Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH:16][C:17](=[O:31])[CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[C:1]1([CH:7]([NH:16][C:17](=[O:31])[CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(CC(NC(=O)C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(CC(NC(=O)C(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
Treat the product of Example 3 with methanesulfonylchloride to obtain N-[1-phenyl-2-(4-methanesulfonylaminophenyl)ethyl]-α-phenyl-benzeneacetamide, m.p. 200°-202° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:12])C>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][OH:12])=[N:3][CH:4]=1
Reactant: Cc1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Product: Cc1ccc(CO)nc1
Temperature: 25 °C
Yield: 80 %

Procedure:
2,5-Dimethylpyridine 1-oxide (2.5 g, 20.3 mmol) was added to acetic anhydride (8.2 mL) at 100° C. over a period of 30 min. Then the mixture was refluxed 1 h. The mixture was cooled to room temperature and carefully quenched with ethanol (11 mL). The reaction mixture was concentrated. The residue was treated with 1N HCl (6 mL) and refluxed 1 h. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give (5-methylpyridin-2-yl)methanol (2 g, 80.0% yield) as a light yellow oil. LCMS MH+ 124.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1.C(O)(=O)C>CCCCCC.O1CCCC1.CCOCC.O>[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]([C:3]([O:6][CH3:7])=[O:8])[C:18]2=[O:21])=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCc2ccc(OC)cc2C1=O
Temperature: 25 °C

Procedure:
A 50% slurry of NaH (30 g, 0.62 moles) in hexane was filtered through a fritted glass funnel to remove the mineral oil. The NaH was then added to a 2L flask, covered with 300 ml of tetrahydrofuran (THF), and placed under a N2 atmosphere. Upon the addition of 0.62 moles of dimethyl carbonate at one time with stirring, the reaction mixture was heated to 40°-50° C., whereupon 50 g (0.28 moles) of commerically available 7-methoxy-1-tetralone in 150 ml of THF was added at a rate to minimize foaming (1 hr.). Afte refluxing the reaction mixture for 2 hrs., the solution (red) was cooled to room temperature and slowly acidified by the addition of 45 ml of acetic acid. The resulting paste was dissolved upon addition of 50 ml of water. Ether was added and the layers were separated. The organic phase was washed with H2O, 3% NaHCO3 solution, and dried (Na2SO4 ). After filtration, the solvent was evaporated on a rotary evaporator. The residue was distilled at 168°-170° C. at 0.2 mm Hg.
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2[CH:20]=CC=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=C[CH:10]=2)C=CC=CC=1.CC(C)([O-:25])C.[K+].CC(C1C(=O)CC(O)C=1)C=C.P([O-])(O)(O)=O.[Na+]>CCOCC.C(O)(C)(C)C>[CH3:20][CH:15]([C:8]1[C:9](=[CH2:10])[CH2:14][CH:13]([OH:25])[CH:12]=1)[CH:16]=[CH2:17]
Reactant: CC(C)(C)[O-]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CC(C)C1=CC(O)CC1=O
Agent: O=P([O-])(O)O
Agent: [Br-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: C=CC(C)C1=CC(O)CC1=C
Temperature: 25 °C
Yield: 12.4 %

