Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18]([O:23]C)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.S(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[C:18](=[O:23])[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:15]1
Reactant: COc1nccnc1CN1CCC(/C=C/c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1[nH]ccnc1CN1CCC(/C=C/c2ccccc2F)CC1
Yield: 63.5 %

Procedure:
After dissolving 296 mg of (E)-3-[4-[2-(2-fluorophenyl)vinyl]piperidino]methyl-2-methoxypyrazine in 5 ml of ethanol, 1 ml of thionyl chloride was added and the mixture was heated to reflux for 9 hours. Aqueous sodium carbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the mixture was filtered to obtain the title compound (180 mg, 63% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:9]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(OC)cc2)c(Nc2ccc(OC)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene 1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.0 g (24 mmol) of 4-anisidine in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 1:1 and the product fractions are concentrated by evaporation, yielding the title compound in the form of a yellow foam, FAB-MS: 437 [M+ +H].
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12](Cl)=[O:13])[C:8]([F:15])=[C:7]([F:16])[C:3]=1[C:4](Cl)=[O:5].[F:17][C:18]([F:30])([F:29])[C@H:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C1C=CC=CN=1)C.[CH2:40]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([OH:62])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].Cl>C(N(CC)CC)C.C(Cl)Cl>[CH2:40]([C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59]([O:62][C:4]([C:3]3[C:7]([F:16])=[C:8]([F:15])[C:9]([C:12]([O:28][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:18]([F:29])([F:30])[F:17])=[O:13])=[C:10]([F:11])[C:2]=3[F:1])=[O:5])=[CH:58][CH:57]=2)=[CH:54][CH:55]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCC[C@@H](O)C(F)(F)F
Reactant: O=C(Cl)c1c(F)c(F)c(C(=O)Cl)c(F)c1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc(-c2ccc(OC(=O)c3c(F)c(F)c(C(=O)OC(CCCCCCCC)C(F)(F)F)c(F)c3F)cc2)cc1
Reaction time: 8 h
Yield: 41 %

Procedure:
To methylene chloride (20 ml) were added 2,3,5,6-tetrafluoroterephthalic acid chloride (0.27 g), (R)-(+)-1,1,1-trifluoro-2-decanol (0.1 g), triethylamine (0.05 g) and dimethylaminopyridine (0.02 g). After the mixture was left to stand for 8 hours in order to allow a reaction to proceed, 4-decyl-4'-hydroxybiphenyl (0.15 g) and triethylamine (0.05 g) were added thereto. The mixture was left for about 8 hours in order to allow a reaction to proceed, made acidic with 1N aqueous hydrochloric acid solution and extracted with methylene chloride. The extracted layer was washed with lN aqueous sodium carbonate solution, water, aqueous sodium chloride solution (saturated) and water, in this order, to make it neutral. The layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure in order to remove the solvent. The solid product obtained was purified by silica-gel column chromatography to obtain the titled compound (0.14 g).
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:7]=[CH:8][C:9]2[S:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[S:14]1[C:13]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:22])=[CH:12][C:10]2[CH:11]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc2ccccc2s1
Reaction time: 1 h
Yield: 86 %

Procedure:
n-Butyl lithium (35 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of thianaphthene (11.5 g, 85.6 mmol) in THF (300 mL) at -78° C. under a dry N2 atmosphere. After 1 h, benzaldehyde (9.6 mL, 94.4 mmol) was added and the cold bath was removed. After an additional 30 minutes, sat. aq. NH4Cl was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated. The resultant solid was triturated with pet. ether and filtered to provide the title compound as a white solid (17.7 g, 86%): NMR (CDCl3); δ 7.78 (m, 1H, thiopheneH), 7.68 (m, 1H, thiopheneH), 7.22-7.56 (m, 7H), 7.12 (s, 1H, thiopheneH), 6.12 (d, 1H, OH), 2.51 (d, 1H, CH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:19]=[O:20])=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].CCCCCC.[Cl-].[NH4+]>C1COCC1>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:12]1[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[S:10][C:11]=1[CH:19]([OH:20])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C=O)s1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Compound 92 (298 mg, 1.01 mmol) was dissolved in THF (10 mL), and a 1.59 mol/L solution of n-butyllithium in n-hexane (5.70 mL, 9.06 mmol) was added thereto in a stream of argon at −78° C., followed by stirring at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydro us magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the entitled Compound 395 (224 mg, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][NH2:10])#[N:2].O1CCCC1.C(=O)(O)[O-].[Na+].[C:25](Br)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][NH:10][C:25]([CH3:28])([CH3:27])[CH3:26])#[N:2]
Reactant: N#Cc1cccc(OCC(O)CN)c1
Reactant: CC(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)NCC(O)COc1cccc(C#N)c1

