s, 2H), 7.34-7.35 (m, 2H), 7.48 (d, J=7.6 Hz, 2H), 7.64-7.65 (m, 1H), 7.74-7.76 (m, 1H), 7.80 (s, 1H), 7.92 (d, J=7.6 Hz, 2H), 8.94 (s, 1H). LCMS (ESI+) 340 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@@H:27]1OC(=N)C(Cl)(Cl)Cl)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl>[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@H:27]1[O:21][C:17]1[C:16]2[C:12]([CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)=[CH:13][O:14][C:15]=2[CH:20]=[CH:19][CH:18]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)c1ccc(CCc2coc3cccc(O)c23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(N)=O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a mixture of 3-[2-(4-carbamoylphenyl)ethyl]-4-hydroxybenzofuran (50 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (96 mg) in dichloromethane (3 mL) was added borontrifluoride-diethyl ether complex (0.022 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-carbamoylphenyl)ethyl]benzofuran (80 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with dichloromethane. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (13 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12](OCC)=O)=[C:5]([CH3:11])[C:6]=1[CH2:7][CH:8]([CH3:10])[CH3:9].C=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[C:5]([CH3:11])[C:6]=1[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)c1[nH]c(C)c(CC(C)C)c1C
Agent: C=O
Product: Cc1[nH]c(C)c(CC(C)C)c1C

Procedure:
2,4-Dimethyl-3-isobutyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4,5-trimethyl-3-isobutyl-pyrrole. ##STR98##
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH2:12][OH:13])=[CH:10][CH:11]=1.COC(=O)CCl.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH3:34]>CO>[OH:13][CH2:12][C:9]1[N:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([NH2:34])=[O:2])=[CH:11][CH:10]=1
Reactant: N
Reactant: COC(=O)COc1ccc(CO)nc1
Agent: COC(=O)CCl
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: NC(=O)COc1ccc(CO)nc1
Yield: 100 %

Procedure:
1.25 g (6.35 mmol) of (6-Hydroxymethyl-pyridin-3-yloxy)-acetic acid methyl ester (prepared from 6-methyl-pyridin-3-ol by reaction with: 1) Chloro-acetic acid methyl ester, 2) m-Cl-perbenzoic acid and 3) trifluoroacetic acid anhydride) was treated with 31 ml 7M NH3 in MeOH for 2.5 h at RT. The suspension was evaporated to give 1.19 g (100%) of the title compound as a white solid. MS: 183.3 (MH+).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: N#Cc1ccc(NN)cc1
Product: N#Cc1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-benzonitrile according to example 43 gave the desired product. MS: M=424.2 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7]O)[CH:2]=[CH2:3].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][N:29]=[N+:30]=[N-:31])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C=CCOc1ccc(OC)cc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=CCOc1ccc(OC)cc1CN=[N+]=[N-]
Yield: 86 %

Procedure:
Step AS (3). To a solution of 2-allyloxy-5-methoxybenzyl alcohol (5 g, 26 mmol) in 75 mL of anhydrous THF was added diphenylphosphoryl azide (6 mL, 28.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (4.6 mL, 31 mmol) at 0° C. The mixture was refluxed for 1 h. The reaction was concentrated and the residue purified by silica gel chromatography eluting with 25% EtOAc in hexane to yield 2-allyloxy-5-methoxybenzyl azide as a colorless oil (4.9 g, 87%). (M−N3)+=177; 1H NMR (400 MHz, CDCl3) δ ppm 3.76 (s, 3H) 4.36 (s, 2H) 4.47-4.57 (m, 2H) 5.21-5.31 (m, 1H) 5.31-5.46 (m, 1H) 5.95-6.14 (m, 1H) 6.79-6.82 (m, 2H) 6.83-6.85 (m, 1H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:24]=[C:12]2[CH2:13][N:14](CC3C=CC=CC=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[O:1]([CH2:8][C:9]1[CH:24]=[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCn3nc(COc4ccccc4)cc3C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(OCc2cc3n(n2)CCNC3)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 126.5 %

