Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:12]([O:14]C)=[O:13])[CH2:7][C:4]([C:8]([O:10][CH3:11])=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1COCC1.[OH-].[Na+]>CO>[CH3:11][O:10][C:8]([C:4]12[CH2:7][C:1]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:9]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C12CCC(C(=O)O)(CC1)C2
Temperature: 15 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A 12-L, 3-neck, round bottom flask was equipped with a mechanical stirrer, a J-KEM temperature controller, and a 250 mL addition funnel. The flask was charged with dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (208 g, 980 mmol) and THF (6.7 L). The resulting solution was cooled to 15° C. using an ice/water bath. Sodium hydroxide pellets (39.2 g, 980 mmol) were dissolved in methanol (400 mL) and slowly added to the stirring solution over 30 min. After the addition was complete, white solids began to precipitate. The reaction mixture was stirred at room temp for 16 h when TLC analysis (100% ethyl acetate) indicated about 90% conversion. The reaction mixture was concentrated to dryness, slurried in hexane (2 L), filtered, and washed with hexane (2×400 mL). The resulting sodium carboxylate salt was transferred to a 3-L, 3-neck, round bottom flask equipped with a mechanical stirrer, dissolved in water (1 L), and slowly treated with 2 N aqueous hydrochloric acid (430 mL) at 10° C. until pH ˜4. The thick suspension was diluted with ethyl acetate (1 L) and transferred to a reparatory funnel. The layers were separated and the aqueous layer was further extracted with ethyl acetate (2×500 mL), washed with brine (200 mL), dried over sodium sulfate, and concentrated to provide 170 g (87%) of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid. 1H NMR (500 Hz, DMSO-d6) δ ppm 12.21 (s, 1H), 3.60 (s, 3H), 1.91 (d, J=6.7 Hz, 4H), 1.75 (s, 2H), 1.56-1.62 (m, 4H).
Reaction SMILES: [Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]12)=[O:9].C(N(CC)CC)C.[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1.Cl>CN(C)C=O>[Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][O:19][C:35](=[O:36])[CH2:34][C:33](=[O:37])[CH3:32])[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: C=C1CC(=O)O1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved 7β-(2-thienylacetamido-)-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (3.86 g) and, at -5° C., triethylamine (1.40 ml) and diketene (1.50 ml) were added. The reaction was carried out at -5°-0° C. for 1 hour, after which time the reaction mixture was poured in ice-water (200 ml). The mixture was adjusted to pH 2.0 with 4 N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was rinsed with water, diluted with water, brought to pH 7.0 with 5% aqueous sodium hydrogen carbonate solution and separated. The water layer was taken, concentrated and subjected to column-chromatography on Amberlite XAD-2, elution being carried out with water-methanol. The eluate was lyophilized. The above procedure provided 7β-(2-thienylacetamido)-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid sodium salt (4.48 g).
Reaction SMILES: [Cl:1][C:2](=[C:6]([Cl:8])[Cl:7])[C:3](Cl)=[O:4].Cl.[NH2:10][CH2:11][C:12]#[N:13]>C(Cl)(Cl)Cl>[C:11]([CH2:12][NH:13][C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:8])[Cl:7])#[N:10]
Reactant: N#CCN
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N#CCNC(=O)C(Cl)=C(Cl)Cl
Yield: 84.6 %

Procedure:
A slurry of 38.8 g (0.2 mol) trichloroacrylyl chloride and 18.5 g (0.2 mol) aminoacetonitrile hydrochloride in 150 ml chloroform was stirred and heated under reflux for 30 hours, while gases evolved and most of the hydrochloride salt dissolved. The reaction mixture was filtered while hot and the solvent evaporated under reduced pressure to give 36.1 g of N-cyanomethyl trichloroacrylamide, as an off-white solid melting at 56°-59° C. Recrystallization from benzene-hexane gave a white solid melting at 58°-60° C. Elemental analysis for C5H3Cl3N2O showed: %Cl, calc. 49.8, found 50.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1>C(O)C.C(O)(=O)C>[O:21]=[C:18]1[CH2:19][CH2:20][C:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[CH:17]1
Reactant: O=C1CCC(=O)C1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NC2=CC(=O)CC2)cc1
Yield: 33.8 %