Procedure:
A mixture of 12.5 ml of ether, 1.0 ml of t-butanol and 3.85 g of triphenylmethylphosphonium bromide was stirred at an ambient temperature, then 1.21 g of potassium t-butoxide was added to the mixture and stirred at an ambient temperature for five hours. Under ice-water cooling, 1.64 g of (RS)-3-(1-methyl-2-propenyl)4-oxocyclopent-2-en-1-ol dissolved in 2.0 ml of ether was added dropwise to the mixed solution and stirred for two hours. The mixture was subsequently stirred at an ambient temperature for six hours. The reaction solution was poured into a saturated aqueous sodium dihydrogen phosphate solution and extracted with ether. The organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained oily substance was subjected to silica gel column chromatography to yield 0.20 g of (RS)-3-(1-methyl-2-propenyl)-4-methylidene-cyclopent-2-en-1-ol. Yield 12%
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][Br:9])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)nn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A solution of 1.00 g (5.78 mmol) of 3-bromo-6-methylpyridazine and 1.03 g (5.79 mmol, 1.0 eq) of recrystallized N-bromosuccinimide in 20 mL of carbon tetrachloride was added 95 mg of AIBN. The reaction mixture was purged twice with argon and evacuated and set to reflux under argon. After 3 h, the reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated to give a yellow oil. The mixture was directly purified by silica gel chromatography using hexanes/dichloromethane (1:9) as eluant (5×12 cm column), to give a colorless oil, 444 mg, 30% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14](Br)=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[F:32])#[CH:19]>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14]([C:19]#[C:18][C:20]2[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2[F:32])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ncc(Cl)cc1Br
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1F
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)cnc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 182, starting from tert-butyl[(3-bromo-5-chloropyridin-2-yl)oxy]acetate (Intermediate 183) and 2-ethynyl-1-fluoro-4-(propane-1-sulfonyl)-benzene (Intermediate 109), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: CS(Cl)(=O)=O.N[C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1OC)[C:10]([NH:12]C1C=CC(F)=C(F)C=1)=[O:11]>>[C:10]([NH2:12])(=[O:11])[C:9]1[CH:21]=[CH:22][CH:23]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: CS(=O)(=O)Cl
Product: NC(=O)c1ccccc1
Yield: 110.1 %

Procedure:
The title compound was synthesized as in Example 37 using methyl sulfonyl chloride (0.8 g, 6.2 mmol) and 3-amino-N-(3,4-difluoro-phenyl)-4methoxy-benzamide (1.0 g, 3.6 mmol) to give 0.48 g of benzamide, N-(3,4-difluorophenyl)-4-methoxy-3-[[(methylamino) sulfonyl]amino]-. Microanalysis: C15H15F2N3O4S. 0.04 CH2Cl2.0.91H2O; calculated: C=46.18; H=4.35; N=10.74. found: C=46.18; H=4.36; N=10.64. MS: M++1=372 Da. 1HNMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.60 (s, 1H), 7.93-7.88 (m, 2H), 7.74 (d, 8.4 Hz, 1H), 7.52-7.50 (m, 1H), 7.36 (q, J=9.4, 10.4 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 3.88 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1>>[CH3:17][C@@:3]1([C:1]#[C:2][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1cccs1
Reactant: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(C#Cc1cccs1)O2

Procedure:
This enantiomer was obtained as described in Example 4 by reacting the (S)-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol from Example 11 with 2-iodothiophene. It was isolated by chromatography as above and was crystallized from ether/hexane to yield colorless crystals with m.p. 131°-134° C. [α]D 25 =+34.9° (c=1.14in MeOH).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8]Br)[N:6]=1.[OH:11][CH2:12][CH2:13][NH:14][CH:15]([CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](OC)=[O:26])=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[OH:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]([N:14]([CH2:13][CH2:12][OH:11])[CH2:8][CH:7]([OH:10])[C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH3:29])=[CH:18][CH:19]=1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCCO)cc1)N(CCO)CC(O)c1csc(Cl)n1

Procedure:
Prepared by analogy to Example 30 by reaction of 2-chloro-4-bromoacetyl-thiazole with N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed by reduction in methanol with sodium borohydride at room temperature. The crude product is purified on a silica gel column using chloroform/ ethyl acetate/ methanol=10:9:1 as eluant.
Reaction SMILES: N.C(OC([O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])=[O:17])=[CH:10][CH:9]=1)=O)C>CC(C)=O.N1C=CC=CC=1>[OH:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])=[O:17])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)OCCCCCCCl)cc1
Agent: N
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1)OCCCCCCCl
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
A 25% NH3 solution diluted in 780 mL of acetone is added dropwise to a solution of 89.3 g (247 mmol) of 6-chlorohexyl(2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoate in 752 mL of pyridine. The mixture is allowed to stir for 20 hours at room temperature. The reaction mixture is then partitioned between ethylacetate and water. The organic phase is then washed repeatedly with water, dried over sodium sulfate, filtered off and concentrated by rotary evaporation. The solid is dried under vacuum to yield 70 g (100%) of pure 6-chlorohexyl(2E)-3-(4-hydroxyphenyl)prop-2-enoate as a white powder.
Reaction SMILES: Cl[CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1.[NH3:18]>CCO>[NH2:18][CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1
Reactant: CNC(=O)c1cccc(C2=CC(Cl)NN=C2)c1
Reactant: N
Solvent: CCO
Product: CNC(=O)c1cccc(C2=CC(N)NN=C2)c1
Temperature: 160 °C

