Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[Si:29]([O:36][CH2:37][CH2:38][C@@H:39]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:40]([NH:42][NH:43][C:44](=O)[C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=1)=[O:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Si:29]([O:36][CH2:37][CH2:38][C@@H:39]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:40]1[O:41][C:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=2)=[N:43][N:42]=1)([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:31])[CH3:30]
Reactant: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (polymer bound, 3.0 mmol/g loading) (1 g, 3 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (60 mL) followed by addition of solid iodine (688 mg, 2.71 mmol). This was allowed to stir at room temperature for a period of 10 min followed by slow addition of triethylamine (1 mL, 7.24 mmol). (R)—N′-(4-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-cyanobenzohydrazide (950 mg, 1.81 mmol) was taken up in methylene chloride (15 mL) and slowly added to the stirred reaction mixture. After a period of 30 min, the solid polymer was filtered out and washed with additional methylene chloride (50 mL). The organic filtrate was then washed with 10% sodium thiosulfate/water (2×25 mL), brine (1×30 mL) and dried (Na2SO4). The solution was then filtered and concentrated under reduced to reveal a brown solid (1.03 g). Purification by flash column chromatography [EtOAc-hexanes (1:2) as eluent] afforded the title compound as a white crystalline solid (900 mg, 98%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.19 (d, J=9 Hz, 2H), 8.00 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz, 1H), 6.98 (d, J=9 Hz, 1H), 6.05 (d, J=9 Hz, 1H), 5.4 (m, 1H), 4.00-3.95 (m, 1H), 3.94-3.89 (m, 1H), 2.57-2.40 (m, 2H), 2.38 (s, 3H), 0.88 (s, 9H), 0.04 (s, 3H) and 0.00 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17](=[NH:19])[NH2:18])=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:22](CC)CC)C.O.NN>C(O)C>[CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17](=[NH:18])[NH:19][NH2:22])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Reactant: CCN(CC)CC
Agent: NN
Solvent: CCO
Solvent: O
Product: N=C(NN)c1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.400 g (5.358 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide were initially charged in 26 ml of ethanol, and the mixture was cooled to 0° C. 2.169 g (21.431 mmol) of triethylamine and 335 mg (5.358 mmol) of 80% strength hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and dried under high vacuum. This gave 1.070 g (purity 77%, 56% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.[S:19](Cl)([Cl:22])(=[O:21])=[O:20]>CCOCC.C(OCC)(=O)C>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([S:19]([Cl:22])(=[O:21])=[O:20])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Temperature: -78 °C
Yield: 51.4 %

Procedure:
2-Bromobiphenyl (2.33 g, 10 mmol) was dissolved in ether (10 ml) and cooled to −78° C. n-Butyllithium (2.5 M solution in hexane, 4.8 ml, 12 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at −70° C. to −60° C. for 1 h. The reaction mixture was cooled to −78° C. and sulfuryl chloride (0.88 ml, 11 mmol) was added dropwise. After addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgSO4. Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography, using hexane followed by 5% ethyl acetate in hexane as eluent, to give 2-biphenylsulfonyl chloride as a solid (1.3 g, 51% yield).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.Cl[C:22]1[N:27]=[C:26]([NH2:28])[N:25]=[C:24]2[NH:29][N:30]=[CH:31][C:23]=12.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH:20][C:22]3[N:27]=[C:26]([NH2:28])[N:25]=[C:24]4[NH:29][N:30]=[CH:31][C:23]=34)[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc2[nH]ncc12)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 54.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (500 mg, 1.71 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (436 mg, 2.57 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.895 mL, 5.14 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was diluted with MeOH/DMSO and purified by preparative HPLC (basic mode) eluting with 35% ACN in water. The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (360 mg, 54.2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.83 Hz, 3 H), 3.59-3.68 (m, 3 H), 3.83 (s, 3 H), 5.57 (dd, J=13.42, 6.59 Hz, 3 H), 6.46 (d, J=1.46 Hz, 1 H), 6.61 (d, J=2.93 Hz, 1 H), 7.55 (d, J=1.46 Hz, 1 H), 7.72 (d, J=3.42 Hz, 1 H), 7.89 (s, 1 H), 7.95-8.03 (m, 2 H), 12.33 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H20N10,389; found 389.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([NH:33][CH3:34])[CH3:32])[CH:24]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)NC)c1
Reaction time: 4 h
Yield: 112.6 %

Procedure:
To a suspension of (S)-tert-butyl (1-((3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C8, 325 mg) in 1,4-dioxane (6 mL), a 4.0 mol/L solution of hydrochloric acid in 1,4-dioxane (6 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the solid matter was taken by filtration to obtain (S)-2-((4-cyanophenyl)amino)-N-(3-(2 -(methylamino)propanamido)phenyl)-4-(propylamino)pyrimidine-5-carboxamide (E1) dihydrochloride (302 mg).