Procedure:
0.51 g of 4,5-dihydro-6-(4-aminophenyl)-5-methyl-3(2H)-pyridazinone and 0.25 g of cyclopentane-1,3-dione were suspended in a mixture of 5 ml of ethanol and 5 ml of acetic acid and the resulting suspension was refluxed for 7 hours. After cooled, deposited crude crystal was collected by filtrating and recrystallized from DMF-heptane-CHCl3 to give 0.24 g of the title compound. m.p. >300° C. NMR (solvent DMSO-d6 -CDCl3) δ 1.20 (d, 3H), 2.32-3.32 (m, 7H), 5.60 (S, 1H), 7.56 (dd, 4H), 9.82 (S, 1H), 10.80 (S, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25]C)[C:15]2[C:20]([CH:21]=[C:22](C)[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([OH:46])=O>[OH-].[OH-].[Pd+2]>[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([CH2:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:46]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [OH-]
Product: CCCc1cccnc1N(C)C1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 20 and making non-critical variations but starting with 1-benzyl-4-(N-methyl-N-(3-(1-propenyl)-2-pyridinyl)amino)piperidine (XXII, EXAMPLE 14, 0.46 g, mmol), Pearlman's catalyst (0.1 g), CDI (0.46 g, 2.85 mmol) and pyrrole-2-carboxylic acid (0.32 g, 2.85 mmol), the title compound is obtained, mp 88°-90°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27](OC)=[O:28])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:32][NH2:33]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27]([NH:33][CH3:32])=[O:28])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: CN
Solvent: CCCCO
Product: CNC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Yield: 19.9 %

Procedure:
Methyl 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinate (0.010 g, 0.023 mmol) and methylamine (0.124 g, 0.004 mol) were mixed in 1-butanol (2.00 mL) and the resulting mixture subjected to microwave radiation for 2000 seconds at 170° C., followed by irradiation for 4000 seconds at 180° C. The solvent was removed by evaporation, and the product purified by preparative HPLC to give 2 mg (20%) 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}-N-methylnicotinamide hydroformate as a white solid. MS [M+H]=437.1, LC/MS (EI) tR 3.55 min (Method D), 1H NMR (10% MeOD/CDCl3) δ (ppm) 8.93 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.40-7.28 (m, 4H), 7.11 (t, J=8.7 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.95 (d, J=3.6 Hz, 3H), 2.67 (t, J=7.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.59-1.45 (m, 2H)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[CH:14]1([C:17]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[C:20]([OH:27])=[CH:19][C:18]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH2:16][CH2:15]1>O>[Cl:1][C:19]1[C:20]([OH:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35]
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1O
Reaction time: 3 h
Yield: 91 %

