Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:31][C:32](=[NH:50])[C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[CH:36][N:37]2[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:50]=[C:32]([C:33]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:34]=3[CH:35]=[CH:36][N:37]4[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CCOC(=O)CCCn1ccc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
A mixture of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (1.21 g, 5.88 mmol), EDC (1.35 g, 7.05 mmol) and HOBt (1.08 g, 7.05 mmol) in dry DMF (85 ml) was stirred for 20 minutes at RT. Added ethyl 4-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}butanoate (D59) (1.70 g, 5.88 mmol) and stirred at RT for 1 hour. Heated mixture at 80° C. for 5 hours and left overnight at RT. Heated at 80° C. for 6 hours then evaporated off the DMF. Added EtOAc (200 ml) and washed with sat. NaHCO3 (200 ml) and water (200 ml). Dried over MgSO4 and evaporated off the solvent. Subjected the residue to chromatography using the biotage (EtOAc/hexane 1:2) and evaporated the cleanest fractions to yield 1.42 g the title compound as a white solid. δH (400 MHz, d6-DMSO) 1.15 (3H, t), 1.39 (6H, d), 2.04 (2H, apparent quintet), 2.24 (2H, t), 4.00 (2H, q), 4.31 (2H, t), 4.94-5.04 (1H, m), 7.10 (1H, dd), 7.31 (1H, t), 7.56-7.60 (2H, m), 7.77 (1H, d), 7.95 (1H, d), 8.45 (1H, dd), 8.56 (1H, d). MS (ES) C26H26N4O4 requires 458; found 459 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11](=[O:12])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[CH3:1][C:2]1([CH3:13])[CH:11]([OH:12])[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3]1
Reactant: CC1(C)CC2(CCC1=O)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC1(C)CC2(CCC1O)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 7,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-one (1.0 equiv.) in MeOH (0.5 M) was added sodium borohydride (1.0 equiv.) slowly at 0° C. under nitrogen, and the resulting reaction mixture was stirred at room temperature for 60 min. TLC (petroleum ether:ethyl acetate=10:1) showed that the reaction was completed. Water was added, and the solvent was removed under reduced pressure. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give 7,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (99% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.85-3.94 (m, 4H), 3.37-3.40 (m, 1H), 1.41-1.81 (m, 7H), 0.97 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:8]1=[O:31].[F-].[NH4+].C(OCC)(=O)C>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([CH2:12][CH2:13][CH2:14][OH:15])[C:8]1=[O:31]
Reactant: COc1cc(CN2CCC(CCCO[Si](C)(C)C(C)(C)C)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CN2CCC(CCCO)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-(t-butyldimethylsilyloxy)propyl)-2-oxopyrrolidine (1.08 mmol) and ammonium fluoride (0.24 g, 6.48 mmol) in methanol (10 mL). Heat to reflux. After 2 hours, cool to ambient temperature and pour the reaction mixture into a brine (30 mL). Extract five times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.30 (silica gel, ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[N:13]1([CH2:18][C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14]1.[NH4+].[Cl-]>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19](=[O:20])[CH2:18][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1
Reactant: Brc1ccccn1
Reactant: CCOC(=O)Cn1cccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cn1cccc1)c1ccccn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 63.1 %

Procedure:
To a solution of 2-bromopyridine (380 μL, 4.0 mmol) in dry THF (15 mL) was added n-BuLi (1.6 M in hexanes, 2.5 mL, 4.0 mmol) at −78° C. The dark brown mixture was stirred for 30 minutes before a solution of ethyl 1H-pyrrol-1-ylacetate (720 mg, 4.7 mmol) in THF (5 mL) was added. The brown solution was stirred at −78° C. for 40 minutes and then at room temperature for 2 hours. The solution was poured into a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a dark yellow oil that was purified by flash chromatography (Biotage SP4, 40 g cartridge, gradient 0-60% EtOAc in hexanes). To give 1-(Pyridine-2-yl)-2-(1H-pyrrol-1-yl)ethanone as a oil (470 mg, yield 63%). 1H-NMR (400 MHz, CDCl3): δ 5.60 (s, 2H), 6.23-6.27 (m, 2H), 6.69-6.72 (m, 2H), 7.54 (ddd, 1H, J 7.5, 4.8, 1.1 Hz), 7.88 (dt, 1H, J 7.7, 1.7 Hz), 8.06-8.10 (m, 1H), 8.69-8.73 (m, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]([O:18]CC)=O)[CH:13]=[CH:14][C:8]=2[S:7](=[O:22])(=[O:21])[N:6]=1)([CH3:3])[CH3:2].[CH:23]1([C:26](=[N:28]O)[NH2:27])[CH2:25][CH2:24]1.[H-].[Na+].ClCCl>CN(C)C=O.C(O)(=O)C>[CH:23]1([C:26]2[N:28]=[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:8]4[S:7](=[O:21])(=[O:22])[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[NH:10][C:9]=4[CH:11]=3)[O:18][N:27]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)Cc1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O
