Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22]>>[CH2:21]([O:23]/[CH:24]=[C:11]1\[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[C:10]\1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:22]
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Reactant: CCOC(OCC)OCC
Product: CCO/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one [(Example 107, Step 1), 85 mg, 0.31 mmol] and triethylorthoformate (0.057 mL, 0.34 mmol, 1.1 equiv) were combined and placed into a preheated oil bath at 100° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].[CH2:19]([O:21][CH:22]([O:25]CC)[CH:23]=[CH2:24])[CH3:20].C(N(CCCC)CCCC)CCC.CCOC(C)=O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:19]([O:21][C:22](=[O:25])[CH2:23][CH2:24][C:15]1[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)[CH3:20]
Reactant: C=CC(OCC)OCC
Reactant: CCOc1ccc(C#Cc2ccc(I)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)CCc1ccc(C#Cc2ccc(OCC)cc2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
To 1.80 g (5.17 mmol) 1-ethoxy-4-((4-iodophenyl)ethynyl)benzene (XII.1) in 24 mL DMF are added 2.36 mL (15.5 mmol) 3,3-diethoxy-propene, 3.69 mL (15.5 mmol) tributylamine, 1.44 g (5.17 mmol) tetrabutylammoniumchloride and 0.04 g (0.16 mmol) palladium(II)acetate under argon. The mixture is stirred at 120° C. for 12 h. After that time, 1.18 mL (7.76 mmol) 3,3-diethoxy-propene are added and the mixture is stirred at 120° C. for 5 d. After cooling, EtOAc is added and the mixture is washed with 1N potassium hydrogensulfate solution and water. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; PE:DCM 1:1) to yield the desired product.
Reaction SMILES: [CH2:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9](O)=[S:10])[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH2:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9]([Cl:24])=[S:10])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1ccccc1C=CC(O)=S
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1ccccc1C=CC(=S)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylene chloride (564 ml) is added to 2-n-butylthiocinnamic acid (40.0 g, 0.69 mol) and cooled in an ice bath. To the mixture is added DMF (13.1 ml, 0.169 mol) and then oxalyl chloride (34.0 ml, 0.389 mol) dropwise with the vigorous evolution of gas. After the oxalyl chloride addition is complete, the ice bath is removed and the reaction stirred at room temperature for 2 hours to afford 2-n-butylthiocinnamic acid chloride. Methylhydroxylamine hydrochloride salt (56.5 g, 0.677 mol) is dissolved in THF (50 ml) and water (70 ml) and further THF (96 ml) is added. The acid chloride is added dropwise then stopped so an additional THF (175 ml) and water (35 ml) can be added for solubility. The acid chloride addition is then continued with the reaction mixture being cooled in an ice bath. After the addition is complete, the reaction mixture is stirred at room temperature overnight.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C@@H:3]1[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH3:19]I>CN(C=O)C.O>[CH3:19][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C@H:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:2]1=[O:1]
Reactant: CI
Reactant: COC(=O)C[C@H]1Nc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@H]1Nc2ccccc2N(C)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 650 mg, 2.95 mmol) in DMF (5 mL) at 0° C. was added NaH (142 mg, 3.54 mmol). After stirring at 0° C. for 20 minutes, MeI (220 uL, 3.54 mmol) was added and the reaction mixture was stirred for an additional 15 minutes at 0° C. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (1×50 mL), dried over sodium sulfate, filtered, and concentrated to give methyl [(2R)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate, which was used without further purification. LCMS (ES) 235.1 m/z (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([O-])=[O:10])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)[O-])c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(Br)cc1

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanoate (8.9 g, 33 mmol) in THF (100 mL) under nitrogen was added LiAlH4 (1.6 g, 43 mmol) in portions at 0° C. The resulting solution was stirred at 0° C. for 1 hour before the addition of saturated aqueous NH4Cl (50 mL). The mixture was then extracted with EtOAc (3×80 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel with 2-5% EtOAc/hexane to afford 2-(4-bromophenyl)-2-methylpropan-1-ol as a colorless oil. MS ESI: [M+H]+ m/z 229, 231; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=6.8 Hz, 2H), 7.28 (d, J=6.8 Hz, 2H), 3.61 (s, 2H), 1.58 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(N(Cc2ccccc2)Cc2ccccc2)ccc1Br
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.9 %

