Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14]C)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[OH:14])=[O:4]
Reactant: COc1ccc(NC(=O)CCl)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCl)c(O)c1
Temperature: 0 °C
Yield: 92 %

Procedure:
2-Chloro-N-(2,4-dimethoxy-phenyl)-acetamide (45.8 g, 0.2 mol) was dissolved in 1000 mL methylene chloride, and the reaction mixture was stirred at 0° C. under nitrogen. Aluminum trichloride (78.9 g, 0.6 mol) was added in portions over 30 minutes, and the reaction mixture was allowed to stir for 17 hours at room temperature. The reaction mixture was concentrated to 200 mL volume under reduced pressure, and then poured onto ice. Solids were removed by filtration, and the liquid was taken up in EtOAc, washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure to yield 39.67 g of 2-Chloro-N-(2-hydroxy4-methoxy-phenyl)-acetamide. MS (M+H)=216.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:52][OH:53])[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:52][OH:53])[CH2:50][OH:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 5j (4.36 g, 5.93 mmol) was dissolved in 50 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of sodium borohydride (0.45 g, 11.9 mmol). The reaction mixture was stirred for 30 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 5k (1.26 g, white solid), yield: 28.8%. 1H NMR (400 MHz, CD3OD): δ 7.53 (dd, 1H), 7.44 (d, 1H), 7.35 (d, 1H), 7.31-7.26 (m, 5H), 7.25-7.18 (m, 8H), 7.04-7.02 (m, 2H), 6.90 (s, 1H), 6.80 (d, 1H), 6.54 (d, 1H), 4.90-4.79 (m, 4H), 4.73 (d, 1H), 4.54 (d, 1H), 4.46-4.41 (m, 2H), 4.20 (t, 1H), 4.10-4.00 (m, 5H), 3.88 (dd, 2H), 3.74 (d, 1H), 3.15 (s, 3H), 3.06-3.00 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH:7]1(B(O)O)[CH2:9][CH2:8]1.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Na+].[Na+].[NH4+].[Cl-]>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:9][CH2:8]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: Brc1cnn(C2CC2)c1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (0.50 g), cyclopropylboronic acid (0.65 g), copper(II) acetate (0.65 g), 2,2′-bipyridine (0.56 g), and sodium carbonate (0.80 g) in 1,2-dichloroethane (15 mL) was stirred at reflux temperature for 4 h. Then another portion of cyclopropylboronic acid (0.65 g) and sodium carbonate (0.80 g) were added and the mixture was further stirred at reflux temperature overnight. After cooling to room temperature, aqueous NH4Cl solution was added and the resulting mixture was extracted with dichloromethane. The combined extracts were dried (Na2SO4) and the solvent was evaporated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 95:5->80:20) to afford the title compound as a colorless oil. Yield: 0.32 g (48% of theory); Mass spectrum (ESI+): m/z=187/189 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([SH:8])[CH:7]=1.[OH-].[Na+].O.[CH2:14](Cl)[C:15]#[CH:16]>[Cl-].C([N+](CCCC)(CCCC)CC1C=CC=CC=1)CCC.C(OCC)C>[Cl:9][C:5]1[C:6]([S:8][CH2:16][C:15]#[CH:14])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: C#CCCl
Reactant: Nc1cc(S)c(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C#CCSc1cc(N)c(F)cc1Cl
Yield: 31.9 %

Procedure:
To a mixture of 5-amino-2-chloro-4-fluorothiophenol (8.4 g), sodium hydroxide (3 g), water (80 ml), diethyl ether (40 ml) and tributylbenzylammonium chloride (0.1 g), propargyl chloride (5.2 g) was dropwise added at room temperature (ca. 20° to 25° C.), and the resultant mixture was stirred at the same temperature for 3 hours. The water layer was separated and extracted with ether. The ether extract was combined with the ether layer, washed with water, dried and concentrated under reduced pressure. The residue was crystallized from methanol to give 3.25 g of 4-chloro-2-fluoro-5-propargylthioaniline. M.P., 58°-59.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:11](=[O:12])[NH:10][CH:9]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[NH:8][C:7]1=[O:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:11](=[O:12])[NH:10][CH:9]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:19](=[O:21])[CH3:20])[NH:8][C:7]1=[O:18]
Reactant: CC(C)CNC1NC(=O)N(c2cccs2)C(=O)N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(CC(C)C)C1NC(=O)N(c2cccs2)C(=O)N1
Temperature: 25 °C

