Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([NH:19][NH2:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC2N(O)N=NC=2C=1.[CH3:31][O:32][C:33]1[C:42]2[C:37](=[C:38]([O:43][CH3:44])[CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:45]([N:47]2[CH2:52][CH2:51][C:50]3([CH2:61][C:60](=[O:62])[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:63](O)=[O:64])[CH:58]=4)[O:53]3)[CH2:49][CH2:48]2)=[O:46])[CH:34]=1>C(OCC)(=O)C.CN(C=O)C>[CH3:31][O:32][C:33]1[C:42]2[C:37](=[C:38]([O:43][CH3:44])[CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:45]([N:47]2[CH2:52][CH2:51][C:50]3([CH2:61][C:60](=[O:62])[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:63]([NH:20][NH:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:64])[CH:58]=4)[O:53]3)[CH2:49][CH2:48]2)=[O:46])[CH:34]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)O)ccc2O3)nc2c(OC)cccc12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NNC(=O)OC(C)(C)C)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.5 %

Procedure:
50.6 mg of EDCI was added to a mixture of 29.1 mg of Boc-hydrazine, 33.7 mg of HOBT, 105 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(carboxy)spiro[chroman-2,4′-piperidin]-4-one and 2.2 mL of DMF, and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with 15 mL of ethyl acetate, washed with water and aqueous saturated NaHCO3 solution, and dried over sodium sulfate. The residue was purified through silica gel chromatography (2% MeOH/CHCl3) to obtain 119 mg of tert-butyl 2-({1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}carbonyl)hydrazinecarboxylate. 2 mL of 4 N HCl in dioxane was added to 59.1 mg of the product, and stirred at room temperature for 1 hour, and then concentrated. The residue was suspended in 2.5 mL of THF, and 0.049 μL of triethylamine and 24.3 mg of CDI were added thereto at 0° C., and stirred at room temperature for 14 hours. Water was added to the reaction solution, and extracted with chloroform, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified through silica gel thin-layer chromatography (17% MeOH/CHCl3) to obtain the intended compound. 1H-NMR (CDCl3) δ: 8.85 (1H, br s), 8.38 (1H, d, J=2.2 Hz), 7.97 (1H, dd, J=2.2, 8.8 Hz), 7.77 (1H, dd, J=8.5, 1.0 Hz), 7.47 (1H, dd, J=7.8, 8.5 Hz), 7.20 (1H, s), 7.13 (1H, d, J=8.8 Hz), 7.08 (1H, dd, J=1.0, 7.8 Hz), 4.64-4.56 (1H, m), 4.24-4.16 (1H, m), 4.09 (3H, s), 4.03 (3H, s), 3.67-3.58 (1H, m), 3.43-3.34 (1H, m), 2.87 (1H, d, J=16.8 Hz), 2.81 (1H, d, J=16.8 Hz), 2.26-2.18 (1H, m), 2.11-2.04 (1H, m), 2.01-1.87 (2H, m). MS [M+H]+=517.
Reaction SMILES: I(O)(=O)(=O)=O.OC[C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C:23](=[CH:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][C@H:10]1C.[CH3:31][OH:32]>O>[CH3:31][O:32][C:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]2[C@H:13]3[C:23](=[CH:24][CH2:25][C@:26]12[CH3:27])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)=[O:30]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Reactant: CO
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C

Procedure:
Periodic acid (14.73 g) is dissolved in water (162 ml) and is then slowly added to a stirred solution of 21-hydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione (10.34 g) in methanol (675 ml) at 26°-28°. The reaction mixture is stirred for an additional hour at 20°-25° and then concentrated under reduced pressure with concurrent addition of water (1675 ml). The mixture is cooled and filtered to give 9.94 g of 16°-methylandrosta-4,9(11)-dien-3-one 17β-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=[C:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]3[N:13]=[C:15]([CH3:22])[CH:16]=[C:17]([OH:18])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Solvent: Cc1ccccc1C
Product: Cc1cc(O)n2nc(-c3cccc(Cl)c3)cc2n1
Temperature: 157.5 °C
Yield: 88 %