Procedure:
To a suspension of 4-bromo-3-fluoroaniline (10.0 g, 52.6 mmol, 1.0 eq) and K2CO3 (21.7 g, 157.8 mmol, 3.0 eq) in MeCN (10 mL) was added benzyl bromide (19.8 g, 115.8 mmol, 2.2 eq) and the mixture was stirred for 16 h at 80° C. and then filtered through celite pad, and the solvents was evaporated under vacuum and washed with PE (100 mL) to get N,N-dibenzyl-4-bromo-3-fluoroaniline (13.8 g, 55%; TLC system: EtOAc/PE (1:9), Rf: 0.6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[OH:24].[C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](O)=[O:37])[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[C:28]([O:27][C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](=[O:37])[NH:21][CH2:20][C:19]([C:10]2[O:11][C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:24])[CH:4]=3)[CH:9]=2)([CH3:22])[CH3:23])[CH2:34][CH2:33]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(CN)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(C)(C)c2cc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)o2)CC1

Procedure:
The title compound was prepared from the product of Example 7 Step 2 and N—BOC-isonipecotic acid as described in Example 4 Step 3; MS (ES+) m/e 554, 556 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16](I)[CH:17]=1)[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=[NH:32])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Cl.[OH-].[Na+].[Cl-].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O.C1COCC1>[C:1]([C:5]1[CH:17]=[C:16]([NH2:32])[CH:15]=[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(I)cc(CN2CCOCC2)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)cc(CN2CCOCC2)c1
Temperature: 50 °C
Yield: 83 %

Procedure:
Combine 4-(3-tert-butyl-5-iodo-benzyl)-morpholine (0.785 g, 2.2 mmol), benzophenone imine (0.44 mL, 1.2 equiv.), sodium tert-butoxide (0.29 g, 1.4 equiv.), racemic BINAP (0.061 g, 4.5 mol %), and THF (10 mL). De-gas with nitrogen then add bis(dibenzylideneacetone) palladium (0.037 g, 3 mol %) and heat reaction at 50° C. overnight under nitrogen. In the morning add approximately 4 mL of 5 N HCl (aq) and heat for one hour at 50° C. Let cool to room temperature then dilute with ethyl acetate and make basic with 1 N NaOH (aq). Wash organics with water then aqueous saturated sodium chloride. Dry organics with MgSO4, filter and concentrate in vacuo. Purify on silica gel (4:1 Hexanes:Ethyl Acetate→10% Methanol: DCM) to give product (0.449 g, 83%). MS (ES), m/z 249.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][NH:7][C:6]=2[CH:17]=1.I[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.N#N>CC1C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NC[C@H]2C
Reactant: CS(=O)(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Temperature: 90 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
To a solution of (R)-8-bromo-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (100 mg, 0.34 mmol) in Methylbenzene (5 mL), were added 1-iodo-4-(methylsulfonyl)benzene (115.2 mg, 0.40 mmol) and 1-iodo-4-(methylsulfonyl)benzene (115.2 mg, 0.40 mmol). Cs2CO3 (222.3 mg, 0.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (31.4 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (39.22 mg, 0.07 mmol) were added. The mixture was via vacuo/N2 and stirred at 90° C. for 18 h under N2 atmosphere. After concentration, the mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL×3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by prep-TLC (elute: DCM:CH3OH=10:1) to give (R)-8-bromo-1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (60 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[N:14]\[OH:15])/[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:15]/[N:14]=[C:5](/[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13])\[C:4]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([Cl:1])[C:3]=1[OH:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(=N\O)c2cc(F)ccc2F)c(O)c1Cl
Product: COc1ccc(/C(=N\OC(C)=O)c2cc(F)ccc2F)c(O)c1Cl
Temperature: 60 °C