Procedure:
9.6 gm (0.05 mol of 1-(3-cyanophenoxy)-2-hydroxy-3-amino propane were dissolved in 40 ml of dimethylformamide and 100 ml of tetrahydrofuran and 4.2 gm (0.05 mol) of pulverized sodium bicarbonate were added thereto. Then, 6.9 gm (0.05 mol) of tert.-butylbromide were added and the mixture was refluxed for 24 hours. After the mixture had been cooled, the inorganic solid was filtered off and the solvent mixture was distilled off in vacuo. The residue was dissolved by heating in ethyl acetate and the insoluble inorganic portions were vacuum filtered off and the filtrate was admixed with petroleum ether. The base precipitated in solid form and was isolated and recrystallized from ethyl acetate with an addition of petroleum ether to obtain 1-(3-cyanophenoxy)-2-hydroxy-3-tert.-butylamino propane having a melting point of 108°-110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[Br:17]Br.BrBr.C(O)(=O)C>C(O)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH2:15][Br:17])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CC(=O)c1ccccc1-c1ccc(C)cc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Temperature: 30 °C
Yield: 943.7 %

Procedure:
A solution of 4'-methyl-2-acetyl-1,1'-biphenyl (2.06 g, 9.79 mmol) in 10 mL of glacial acetic acid was treated dropwise with a solution of bromine (1.722 g, 1.07 mmol) dissolved in 3.0 mL of glacial acetic acid. After initiating the reaction with the first few drops of the bromine/acetic acid reagent by heating the reaction mixture at 30° C., the remainder of the bromine solution was added dropwise at 25°-30° C. The reaction mixture was stirred at room temperature until the consumption of bromine was complete (approximately 2 hrs). The reaction mixture was diluted with 150 mL of hexane then washed with water (3×50 mL). The organic layer was removed, dried over magnesium sulfate, filtered and evaporated under vacuum to give 2.92 g of an oil that was used in the next step without purification. 1H NMR (crude product) (200 MHz,CDCl3): 2.38 (s,3H), 3.66 (s,2H), 7.21 (s,4 H), 7.3-7.6 (m,4H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11](CCC)=[CH:10][CH:9]=2)[CH2:3]1.BrC1C=C[C:21]([O:24]CCC)=[CH:20][CH:19]=1>>[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([O:24][CH2:21][CH2:20][CH3:19])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: CCCOc1ccc(Br)cc1
Reactant: CCCc1ccc(N2CCN[C@H](C)C2)cc1
Product: CCCOc1ccc(N2CCN[C@H](C)C2)cc1
Yield: 34 %

Procedure:
The title compound was prepared following the procedure of Intermediate 17, but starting from 1-bromo-4-propoxybenzene. Purification by chromatography (DCM/MeOH 80/20) afforded the title compound as a brown oil (34%). HPLC (Condition A), Rt: 1.9 min (HPLC purity: 80.2%). M+(ESI): 235.2
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].Cl.[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:19][CH3:20])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: COc1cc(CCl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2cc3ncnc(Oc4ccccc4)c3cc2OC)cc(Cl)n1
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.1 g, 4.1 mmol), (prepared as described for the starting material in Example 13), 2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 3.9 mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (20 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool, diluted with water and the precipitated product collected by filtration, washed with water and dried to give 7-((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (1.38 g, 79%).
Reaction SMILES: C[C:2]([CH:5]([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:10]1)[C:6]([O-])=O)(C)C.Cl.[C:33](NN)(C)(C)C>>[CH3:33][C:5]([N:9]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[N:10]1)([CH3:2])[CH3:6]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(C(=O)[O-])n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Product: CC(C)(C)n1ccc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the minor isomer. ESMS (M−C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO)8.20 (d, 2H), 7.86 (d, 2H), 7.7(d, 1H), 6.55(d, 1H), 1.25 (s, 9H)
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH3:29])[CH:18]=2)O1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:19]1[CH:18]=[C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccccc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cccnc2N)ccc1-c1ccccc1