Procedure:
10% Palladium on charcoal (0.21 g, 0.2 mmol) was added to a stirred suspension of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine (0.65 g, 2.0 mmol) and ammonium formate (0.38 g, 6.1 mmol) in MeOH (14 mL) in a sealed tube under N2. The mixture was stirred at 90° C. for 1 hour, filtered through a pad of diatomaceous earth and washed with DCM. The solvents were evaporated in vacuo to yield 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.58 g, 66% yield) as a clear oil that was used in the next step without further purification. C13H15N3O LCMS: Rt 1.19, m/z 230 [M+H]+ (see LCMS Method 1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[S:28][CH:29]=[C:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:37])([F:17])[F:36])[CH:20]=4)[N:26]=3)[CH2:31][CH2:32]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: FC(F)(F)c1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(C(F)(F)F)c4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 43.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (154 mg, 0.536 mmol), 1-[4-(3-trifluoromethylphenyl)-1,3-thiazol-2-yl]piperazine (150 mg, 0.487 mmol) and diisopropylethylamine (0.170 ml, 0.974 mmol) in dimethyl sulfoxide (2.0 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 94.8 mg (43.1%) of the desired product as a solid. mp 230-231° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:28]1([CH2:14][CH2:13][C@@H:12]([C@@H:11]2[C@:17]3([CH3:25])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:21]([C:20]=4[CH2:19][CH2:18]3)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]5([CH3:27])[CH3:26])=[CH:9][CH2:10]2)[CH3:16])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCCCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with piperidine and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(piperidin-1-yl-)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:40][S:41]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)(=[O:43])=[O:42].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:50][CH:47]4[CH2:48][CH2:49][N:44]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:45][CH2:46]4)=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)N1CCC(N)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: C=C(CC)C1N(CC(=O)NC2CCN(S(C)(=O)=O)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 43.6 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 107a was reacted with 1-methanesulfonyl-piperidin-4-ylamine trifluoroacetic acid salt (0.2 g, 0.34 mmol), N-methylmorpholine (0.2 g, 2 mmol) and 4-dimethylaminopyridine (1 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[(1-methanesulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 58 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[N:17]1[N:18]=[C:19]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[NH:20][CH:21]=1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:19]4[NH:18][N:17]=[CH:21][N:20]=4)=[O:25])[CH2:12][CH:11]3[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4ccccc4-c4ncn[nH]4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI): mass calculated for C21H23N7O, 389.46; m/z found 390.2 [M+H]+.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([O:23][CH3:24])[CH:11]=1.Cl>[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN1CCCC1=O>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:12]([O:23][CH3:24])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[Mg]Cl
Reactant: COc1cc(Cl)ccc1Oc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CCCCCCc1ccc(Oc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under nitrogen, ZnCl2 (0.5 M solution in tetrahydrofuran; 6.8 mL, 3.41 mmol) was added by syringe to a round-bottomed flask sealed with a rubber septum and purged with nitrogen. Hexyl magnesium chloride (1.0 M solution in THF; 4.0 mL, 4.26 mmol) was then added dropwise by syringe, and the resulting solution was stirred at room temperature for 20 minutes. Next, N-methylpyrrolidinone (4.7 mL) was added by syringe. After 5 minutes, 21.7 mg (0.0426 mmol) Pd(P(t-Bu)3)2 and 500 mg (2.13 mmol) of compound (3) were added. The flask was then fitted with a reflux condenser and heated under refluxed for 48 hours. The flask was then gradually cooled to room temperature, and 20 mL of a 1.0M aqueous HCl solution was added. The resulting mixture was extracted with diethyl ether and the ether extract was washed with water, then dried over anhydrous MgSO4 and concentrated under vacuum to give the crude product. Purification by flash chromatography on silica gel afforded analytically pure compound (4a): 1H NMR (300 MHz) (CDCl3): δ 7.36-6.80 (m, 8H), 3.90 (s, 3H), 2.71-2.66 (t, 2H), 1.74-1.67 (m, 2H), 1.42-1.33 (m, 6H), 1.01-0.97 (t, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)#[CH:12].N>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: C#Cc1cc(OC)cc(OC)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: COc1cc(OC)cc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3,5-dimethoxybenzene (Aldrich, 81 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ3.85 (s, 6H), 6.69 (t, J=2.2 Hz, 1H), 7.07 (d, J=2.4 Hz, 2H), 7.68 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.78 (s, 1H), 8.38 (dt, J=7.6, 1.9 Hz, 1H), 8.77 (dd, J=4.9, 1.5 Hz, 1H), 9.14 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 283 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.N.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][C:29]1=[O:38]>CC(=O)CC.C(OCC)(=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][C:29]2=[O:38])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCc2ccccc2N1CCCCBr