Reactant: NC(=NO)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)NC1=NS(=O)(=O)c2ccc(Cc3nc(C4CC4)no3)cc2N1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl (3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetate (0.20 g), crushed 4 Å molecular sieves (0.6 g), cyclopropanecarboxamide oxime (0.30 g), and sodium hydride (40 mg of a 60% oil dispersion) in 5 ml of dry dimethylformamide was stirred at room temperature for 45 min. Two drops of glacial acetic acid and 20 ml of dichloromethane were added and the mixture was stirred for 10 min. and filtered through celite. The solvents were removed in vacuo from the filtrate. The remaining oil was stirred with 5 ml of water for 15 min and the resulting precipitate was collected by filtration and dried to give the title compound; m.p. 255-259° C.
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+]>C(Cl)(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: [C-]#N
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.2 %

Procedure:
In 120 ml of carbon tetrachloride are dissolved 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 2.44 g of tri-n-octylmethylammonium chloride and, under stirring, a solution of 2.15 g of potassium cyanide in 30 ml of water is added. The mixture is stirred vigorously at the same temperature for 15 minutes and the organic layer is separated, while the aqueous layer is extracted with chloroform. The organic layers are combined, washed with water and treated in the same manner as (1) of Example 13 to give 7.66 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(Br)c(Br)c4)ncnc3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Nc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 46 h
Yield: 78.9 %

Procedure:
To a stirred heterogeneous mixture of compound 216 (4.08 g, 7.92 mmol) and DCM (80 mL) was added trifluoroacetic acid (6.07 mL, 79.2 mmol), followed by anisole (1.73 mL, 15.8 mmol), and the mixture was stirred further at room temperature for 46 h. It was poured into petroleum ether (500 mL) and stirred at room temperature for ca. 15 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (400 mL). The solid left behind was dissolved in minimum MeOH (120 mL) and 5M NH3 (150 mL) was added at 0° C. and stirred at room temperature for 15 min. The solid was collected and washed successively with water (5×20 mL), petroleum ether-ethyl acetate=5:1 (5×20 mL), and dried to give N4-(3,4-dibromophenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (225) (2.47 g, 79%), mp 265-268° C.; 1H NMR δ [(CD3)2SO] 9.80 (s, 1H), 8.72 (s, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.42 (s, 1H), 7.90 (dd, J=8.8, 2.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 2H). Anal. Calcd for C13H9Br2N5.0.1hexane: C, 40.47; H, 2.60; N, 17.35. Found C, 40.16; H, 2.45; N, 17.20.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CO.[OH-].[NH4+]>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cn1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of N-tert-butyl-2-(1-methyl-1H-pyrazol-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 316 μmol) in dichloromethane (3.5 mL) was added trifluoroacetic acid (720 mg, 486 μL, 6.31 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained dissolved in dichloromethane (3 mL), methanol (1.5 mL), and ammonium hydroxide (0.65 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with ether and water. The solid was collected by filtration then dried in vacuo to give N-tert-butyl-2-(1-methyl-1H-pyrazol-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (44 mg, 140 μmol, 45%) as a brown solid. 1H NMR (400 MHz, methanol-d) δ ppm: 8.07 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.35 (d, J=2.2 Hz, 1H), 6.32 (d, J=2.2 Hz, 1H), 3.67 (s, 3H), 1.35 (s, 9H); MS (EI/CI) m/z: 314.1 [M+H].
