Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1.ClCCl.ClC1C=CC=C(C(OO)=[O:29])C=1>C(OC)(C)(C)C>[CH3:17][C:2]1([CH2:3][C:4]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH2:1][O:29]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC1(c2ccccc2)CCNC(=O)O1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC1(CC2(c3ccccc3)CCNC(=O)O2)CO1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a 1.0 L 2-neck RBF was charged (R)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at rt (Tint=20-25° C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is <2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (6S)-3-(S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one which was used directly in Step 5.
Reaction SMILES: [Mg].[CH3:2]I.[CH:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][C:5]2=[O:11].[Cl-].[NH4+]>C(OCC)C>[CH3:2][C:5]1([OH:11])[CH2:6][CH:7]2[CH2:10][CH:4]1[CH2:9][CH2:8]2
Reactant: O=C1CC2CCC1C2
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CC2CCC1C2
Temperature: 25 °C
Yield: 97 %

Procedure:
A Grignard reagent was prepared from 96 g (4.0M) of magnesium flakes and 553.0 g (3.9M) of methyl iodide in 600 ml of absolute diethyl ether under a nitrogen gas stream in the conventional manner. 225.0 g (2.05M) of norbornanone (I) (manufactured by Aldrich Chemical Co., Inc.) was added dropwise thereto at room temperature and the resulting mixture was stirred at room temperature over night. The reaction mixture was poured into 800 ml of a saturated aqueous solution of ammonium chloride. The organic phase was collected and dried over anhydrous magnesium sulfate. After evaporation of the ether, the residue was distilled under reduced pressure to give 250.1 g (theoretical yield: 97%) of the aimed compound (II) as a colorless oily material. b.p.: 75° C./18 mmHg.
Reaction SMILES: [BrH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC>CO.[Pd]>[BrH:1].[BrH:1].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCCC2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Br
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(OCCN2CCCCC2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.4 %

Procedure:
A mixture of 2-benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine hydrobromide (500 mg, 1.19 mmol) and Pd/C (10%, 50 mg, Aldrich) in MeOH (25 mL) was shaken under H2 (20-30 psi, Parr) for 2 h at 25° C. The catalyst was removed by filtration (Celite). The resulting solution was acidified with a dilute solution of HBr in MeOH (pH paper to red). The MeOH was removed in vacuo (rotoevaporator, 35-40° C.) to give a syrup. Ether (45 mL) was added and the resulting mixture was vigorously stirred at 25° C. for 24 h. A yellow suspension was obtained. The solid was collected, washed with ether (3×2 mL) and dried in vacuo (0.005 Torr, 56° C.) to give a beige powder (358 mg, 64%): mp 130° C.; 1H NMR (DMSO-d6) 1.28-1.95 (m, 6H), 2.69-3.95 (m, 7H), 4.60-4.55 (m, 2H), 7.08-7.42 (m, 9H), 9.60-10.25 (m, 4H); HRMS Calcd for C20H26N20: 310.2045. Found: 310.2040.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH3:16][NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[S:19]>CC(C)=O>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:19][C:18](=[N:20][CH:21]([CH3:23])[CH3:22])[N:17]2[CH3:16])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CNC(=S)NC(C)C
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CC(C)=O
Product: Br
Product: CC(C)N=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.1 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone were heated with 2.4 g of 1-methyl-3-isopropylthiourea in 50 ml of acetone for 10 minutes to 40° C., the separating oil was triturated to form crystals and the crystalline suspension was stirred for 1 hour at room temperature. Colorless solid body: melting point: 195° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromoiodobenzene (10.0 g, 35.3 mmol) in triethylamine (Et3N, 100 mL) was added propargyl alcohol (2.7 mL, 2.57 g, 45.9 mmol), Cul (0.81 g, 4.24 mmol), and Pd(PPh3)4 (1.63 g, 1.41 mmol). The mixture was stirred overnight, then the reaction mixture was concentrated. Column chromatography (20-35% EtOAc/hexanes) provided 1-(4-bromophenyl)-1-propyne-3-ol B (6.58 g, 88%) as a yellow/orange solid. 1H NMR (300 MHz, CDCl3) 1.77 (t, 1H), 4.48 (d, 2H), 7.29 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: [ClH:1].[C:2]([Cl:5])(=[O:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:16]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[NH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:37]O>>[OH2:4].[ClH:5].[ClH:6].[ClH:1].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH2:37][C:2]#[CH:3])[N:15]=[C:16]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reactant: CC(=O)Cl
Reactant: CO