Procedure:
A mixture of 3-(thien-2-yl)-6-isobutylamino-tetrahydro-1,3,5-triazine-2,4-dione (1.4 g.) and acetic anhydride (10 ml.) was heated under reflux for 4 hours. The mixture was then distilled to half volume at atmospheric pressure, cooled to room temperature, and diluted with water (20 ml.). The solid which formed was separated by filtration, washed with water, and then crystallised from ethanol to give 3-(thien-2-yl)-6-[N-(acetyl)isobutylamino]-tetrahydro-1,3,5-triazine-2,4-dione as a white solid (0.6 g., 37%), m.p. 138°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[O:18][C:19]=2[CH3:20])(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(OC)c(OC)c3)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1OC
Yield: 96.1 %

Procedure:
Reaction of benzoate 40 (355 mg, 0.82 mmol) and 2 M NaOH (10 mL) in dioxane (10 mL) gave acid 41 (329 mg, 96%) as a white solid: mp (H2O) 221-223° C.; 1H NMR δ 13.16 (br s, 1H, CO2H), 8.05 (d, J=8.4 Hz, 2H, H-2, H-6), 7.94 (d, J=8.4 Hz, 2H, H-3, H-5), 7.33 (dd, J=8.5, 2.0 Hz, 1H, H-6′), 7.26 (d, J=2.0 Hz, 1H, H-2′), 7.14 (d, J=8.5 Hz, 1H, H-5′), 4.63 (s, 2H, CH2SO2), 3.84 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 2.16 (s, 3H, CH3); MS m/z 418.6 (MH+, 100%). Anal. calcd for C20H19NO7S.½H2O: C, 56.33; H, 4.73; N, 3.29. Found: C, 56.02; H, 4.59; N, 3.36%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Reaction time: 8 h

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (1.0 g) and methanesulfonyl chloride (0.27 ml) in pyridine (10 ml) was stirred overnight. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and treated with 4N sodium hydroxide (1.8 ml) for 2 hours. Ethyl acetate and water were added and the mixture was separated. The aqueous layer was acidified and extracted with ethyl acetate. The extract was dried and concentrated to dryness. The residue (1.1 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (3:1) to give a pale brown powder of N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}methanesulfonamide (0.79 g).
Reaction SMILES: [Na+:1].[C:2]([N:5]([CH2:14][CH:15]1[O:19][CH2:18][CH:17]([S:20][C:21]2[CH:27]([CH3:28])[CH:26]3[N:23]([C:24](=[O:32])[CH:25]3[CH:29]([OH:31])[CH3:30])[C:22]=2[C:33]([O-:35])=[O:34])[CH2:16]1)[O:6]CC1C=CC=CC=1)(=[O:4])[CH3:3].[2H]O[2H]>[Pd]>[Na+:1].[C:2]([N:5]([CH2:14][CH:15]1[O:19][CH2:18][CH:17]([S:20][C:21]2[CH:27]([CH3:28])[CH:26]3[N:23]([C:24](=[O:32])[CH:25]3[CH:29]([OH:31])[CH3:30])[C:22]=2[C:33]([O-:35])=[O:34])[CH2:16]1)[OH:6])(=[O:4])[CH3:3]
Reactant: CC(=O)N(CC1CC(SC2=C(C(=O)[O-])N3C(=O)C(C(C)O)C3C2C)CO1)OCc1ccccc1
Agent: [Pd]
Agent: [2H]O[2H]
Agent: [Na+]
Product: CC(=O)N(O)CC1CC(SC2=C(C(=O)[O-])N3C(=O)C(C(C)O)C3C2C)CO1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 0.010 g of product from Example 75, 0.014 g of 10% palladium/carbon, and 1 ml of deuterium oxide is reduced in a Parr apparatus for 2 hours at 30 psi. The reaction solution is filtered and lyophilyzed to give 0.007 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:43]=[CH:42][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[NH:14][C@@H:15]([CH3:27])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C([O-])=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[N+:1]([C:4]1[CH:43]=[CH:42][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:28][C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[NH:14][C@@H:15]([CH3:27])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)[O-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1

