Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][N:46]([CH2:48][C:49]([CH3:52])([OH:51])[CH3:50])[CH:47]=2)=[CH:38][C:37]=1[CH3:53].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:37]([CH3:53])=[CH:38][C:39]([C:43]3[CH:44]=[N:45][N:46]([CH2:48][C:49]([OH:51])([CH3:50])[CH3:52])[CH:47]=3)=[CH:40][C:41]=2[CH3:42])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cnn(CC(C)(C)O)c2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnn(CC(C)(C)O)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 1-(4-(4-bromo-3,5-dimethylphenyl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.23 min; Mass spectrum (ESI+): m/z=585 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:17](O)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17](=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)CCc1ccccc1
Product: O=C(CCc1ccccc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 54 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and hydrocinnamic acid in 54% yield following procedure 1. The product was crystallized from methanol. 99% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=341, 1H NMR (DMSO-d6): 2.65 t, 7.5 Hz (2H), 2.91 t, 7.5 Hz (2H), 6.50 s (1H), 7.00 t, 7 Hz (1H), 7.10 t, 7 Hz (1H), 7.19–7.34 m (7H), 7.39 d, 8 Hz (1H), 7.51 d, 8 Hz (1H), 7.60–7.62 m (2H), 9.39 s (1H), 11.32 s (1H).
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([SH:13])=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[Na+].Cl.[CH3:19][O:20][C:21]1[C:22]([CH2:29]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O.C(O)C>[C:1]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([S:13][CH2:29][C:22]3[C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][N:23]=3)=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccnc(CCl)c1OC
Reactant: CCOC(=O)c1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]c(SCc3nccc(OC)c3OC)nc2c1
Reaction time: 6 h
Yield: 71 %

Procedure:
5-Carbethoxy-2-mercapto-1H-benzimidazole (2.0 g, 9 mmol) and NaOH (0.36 g, 9 mmol) in H2O (1 ml) were dissolved in ethanol (30 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (≈6.6 mmol) as a crude material were added and the mixture was heated to boiling. NaOH (0.26 g, 6.6 mmol) in H2O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. Crystallizing from CH3CN gave the desired product (1.75 g, 71%).
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:14])=O>>[C:1]([Cl:14])(=[O:11])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCCC=CCC(=O)O
Product: CCCCCC=CCC(=O)Cl

Procedure:
A mixture of 22 g. of 3-nonenoic acid and 100 ml. of thionyl chloride is stirred at room temperature for about an hour, then 150 ml. of 1:1 ether-benzene mixture is added. The solvents are removed by evaporation under reduced pressure, then another 150 ml. of 1:1 ether benzene mixture is added to the residue, and removed by evaporation under reduced pressure, leaving a residue comprising 3-nonenoyl chloride. This residue is then dissolved in 30 ml. of benzene.
Reaction SMILES: C(C[C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([OH:12])=O)(O)=O.O.[O:14]1CC[CH2:16][CH2:15]1>>[OH:12][CH2:10][C:9]1([CH2:16][CH2:15][OH:14])[CH:8]=[CH:7][S:6][CH2:5]1
Reactant: C1CCOC1
Reactant: O=C(O)Cc1sccc1C(=O)O
Solvent: O
Product: OCCC1(CO)C=CSC1
Temperature: -2 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
0.45 g of the compound obtained in Example 4 was dissolved in 10 mL of anhydrous tetrahydrofuran, and the resulting solution was cooled to −2° C. 3.7 mL of 2M solution of borane-dimethylsulfide complex in tetrahydrofuran was slowly added thereto, and the resulting mixture was allowed to react for at least 1 hour at −1° C. The reaction mixture was warmed to room temperature and further added thereto was 3.7 mL of a 2M solution of borane-dimethylsulfide complex in tetrahydrofuran. The resulting mixture was kept at room temperature for 2 hours, and cooled to 0° C. After adding water thereto, the resulting solution was extracted three times with 15 mL portions of ethyl acetate, and the organic layers were combined, washed with 20 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.22 g (yield of 57%) of the title compound as an oil.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([CH:21]=1)[NH2:20].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([CH:21]=1)[NH:20][C:5](=[O:13])[C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(Cl)ccc1Oc1ccccc1)c1ccncc1
Reaction time: 0.5 h

