Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([NH:11][C:12]([N:14]([CH3:17])N=O)=[O:13])[O:9][C@H:8]([CH3:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Cl.[Cl:19][CH2:20]CN.C(N(CC)CC)C.C(O)C>O>[Cl:19][CH2:20][CH2:17][NH:14][C:12]([NH:11][C@@H:1]1[O:9][C@H:8]([CH3:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3])=[O:13]
Reactant: NCCCl
Reactant: C[C@H]1O[C@@H](NC(=O)N(C)N=O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H]1O[C@@H](NC(=O)NCCCl)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 234 mg (0.91 mmol) of 1-(6-deoxy-β-D-glucopyranosyl)-3-methyl-3-nitrosourea in 2 ml of water was admixed with a solution of 401 mg (3.5 mmol) of 2-chloroethylamine hydrochloride and 0.5 ml (3.3 mmol) of triethylamine in 3 ml of aqueous 50% ethanol. The admixture was stirred for 2 hours at ambient temperature, and the reaction mixture was passed through a column (10×160 mm) of Amberlite IRA-400 (OH- form), which was then washed with water. The effluent was concentrated to dryness under a reduced pressure, and the crystalline residue so obtained was subjected to chromatography in a column (8×350 mm) of silica gel (8 g) using chloroformmethanol (5:2 by volume) as eluent. Such fractions of the eluate which gave a single spot at Rf 0.50 were combined together and concentrated to dryness by evaporation of the solvent under a reduced pressure. Recrystallization of the residue from acetone gave the titled compound. Yield 98 mg (37.7%). mp. 130°-132° C. [α]D24 -25.5° (c 0.5, water).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:6]=[CH:7]2.[CH3:28]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:19][C:16]1[C:17]([CH3:18])=[C:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[C:5]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:6]=[CH:7]3)=[C:2]([CH3:28])[N:11]=2)[CH:13]=[N:14][CH:15]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1c(F)cncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2c(Cl)n1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2c(C)n1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
A mixture of tert-butyl 5-chloro-7-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridin-3-ylcarbamate (230 mg, 0.592 mmol), trimethylboroxine (225 mg, 1.78 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (42 mg, 0.059 mmol), and potassium carbonate (165 mg, 1.18 mmol) in dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-100% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as pale yellow solid (110 mg, 50%), which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH2:12][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (4 mL, 48.5 mmol) was added to a solution of 5-chloro-2-nitrobenzaldehyde (6 g, 32.2 mmol) in dichloromethane (150 mL) and the solution was stirred at room temperature for 30 minutes. The solution was then cooled in ice, and sodium triacetoxyborohydride (10.3 g, 48.5 mmol) was added portionwise. Once addition was complete, the reaction was stirred at room temperature for 4 hours. The reaction was washed with sodium carbonate solution, dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ethyl acetate:pentane (86:14) to afford the title compound as a pale yellow solid, 6.3 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][C:28]#[CH:29])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[CH:31]1([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41](I)[CH:40]=2)(=[O:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>CC#N.C(N(CC)CC)C>[CH:31]1([S:36]([C:39]2[CH:40]=[C:41]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]3[CH2:13][C@@H:12]([C:10]4[CH:9]=[CH:8][C:6]5[O:7][C:2]([CH3:30])([CH3:1])[O:3][CH2:4][C:5]=5[CH:11]=4)[O:16][C:15]3=[O:17])[CH:42]=[CH:43][CH:44]=2)(=[O:37])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=S(=O)(c1cccc(I)c1)C1CCCC1
Reactant: C#CCCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCC#Cc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Reaction time: 4 h
Yield: 78.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(4-pentyn-1-yloxy)hexyl]-1,3-oxazolidin-2-one (207 mg) and 1-(cyclopentylsulfonyl)-3-iodobenzene (Example 8iii.) (202 mg) in MeCN (8 ml) and triethylamine (4 ml) was deoxygenated by bubbling a nitrogen stream through for 10 min. Copper (I) iodide (10 mg) and dichlorobis(triphenylphosphine)palladium (II) (18 mg) were added and the mixture stirred at 20° for 4 h. The solvent was evaporated in vacuo and the residues purified by using a SPE silica bond elut cartridge (10 g, silica). Elution with DCM (1vol), EtOAc-cyclohexane (1:4) (3vols), (1:3) (1vol) then (1:1) (3vols) gave the title compound (243 mg). LCMS RT=3.79 min.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:30][C@@H:31]([C@H:33]1[C:62](=[O:63])[N:35]2[C:36]([C:56]([O:58][CH2:59][CH:60]=[CH2:61])=[O:57])=[C:37]([C:40]3[S:44][C:43]4=[C:45]([C:48]([C:50]5[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=5)=[O:49])[N:46]=[CH:47][N:42]4[CH:41]=3)[C@H:38]([CH3:39])[C@H:34]12)[CH3:32])(C(C)(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[OH:30][C@@H:31]([C@H:33]1[C:62](=[O:63])[N:35]2[C:36]([C:56]([O:58][CH2:59][CH:60]=[CH2:61])=[O:57])=[C:37]([C:40]3[S:44][C:43]4=[C:45]([C:48]([C:50]5[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=5)=[O:49])[N:46]=[CH:47][N:42]4[CH:41]=3)[C@H:38]([CH3:39])[C@H:34]12)[CH3:32]
Reactant: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4cccnc4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4cccnc4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 36 h
Yield: 53.4 %