Procedure:
To a solution of the compound (1.59 g), which had been obtained in (1), in anhydrous dichloromethane (6 ml), trifluoroacetic acid (3 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8](C3C=CC=CC=3C=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1>O1CCOCC1.[OH-].[K+]>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1-n1ccc2ccc(Br)nc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Brc1ccc2cc[nH]c2n1
Temperature: 25 °C

Procedure:
(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone 155 was dissolved in 20 mL of dioxane and 20 mL of 2M KOH (aq). This was stirred at ambient temperature until analysis indicated all of the starting material had been consumed (2 to 4 hours). The reaction was diluted with 50 mL of ethyl acetate and washed with 2×25 mL of NaHCO3 (aq. satd.) and 25 mL of brine. The organic layer was dried with sodium sulfate, evaporated and purified by column chromatography. Combined steps 2 and 3 gave approximately 65% overall yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[CH:3]1[OH:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[Na+]>CN(C)C=O>[OH:14][CH:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:23][C:24]([OH:26])=[O:25])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1O

Procedure:
(1-Hydroxy-2,2-dimethyl-6,7-dichloro-5-indanyloxy)acetic acid is prepared following substantially the same procedure described in Example 4, Step F, using the following substances: 2,2-dimethyl-6,7-dichloro-1,5-indanediol (3.7 g., 0.015 mole); potassium carbonate (3.6 g.); ethyl bromoacetate (3.1 ml.); and dimethylformamide (35 ml.), and hydrolyzing the resultant ester with aqueous sodium hydroxide in accordance with Example 4, Step F, gives (1-hydroxy-2,2-dimethyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:16])[CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH3:7].[Br:17]Br>C(O)(=O)C>[Br:17][CH:10]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[C:9]([O:8][CH2:6][CH3:7])=[O:16]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(Br)C(=O)C(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium acetate (1.9 g) in glacial acetic acid (15 ml) was added 4-methyl-3-oxo-pentanoic acid ethyl ester (2 g) and the reaction mixture cooled to 10° C. Bromine (0.7 ml) was then added dropwise. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction was complete (by TLC) and was concentrated in vacuum affording 3.8 g crude ethyl product which was used directly in the next synthetic step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:26]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOc1cccc(NC(=N)c2ccc(F)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 30% ethyl acetate in hexanes gradient then 30% ethyl acetate in hexanes) gave the title compound as a viscous yellow oil. LC/MS 355.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCCCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 4-phenyl-1-butanol and DBU in DME. ES-MS m/e (%): 357 (M+Na+, 20), 335 (M+H+, 100).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]([C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[CH:12]=1)=[O:10]>>[ClH:17].[NH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:13]2[CH:12]=[C:11]([CH:16]=[C:15]([Cl:17])[N:14]=2)[C:9]([NH2:8])=[O:10])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 211.9 %