Procedure:
A 100 ml. portion of thionyl chloride is added dropwise to 28.0 g. of isonicotinic acid over 30 minutes. After an additional 30 minutes the mixture becomes honogeneous. The volatiles are removed in vacuo, 250 ml. of benzene is added and then removed to leave a residue. This residue is suspended in 300 ml of dry tetrahydrofuran and a solution of 25.0 g. of 5-chloro-2-phenoxyaniline in 63 ml. of triethylamine is added dropwise over 30 minutes and the mixture is stirred overnight. The mixture is poured into 500 ml. of 1 N-sodium hydroxide. The organic layer is separated. The basic layer is extracted with two 100 ml. portions of ether. The ether extracts and organic layer are combined, washed with 250 ml. of water and then with four 200 ml. portions of 10% hydrochloric acid. The combined acid washings are neutralized with concentrated ammonium hydroxide and extracted with three 250 ml. portions of ether. These ether extracts are dried and evaporated giving 5'-chloro2'-phenoxy-isonicotinanilide as a brown solid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)(=O)C>[C:8]([NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(N)=O
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)O
Product: CCOC(=O)NC(=O)CC(C)=O
Yield: 42.7 %

Procedure:
A mixture of diketene (25 g), urethane (20 g), and acetic acid (75 ml) was refluxed for 25 minutes. Evaporation of the acetic acid under reduced pressure gave a syrup which crystallized on scratching. Recrystallization from benzene gave 16.6 g (32.5%) of N-carbethoxyacetoacetamide as colorless needles.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8](C(F)(F)F)[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3].FC1C=C([C:21]([F:24])([F:23])[F:22])C=CN=1>>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:21]([F:24])([F:23])[F:22])=[CH:6][N:5]=1)=[N+:2]=[N-:3]
Reactant: Fc1cc(C(F)(F)F)ccn1
Reactant: [N-]=[N+]=Nc1cc(C(F)(F)F)ccn1
Product: [N-]=[N+]=Nc1ccc(C(F)(F)F)cn1

Procedure:
The following were prepared analogously and analyzed by nmr spectroscopy: 2-azido-4-(trifluoromethyl)pyridine, off white crystals (from 2-fluoro-4-(trifluoromethyl)pyridine; and 2-azido-4,6-bis(trifluoromethyl)pyridine, pale yellow oil crystallizing on standing (from 2-chloro-4,6-bis(trifluoromethyl)pyridine.
Reaction SMILES: C([O:5][C:6]([C:8]1(C(OC(C)(C)C)=O)[C:17]2[C:12]3=[C:13]([C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:11]3[N:10]([CH3:30])[CH2:9]1)[C:14]([F:20])=[C:15]([F:19])[C:16]=2[F:18])=[O:7])(C)(C)C.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[F:18][C:16]1[C:15]([F:19])=[C:14]([F:20])[C:13]2[C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:11]3[C:12]=2[C:17]=1[CH:8]([C:6]([OH:7])=[O:5])[CH2:9][N:10]3[CH3:30]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)CN2C
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)O)CN2C
Temperature: 60 °C
Yield: 95.3 %

Procedure:
1.0 g of the compound (196) obtained in Example 67 was dissolved in 2 ml of trifluoroacetic acid, and the solution was heated at 60° C. for 2 hours. The reaction solution was added to 50 ml of isopropyl ether, and deposited solids were filtered off to obtain 0.67 g of the subject compound (197) in a 99% yield.
Reaction SMILES: N[C@@H]1C(=O)N2C(C(OCC3C=CC=CC=3)=O)=C(OS(C(F)(F)F)(=O)=O)CC[C@H]12.C(N(CC)CC)C.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)C[NH:44][C:45]2[S:46][CH:47]=[C:48]([C:50](=[N:81][O:82][CH3:83])[C:51]([NH:53][C@@H:54]3[C:79](=[O:80])[N:56]4[C:57]([C:69]([O:71]CC5C=CC=CC=5)=[O:70])=[C:58]([O:61][S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH2:59][CH2:60][C@H:55]34)=[O:52])[N:49]=2)C=CC=CC=1.C(O)=O>C(#N)C>[NH2:44][C:45]1[S:46][CH:47]=[C:48]([C:50](=[N:81][O:82][CH3:83])[C:51]([NH:53][C@@H:54]2[C:79](=[O:80])[N:56]3[C:57]([C:69]([OH:71])=[O:70])=[C:58]([O:61][S:62]([C:65]([F:67])([F:66])[F:68])(=[O:63])=[O:64])[CH2:59][CH2:60][C@H:55]23)=[O:52])[N:49]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(NCC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(N)n1