Procedure:
Acetic acid (0.23 ml) and 0.72 ml of a 1 M tetrahydrofuran solution of tetrabutylammonium fluoride was added to a solution of 0.14 g of allyl (1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate in 2 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 36 hr. The reaction mixture was diluted with 50 ml of ethyl acetate, and the diluted reaction solution was washed with a 50% aqueous sodium bicarbonate solution and 10% brine in that order. The organic layer was dried, and the solvent was then removed by evaporation. The resultant crude product was purified by column chromatography on silica gel (eluted with 10% methanol/ethyl acetate) to give 60.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate. This product was analyzed by NMR. The results were in agreement with the results of analysis in Example 26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])=[O:31])[C:10]=2[CH:9]=1>C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][S:33]([CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])(=[O:35])=[O:34])=[O:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)NS(=O)(=O)CCN(C)C)C(=O)NC3=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCS(=O)(=O)NC(=O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Yield: 23.4 %

Procedure:
Reaction of methyl ether (267) (35 mg, 0.06 mmol) prepared as described in example 224 according to the proceedure described in example 81, except that the reaction mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with methanol/dichloromethane (1:9 to 1:3), gave acylsulfonamide (271) (8 mg, 23%) as an orange powder, mp 229–233° C. 1H NMR δ [(CD3)2SO] 11.05 (br s, 1H), 9.37 (br s, 1H), 8.37 (d, J=2.5 Hz, 1H), 7.74 (s, 1H), 7.61–7.52 (m, 3H), 7.50–7.43 (m, 2H), 7.14 (dd, J=8.7, 2.5 Hz, 1H), 4.63 (m, 2H), 3.21 (partially obscured m, 2H), 2.81 (m, 2H), 2.59 (t, J=6.8 Hz, 2H), 2.38 (s, 6H). FABMS found [M+H]+: 569.1255, 571.1204. C27H25ClN4O6S requires 569.1262, 571.1232.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][C:13]([CH2:18][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[OH:20])([CH3:17])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[CH2:28][CH3:29]>>[CH2:28]([O:20][CH:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][C:13]1([CH3:17])[CH2:14][CH2:15][C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:29]
Reactant: CC1(CC(O)c2ccccc2)CCc2c(cnn2-c2ccc(F)cc2)C1
Reactant: CCI
Product: CCOC(CC1(C)CCc2c(cnn2-c2ccc(F)cc2)C1)c1ccccc1

Procedure:
Using a procedure analogous to Example 35, the alcohols from Examples 117 and 118 were reacted with iodoethane to give Examples 119 and 120, respectively. MS found: (M+H)+=379.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C@@H:14]2[C@@H:9]([C:10](=[O:15])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH:14]2[CH:9]([CH:10]([OH:15])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@@H]2C(=O)CCC[C@@H]21
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2C(O)CCCC21