Procedure:
4 N HCl/Dioxane solution (6 ml) was added to tert-butyl 1-[4-(aminocarbonyl)-6-chloropyridin-2-yl]piperidin-4-ylcarbamate (Intermediate 16, 100 mg, 0.282 mmol). The mixture was stirred at room temperature for 90 minutes. The solvent was removed in vacuo and the anhydrous diethylether (25 ml) was added. The solvent was removed in vacuo and light yellow solid that resulted was dried under vacuum for several hours to give the title compound as an off-white solid (87 mg).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+]>C(O)C>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:8]3[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][N:7]=3)=[O:22])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1cnc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)s1
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)s1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A mixture of the product of Example 161A (500 mg, 1.472 mmol), 4-aminothiophenol (350 mg, 2.796 mmol) and anhydrous sodium acetate (604 mg, 7.36 mmol) in anhydrous ethanol (15 mL) was heated at reflux under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation. The residue was partitioned with water (50 mL) and ethyl acetate (100 mL), and the organic phase washed with water (2×50 mL) and brine (50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration of the solid with 4% ethyl acetate/methylene chloride (25 mL) afforded the title compound (452 mg, 72%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:19]=[C:20]=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:20](=[O:21])[NH:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCN=C=O
Reactant: Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
A mixture of quinolin-6-ol (0.29 g., 2 mmol), heptyl isocyanate (0.386 ml 2.4 mmol) and pyridine (1 ml) in dry tetrahydrofuran (10 ml) was heated at 65° C. with stirring for 5 hours. The reaction mixture was cooled and then quenched with water (1 ml), the reaction mixture was concentrated under vaccum and the separated solid was washed with water (2×5 ml) and crystallised with ether to give 1b; yield: 0.25 g. (43.7%), m.p. 78° C., C17H22N2O2; 1H NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.33-1.34 (m, 8H), 1.57-1.62 (m, 2H), 3.25-3.35 (m, 2H) 5.10 (s, 1H), 7.36-7.52 (m, 1H), 7.47-7.52 (m, 1H), 7.60-7.61 (m, 1H), 8.07-8.12 (m, 2H), 8.86-8.88 (m, 1H), IR vmax (KBr) (cm−1) 478, 648, 731, 771, 838, 910, 977, 1024, 1157, 1215, 1363, 1464, 1498, 1532, 1600, 1719, 2371, 2861, 2944, 3022, 3359, 3762; MS: m/z: 287 (M+).
Reaction SMILES: [Cl:1][C:2]12[CH2:9][N:8](C(OCC)=O)[CH2:7][CH:6]1[N:5]([CH3:15])[CH:4]([CH3:16])[CH2:3]2>Cl>[Cl:1][C:2]12[CH2:9][NH:8][CH2:7][CH:6]1[N:5]([CH3:15])[CH:4]([CH3:16])[CH2:3]2
Reactant: CCOC(=O)N1CC2N(C)C(C)CC2(Cl)C1
Agent: Cl
Product: CC1CC2(Cl)CNCC2N1C

Procedure:
7.6 g (30.8 mmol) of ethyl 5-chloro-2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate together with 30 ml of concentrated hydrochloric acid are refluxed overnight. The mixture is concentrated, the concentrate is taken up in 30 ml of water, this mixture is rendered alkaline using potassium carbonate and extracted five times using 50 ml portions of chloroform, and the extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:43])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41]C)=[O:40])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:43])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:35][CH:36]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A solution of chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoate (58.8 mg, 0.0936 mmol) in THF (5 ml) was treated with LITHIUM HYDROXIDE MONOHYDRATE (15.7 mg, 0.374 mmol) in water (2.5 ml) and stirred at rt overnight. The mixture was then treated with 1 N HCl to pH 3-4, extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over sodium sulfate and concentrated to give chiral 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoic acid (57.7 mg, 100%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 614.17. found: 614.2.
Reaction SMILES: N.C1O[CH:5]([C:6]2[C:7]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:8][N:9](C(OC)=O)[CH:10]=2)[O:4]C1.Cl>O1CCOCC1.O>[N+:20]([C:17]1[O:16][C:15]([C:7]2[C:6]([CH:5]=[O:4])=[CH:10][NH:9][N:8]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: COC(=O)n1cc(C2OCCO2)c(-c2ccc([N+](=O)[O-])o2)n1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 0.2 h

Procedure:
Add 54 ml of concentrated ammonia solution dropwise to a suspension of 95.5 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-ethyleneacetal in 750 ml of dioxan. Stir the resulting admixture for 12 minutes. Then add thereto 160 ml of 2N hydrochloric acid to adjust its pH to 1. Stir the thus-acidified product for 30 minutes before diluting it with 2000 ml of water. Allow the resulting precipitate to stand overnight in a cooling cupboard to obtain a quantitative yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde with a melting point of 184° to 186° C.