Procedure:
syn-2-(2-Triphenylmethylthiazol-4-yl)-2-methoxyiminoacetyl chloride is reacted in acetonitrile with benzyl 7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate in the presence of triethylamine and the acylation product, benzyl 7β-[2-(2-triphenylethylaminothiazol-4-yl)-2-methoxyiminoacetylamino]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate is treated with formic acid to remove the triphenylmethyl group and with aluminum chloride ih anisole to remove the benzyl ester group to provide the title compound.
Reaction SMILES: [P:1]([O-])([O-:4])([O-:3])=[O:2].[Ca+2:6].[P:7]([O-])([O-:10])([O-:9])=[O:8].[Ca+2].[Ca+2]>[NH4+]>[O-:4][P:1](=[O:3])=[O:2].[O-:10][P:7](=[O:9])=[O:8].[Ca+2:6]
Reactant: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [NH4+]
Product: O=P(=O)[O-]

Procedure:
A fertilizer rich in calcium metaphosphate is produced by reacting phosphorite or other calcium phosphate-bearing mineral, with ammonium bisulphate to produce a precipitate of calcium sulphate and an aqueous solution rich in ammonium mono- and biphosphates. The latter is then heated in a furnace in the presence of further calcium phosphate-bearing mineral, to produce calcium metaphosphate. The calcium sulphate can be converted to calcium carbonate by reaction with ammonium carbonate, to produce ammonium sulphate. The ammonium sulphate can be heated with the furnace gases from the production of calcium metaphosphate, to produce the required ammonium bisulphate for reaction with phosphorite and the required ammonium carbonate for a conversion of the calcium sulphate to calcium carbonate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][N:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]2[CH:34]=[CH:35][N:36]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:21]=2[C:20]1=[O:47]>>[CH3:18][N:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][CH:8]=[N:7][C:6]=3[C:10]=2[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]2[CH:34]=[CH:35][N:36]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:21]=2[C:20]1=[O:47]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: Brc1ccc2ocnc2c1Oc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5ocnc5c4Oc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-phenoxy-1,3-benzoxazole and 6-methyl-1[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C28H22N3O5S (M+H)+: m/z=512.1. found: 512.0.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8](O)[CH:9]=1.Cl.Cl[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CN(C=[O:26])C>O>[I:3][C:4]1[CH:9]=[CH:8][C:7](=[O:26])[N:6]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=1
Reactant: Oc1cncc(I)c1
Reactant: CN(C)C=O
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=c1ccc(I)cn1CCCN1CCCCC1
Temperature: 0 °C
Yield: 40 %

Procedure:
Sodium hydride (0.073 g, 3.0 mmol) was stirred in 4 mL anhydrous DMF under Ar. The solution was cooled to 0° C. and 3-iodo-5-hydroxypyridine (0.305 g, 1.38 mmol) was added gradually. After bubbling had subsided N-chloropropylpiperidine hydrochloride (0.330 g, 1.67 mmol) was added slowly. The reaction was then allowed to warm to ambient temperature. After 40 h the reaction was diluted with water and extracted 3× with EtOAc. The combined organic phases were washed was washed with saturated NaCl (aq), dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (2×16 cm silica, 9:1 CH2Cl2/MeOH) afforded 192 mg 5-iodo-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (18) (40% yield). 1H NMR (CDCl3) δ7.72 (d, J=2.6 Hz, 1H), 7.40 (dd, J=2.6, 9.5 Hz, 1H), 6.37 (d, J=9.5 Hz, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.35 (bs, 4H), 2.26 (t, J=6.6 Hz, 2H), 1.92 (t, 6.6 Hz, 2H), 1.60 (m, 4H), 1.46 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][CH:29]([CH3:31])[CH3:30])[N:22]=3)=[CH:19][N:20]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][CH:29]([CH3:30])[CH3:31])[N:22]=3)=[CH:19][N:20]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:33]
Reactant: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1O
Reaction time: 18 h
Yield: 97.7 %