Procedure:
Pd(dppf)Cl2 (0.089 g) was added to a mixture of 4-bromo-2-methylbiphenyl (1.5 g), potassium acetate (1.787 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.312 g) in DME (25 mL) and DMSO (1.25 mL). The mixture was stirred at 80° C. under nitrogen overnight. Activated-carbon powder was added and the mixture was stirred for 5 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo to give crude 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (173 mg) was added to a suspension of 3-bromopyridin-2-amine (865 mg), the prepared 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane and sodium carbonate decahydrate (2861 mg) in DME (30 mL) and water (6 mL) and the mixture was stirred at 80° C. under nitrogen for 6 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (1.25 g) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH:4](O)[CH:5]=[CH2:6].C=CCCC=C.S(Br)([Br:18])=O>ClCCCl>[Br:18][CH2:6]/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C=CC(O)CC(C)(C)C
Reactant: O=S(Br)Br
Agent: C=CCCC=C
Solvent: ClCCCl
Product: CC(C)(C)C/C=C/CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of Example 35A (2.38 g, 18.56 mmol) and 1,5-hexadiene (1.65 mL, 13.9 mmol) in 1,2-dichloroethane (30 mL), stirring at 0° C., was added thionyl bromide (2.16 mL, 27.8 mmol). The reaction was stirred for 2 hours at 0° C. and then quenched with water. The mixture was extracted with diethyl ether and the diethyl ether layer was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound 3.15 g, 89%). 1H NMR (300 MHz, CDCl3): δ ppm 0.87 (m, 9 H) 1.94 (m, 2 H) 3.97 (m, 2 H) 5.74 (m, 2 H).
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]>C1COCC1.CO.O>[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COC(=O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (5.67 g, 135 mmol) was added to a solution of 5A (11.4 g, 45.0 mmol) in THF (120 mL), MeOH (120 mL) and H2O (40.0 mL). The above mixture was then heated to 50° C. for 1 h. After 1 h, the heating was reduced to rt and stirring was continued for overnight. To the reaction mixture was then added H2O (50 mL) and the organics were concentrated. The remaining aqueous layer was made acidic with 1.0 N HCl solution to precipitate out the solids. The solids were collected by filtration, washed with H2O and dried under vacuum overnight to give 5B. 1H NMR (400 MHz, DMSO-d6) δ 13.68 (br. s., 1H), 8.36 (d, J=1.5 Hz, 1H), 8.25 (dd, J=8.1, 1.3 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 6.38 (s, 1H), 4.05-3.89 (m, 4H) ppm.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][NH:17][C:18]([NH2:20])=[S:19].C(O)C>C(O)(=O)C.O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=[N:16][NH:17][C:18]([NH2:20])=[S:19])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reactant: NNC(N)=S
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=S)NN=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 96 h
Yield: 95 %

Procedure:
Stir 4.14 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde together with 2.0 g. of thiosemicarbazide, 2 drops of glacial acetic acid and 40 ml of ethanol for 2 hours at 50° C and then for 4 days at room temperature. Dilute the resulting product with water to produce a 95% yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde-thiosemicarbazone [m.p. above 350° C (with decomposition)].
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].C(NC(C)C)(C)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])=[C:32]([S:43][CH:44]([CH3:46])[CH3:45])[CH:31]=2)=[CH:26][CH:25]=1.O1CCOCC1.[ClH:53]>CN(C)C=O>[ClH:53].[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C@@H:2]([NH:1][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])=[C:32]([S:43][CH:44]([CH3:45])[CH3:46])[CH:31]=2)=[CH:28][CH:29]=1)[CH3:12]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CC(C)Sc1cc(-c2ccc(OCCBr)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)Sc1cc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[(1R,2S)-2-amino-1-hydroxypropyl]-phenol (96.6 mg) in N,N-dimethylformamide (1.00 ml) were added diisopropylamine (156 μl) and 4′-(2-bromoethoxy)-3-(isopropylthio)-N-(methylsulfonyl)-4-biphenylcarboxamide (210 mg) at room temperature and stirred at 100° C. for 5 hours. To the reaction mixture was added hydrogen chloride 1,4-dioxane solution (4M, 464 μl) and stirred at 0° C. The mixture was filtrated and the filtrate was concentrated in vacuo. The residue was washed with ethyl ether three times, dried and purified with reverse phase silica gel column chromatography. To the resulting solution was added hydrogen chloride ethyl acetate solution (4M, 111 μl) and concentrated in vacuo to give 4′-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethoxy]-3-(isopropylthio)-N-(methylsulfonyl)-4-biphenylcarboxamide hydrochloride (108 mg).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Cl:24])[CH:15]=2)[NH:11][CH:12]=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>C(COC)OC>[Cl:24][C:16]1[CH:15]=[C:14]([CH:10]([N+:11]#[C-:12])[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(C(NC=O)S(=O)(=O)c2ccc(C)cc2)cc(Cl)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: [C-]#[N+]C(c1cc(Cl)c(OC)c(OC)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 3a (4.57 g, 11.92 mmol) was suspended in dry dimethoxyethane (100 mL) and cooled to −10° C. POCl3 (3.4 mL, 36.1 mmol) was added and a mixture of triethylamine (8.3 mL, 59.5 mmol) in dimethoxyethane (10 mL) was dropped slowly to the reaction mixture. After stirring for 2 h at −5° C., the reaction mixture was poured into ice water. The aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuum. Upon refrigeration (4° C.) over night a yellow solid crystallized, which was collected and dried in vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=2)[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=3)[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)c1ccc2cc(OC)ccc2c1
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc2cc(OC)ccc2c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate (from Example D3 above), the title compound was prepared as a solid (mp=177-178° C.). The product was purified by tituration using hexanes/EtOAc.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH:19]1([CH:22]([NH2:25])[CH2:23][CH3:24])[CH2:21][CH2:20]1>>[CH:19]1([CH:22]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[CH:5]=[CH:4][N:3]=2)[CH2:23][CH3:24])[CH2:21][CH2:20]1
Reactant: CCC(N)C1CC1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Product: CCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 63.4 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.34 g, 1.12 mmol) and 1-cyclopropyl-propylamine (0.30 g, 2.24 mmol) were treated substantially as described in Part D of Example 9 to produce 0.26 g (83%) of crude (1-cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 366.3 [(M+H)+, 100].