Agent: Cl
Product: C#CCn1nc(N2CCNCC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Product: O
Temperature: 5 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of HCl in methanol (5 mL) was generated by addition of acetyl chloride (200 mg) to methanol while cooling (5° C.). 3-(4-Chlorophenyl)-4-(4-pyridyl)-5-(4-N-tert.-butoxycarbonylpiperazinyl)pyrazole (100 mg, 0.2 mmol) prepared above was added and the reaction stirred in the cold for one hour. The reaction mixture was concentrated in vacuo and the residue azeotroped with toluene to give 100 mg of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1-(2-propynyl)-1H-pyrazol-3-yl]piperazine, trihydrochloride monohydrate (90%), m.p.=231-233° C. (dec.). Anal. Calc'd. for C21H20N5Cl.3HCl.H2O: C, 49.92; H, 4.99; N, 13.86. Found: C, 49.71; H, 4.89; N, 13.61.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[CH2:20][C:21]([OH:23])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH:34]3C)=[CH:32][C:27]=2[O:26][CH2:25]1.Cl.[CH2:41](N=C=NCCCN(C)C)C>C1COCC1.CN(C=O)C.[Cl-].[Na+].O>[O:26]1[C:27]2[CH:32]=[CH:41][C:30]([CH2:31][N:33]3[CH2:34][CH2:35][N:36]([C:21](=[O:23])[CH2:20][N:15]4[C:16]5[C:12](=[C:11]([O:10][C:7]6[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=6)[CH:19]=[CH:18][CH:17]=5)[CH:13]=[CH:14]4)[CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:24][CH2:25]1
Reactant: O=C(O)Cn1ccc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Reactant: CC1CNCCN1c1ccc2c(c1)OCO2
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cn1ccc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Yield: 74.7 %

Procedure:
[4-(5-Nitropyridin-2-yloxy)indol-1-yl]acetic acid (0.210 g, 0.670 mmol) was dissolved in a mixture of THF (10 mL)-DMF (2 mL). To the solution were added 1-benzo[1,3]dioxol-5-yl-methylpiperazine (0.148 g, 0.670 mmol), then 1-ethyl-3-(3-di-methylaminopropyl)carbodiimide hydrochloride (0.129 g, 0.670 mmol), and the resulting solution was stirred for 3 hours at room temperature. Brine (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate to yield 0.258 g of the title compound as pale brown powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[P:11]([O:19][CH:20]([O:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21]I)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12].CCOCC.C(Cl)Cl>C1(C)C=CC=CC=1.CCOCC>[P:11]([O:19][C:20]([O:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH2:21])([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOP(=O)(OCC)OC(CI)OC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=C(OC(=O)c1ccccc1)OP(=O)(OCC)OCC
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M solution in hexanes, 1.752 ml, 1.752 mmol) was added dropwise to a solution of the iodobenzoate XIX (0.250 g, 0.584 mmol) in toluene (50 ml) at -78° C. and allowed to stir for 30 min. The reaction mixture was then diluted with Et2O (150 ml), washed with saturated aqueous NaHSO4 (3×25 ml), 10% aqueous sodium phosphate buffer (pH=7) (1×25 ml), dried (MgSO4), and concentrated in vacuo. Flash chromatography (5% Et2O/CH2Cl2) afforded the geminal benzoate XX (78.6 mg, 44.8% yield) as a clear, colorless oil: 1H NMR (CDCl3, 400 MHz) d 8.10 (d, 2 H, J=7.5 Hz, C7 - and C8 -H), 7.63 (t, 1 H, J=7.5 Hz, C9 - and C8 -H, C9 - and C7 -H), 7.48 (t, 2 H, J=7.5 Hz, C8 - and C7 -H, C8 - and C9 -H), 4.78 (dd, 1 H, J=3.5 Hz, C2b - and C2a -H; J=2.2 Hz, C2b -H and P), 4.54 (dd, 1 H, J=3.5 Hz, C2a - and C2b -H; J=1.1 Hz, C2a -H and P), 4.23 (m, 4 H), 1.34 (dt, 6 H, J=7.0 Hz, C4- and C3 -H; J=1.1 Hz, C4 -H and P); 13C NMR (CDCl3, 100 MHz) d 164.0, 149.3 (d, J=5 Hz), 134.9, 131.1, 129.4, 128.9, 86.1 (d, J=3 Hz), 65.4 (d, J=6 Hz), 16.1 (d, J=7 Hz); 31P NMR (H3PO4, 146 MHz) d -7.19; IR (NaCl solution cell, CDCl3) 2988, 2932, 1752, 1672, 1277, 1204, 1177, 1063, 1034, 999, 916, 706; LRMS, m/e (relative intensity) 301.1 (15.8), 259.0 (55.9), 155.0 (6.7), 106.0 (22.1), 105.0 (100.0), 81.0 (7.3), 77.0 (37.7), 51.0 (10.3); HRMS for C13H17O6P [M+H+ ], calcd. 301.0763; found, 301.0843.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21]O)[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:46]1[CH:50]=[N:49][N:48]=[N:47]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][N:46]3[CH:50]=[N:49][N:48]=[N:47]3)[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2cnnn2)CC1
Reaction time: 12 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.77 mmol), triphenylphosphine (0.73 g, 2.78 mmol), and tetrazole (0.24 g, 3.38 mmol) in tetrahydrofuran (25 mL). Add a solution of diethylazodicarboxylate (0.59 g, 3.38 mmol) in tetrahydrofuran (1 mL). After 12 hours, concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give 1-(t-butoxycarbonyl)-4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.57 (silica gel, 1/1 hexane/ethyl acetate).