Procedure:
A mixture of 19 g of E-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone oxime and 10 ml of acetic anhydride was warmed at 60° C. for 30 minutes. On cooling the mixture solidifies. The residue is partitioned between ethyl acetate and 10%NaHCO3. The ethylacetate extract is washed with water, dried over Na2SO4 and evaporated to give E-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 130°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:19](=[O:21])[CH3:20])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>CO>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:10]([CH:19]([OH:21])[CH3:20])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(=O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[8-(3,5-difluorophenyl)quinolin-7-yl]ethanone (0.057 g, 0.20 mmol) in methanol (0.5 mL) was added sodium tetrahydroborate (0.0076 g, 0.20 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting residue was used in next step (48 mg, 84.1%). LCMS calculated for C17H14F2NO(M+H)+: m/z=286.1; found: 286.0.
Reaction SMILES: Cl(O)(=O)(=O)=O.[C:6]1([CH3:24])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[S:14]([O:17][N:18]=C(OCC)C)(=[O:16])=[O:15].O>C1COCC1>[C:6]1([CH3:24])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[S:14]([O:17][NH2:18])(=[O:16])=[O:15]
Reactant: CCOC(C)=NOS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
70% aq. perchloric acid (4.34 g, 2.6 ml, 43.2 mmol, Eq: 4.12) was added to ethyl N-mesitylsulfonyloxyacetimidate (2.99 g, 10.5 mmol, Eq: 1.00) in THF (4 ml) at 0° C. The reaction mixture was stirred for 1 h at 0° C. The mixture was poured into water (60 ml) and extracted with CH2Cl2 (20 ml+2×10 ml). The combined organic layers were dried over Na2SO4. The solution was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B, 25 g, 55.1 mmol) was dissolved in DCM (100 ml, sonication required) and slowly charged with MeOH (100 ml). The solution was cooled in an ice bath then charged with sodium borohydride (2.60 g, 68.8 mmol) portion wise (exothermic) and allowed to stir for 1 h at RT. A large exotherm was observed and the reaction turned dark red. TLC showed product had formed after 20 minutes. The reaction was diluted with 500 mL DCM and 200 mL water. A large amount of dark red to brick red material was filtered off. The aq. layer was extracted with 1×200 mL DCM and the combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel, 0-10% EtOAc/DCM gave (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (35B, 15 g, 32.9 mmol, 59.7% yield) as a pale yellow solid. MS: [M+H]+ m/z 456. 1H NMR (500 MHz, CDCl3) δ 7.34-7.27 (m, 10H), 7.23-7.18 (m, 5H), 5.78 (s, 1H), 4.99 (s, 2H), 3.93 (s, 3H), 3.86 (s, 1H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([C@@H:17]1[CH2:22][C@H:21]2[C@H:19]([CH2:20]2)[N:18]1[C:23](=[O:47])[C@@H:24]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][C:27]([OH:35])([CH2:28]3)[CH2:26]1)[CH2:32]2)(=O)[NH2:15].C(OCC)(=O)C1C=CC=NC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO.O>[C:14]([C@@H:17]1[CH2:22][C@H:21]2[C@H:19]([CH2:20]2)[N:18]1[C:23](=[O:47])[C@@H:24]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:25]12[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][C:27]([OH:35])([CH2:33]3)[CH2:26]1)[CH2:34]2)#[N:15]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: CCOC(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Yield: 80 %