Procedure:
N-Chlorosuccinimide (1.65 g) was added at room temperature to a DMF (40 mL) solution of methyl 2-cyclopropyl-2′,4′-difluoro-5-hydroxybiphenyl-4-carboxylate (3.13 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. Then, N-chlorosuccinimide (0.549 g) was further added thereto, and the mixture was stirred at the same temperature as above for 16 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was stirred at 0° C. for 1 hour. The deposited crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (3.17 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.O>[F:20][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: Fc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Into a reaction vessel under an atmosphere of nitrogen, 4-propyl phenylboronic acid (T16; 200.0 g), 1-bromo-3-fluorobenzene (T8; 177.8 g), potassium carbonate (281.9 g), Pd(Ph3P)2Cl2 (7.2 g), toluene (600 ml), and Solmix A-11 (600 ml) were put and heated under reflux for 2 hours. After the reaction mixture had been cooled to 25° C., the solution was poured into water (2,000 ml) and toluene (1,000 ml), and mixed. The mixture was then allowed to stand to be separated into two layers of an organic layer and an aqueous layer. Extraction into an organic layer was carried out and the resulting organic layer was fractionated. The extracts were washed with water, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by means of fraction-collecting column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The solution was further purified by recrystallization from Solmix A-11 and then dried, whereby 175.5 g of 3-fluoro-4′-propylbiphenyl (T17) was obtained. The yield based on the compound (T8) was 80.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([CH:20]=[C:21]([C:27]#[N:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)[N:12]=1.O1CCOCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]([C:27]#[N:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:29][CH:30]=2)[N:12]=1
Reactant: CCOC(=O)C(C#N)=Cc1ccc(OCCc2nc(-c3ccccc3Cl)oc2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(C#N)Cc1ccc(OCCc2nc(-c3ccccc3Cl)oc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a mixture of ethyl 4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]-α-cyanocinnamate (2.25 g) and dioxane (30 ml)--ethanol (30 ml) was added sodium borohydride (0.06 g) under ice-cooling. The mixture was stirred for one hour at the same temperature. The reaction mixture was poured into ice-water, which was made acid and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fractions eluted with chloroform-methanol (50:1, v/v), was obtained ethyl 3-[4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]phenyl]-2-cyanopropionate (2.25 g, quant.) as an oily product. NMR(δ ppm in CDCl3): 1.27(3H,t,J=7Hz), 2.39(3H,s), 3.00(2H,t,J=6.5Hz), 3.12(1H,dd,J=14&8Hz), 3.22(1H,dd,J=14&6Hz), 3.66(1H,dd,J=8&6Hz), 4.22(2H,q,J=7Hz), 4.24(2H,t,J=6.5Hz), 6.87(2H,d,J=9Hz), 7.17(2H,d,J=9Hz), 7.25-7.5(3H,m), 7.85-8.0(1H,m).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][OH:19])=[CH:15][CH:14]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:19][CH2:18][CH2:17][C:16]1[CH:20]=[CH:21][C:13]([Br:12])=[CH:14][CH:15]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc(CCOC2CCCCO2)cc1

Procedure:
p-Toluenesulfonic acid (0.30 g) was added to a solution of 4-bromophenethyl alcohol (9.50 g, 47.24 mmol) in methylene chloride (50 ml), and the mixture was stirred under ice-cooling. To the mixture was added 3,4-dihydropyran (5.53 g, 65.74 mmol). After stirring under ice-cooling for 20 minutes, a saturated aqueous solution of sodium bicarbonate (40 ml) was added to the reaction mixture. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene was obtained (13.40 g, 99%).
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=O.[ClH:17]>C1COCC1>[ClH:17].[CH3:1][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc2c1CCCC2CNC=O
Agent: Cl
Solvent: C1CCOC1
Product: CNCC1CCCc2c(OC)cccc21

Procedure:
The product from Example 16 (3.8 g) in dry THF (80 ml) was treated with 1M solution of BH3 in THF (38 ml). After the addition was complete, the reaction was heated at reflux for 1 hr, followed by cooling. The reaction was treated with saturated methanolic HCl (30 ml), heated at reflux for 1 hr and concentrated to afford a solid. Crystallization from Et2O/CH3OH afforded 4.1 g of desired product. Anal. calcd. for C13H20C1NO: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.68; H, 8.49; N, 5.78.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[C:22]([F:21])([F:32])[F:33])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccccc1C(F)(F)F)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2-trifluoromethylbenzoic acid.
Reaction SMILES: Br[C:2]1[C:3]([N:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[O:20])[CH:18]=[CH2:19])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].C1COCC1>[Cl-].[Na+].O>[CH3:15][C:10]1[N:9]([C:5]2[N:6]=[C:7]([CH3:8])[C:2]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:3]=3[N:4]=2)[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: C=CC(=O)N(c1nc(-n2c(C)ccc2C)nc(C)c1Br)N1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2c(C)ccc2C)nc2c1ccc(=O)n2N1CCCC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a microwave vial was added N-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)-N-(pyrrolidin-1-yl)acrylamide (2.0 g, 4.95 mmol) silver carbonate (2.73 g, 9.89 mmol) and anhydrous THF (100 ml). The reaction suspension was bubbled in nitrogen for 2 mins and then added the palladium tetrakis tert-(triphenylphosphine) (286 mg, 0.25 mmol). After stirring at 70° C. oil bath for 3 h, the reaction mixture was cooled to R.T. and diluted with 20 ml of brine. After stirring at R.T. for 5 mins, the reaction mixture was filtered through a celite pad. The cake was washed with ethyl acetate. The layers were separated. The organic layer was washed with brine 20 ml, dried with potassium carbonate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluted with 40% EtOAc:hex to give the titled compound weighted 480 mg 30%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[CH:29][CH:30]=1.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:6][CH:7]=1
Reactant: COc1cccc(O)c1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)c1
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (500 mg), 3-methoxyphenol (390 mg), tributylphosphine (640 mg) and tetrahydrofuran (20 ml) was added dropwise a toluene solution of diethyl azodicarboxylate (40%, 1.37 g) at room temperature, and the resulting mixture was stirred for 3 hours. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(3-methoxylphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole (470 mg, 70%) was obtained as an oil from an ethyl acetate-hexane (2:3, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:24][N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.[OH-].[K+].O>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:12]=[C:11]2[C:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: CN1CCC(=O)CC1
Reactant: CNS(=O)(=O)CCc1ccc2c(ccn2Cc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2c(c1)c(C1=CCN(C)CC1)cn2Cc1ccccc1
Temperature: 62.5 °C
Reaction time: 0.25 h