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:30])[CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([NH2:29])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9]>CO>[NH2:29][C@H:19]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:17]([CH2:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:8]([CH3:9])[CH2:7][CH2:6][C:5]([OH:30])=[O:4])[CH2:18]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 45 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A 1 M solution of NaOH (16.6 mL; 16.6 mmol) was added dropwise to a solution of (3β,5β)-3-aminocholan-24-oic acid methyl ester (5.0 g; 12.8 mmol) in MeOH (65 mL) at 45° C. After 3 h stirring at 45° C., the mixture was concentrated to 25 mL and H2O (40 mL) and 1 M HCl (22 mL) were added. The precipitated solid was filtered, washed with H2O (2×50 mL) and vacuum dried to give B as a white solid (5.0 g; 13.3 mmol). Yield 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH:11]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)=[O:18])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Sn]>>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([CH:11]2[CH2:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH2:13][N:12]2[CH2:15][CH3:16])=[O:18])=[CH:21][CH:22]=1
Reactant: CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Sn]
Product: CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1C(=O)Nc1ccc(N)cc1

Procedure:
In a manner similar to preparation 20, react 4-(3,4-dichlorophenyl)-1-ethyl-N-(4-nitrophenyl)-2-piperazinecarboxamide with tin II chloride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[C:33]([C:41]([F:43])([F:44])[F:42])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:45])=[C:16]([F:22])[CH:17]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
In a 50 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-(trifluoromethyl)benzoate (290 mg, 434 μmol, Eq: 1.00) was combined with THF (8 ml) and MeOH (8.00 ml) to give a colorless solution. 1.5 M NaOH (3 ml, 4.5 mmol, Eq: 10.4) was added. The reaction mixture was heated to 50° C. and stirred for 3 h. The reaction mixture was acidified with 1N HCl and was extracted with EtOAc (3×15 mL). The organic layers were combined, washed with saturated NaCl (1×10 mL), dried over Na2SO4 and concentrated in vacuum. The crude material was dissolved in DMSO and purified by preparative HPLC (70-100% ACETONITRILE/water). Obtained was a white solid (130 mg, 46% yield). MS (ES+) m/z Calcd: [(M+H)+]: 654. found: 654.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH3:23])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH:9]([CH:20]=O)[C:8]2=[O:22].O=S(Cl)[Cl:26]>ClCCl>[Cl:26][CH:20]=[C:9]1[C:10]2([CH2:13][CH2:12][CH2:11]2)[O:14][C:15]2[C:7](=[C:6]([CH3:23])[C:5]([OH:4])=[C:17]([CH3:18])[C:16]=2[CH3:19])[C:8]1=[O:22]
Reactant: COCOc1c(C)c(C)c2c(c1C)C(=O)C(C=O)C1(CCC1)O2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)C(=O)C(=CCl)C1(CCC1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-(methoxymethoxy)-5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-3-carbaldehyde (2.0 g) in 20 mL of dichloromethane was added dropwise 5 mL of SOCl2. The reaction was allowed to stir at room temperature for 2 hr. After the reaction was complete, the mixture was concentrated and the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 1.46 g of 3-(chloromethylene)-6-hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one, as a yellow solid. It is a mixture of two isomers with a ratio of about 3:1, as indicated by TLC analysis.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([NH:8][C:9]([C:17]([OH:19])=[O:18])=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(=[O:3])[CH3:2]>C(O)C>[C:1]([NH:4][CH2:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)NC(=Cc1ccccc1)C(=O)O
Solvent: CCO
Product: CC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In each case 4.0 grams of degassed N-acetyl-glycyl-dehydrophenylalanine were suspended in 75 ml ethanol and treated with 5.0 ml of an ethanolic solution which contained per ml 4 mg of catalyst. The hydrogenation was undertaken at 25° C. After the end of the reaction time in each case the reaction vessel was ventilated and the solvent removed under reduce pressure. In all cases there remained in the form of a white crystal mass in practically quantitative yield crude N-acetyl-glycyl-phenylalanine. The reaction conditions and results are collected in Table II
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.C(O)(=O)C>C(O)C.O1CCOCC1.[Pd]>[NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([CH:39]([CH3:40])[CH3:41])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CC=C(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(N)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)CC1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.1 g, 0.178 mmol) in ethanol (5 mL), 1,4-dioxane (2 mL) and acetic acid (0.051 mL, 0.890 mmol) was added 10% palladium on carbon (0.095 g, 0.089 mmol). The mixture was evacuated and refilled with nitrogen three times then was stirred under 1 atmosphere of hydrogen gas for 16 h. The mixture was evacuated and flushed with nitrogen, then was filtered through celite and was concentrated under reduced pressure to give the expected product (0.100 g, 0.178 mmol, 100% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ=5.36 (br. s., 1H), 5.19 (d, J=5.8 Hz, 1H), 4.19-4.11 (m, 2H), 2.57-2.47 (m, 1H), 2.31 (dd, J=2.9, 2.1 Hz, 2H), 2.17 (dd, J=4.6, 2.6 Hz, 2H), 2.12-0.70 (m, 52H).