Reaction SMILES: C(N(CC)CC)C.N1C=CC=CC=1.[OH:14][CH:15]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[C:18](=[O:27])[C:17]2[O:28][CH2:29][CH2:30][S:31][C:16]1=2.Cl.Cl[C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35]>C(Cl)Cl.O>[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:34]([O:14][CH:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[C:18](=[O:27])[C:17]3[O:28][CH2:29][CH2:30][S:31][C:16]2=3)=[O:35])[CH2:37][CH2:38]1
Reactant: Cc1ccc(N2C(=O)C3=C(SCCO3)C2O)nc1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(N2C(=O)C3=C(SCCO3)C2OC(=O)N2CCN(C)CC2)nc1
Yield: 65.4 %

Procedure:
Triethylamine (6.2 cc.) followed by anhydrous pyridine (27.5 cc.) is added to a suspension of 5-hydroxy-6-(5-methylpyrid-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (2.9 g.) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (6.6 g.) in methylene chloride (55 cc.). The reaction mixture is then heated under reflux for 6 hours. After cooling, water (150 cc.) and methylene chloride (50 cc.) are added. The aqueous phase is decanted and washed with methylene chloride (50 cc.). The organic phases are combined and washed by decanting successively with water (2 × 50 cc.), N aqueous sodium hydroxide solution (50 cc.) and water (2 × 50 cc.). After drying over sodium sulphate and treatment with decolourising charcoal, the organic phase is evaporated to dryness under reduced pressure. Recrystallisation of the residue from acetonitrile (40 cc.) gives 5-(4-methylpiperazin-1-yl)carbonyloxy-6-(5-methylpyrid-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (2.8 g.) melting at 183° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:28])=[C:18]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:28])=[C:18]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:19]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1cc(Br)ccc1F
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cc(Br)ccc1F)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 40.6 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (15.3 mL, 13.3 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (8.9 mL, 13.3 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then 3-(5-bromo-2-fluoro-phenyl)-N-methoxy-N-methylacrylamide (1.3 g, 4.4 mmol, in tetrahydrofuran 10.0 mL) prepared in Step 3 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 620.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:31])[C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][CH:17]3[CH2:22][CH:21]4[CH2:23][CH:18]3[CH2:19][CH:20]4[O:24]C(=O)C)[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:1][C:2]1[N:3]([CH3:31])[C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][CH:17]3[CH2:22][CH:21]4[CH2:23][CH:18]3[CH2:19][CH:20]4[OH:24])[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: CC(=O)OC1CC2CC1CC2Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC4CC3CC4O)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of acetic acid 5-[3-((S)-2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-4-yl)-4-fluoro-phenylamino]-bicyclo[2.2.1]hept-2-yl ester (example 93, 0.05 mmole) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH 1N (0.1 mmole) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, the residue dissolved in aqueous HCl (0.5N) until pH=5 and washed with EtOAc. The aqueous phase was basified to pH=8 with a saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to yield a mixture of isomers of the title compound as a colorless waxy solid. MS (ESI): m/z=389.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(Cl)c1N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1N=C=S
Yield: 27.2 %

Procedure:
The title compound was prepared following the procedure described for Intermediate-2 using 2-chloro-6-methylaniline (1.0 g, 0.01 mol), thiophosgene (1.15 g, 0.01 mol) and N-ethyl di-isopropyl amine (2.58 g, 0.020 mol) to afford 0.500 g of the desired product. 1HNMR (CDCl3): δ 2.39 (s, 3H), 7.10 (s, 2H), 7.21-7.25 (m, 1H); MS [M+H]+: 183.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)=[CH:14][CH:13]=3)[C@@H:10]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:9]2=[O:36])=[CH:4][CH:3]=1.[Br-:37].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+].C(#N)C>C(Cl)(Cl)Cl.O>[Br:37][C:23]1[CH:22]=[CH:21][C:20]([OH:24])=[CH:19][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([C@H:11]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:36])[C@@H:10]2[CH2:25][CH2:26][C@@H:27]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[OH:28])=[CH:17][CH:16]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)cc2)N1c1ccc(F)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cc(O)ccc3Br)cc2)N1c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one (19.2 mg, 0.04 mmol) was dissolved in chloroform (0.4 mL) and tetrabutylammonium tribromide (18.8 mg, 0.04 mmol) was added at room temperature. After 10 minutes, saturated aqueous sodium thiosulfate (2 mL) was added to quench the reaction. The mixture was poured into a seperatory funnel, extracted with dichloromethane (4×10 mL), dried over sodium sulfate, filtered and concentrated. (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one was purified by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) and then by reverse-phase HPLC (21 mm column, 50% to 100% acetonitrile-0.1% trifluoroacetic acid in water) to afford (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (8.0 mg, 34% yield) as a clear foam; Rf 0.51 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8.7 Hz, 1H), 7.40 (m, 4H), 7.29 (m, 4H), 7.02 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 6.80 (d, J=3.3, 1H), 6.73 (dd, J=3.0, 3.0 Hz, 1H), 4.74 (t, J=6.2 Hz, 2H), 4.67 (d, J=2.1 Hz, 1H), 3.14 (m, 1H) 1.99 (m, 4H) ppm; MS [M−OH] 547.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Sn](Cl)Cl>C(O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:18][C:4]=2[CH:3]=1
Reactant: Cc1ccc(Nc2ccc(Cl)cc2[N+](=O)[O-])c(C#N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1ccc2c(c1)C(N)=Nc1cc(Cl)ccc1N2
Reaction time: 16 h
Yield: 139.8 %

Procedure:
Heat a solution of 2-(4-chloro-2-nitro-phenylamino)-5-methyl-benzonitrile (1.63 g, 6.44 mmol) in ethanol (25 ml) to 60° C. To this add a solution of tin (II) chloride (3.22 g, 17.00 mmol) in 5.0 N hydrochloric acid (25 ml). Heat the resulting mixture to reflux for 16 hours. Cool the reaction to room temperature and place in a freezer for 16 hours. Collect by filtration the precipitated product from the solution and to obtain 1.325 g of the title compound (4.50 mmol, 80% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 258(M+1).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:55][CH:56]([CH2:69][C:70]1[CH:75]=[CH:74][C:73]([O:76][CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[CH:72][CH:71]=1)[C:57]([NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][N:62]([CH2:66][CH2:67][CH3:68])[CH2:61]1)=[O:58]>CN(C=O)C.C(OCC)(=O)C>[CH2:77]([O:76][C:73]1[CH:74]=[CH:75][C:70]([CH2:69][CH:56]([NH:55][C:12](=[O:14])[CH:11]([N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:21][CH:20]=2)[CH3:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:57](=[O:58])[NH:59][CH:60]2[CH2:65][CH2:64][CH2:63][N:62]([CH2:66][CH2:67][CH3:68])[CH2:61]2)=[CH:71][CH:72]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)Cc1ccc(C(C)(C)C)cc1