Procedure:
A solution of 25.8 g cis-perhydro-4-oxo-1-indoline carboxylic acid ethyl ester in 200 ml absolute tetrahydrofuran is added at -30° to -40° to 1 mole of lithium 3,4-dimethoxyphenylacetylide in tetrahydrofuran (formed from 2 moles 2 molar butyl lithium in hexane and 1 mole 1-(2,2-dibromovinyl)-3,4-dimethoxybenzene in 300 ml benzene at -70°). The mixture is stirred over-night. 100 ml concentrated ammonium chloride solution is added with ice cooling. The organic phase is worked up to give (3aRS,4RS,7aRS)-4-(3,4-dimethoxy)-phenylethinyl)-hexahydro-4-hydroxy-1-indoline carboxylic acid ethyl ester; M.Pt. 153°-155° (from ether).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1csc(C(=O)CBr)n1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nc(C)cs2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (Step 1 of Example 8, Method A) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William B. et al., Aust. J. Chem., 1985, 38, 1257).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[CH3:38])[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+]>[CH:32]1([C:30]([NH:29][C:27]2[N:28]=[C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]4[CH:35]=[CH:36][C:37]([CH3:38])=[C:16]([NH:15][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][C:4]=5[CH3:10])=[O:9])[CH:17]=4)=[CH:25][N:24]3[N:26]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: Cc1nc(C(=O)O)c(C)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of 2,5-dimethyl-1,3-thiazole-4-carboxylic acid (107 mg, 0.681 mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (2 drops) and thionyl chloride (118 μL, 1.36 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (6 mL). N-[6-(3-Amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, the residue was and recrystallized from ethanol to give the title compound (248 mg, 87%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[OH:22]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][S:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:10]=3[NH:9]2)=[CH:6][CH:7]=1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)-c1ccccc1SC2
Reactant: OO
Solvent: CC(=O)O
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1)-c1ccccc1S(=O)C2
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a 50 ml. round bottom flask under nitrogen was placed 2-(p-chlorophenyl)-1,2,3,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazole-3-one (0.5 g., 0.0016 mole) 8.33 ml. of glacial acetic acid and 3 ml. of 30% hydrogen peroxide. After stirring at 0° C., for 3.5 hours, the resulting solid was removed by filtration, washed with glacial acetic acid and dried in vacuo over phosphorous pentoxide to afford product, m.p. 193° C. (dec.). Weight 0.42 g. (80%). A second crop (0.4 g., 8%) was obtained from mother liquors.
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[BH4-].[Na+].O>C(O)C>[CH3:3][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[CH:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=2)=[N:11]1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C=O)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A solution of 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carbaldehyde (0.62 g, 1.7 mmol), prepared as in Example 8 or 9, and sodium borohydride in 30 mL of absolute ethanol was stirred at room temperature for 1 hour. The mixture poured into 150 mL of water and the mixture was extracted withethyl acetate. The ethyl acetate layer was dried over magnesium sulfate andthen concentrated. The residue was dissolved in approximately 10 mL of absolute diethyl ether and the solution was cooled in an ice bath giving aprecipitate. The precipitate was isolated by filtration and drying gave 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-methanol (0.37 g, 1.0 mmol), m.p. 119°-120° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([C:15]([F:18])([F:17])[F:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:19][CH2:13][C:12]([C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][O:9][C:10]=1[C:15]([F:17])([F:18])[F:16])=[O:14]
Reactant: CC(=O)c1c(-c2ccccc2)noc1C(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1c(-c2ccccc2)noc1C(F)(F)F
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of 1-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-ethanone (2.88 g, 11 mmol) in chloroform (11 mL) and AcOH (0.6 mL) at 48° C. was added a solution of bromine (0.61 mL, 12 mmol) in chloroform (3.5 mL) over 5 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 4:1) afforded the title compound (2.2 g, 59%) which was obtained as a light yellow oil. MS: m/e=334.3/336.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:14]1[C:13]2[CH:17]=[CH:18][C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][N:6]([CH3:7])[C:2]=3[NH:1][S:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)(=[O:29])=[O:28])=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OC)nn2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.9 %