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C1CCc2ccccc2N1CCCCN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
The free base of 1-(2,3-dichlorophenyl)piperazine, hydrochloride (6.0 g) was liberated by the use ethyl acetate and aqueous ammonia. The remaining oil was dissolved in butanone (500 mL) followed by the addition of potassium carbonate (9.7 g), and the mixture was heated to reflux temperature. To this mixture was added a solution of 1-(4-bromobutyl)-3,4-dihydroquinolin-2(1H)-one (7.9 g) in butanone (150 mL), and the resulting mixture was boiled under reflux for 10 h. The mixture was filtered hot and purified by flash chromatography (eluent:ethyl acetate/triethylamine 100:4) giving the title compound which was precipitated as the hydrochloride salt (2.5 g). Mp 234–235° C. 1H NMR (DMSO-d6): 1.55–1.65 (m, 2H); 1.75–1.85 (m, 2H); 2.55 (t, 2H); 2.85–2.90 (m, 2H); 3.05–3.20 (m, 4H); 3.25 (t, 2H); 3.40 (d, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 7.00 (t, 1H); 7.15 (d, 1H); 7.20–7.30 (m, 3H); 7.30–7.40 (m, 2H); 11.35 (b s). MS m/z: 432 (MH+).
Reaction SMILES: C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=C(CC3NC(CC)=NC=3C)C(=O)O2)CCCC1.[CH:37]1([C:42]2([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([C:58]4([C:63]#[N:64])[CH2:62][CH2:61][CH2:60][CH2:59]4)=[C:54]([F:65])[CH:53]=3)[CH2:47][C:46](=[O:48])[CH2:45][C:44](=[O:49])[O:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1.[CH3:93][C:94]1[CH:99]=[C:98]([CH3:100])[N:97]2[N:101]=[C:102]([CH:104]=O)[N:103]=[C:96]2[N:95]=1.C(C1NC(C=O)=C(C)N=1)C>>[CH:37]1([C:42]2([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([C:58]4([C:63]#[N:64])[CH2:59][CH2:60][CH2:61][CH2:62]4)=[C:54]([F:65])[CH:53]=3)[CH2:47][C:46]([OH:48])=[C:45]([CH2:104][C:102]3[N:103]=[C:96]4[N:95]=[C:94]([CH3:93])[CH:99]=[C:98]([CH3:100])[N:97]4[N:101]=3)[C:44](=[O:49])[O:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCCC1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Agent: CCc1nc(C)c(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(F)c3)(C3CCCC3)OC2=O)[nH]1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CCCC5)c(F)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared analogously to Example A(97) 2-[4-(2-{2-cyclopentyl-5-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile where 1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile Example A(189) was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ: 1.44–1.96 (m, 17 H), 2.14–2.22 (m, 2H), 2.56–2.62 (m, 8 H), 2.70–2.74 (m, 2 H), 3.79 (d, J=16 Hz, 1 H), 3.92 (d, J=16 Hz, 1 H), 7.12 (s, 1 H), 7.24 (s, 1 H), 7.26 (d, J=5 Hz, 1 H), 7.42–7.47 (m, 1 H), 10.9 (s, 1 H). Anal. Calcd. For C32H36FN5O3: C, 68.92; H, 6.51; N, 12.56. Found: C, 68.74; H, 6.60; N, 12.47. MS (ESI): 558 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4](=[CH:9][CH:10]1[CH2:14][O:13][C:12](C)(C)[O:11]1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18]O>>[CH3:8][O:7][C:5]([CH:4]1[C:3](=[O:2])[O:17][CH:10]2[CH2:14][O:13][CH:12]([O:11][CH3:18])[CH:9]12)=[O:6]
Reactant: COC(=O)C(=CC1COC(C)(C)O1)C(=O)OC
Reactant: CO
Product: COC(=O)C1C(=O)OC2COC(OC)C21

Procedure:
Due to the fact that the obtained di-carboxylated intermediate is a viscous oil, i.e. 2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethylene)-malonic acid dimethyl ester, it needs to be introduced into the subsequent Michael addition as a solution in methanol. Methanol distillation after quench into aqueous NaHCO3 solution, after the acidic Nef and cyclization reactions, but before extraction with an organic solvent such as ethyl acetate has disadvantages. Since the intermediate resulting from the acidic Nef and cyclization reactions, i.e. 4-methoxy-2-oxo-hexahydro-furo[3,4-b]furan-3-carboxylic acid methyl ester, is a labile compound in water, and the methanol distillation requires relatively high temperatures (up to 30° C. to 40° C.), decomposition of the intermediate occurs to polar compounds. These polar compounds remain in the aqueous phase and are further lost because they are not extracted to the organic phase. Since the methanol can not be removed prior to the extractions, a considerable volume is required in the work-up of 4-methoxy-2-oxo-hexahydro-furo[3,4-b]furan-3-carboxylic acid methyl ester.