Reactant: CCCN1CCCC(NC(=O)C(N)Cc2ccc(OCc3ccccc3)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN1CCCC(NC(=O)C(Cc2ccc(OCc3ccccc3)cc2)NC(=O)C(CC(C)C)N(C)Cc2ccc(C(C)(C)C)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a solution of (S)-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid (0.3 g, 1.01 mmol) in 15 mL of DMF was added HBTU (0.38 g, 1.01 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol). The mixture was stirred for 30 minutes at 0° C. A solution of 2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide (0.4 g, 1.01 mmol) in 15 mL of DMF was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and was stirred for another 30 minutes. The mixture was diluted with 20 mL of ethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO3 (2×10 mL) and saturated solution of brine (2×10 mL). The organic layer was separated, dried with Na2SO4 and evaporated to dryness. The crude residue was purified by chromatography (silica gel, 7:3 hexane/ethyl acetate). The purified product was dissolved in minimum volume of diethylether and an ethereal solution of HCl was added dropwise. The solid which formed was washed several times with diethylether. The solid was dissolved in methanol and treated with activated charcoal, filtered, and evaporated. The residue was crystallized from methanol-ether to give the title compound (0.16 g, 23%) as a light yellow powder; mp 160-164° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]=[C:5]2[C:14]3[CH:13]=[C:12]4[CH2:15][CH2:16][CH2:17][CH2:18][C:11]4=[CH:10][C:9]=3[NH:8][C:7](=[O:19])[C:6]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:3]1[C:2]([CH3:1])=[C:6]2[C:7](=[O:19])[NH:8][C:9]3[CH:10]=[C:11]4[CH2:18][CH2:17][CH2:16][CH2:15][C:12]4=[CH:13][C:14]=3[C:5]2=[N:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]nc2c1c(=O)[nH]c1cc3c(cc12)CCCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)[nH]c3cc4c(cc3c2nn1Cc1ccccc1)CCCC4
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-methyl-2,5,7,8,9,10-hexahydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-6) (10.2 g, 40.3 mmol, 1 equiv) and potassium carbonate (30.0 g, 217 mmol, 5.38 equiv) in DMF (100 mL) under nitrogen was added benzyl bromide (35.0 g, 205 mmol, 5.09 equiv) and the resulting mixture was stirred at 23° C. for 16 h. The reaction mixture was filtered and the filtered solid was washed with ether (3×200 mL) followed by water (3×250 mL) and dried to yield 2-benzyl-3-methyl-2,5,7,8,9,10-hexahydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-7) as a white solid. LRMS m/z (M+H) 344.2 found, 344.2 required.
Reaction SMILES: C(OC(=O)N[C@@H](CC1C=CC=CC=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)(C)(C)C.[CH3:31][C:32]1([CH3:39])[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1.[CH:40]([O:43][C:44]1[CH:45]=[C:46]([CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=1)[C:47]([NH:49][C@H:50]([C@@H:58]1[CH2:62][C@@H:61]([CH3:63])[C:60](=[O:64])[O:59]1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])([CH3:42])[CH3:41]>>[CH2:51]([C@H:50]([NH:49][C:47](=[O:48])[C:46]1[CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=[C:44]([O:43][CH:40]([CH3:42])[CH3:41])[CH:45]=1)[C@@H:58]([OH:59])[CH2:62][C@H:61]([C:60](=[O:64])[NH:38][CH:35]1[CH2:36][CH2:37][C:32]([CH3:39])([CH3:31])[CH2:33][CH2:34]1)[CH3:63])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Reactant: CC1(C)CCC(N)CC1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CCC(C)(C)CC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from 4,4-dimethylcyclohexylamine (D53) and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>CCOCC>[C:1]([N:5]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)=NNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=NN(C(=O)c1ccccc1)C(C)(C)C

Procedure:
Acetone tert-butylhydrazone (2.0 g) is admixed with 4.4 g of benzoyl chloride and 15 mL of 10% sodium hydroxide. The mixture is stirred until the benzoyl chloride odor is no longer detectable. The resulting product is then dissolved in ether and dried over magnesium sulfate. Evaporation of the solvent from the mixture leaves acetone N-tert-butyl-N-benzoylhydrazone, b.p. 100°-103° C. This product also is referred to as 1-tert-butyl-2-isopropylidenehydrazide of benzoic acid.