Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:32]=[CH:31][C:24]([C:25]([NH:27][NH:28][CH:29]=O)=O)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:32]=[CH:31][C:24]([C:25]3[S:34][CH:29]=[N:28][N:27]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NNC=O)cc2)c1Sc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nncs3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 55 °C

Procedure:
4-{5-[(4-Chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}-N′-formylbenzohydrazide (Example 49, 450 mg, 0.98 mmol) was treated with P2S5 (218 mg, 0.98 mmol) in 12 mL of dioxane. After the reaction mixture was heated at 55° C. overnight, the volatiles were removed in vacuo. The residue was diluted with EtOAc, washed with 1N NaOH, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was subjected to silica gel column chromatography eluting with 30-85% EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, (CDCl3): 9.13 (s, 1H), 8.67 (d, 1H), 8.43 (broad d, 1H), 8.38 (d, 2H), 8.06 (d, 2H), 7.89 (t, 1H), 7.39 (t, 1H), 7.25 (d, 2H), 7.04 (d, 2H), 4.16 (s, 3H). LCMS: m/z 462 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([Cl:20])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccccc3)c2O1
Agent: [Pt]
Product: NCC1Cc2cc(Cl)cc(-c3ccccc3)c2O1
Yield: 40 %

Procedure:
Treatment of (±)-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.55 g, 1.33 mmol) with sodium azide (0.345 g, 5.31 mmol) generally according to the procedure described for Intermediate 98 provided 0.35 g of (±)-2-(azidomethyl)-5-chloro-7-phenyl-2,3-dihydro-1-benzofuran as a colorless oil. Treatment of the azide with sulfided platinum on carbon (90 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.14 g (40%) of (±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 258° C. (dec); Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.13; H, 4.95; N, 4.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:2]=1.C(N(C(C)C)C(C)C)C.CN(C=O)C.[Cl:31][CH2:32][CH2:33][CH2:34]I>O>[Cl:31][CH2:32][CH2:33][CH2:34][N:9]([CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: ClCCCI
Reactant: c1cncc(CCNCc2ccncc2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: ClCCCN(CCc1cccnc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (210 mg) and N-ethyldiisopropylamine (0.34 ml) were added to a DMF solution (2 ml) of 1-chloro-3-iodopropane (0.16 ml). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound (74 mg) as a colorless oily matter.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:31](O)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].[PH2](O)=O>>[C:31]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)OCCCO
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Agent: O=[PH2]O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCCCCCCCCCCC/C=C\CCCCCCCC
Temperature: 160 °C
Reaction time: 5 h

Procedure:
A mixture of 1-hydroxy-3-(z-15-tetracosenoyloxy)propane, prepared according to Description 3, (0.045 mol, 19.0 g), z,z,z-6,9,12-octadecatrienoic acid (0.054 mol, 15.0 g) and hypophosphorous acid (0.4 g) was heated with stirring to 160° C. under nitrogen. After 5 h, TLC (80:18:2 petroleum ether-ethyl ether-acetic acid) indicated that most of the mono-ester had reacted (Rf: 0.60). The mixture was cooled down to room temperature and petroleum ether (800 mL) was added. The resulting solution was washed with saturated sodium bicarbonate (3×80 mL) and saturated sodium chloride (3×80 mL). It was then dried over anhydrous sodium sulphate, concentrated and purified by flash chromatography on silica gel (19:1 petroleum ether-ethyl ether) to yield 1-(z,z,z-6,9,12-octadecatrienoyloxy)-3-(z-15-tetracosenoyloxy)propane as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][CH:5]([CH3:12])[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].ClCCl.CO.N>CO>[Cl:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[O:4][CH:5]([CH3:12])[CH2:6][N:7]([CH2:8][CH3:9])[CH2:10][CH3:11]
Reactant: CCN(CC)CC(C)Oc1ccc([N+](=O)[O-])cc1Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CC(C)Oc1ccc(N)cc1Cl

Procedure:
Prepared analogously to Example 3.1.b. from [2-(2-chloro-4-nitrophenoxy)propyl]diethylamine in methanol in a reaction time of 8 hours. Yield: 6.7 g (93.5% of theory); C13H21ClN2O (M=256.77); calc.: molecular ion peak (M+H)+: 257/259; found: molecular ion peak (M+H)+: 257/259; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (50:10:0.1)).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: COCCNc1ccc2c(n1)CCN(Cc1ccccc1)C2