Procedure:
2-(1-benzyl-1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in methanol (1000 ml) and N-methyl-4-piperidone (100 ml) was added thereto at 25° C. The reaction mass was stirred for 15 minutes and potassium hydroxide (200 g) was added at 25° C. The reaction mass was heated to 60-65° C. for 8 hours and cooled gradually to 25° C. Water (2500 ml) was added slowly and stirred the mixture till solid is obtained. The solid was filtered and dried at 50-55° C. under vacuum to obtain the title compound (Yield: 98 g, HPLC Purity: 99%).
Reaction SMILES: [C:1]([O-])(O)=O.[Na+].C([O:8][CH:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:10][CH2:11][C:12]1[NH:13][C:14]([CH3:36])=[C:15]([C:32]([O:34][CH3:35])=[O:33])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:17]=1[C:18]([O:20][CH2:21]C)=[O:19])=O>CO>[C:37]1([CH:9]([OH:8])[CH2:10][CH2:11][C:12]2[NH:13][C:14]([CH3:36])=[C:15]([C:32]([O:34][CH2:35][CH3:1])=[O:33])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)C1=C(CCC(OC=O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(CCC(O)c2ccccc2)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
0.3 ml of 5% NaHCO3 aqueous solution are added to a solution of the most polar diastereoisomer of 2-[3-formyloxy-3-phenyl-propyl]-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (2.5 g) in methanol (20 ml). The mixture is refluxed for 30 minutes, then it is cooled to 25° C. and evaporated to a small volume (2 ml) under reduced pressure. The sticky mass is diluted with ethyl ether (70 ml) and water (30 ml) and the phases are separed. The organic phase is washed with water (2×30 ml) and dried on sodium sulphate. The solvent is evaporated under reduced pressure, obtaining 2.3 g of the most polar diastereoisomer of 2-(3-phenyl-3-hydroxy-propyl)-3-carbomethoxy-5-carboethoxy-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine as yellow foam.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Product: CNCC1Cc2ccc(Cl)c(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.02 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.23 mmol) and methylamine (0.24 g, 7.8 mmol). mp 158-160° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)[CH:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(F)ccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3ccc(F)cc3C1O)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
11.0 g of 8-[(7-fluoro-1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)-methyl]-1-phenyl-1,3,8-traizaspiro[4.5]decan-4-one (see example 187) is taken up in methanol (240 ml), cooled in an ice-bath and treated over a 20 minute period with 6.6 equivalents of sodium borohydride in water (58 ml). The mixture is then allowed to warm up to room temperature and stirred for 48 hours. The reaction mixture is diluted with ice-water (400 ml), stirred for 30 minutes and the precipitates that form are filtered off and dried in vacuo at 80° C to give the title compound (6.9 g), melting point 210°-212° C. The filtrate is extracted with 500 ml of methylene chloride to give another 4.3 g of crude product.