Procedure:
3-(6-Chloro-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide (1 eq, 2.46 mmol, 610 mg) is dissolved in a solution of NH3 (7N, 20 ml) in EtOH and heated at 160° C. in a sealed tube for 48 h. The solvent is then removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2:0.5 DCM/MeOH/NH3 to give 3-(6-Amino-1,6-dihydro-pyridazin -4-yl)-N-methyl-benzamide as a brown solid; [M+H]+=229
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH3:17])[CH:8]=2)[C:3]=1[CH:18]=[O:19].[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([OH:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([CH:26]=1)[O:27][C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH3:17])[CH:8]=2)[C:3]=1[CH:18]=[O:19]
Reactant: Cc1ccc(F)cc1O
Reactant: Cc1cnc2c(C=O)c(Cl)n(-c3ccccc3)c2c1
Product: Cc1cnc2c(C=O)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2c1

Procedure:
The title compound was prepared analogously as described in example 1, step 6, from the compound of example 51, step 6, (150 mg, 554 μmol) and 5-fluoro-2-methylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[NH:11][C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.[Br:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:33][CH2:34][CH2:35][N:11]1[C:10]2[N:9]=[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:15]=2[C:14](=[O:16])[N:13]([CH3:17])[C:12]1=[O:18]
Reactant: Cn1c(=O)[nH]c2nc(Oc3cccc(OC(F)(F)F)c3)n(Cc3ccc(Cl)cc3)c2c1=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(CCBr)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol) in DMF (3 mL) was added 1,2-dibromoethane (0.2 mL, 2.32 mmol), followed by potassium carbonate (60 mg, 0.435 mmol). The mixture was stirred at 50° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, filtered and concentrated to give the crude product (110 mg, 91.6% yield) as white solid. LCMS retention time 2.099 min; LCMS MH+ 573.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCN(c4ccccc4F)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][N:15]1[C:19]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:40][C:41](=[O:54])[C:42](=O)[CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH:17]=[N:16]1.O>O1CCCC1>[C:1](/[CH:3]=[C:42](/[C:41]([NH:40][C:18]1[CH:17]=[N:16][N:15]([CH3:14])[C:19]=1[NH:20][C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:54])\[CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:51])[CH3:50])#[N:2]
Reactant: Cn1ncc(NC(=O)C(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(NC(=O)/C(=C/C#N)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.7 %

Procedure:
To a stirred solution of diethyl (cyanomethyl)phosphonate (704 mg) in tetrahydrofuran (20 ml) was added sodium hydride (159 mg, 60% oil suspension) under ice-cooling. The mixture was stirred for 45 minutes with warming to room temperature. tert-Butyl (4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxobutyl)carbamate (2 g) was added to the mixture, and the whole mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a residual oil, which was triturated with a small amount of ethyl acetate and diluted with diisopropyl ether. The resulting precipitate was collected by filtration to give tert-butyl [(3E)-4-cyano-3-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-3-buten-1-yl]carbamate (1.41 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:46])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH3:44])[CH:38]=3)[C:32]=2[F:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C(O)C.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:46])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH3:44])[CH:38]=3)[C:32]=2[F:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(F)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CNC(=O)c2nn3c(-c4cc(F)c5c(c4C)CCCO5)c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3c2F)ccc1F
Temperature: 60 °C