Procedure:
To a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and 4-dimethylaminopyridine (50 mg) in pyridine (4 ml) at room temperature was added 4-methoxybenzenesulfonyl chloride (145 mg), the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue quenched with citric acid (10%, 10 ml) and then extracted with ethyl acetate (2×10 ml). The organic fractions were combined and washed with saturated aqueous sodium chloride solution (50 ml) the organic fraction was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (259 mg) was purified by preparative HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an amorphous white solid (10 mg).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([C:23]1[CH:27]=[CH:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH:24]=1)[C:12]([NH:14][C@H:15]1[C:19]([CH3:21])([CH3:20])[CH2:18][O:17][C:16]1=[O:22])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH:26]=[CH:27][C:23]([C@@H:11]([C:12]([NH:14][C@H:15]4[C:19]([CH3:20])([CH3:21])[CH2:18][O:17][C:16]4=[O:22])=[O:13])[CH2:10][C:9]([OH:42])=[O:8])=[CH:24]3)=[CH:33][CH:32]=2)=[CH:35][CH:36]=1)#[N:41]
Reactant: CC1(C)COC(=O)[C@H]1NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)COC(=O)[C@H]1NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 81 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid benzyl ester was hydrogenolyzed in EtOH/EtOAc for 3 h to give a 81% yield of 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid: 1HNMR (DMSO-d6): δ 12.2 (bs, 1H), 8.48 (d, 1H, J=8.8 Hz), 7.92 (s, 4H), 7.86 (d, 2H, J=8.5 Hz), 7.67 (d, 2H, J=8.5 Hz), 7.40 (s, 1H), 7.37 (s, 1H), 6.33 (s, 1H), 4.75 (d, 1H, J=8.8 Hz), 4.08, 4.00 (AB quartet, 2H, J=8.6 Hz), 3.97-3.92 (m, 1H), 3.01-2.92 (m, 1H), 2.64 (dd, 1H, J=16.54, 4.0 Hz), 1.05 (s, 3H), 0.97 (s, 3H); Anal. Calculated for C27H25N3O5.C5H12O (MTBE): C, 68.67; H, 6.66; N, 7.51. Found: 69.00, 68.91; H, 6.37, 6.42; N, 7.60, 7.52.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:25])[NH:12][C:13]2[CH:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:15][C:14]=2[NH2:24])[CH:6]=1)(=O)C.C(N(CC)CC)C>CO>[NH2:24][C:14]1[CH:15]=[CH:16][C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:18][C:13]=1[NH:12][C:11](=[O:25])[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=1
Reactant: CC(=O)Oc1cccc(C(=O)Nc2cc(-c3cccs3)ccc2N)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 91.9 %

Procedure:
A suspension of acetate 296 (349 mg, 0.99 mmol) in dry MeOH (6 mL) was treated with triethyl amine (1.5 mL) and stirred at room temperature for 19 h, concentrated under reduced pressure and triturated with diethyl ether to provide the title compound 297 (282.5 mg, 92% yield).
Reaction SMILES: [CH:1]([C:3]1[C:4]([N:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH2:1][C:3]1[C:4]([N:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:22]
Reactant: CCOC(=O)c1cn(-c2ncccc2C=O)nc1C
Reactant: CNC
Product: CCOC(=O)c1cn(-c2ncccc2CN(C)C)nc1C
Yield: 95 %

Procedure:
This compound is prepared essentially as described in Preparation 7 by using ethyl 1-(3-formyl-2-pyridyl)-3-methyl-pyrazole-4-carboxylate and dimethylamine in a 95% yield and is used with no further purification after workup. MS (m/z): 289 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:4]=1[NH2:5].[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1.N1C=CC=CC=1.O>[Cl:14][CH2:15][CH2:16][C:17]([NH:5][C:4]1[CH:6]=[C:7]([Cl:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1])=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1N
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
17.2 g of 2 -methoxy 4-nitro 5 -chloroaniline dissolved in 150 ml benzene are added with 11.1g of β chloropropionyl chloride dissolved in 40 ml benzene and 2 ml pyridine. The reaction mixture is kept under stirring at room temperature of 2 hours then diluted with 250 ml water. The benzenic phase is separated while the aqueous phase is extracted twice with benzene. The benzenic solutions are united, washed with 2N hydrochloric acid then with water, dried on sodium sulphate, filtered and evaporated to dryness. The dry residue is recrystallised from isopropyl ether and 21.1g of 1(β chloropropionylamino) 2-methoxy 4-nitro 5 -chlorobenzene are recovered (yield 40-50%). It melts at 101°-110° (dec).