Procedure:
A suspension of 3-(3-chlorophenyl)-1H-pyrazol-5-amine (10 g, 51.6 mmol) and ethyl 3-oxobutanoate (26.3 ml, 207 mmol) in o-xylene (200 mL) was heated at reflux (oil bath temp: 155-160° C.) for 20 h. Note: The reaction turned clear solution between 60-70° C. and solids started crashing out at 130° C. Then, cooled, diluted with hexanes (100 mL), filtered, washed with hexanes (100 mL) and dried to afford 2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (11.8 g, 45.4 mmol, 88% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.46 (s, 1H), 8.05 (s, 1H), 8.00-7.95 (m, 1H), 7.56-7.45 (m, 2H), 6.70 (s, 1H), 5.64 (s, 1H), 2.33 (s, 3H). LCMS (M+H) calcd for C13H11ClN6O: 260.06. found: 260.1.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[CH:54][C:55]4[N:61]([CH3:62])[C:60](=[O:63])[CH2:59][CH2:58][N:57]([CH3:64])[C:56]=4[N:65]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)=[CH:54][C:55]4[N:61]([CH3:62])[C:60](=[O:63])[CH2:59][CH2:58][N:57]([CH3:64])[C:56]=4[N:65]=3)=[CH:50][CH:51]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: CN1CCC(=O)N(C)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc21
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: CN1CCC(=O)N(C)c2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc21
Yield: 97 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1,5-dimethyl-2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.03 mmol) was reacted to afford the title compound (12 mg, 64%). LCMS (Method D): RT=0.880 min, M+1=413. 1H NMR (500 MHz, MeOD): 7.65 (1H, s), 7.53 (2H, d), 7.39 (2H, d), 7.31-7.28 (3H, m), 7.24-7.22 (2H, m), 3.73 (2H, t), 3.37 (3H, s), 3.02 (3H, s), 2.81-2.75 (2H, m), 2.68 (2H, t), 2.61-2.55 (2H, m), 2.25-2.18 (1H, m), 1.99-1.91 (1H, m).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH2:5]([O:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([O:26]C)[N:16]2[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[C:12]([NH2:28])[N:11]=1)[CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:28][C:12]1[N:11]=[C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:26])[N:16]2[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH3:4])[CH2:21]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CCC)C3)c2n1
Reaction time: 18 h
Yield: 20.7 %

Procedure:
1-Iodopropane (0.1 mmol) was weighed into a vial and an aliquot (0.3 ml, 0.1 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine (802 mg, 2.398 mmol) suspended in DMF (7.2 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and the tube was capped and shaken to aid dispersion then allowed to stand at room temperature (18 hours). An additional portion of 1-iodopropane (0.05 mmol) was added and the reaction allowed to stand for 18 hours. DMSO (400 uL) was added and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.5 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml), and applied to a 0.5 g aminopropyl SPE (preconditioned with methanol, 2 CV). The cartridge was eluted with methanol (2 ml), the solvent was removed to give the title compound (7.5 mg).
Reaction SMILES: [2H][C@@:2]([C:11]([OH:13])=[O:12])([CH:4]([2H])[CH:5]([2H])[C:6](=[O:8])[NH2:7])[NH2:3].C(C1C=CC(=O)NN=1)(O)=O>>[C:11]([C:2]1[CH2:4][CH2:5][C:6](=[O:8])[NH:7][N:3]=1)([OH:13])=[O:12]
Reactant: [2H]C(C(N)=O)C([2H])[C@]([2H])(N)C(=O)O
Agent: O=C(O)c1ccc(=O)[nH]n1
Product: O=C1CCC(C(=O)O)=NN1