Procedure:
To a solution of {4-[2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-oxazol-5-yl]-6-methyl-pyrimidin-2-yl}-isopropyl-amine (27 mg, 61 μmol) in THF (2 mL) and MeOH (2 mL), 10% Pd/C is added (50 mg). The reaction mixture is stirred under H2 atmosphere for 18 h, and is filtered through celite. The filtrate is evaporated to give 2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-oxazol-2-yl]-6-methyl-phenol (21 mg) as a yellow oil; LC-MS: tR=0.88 min, [M+H]+=353.03.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[CH3:15][N:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[C:19]2[CH:31]=[CH:32][N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]=2[C:17]1=[O:44]>>[CH3:14][O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH:6][CH3:7])[CH:8]=[CH:9][C:2]=1[C:20]1[C:19]2[CH:31]=[CH:32][N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]=2[C:17](=[O:44])[N:16]([CH3:15])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: CNc1ccc(Br)c(OC)c1[N+](=O)[O-]
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 4-bromo-3-methoxy-N-methyl-2-nitroaniline and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C23H23N4O6S (M+H)+: m/z=483.1. found: 483.1.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:11])=[O:10].C(OC(C1C2CCCCC=2SC=1N)=O)C.C1(S(Cl)(=O)=O)CCCCC1>>[CH:4]1([S:9]([NH:12][C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:11])=[O:10])[CH2:3][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Agent: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: O=S(=O)(Cl)C1CCCCC1
Product: CCOC(=O)c1c(NS(=O)(=O)C2CCCCC2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 27, starting from ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and cyclohexanesulphonyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(N)cc3)ncnc2n1

Procedure:
The product of Example 64B was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) at room temperature for 30 minutes. The solvents were removed under vacuum to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.37 (d, J=6.99 Hz, 6 H) 3.30 (m, 1 H) 6.65 (d, J=8.46 Hz, 2 H) 6.97 (d, J=8.46 Hz, 1 H) 7.16 (d, J=8.46 Hz, 2 H) 7.30 (m, 2 H) 7.72 (m, 1 H) 7.88 (dd, J=8.46, 1.84 Hz, 1 H) 7.96 (m, 2 H) 8.05 (s, 1 H) 8.92 (s, 1 H) 9.07 (d, J=8.46 Hz, 1 H) 10.37 (s, 1 H) 11.82 (s, 1 H); MS (ESI+) m/z 585, 587 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][C@H:13]([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)=[N:16]2)[CH3:14])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][N:15]([C@H:13]([CH3:14])[CH2:12][NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[N:16]=2)=[CH:21][C:22]=1[C:28]([F:31])([F:29])[F:30])#[N:27]
Reactant: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1
Yield: 58.8 %

Procedure:
(R)-3-acetyl-N-(2-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide of Example 218 (0.1 g, 0.232 mmol) was reacted with sodium borohydride (0.018 g, 0.465 mmol) using the method of Example 84. Yield of the title compound 0.059 g. 1H NMR (400 MHz; CDCl3): δ 1.55 (d, 3H), 1.61 (d, 3H), 3.77 (m, 1H), 3.90 (m, 1H), 4.64 (m, 1H), 5.03 (q, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 7.44 (bs, 1H), 7.51 (d, 1H), 7.83 (d, 1H), 8.06 (dd, 1H), 8.32 (s, 1H), 10.40 (bs, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17]O)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH2:17][CH2:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(S(=O)(=O)CCO)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1ccc(S(=O)(=O)CCCl)cc1
Yield: 109.5 %

Procedure:
A solution of 1.0 ml (14.0 mmol) of thionyl chloride in toluene (15 ml) was added dropwise, while cooling with ice, to a solution of 1.0 g (4.67 mmol) of 2-(4-ethylphenylsulfonyl)-ethanol and 56 μl (0.70 mmol) of pyridine in toluene (20 ml). The mixture was then heated for 3 h under reflux. Quenching with ice and water was then carried out. The phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. There were obtained as crude product 1.19 g of slightly impure 1-(2-chloroethylsulfonyl)-4-ethylbenzene, which was reacted further without additional purification.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([N:12]([CH3:21])[C@H:13]([C:17]([O:19]C)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>O1CCOCC1.[OH-].[Na+]>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:10]([N:12]([CH3:21])[C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@@H](C(=O)O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of Z-Phe-N-Me-Val-OMe (3.39 g) in dioxane (40 ml), 2N NaOH (4 ml) was added, followed by stirring for 2 hours at 50° C. The reaction mixture was mixed with water and washed with methylene chloride. The aqueous layer was adjusted to pH3 by the addition of 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=95:5) to give the titled compound (3.03 g, 92%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:5][N:4]=[N:3]1
Reactant: ClCc1ccccn1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCc1ccccn1
Yield: 23.7 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (2.4 g) and 2-chloromethylpyridine (2.6 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (2.8 g) and patassium iodide (0.1 g), and the mixture is refluxed for 4 hours. After acetone is distilled off, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over sodium sulfate. After chloform is distilled off, the residue is purified by column chromatography (neutral alumina, made by Merck) and eluted with n-hexane to give 1-methyl-5-(2-pyridyl)methylthio-1,2,3,4-tetrazole (1.0 g) as colorless prisms (ethanol), m.p. 78°-81° C.