Reaction SMILES: [Br-].[C:2]([CH:10]([N+:12]1[N:13]=[C:14]([CH2:32][CH2:33][CH2:34][CH3:35])[N:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])=[CH:20][CH:19]=2)[CH:16]=1)[CH3:11])(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:38](CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>>[CH2:32]([C:14]1[N:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])=[CH:20][CH:19]=2)[C:16]2[N:12]([C:10]([CH3:11])=[C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:38]=2)[N:13]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1n[n+](C(C)C(=O)c2ccccc2)cn1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Br-]
Product: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 39 %

Procedure:
A mixture of 303 mg (0.556 mmol) of 5-amino-1-(1-benzoylethyl-3-butyl-4-[(2'-cyanbiphenyl-4-yl)-methyl]-4H-1,2,4-triazolium bromide (from Step E) and 6 g of polyphosphoric acid was stirred at 80° C. under N2 for 5 hours. The cooled mixture was treated with an excess of ice. After the ice had melted, the water was decanted off, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residual oil was dissolved in a minimum volume of CH2Cl2 and treated with 200 μl (145 mg, 1.43 mmol) of triethylamine. The resulting solution was cooled to 0° C. and stirred under N2 as 137 μl (223 mg, 1.23 mmol) of trichloroacetyl chloride was added. The solution was allowed to warm to room temperature. After 1 hour at room temperature, the solution was concentrated in vacuo. The residue was leached with 25 ml of ether. The filtered ether solution was washed with 25 ml of 0.2N HCl and then with 25 ml of 0.2N NaOH. The ethereal phase was dried (Na2SO4), filtered, and evaporated. Column chromatography of the residue on silica gel (elution with 99:1 and then 98:2 CH2Cl2 -MeOH) afforded 95.0 mg (39%) of the title compound as a brown solid of indefinite mp, suitable for use in the next step; homogeneous by TLC in 19:1 CH2Cl2 -MeOH.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]=1[CH3:17])[CH3:2].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]=1[CH:17]=[CH:21][N:24]([CH3:26])[CH3:25])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C=CN(C)C
Temperature: 100 °C
Yield: 26.1 %

Procedure:
A mixture of 2-methyl-3,5-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethyl-amine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice-water. The precipitate was collected via filtration and washed with water to give 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester (11.3 g, 48%).
Reaction SMILES: [F:1][C:2]([F:13])([S:9]([OH:12])(=[O:11])=[O:10])[CH:3]([F:8])[C:4]([F:7])([F:6])[F:5].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([NH2:29])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15].[N:30](OCCC(C)C)=O>O1CCCC1>[F:13][C:2]([F:1])([S:9]([O-:12])(=[O:10])=[O:11])[CH:3]([F:8])[C:4]([F:5])([F:7])[F:6].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([N+:29]#[N:30])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=S(=O)(O)C(F)(F)C(F)C(F)(F)F
Reactant: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc([N+]#N)ccc21
Product: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3 ml of 1,1,2,3,3,3-hexafluoropropanesulfonic acid were added to a solution of 20 ml of tetrahydrofuran (THF) and 4.2 g of 9-ethyl-3-carbazolylamine. After cooling to 0° C., 3 ml of isoamyl nitrite were added dropwise while stirring in such a way that the temperature did not rise above 10° C. After completion of the dropwise addition, the icebath was removed and the stirring of the reaction mixture was continued for a further 4 h. 50 ml of diethyl ether were added, and the precipitate produced was filtered off by suction, washed with a little diethyl ether and dried. 7.4 g of 9-ethyl-3-carbazolediazonium 1,1,2,3,3,3-hexafluoropropanesulfonate was obtained as a yellow, finely crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:11][O:10]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][CH2:18][NH2:19].C(Cl)(Cl)[Cl:26].Cl>C(O)C.C(OCC)C>[ClH:26].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][CH2:18][NH:19][CH2:11][CH:9]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccccc1C1CO1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CCNCC(O)c2ccccc2OC)cc1OC

Procedure:
A mixture of 0.5 g of 2-(2-methoxyphenyl)oxirane (crude product) and 600 mg of 3,4-dimethoxyphenethylamine is heated at 130° to 140° C. for 2 hours. After cooling, chloroform is added to the reaction mixture, and said mixture is washed with water. The mixture is dried and evaporated to remove solvent. 2 ml of ethanol are added to the residue obtained. Then, hydrochloric acid-containing diethylether is added to the ethanol mixture, and crystalline precipitates are collected by filtration. 290 mg of α-(3,4-dimethoxyphenethylaminomethyl)-2-methoxybenzylalcohol hydrochloride are obtained as crystals. M.p. 142°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([S:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1.CC(O)C>O>[CH3:24][S:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CSc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(C(=O)Nc2ccc3ccc(SC)nc3n2)cc1
Temperature: 4 °C
Yield: 83.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (11.8 g), N,N'-carbonyldiimidazole (12.6 g) and 2-amino-7-methylthio-1,8-naphthyridine (9.6 g). The product produced by precipitation in water (15.8 g; m.p. 100° C.) is dissolved in boiling 2-propanol (180 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (10 cc) and then isopropyl ether (2×10 cc), and dried at 40° C. under reduced pressure (0.067 kPa . N-(7-methylthio-1,8-naphthyridin-2-yl)-4-methoxybenzamide (13.6 g) is produced, m.p. 130° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH:20]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:22])[CH3:21]>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[CH:30][CH:29]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)Oc1ccc(N)cc1
Solvent: CC#N
Product: CC(C)Oc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 48.2 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol) and 4-isopropoxyaniline (0.151 g, 1.00 mmol) in MeCN (2 mL) was heated at 120° C. for 35 mins in a microwave reactor. The mixture was evaporated and the residue was purified by silica gel column chromatography using a 5:1 mixture of petroleum ether and EtOAc as eluant, to give the title compound (0.100 g, 48%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.20-7.14 (m, 1H), 7.12-7.08 (m, 4H), 7.04 (s, 1H), 6.62 (d, 1H), 6.48 (d, 2H), 4.34 (sep, 1H), 1.77 (s, 9H), 1.22 (d, 6H); 13C NMR (125 MHz, CDCl3): δ 160.1, 155.5, 131.4, 129.7, 129.3, 128.9, 128.1, 125.2, 124.1, 116.1, 109.9, 70.5, 61.9, 27.9, 22.0; Mass Spectrum: M−H+ 414.
Reaction SMILES: [O:1]1[CH:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[CH:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[C@@:5]23[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3][C@H:4]13
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=C2CCCCC2OCC1
Solvent: ClCCl
Product: C1CC[C@]23O[C@H]2CCOC3C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,5,6,7,8,8a-hexahydro-2H-chromene (3.27 g, 23.66 mmol) in CH2Cl2 (75 mL) at 0° C. was added MCPBA (˜77%, 6.53 g, 28.4 mmol). The mixture was warmed to rt and stirred for 1 hr. The mixture was quenched with sat'd. aq. Na2SO3. The mixture was then partitioned between CH2Cl2 and sat'd. aq. NaHCO3. Extracted with CH2Cl2. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 3.85 (dd, 1H, J=7.8 Hz, 11.7 Hz), 3.54 (dd, 1H, J=4.6 Hz, 11.7 Hz), 3.31-3.38 (m, 1H), 3.19 (d, 1H, J=5.13 Hz), 2.15-2.24 (m, 1H), 1.75-1.97 (m, 4H), 1.52-1.72 (iii, 3H), 1.37-1.49 (m, 1H), 1.30-1.38 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[C:39]([O-:42])(=[O:41])C.[K+].[CH3:44]O>>[C:35]([O:34][C:32]([N:30]1[CH2:29][CH2:28][C:25]2([CH2:26][CH2:27]2)[C@@H:24]([O:23][C:21]2[N:22]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([C:39]([O:42][CH3:44])=[O:41])[CH:3]=4)[N:7]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:6]=3)[CH:18]=[N:19][CH:20]=2)[CH2:31]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: CC(=O)[O-]
Agent: [K+]
Product: COC(=O)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (150 mg, 0.257 mmol), PdCl2dppf (20.96 mg, 0.026 mmol), and potassium acetate (76 mg, 0.770 mmol) in MeOH (2566 μL) was placed in a Symyx/Argonaut reactor for 16 h at 90° C. under CO (70 psi) when clean conversion was observed via 1 cms. The crude was purified via automated flash chromatography (silica gel) with 100% hexanes to 20% EtOAc/hexanes to give methyl 3-(6-((R)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-4-yloxy)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (120 mg, 0.213 mmol, 83% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 564.2 (M+1).