Procedure:
Copper (II) sulphate (200 mg) was added to a solution of 6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (4.5 g, 17.4 mmol)(see reference WO9830560 Example 33 b) in 2-methoxyethylamine and the mixture was heated under reflux for 20 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and water (50 ml). The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 1:99 to 3:97) to give the title compound as an orange oil (1.32 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:9])[CH3:8])(=O)C.[OH-].[Na+].C(O)C>O>[C:11]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]([OH:9])([CH3:8])[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(C)(O)c1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.84 g. of 1-acetoxy-3-p-biphenylyl-3-butanol and 2 g. of NaOH in 30 ml. of 80% ethanol is boiled for 3 hours. Water is added and the mixture is extracted with chloroform and the extract is evaporated to give 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117°.
Reaction SMILES: [OH:1][C:2]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]([C:8]([F:11])([F:10])[F:9])([C:12]([F:13])([F:14])[F:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:21][CH:20]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 144 h

Procedure:
Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) is added dropwise at ambient temperature to a stirred mixture of sodium hydride (2.4 g. of a 60% dispersion in oil) and dimethylformamide (100 ml.). The mixture is stirred for 4 hours 4-chlorobenzyl chloride (8.4 g.) is added, and the stirring is continued for 6 days. The mixture is filtered, and the filtrate is evaporated in vacuo. The residue is fractionally distilled at 0.1 mm. pressure, collecting the fraction, (9.9 g.) b.p. 78°-80° C., m.p. 32°-33° C, which is crystallised from pentane to give ethyl 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, m.p. 33° C.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:18]#[CH:19].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl-].[Na+].O.CC#N.CC#N.Cl[Pd]Cl.C(#N)C>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([C:19]#[C:18][CH2:17][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:3]1
Reactant: Brc1csc2ccccc12
Reactant: C#CCOC1CCCCO1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C(#Cc1csc2ccccc12)COC1CCCCO1
Temperature: 90 °C
Reaction time: 11 h

Procedure:
A mixture of 3-bromobenzothiophene(5.00 g), cesium carbonate (20.0 g), 2-(2-propynyloxy)tetrahydropyran (4.96 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (672 mg), bis(acetonitrile)palladium(II) dichloride (122 mg) and acetonitrile (100 ml) was stirred at 90° C. for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.19 g) as a brown oil.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3].[Br:10][C:11]1[C:12](Cl)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH2:1]([N:4]([C:12]1[C:11]([Br:10])=[CH:16][N:15]=[C:14]([Cl:17])[N:13]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C=CCNC(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C=CCN(c1nc(Cl)ncc1Br)C(CC)CC
Reaction time: 8 h

Procedure:
To a solution of allyl-(1-ethyl-propyl)-amine (10 mmol) is added anhydrous isopropanol (50 ml) and 5-bromo-2,4-dichloropyrimidine (2.979 g, 5 mmol) followed by diisopropylethylamine (2.61 ml, 15 mmol) at ambient temperature. The reaction is stirred overnight and concentrated in vacuo. The residue is purified with column chromatography (SiO2, 1:5 EtOAC/Hexane) to give the desired product.
Reaction SMILES: [CH3:1]C(O)(C#CC1C=CC=C(Br)C=1)C.CC(O)(C)C#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#CC(O)(C)C)[CH:19]=1>>[C:18]1([CH3:17])[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([CH3:1])[CH:23]=1
Reactant: CC(C)(O)C#Cc1cccc(C#CC(C)(C)O)c1
Reactant: CC(C)(O)C#Cc1cccc(Br)c1
Product: Cc1cc(C)cc(C)c1

Procedure:
Referring to Table 1 above, the Conversion ("Conv.") was a weight percent conversion and was calculated by: ##EQU1## Selectivity ("Selec.") in Table 1 means, as appropriate: ##EQU2## The Yield means, as appropriate, the yield of 2-methyl-4-(3-bromophenyl)-3-butyn-2-ol: ##STR15## or 1,3-di(3-methyl-3-hydroxy-1-butynyl)benzene: ##STR16## and was calculated as the product of Conversion times Selectivity. Selectivities and yields were calculated only on isolated crude products by gas chromatography with an appropriate internal standard (mesitylene).
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@H:35]2[CH2:37][O:36]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@H:35]([OH:36])[CH2:37][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OC[C@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C[C@@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 213 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and (2R)-2-[(4-chlorophenoxy)methyl]oxirane using conditions outlined in procedure Y. M.p.=111-112° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.96 (brs, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.73 (d, J=8 Hz, 2H), 7.53 (t, J=7.2 Hz, 2H), 7.47 (m 1H), 7.28 (m, 2H), 6.92 (m, 2H), 4.88 (brs, 1H), 3.95 (brm, 2H), 3.84 (t, 8.8 Hz, 1H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H); LCMS: 562 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[C:37]#[N:38])=[CH:31][CH:30]=1.BrCC1(CBr)C=CC(C2C=CC=CC=2C#N)=CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]([C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[C:37]#[N:38])=[CH:33][CH:34]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: N#Cc1ccccc1C1=CCC(CBr)(CBr)C=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
30.1 g of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate [BAN], 40.8 g of potassium carbonate and 160 ml of acetonitrile were added to the acetonitrile solution in which unreacted 2-(4-methylphenyl)benzonitrile [MPB] and 2-(4,4-dibromomethylphenyl)benzonitrile as an analogue of BMB were contaminated, and the reaction was allowed to proceed at about 82° C. for about 5 hours under stirring. After cooling to room temperature, the precipitated crystals were filtered off, and the filtrate was concentrated to give methyl 2-[N-t-butoxycarbonyl-N-[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate [BBN]. The concentrated material was dissolved in 190 g of methanol, and 106 g of concentrated hydrochloric acid was added dropwise thereto. The resulting solution was heated to a reflux temperature over 2 hours, and stirred for 2 hours under reflux, whereby, the reaction was allowed to proceed. The reaction solution was cooled, and precipitated crystals were collected by filteration and dried to give 35.1 g of methyl 2-[N-(2′-cyanobiphenyl-4-yl)methylamino]-3-nitrobenzoate [MBN] (yield relative to 2-(4-methylphenyl)benzonitrile [MPB] was 76.1%)
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3]1.[H-].[Na+].[Br:17][C:18]1[CH:19]=[CH:20][C:21](F)=[C:22]([CH:25]=1)[C:23]#[N:24].[Cl-].[NH4+]>CN(C)C=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([N:6]2[C:2](=[O:1])[CH2:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5]2)=[C:22]([C:23]#[N:24])[CH:25]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC(=O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)N(c2ccc(Br)cc2C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.5 %