Reaction SMILES: OCC[N+](C)(C)C.[F:8][C:9]([F:19])([F:18])[C:10]1[CH:11]=[C:12]([NH:16][NH2:17])[CH:13]=[CH:14][CH:15]=1.[C:20](#[N:23])[CH:21]=[CH2:22].Cl.C.[OH-].[Na+]>>[F:8][C:9]([F:18])([F:19])[C:10]1[CH:11]=[C:12]([N:16]2[CH2:22][CH2:21][C:20]([NH2:23])=[N:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: C=CC#N
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: C[N+](C)(C)CCO
Agent: Cl
Agent: [Na+]
Product: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
Under ice-cooling, 10 drops of a 50% choline solution was added to a mixture of 20.0 g of 3-(trifluoromethyl)phenylhydrazine and 6.63 g of acrylonitrile, and the mixture was heated at 95° C. for one hour. After allowed to stand for cooling, 22 ml of 1N hydrochloric acid was added and the mixture was stirred at 95° C. for 10 minutes. After subjecting the mixture to hot activated charcoal treatment, the mixture was adjusted to an alkaline pH with a 10% aqueous sodium hydroxide solution under ice-cooling. Precipitated crystals were collected by filtration and washed, and recrystallized from a mixed solution of hexane and ethyl acetate to give 17.27 g of 1-[3-(trifluoromethyl)phenyl]-3-amino-2-pyrazoline (yield: 66%, melting point: 104°-107° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[N:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.[OH-].[Li+].CO.O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[N:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]([OH:17])=[O:16])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-(4-(pyridin-2-ylamino)phenoxy)nicotinate (6.23 g, 18.6 mmol) in THF (0.28 M) was added lithium hydroxide (1.33 g, 55.7 mmol). The reaction was stirred for 16 h before adding an addition equivalent of lithium hydroxide and a volume of methanol and water relative to THF to make a 3:2:1 solution of THF:methanol:water. The resulting suspension was heated to 40° C. for 1.5 h. The solid was filtered away from the filtrate to afford the product as a pale orange solid. MS (ESI, pos. ion) m/z: 308.0 (M+1). IC50 (uM) 8.955.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C@@H:32]3[CH:39]4[CH2:40][N:35]5[CH2:36][CH:37]([CH2:41][CH:33]3[CH2:34]5)[CH2:38]4)=[N:29][CH:30]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N.[ClH:43]>>[ClH:43].[NH:21]1[CH:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C@@H:32]3[CH:39]4[CH2:40][N:35]5[CH2:36][CH:37]([CH2:41][CH:33]3[CH2:34]5)[CH2:38]4)=[N:29][CH:30]=2)[CH:24]=[N:20]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc(OC4C5CC6CC4CN(C6)C5)nc3)cn2)cc1
Agent: Cl
Agent: N
Product: c1cc(OC2C3CC4CC2CN(C4)C3)ncc1-c1cn[nH]c1

Procedure:
Prepared from the product of Example 114A (44.4 mg, 0.080 mmol) according to Method J: 1H NMR (300 MHz, methanol-D4) δ ppm 1.93-1.97 (m, 2H), 2.21 (br s, 1H), 2.36-2.41 (m, 2H), 2.57 (br s, 2H), 3.58 (br s, 2H), 3.66-3.75 (m, 4H), 5.45 (t, J=3.2 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 8.13 (dd, J=8.6, 2.5 Hz, 1H), 8.25 (s, 2H), 8.47 (d, J=1.7 Hz, 1H). MS (DCI/NH3) m/z=297 (M+H)+. Anal. Calcd. for C17H20N4O.2 HCl.1.15H2O: C, 52.11; H, 6.30; N, 14.30. Found: C, 52.14; H, 6.33; N, 14.24.