Procedure:
To a solution of (2S)-ethyl 2-(tert-butoxy)-2-(3-fluoro-2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (22 mg, 0.034 mol, 1 equiv) in ethanol (0.46 mL) and water (0.23 mL) was added lithium hydroxide monohydrate (7.2 mg, 0.172 mmol, 5 equiv). The reaction was heated in an oil bath at 60° C. for 2 h. After cooling to ambient temperature, the reaction was filtered and loaded directly onto reverse phase HPLC (acetonitrile/TFA eluent). Desired compound was isolated as an off white solid (2.0 mg, 9% yield). 1H NMR (400 MHz, CDCl3) δ 7.19-7.14 (m, 1H), 7.14-7.09 (m, 1H), 7.08-7.03 (m, 1H), 6.99-6.92 (m, J=9.3 Hz, 1H), 6.84 (d, J=10.5 Hz, 1H), 5.05 (s, 1H), 4.56 (d, J=6.0 Hz, 2H), 4.33 (t, J=4.8 Hz, 2H), 2.75 (s, 3H), 2.74-2.71 (m, 2H), 2.26 (d, J=1.8 Hz, 3H), 2.20-2.12 (m, 2H), 1.87 (s, 3H), 1.20 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −119.18 (s, 1F), −139.26 (s, 1F), −174.64 (s, 1F); LCMS (ESI, M+1): 611.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#N)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.[PH2]([O-])=[O:21].[Na+].N1C=CC=CC=1>CC(O)=O.N1C=CC=CC=1.O.[Ni]>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:21])=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 55 °C
Yield: 30.1 %

Procedure:
To a solution of (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonitrile (246 mg, 1 mmol) in HOAc/pyridine (3 mL/6 mL) was added a solution of sodium hypophosphite (352 mg, 4 mmol) in H2O (3 mL), followed by Raney-Nickel 2400 (slurry in H2O, 0.2 mL). The resulting mixture was heated at 55° C. (oil temp.) for 1 h then cooled to rt. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined extracts were washed with H2O (20 mL×3), brine (10 mL) and dried (Na2SO4). Removal of solvent gave a yellow solution containing pyridine. H2O (60 mL) was added with swirling and large amounts of yellow precipitate formed which was collected by suction filtration and rinsed with H2O. After dying under high vacuum, the title compound (75 mg, 30%) was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.57 (d, J=5.6 Hz, 2H), 8.40 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.89 (d, J=16.8 Hz, 1H), 7.73-7.69 (m, 3H), 7.55 (d, J=16.4 Hz, 1H). MS ESI 247.0 [M+H]+, calcd for [C15H11N3O+H]+ 247.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8]>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Product: O=C(O)CCc1cc(Cl)cc(Cl)c1
Yield: 99 %

Procedure:
Reaction of 3,5-dichlorocinnamic acid (22.9 g, 0.106 mol) and 3 g palladium/carbon substantially as above yielded 23 g (99%) of 3-(3',5'-dichlorophenyl)propanoic acid as an oil.
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[O:21])C(Cl)(Cl)Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[C:27]([F:33])[CH:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:9]([O:8][C:6]([CH:5]1[N:11]2[CH:15]=[CH:14][CH:13]=[C:12]2[C:16](=[O:21])[N:30]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Br:24])=[CH:26][C:27]=2[F:33])[C:4]1=[O:22])=[O:7])[CH3:10]
Reactant: NCc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1C(=O)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Temperature: 70 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid diethyl ester (40.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (29.0 g) and triethylamine (54.8 g, 75.0 ml) in anhydrous dimethylformamide (100 ml) was stirred under the stream of nitrogen at 70° C. for 1 hour. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (38.0 g, 86.0%) as colorless crystals, mp 114°-115° C.
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42]>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 60 %

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (Example 1, 1.93 g.) and HGly-Leu-DMetNH2 (1.31 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-Leu-DMetNH2 in 60% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Leu-DMetNH2 (1.6 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Leu-DMetNH2, which was isolated as the amorphous white solid phosphate (1:1) slat sesquihydrate in 72% yield.