Procedure:
To a solution of tert-butyl ((S)-5-oxopyrrolidin-3-yl)carbamate (2.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (55% oil, 0.65 g) was added under ice cooling, and the mixture was stirred at the same temperature as above for 10 minutes. 5-Bromo-2-fluorobenzonitrile (3.0 g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Ice water and a saturated aqueous solution of ammonium chloride were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (1.5 g).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH3:37])(=[O:36])=[O:35])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=1[OH:27])(=[O:18])=[O:17])C.[OH-].[Na+].Cl>C(O)C>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([OH:27])=[C:19]([S:16]([NH:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH3:37])(=[O:36])=[O:35])=[CH:8][C:7]=2[O:6][CH2:5][C:4]([OH:38])=[O:3])(=[O:17])=[O:18])[CH:24]=1)#[N:26]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)O)c1
Yield: 101.9 %

Procedure:
To a stirred solution of 154 g of ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonyl-biphenyl-3-yloxy]acetate in 1.23 L of ethanol was added 275 mL of 2mol/L sodium hydroxide solution under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. To the reaction mixture was added dropwise 275 mL of 2 mol/L hydrochloric acid, and ethanol was removed under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was dried over anhydrous magnesium sulfate, and removed under reduced pressure to give 149 g of [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy)acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH2:19][CH2:20][OH:21])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:22]4[N:27]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH2:19][CH2:20][OH:21])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](CCO)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](CCO)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 61 %

Procedure:
(S)—N-(3-Hydroxy-5-(4-((3-hydroxy-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (35 mg, 0.03 mmol, 65% purity) was treated with trifluoroacetic acid (1.0 ml, 12.98 mmol) and a solution of ammonia (7N in methanol, 5.0 ml, 35.0 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 5% dichloromethane-methanol) to obtain 11 mg (59% yield) of the title compound.
Reaction SMILES: C(S[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:15])[C:7](=[O:16])[CH2:6][N:5]=1)C.[CH:17]([NH:19][NH2:20])=O>C(O)CCC>[CH3:15][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]2=[N:20][N:19]=[CH:17][N:5]2[CH2:6][C:7]1=[O:16]
Reactant: CCSC1=NCC(=O)N(C)c2ccccc21
Reactant: NNC=O
Solvent: CCCCO
Product: CN1C(=O)Cn2cnnc2-c2ccccc21
Reaction time: 16 h

Procedure:
A mixture of 1,3-dihydro-5-(ethylthio)-1-methyl-2H-1,4-benzodiazepin-2-one (1 eq.) and formic hydrazide (5.8 eq. Aldrich) in n-butanol (0.1 M in benzodiazepine) was stirred at reflux under N2 for 24 hours. An additional 1.67 eq. of formic hydrazide was added and refluxing continued an additional 16 hours. The yellow solution was evaporated in vacuo and the residue was purified via flash chromatography eluting with a gradient from 98:2 to 96:4 CH2Cl2/MeOH. The product was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[CH:28]5)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5[nH]ccc5c4)ncnc32)CC1
Yield: 37.1 %

Procedure:
4-[4-(1H-Indol-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (29 mg, 38%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 5-hydroxyindole (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 24 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol). Mass spectrum MH+=435.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.O>CN(C=O)C>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 95.3 %

Procedure:
To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60% NaH in oil (20.02 g, 0.50 mol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml). The mixture was then stirred at room temperature overnight. Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml). The filtrate, now containing more solid, was refiltered and washed with petroleum ether. The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95%) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.59 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).