Procedure:
Trifluoro acetic anhydride (41.36 gm) was added to a solution of [benzyl N-[(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate of formula-XV (27 gm) and ethyl nicotinate (30.6 gm) in ethyl acetate at 0-5° C. After 6 hrs water was added to the reaction. Organic phase was washed with 2N HCl solution, dried and concentrated. The crude compound obtained was dissolved in methanol, hydrolyzed with aqueous potassium carbonate (112 gm of K2CO3 in 228 ml water) for 2 hrs at 25° C. Solvent was distilled off from the reaction mass and aqueous phase extracted with ethyl acetate. Organic phase was dried and evaporated and the solid obtained was purified in THF to yield 20.8 gm (80%) of the desired product. M.P: 148-150° C., HPLC Purity: 99.5% (A), H1NMR (300 MHz, CDCl3): 1.06-1.09 (m, 2H), 1.45-1.9 (m, 12H), 2.25 (m, 2H), 2.33-2.38 (dd, 1H), 2.52-2.54 (m, 1H), 3.82-3.84 (dd, 1H), 4.5 (d, 1H), 4.99-5.04 (dd, 1H), 5.08 (s, 2H), 5.59-5.63 (d, 1H), 7.32-7.63 (m, 5H).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O-:10])=[O:9].[Na+].[CH3:20]O>>[O:6]=[C:7]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH3:20])=[O:9]
Reactant: O=C([O-])C(=O)C=Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 ml of concentrated sulfuric acid are added dropwise to a suspension of 5.9 g (30 mmol) sodium 2-oxo-4-phenylbut-3-enoate (1) (Synth. Commun., (1996), 26(11), 2231) in 100 ml of methanol. The mixture is refluxed for 8 hours and stirred overnight at room temperature. A light insoluble material is filtered off and the filtrate is concentrated to half its volume and poured into 300 ml of water. The pasty solid obtained is extracted with dichloromethane and washed with aqueous 5% sodium hydrogen carbonate solution and then with water. The resulting solution is dried over sodium sulfate. The solvent is evaporated off under vacuum. The residue (4.2 g) is purified by flash chromatography (SiO2, 70/30 CH2Cl2/heptane).
Reaction SMILES: C(OC(=O)[CH:5]([C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1)C(OCC)=O)C.Cl>O>[Br:20][C:14]1[CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:11]([CH3:5])=[N:12][CH:13]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 88.8 %

Procedure:
To diethyl(5-bromo-3-nitropyridin-2-yl)malonate (66 g, 0.18 mol) was added water (250 mL) and 12 M HCl (360 mL, 4.32 mol). The mixture was heated at 105° C. until TLC showed starting material was consumed. The reaction mixture was then allowed to cool to rt and brine (0.67 L) was added. The organic solution was separated and the aqueous solution was extracted with DCM (3×0.67 L). The organic solutions were combined, washed with brine, sat, aq. NaHCO3, and brine again, dried over Na2SO4, filtered and concentrated to give 5-bromo-2-methyl-3-nitropyridine (34.7 g, 75%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:32])[CH:9]([NH:24]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=2)[CH:5]=[CH:4][N:3]=1>FC(F)(F)C(O)=O>[NH2:24][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:12]=1)[CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)[OH:32]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
Trifluoroacetic acid (10 ml) was added to 1,1-dimethylethyl (1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate (0.8 g, 1.73 mmol), and the mixture was stirred at room temperature for 10 min. The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave (1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (0.59 g, 93%).
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH:19]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20](O)=[O:21])=[C:17]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:16]3=[N:15]2)=[CH:10][CH:9]=1.CO.O>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]([CH:19]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:20][OH:21])=[C:17]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:16]3=[N:15]2)=[CH:12][CH:13]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Agent: B
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.8 %

Procedure:
Borane-tetrahydrofuran complex (920 ul, 920 umol; 1 M solution in THF) was added to an ice cold solution of [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (143 mg, 370 umol; example 9.3) in THF (1.5 ml). The solution was stirred at ambient temperature for 14 h and cooled to 0° C. Methanol (1.5 ml) and water (1.5 ml) were added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, the residue was dissolved in methanol (4.5 ml) and heated under reflux conditions for 30 min. The solvent was removed under reduced pressure and the residue purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (70 mg, 188 umol; 51%) as colorless oil. MS: m/e=373.2 [M+H+].
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[N+:2]=[N-:3].[C:10]([C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1)#[CH:11]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:1]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:3]=[N:2]2)[CH:5]=1
Reactant: [N-]=[N+]=Nc1cccnc1
Reactant: C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3cccnc3)nn2)CC1
Yield: 12.4 %

Procedure:
3-Azidopyridine (460 mg) prepared in Example 2 and 620 mg of tert-butyl 4-ethynyl-1,2,3,6-tetrahydropyridine-1-carboxylate were dissolved in 8 ml of toluene and the solution was heated to reflux for 20 hours. The reaction solution was returned to room temperature and the solvent was evaporated in vacuo. The resulting residue was separated and produced by a silica gel chromatography (chloroform/methanol=100/1) to give 121 mg of the title compound as a white solid.