Procedure:
A number of deuterated glutamines (starting material for preparing Compound B) have previously been made, including 2,3,4-trideutero-glutamine (i.e., R2=D, R4=D, and Z=D), which was made via the deuterium reduction of 6-carboxy-3(2H)-pyridazone (see Stogniew, J. Labelled Compounds and Radiopharmaceuticals 1981, 18(6), 897-903), and 2,2,3,3,4 pentadeutero-glutamine (i.e., R2-R5=D and Z=D), which was obtained in a multi-step synthesis (see Blomquist, J. Org. Chem. 1966, 12, 4121-27). Stogniew also notes that the 5-mono-deutero-glutamine could be obtained through deuterium reduction of 4,5-dihydro-6-carboxy-3(2H)-pyridazone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:28])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:28])[CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2(C)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
247 mg (558 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoate (racemate) in 1 ml of dichloromethane and 859 μl (11.2 mmol) of TFA were reacted according to General Method 6A. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 95 mg (43% of theory)
Reaction SMILES: C1(NC(C)C)CCCCC1.C([Li])CCC.[C:16]([O:20][C:21]([CH:23]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:24](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[N+:32]([C:35]1[CH:42]=[CH:41][C:38](CBr)=[CH:37][CH:36]=1)([O-:34])=[O:33]>C1COCC1.CCCCCC.CN1CCCN(C)C1=O>[CH2:30]([O:29][CH2:28][CH2:27][CH:23]([CH2:24][C:38]1[CH:41]=[CH:42][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=1)[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH3:31]
Reactant: CCOCCC(C(=O)O)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCCC(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 67.5 %

Procedure:
To a solution of cyclohexylisopropylamine (1.42 ml) in dry THF (3 ml) at -76° C. under argon was added a 2.5M solution of n-butyllithium in hexane (3.5 ml). The resultant solution was stirred at -76° C. for 15 minutes before a solution of the product from step (b) (1 g) in dry THF (7 ml) was added dropwise. On completion of the addition, the reaction mixture was allowed to warm to 0° C. and stirred at that temperature for 15 minutes before a solution of 4-nitrobenzyl bromide (940 mg) in dry THF (3 ml) was added, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.5 ml). The resultant mixture was stirred at ambient temperature for 16 hours and then heated to reflux for 5 hours. The reaction mixture was evaporated to dryness and saturated ammonium chloride solution was added to the residue. The resultant mixture was extracted thoroughly with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and evaporated to give a residue which was purified by flash chromatography on silica by elution with 20% ethyl acetate/hexane to give t-butyl 2-(2-ethoxyethyl)-3-(4-nitrophenyl)propionate (940 mg) as a pale yellow oil: NMR Spectrum (CDCl3) 1.19 (3H, t), 1.33 (9H, s), 1.76 (1H, m), 1.94 (1H, m), 2.78 (1H, m), 2.91 (2H, m), 3.44 (4H, m), 7.35 (2H, d), 8.13 (2H, d); Mass Spectrum m/Z 324 (M+H)+.
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.[Li]C(CC)C.[C:16]([O:20][C:21]([N:23]([C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([Br:38])[C:32]=1[CH3:39])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])([CH3:19])([CH3:18])[CH3:17].IC.[NH4+].[Cl-]>C1COCC1>[C:16]([O:20][C:21]([N:23]([C:31]1[C:36]([F:37])=[C:35]([CH3:1])[CH:34]=[C:33]([Br:38])[C:32]=1[CH3:39])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: Cc1c(Br)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Br)c(C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Temperature: -65 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (699 mg, 4.9 mmol, 2.0 eq) in THF (7.5 mL) at −50° C. was added sec-BuLi (3.8 mL, 1.3 M, 4.9 mmol, 2.0 eq) dropwise. The reaction was stirred for 20 min at −15° C. to −10° C., then cooled to −65° C. and a solution of tert-butyl N-tert-butoxycarbonyl-N-(3-bromo-6-fluoro-2-methylphenyl)carbamate (See example 13) (1 g, 2.47 mmol, 1.0 eq) in THF (7.5 mL) added dropwise. The reaction was stirred a further 2 h at −65° C. Iodomethane (1.05 g, 7.41 mmol, 3.0 eq) was added in one portion and the reaction allowed to warm to −10° C. over 30 min. The reaction was then poured into saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered and evaporated in vacuo to give a crude residue, which was purified by column chromatography (petroleum ether:EtOAc, 100:0 to 30:1) to give the title compound as a white solid (880 mg, 85%).
Reaction SMILES: COC(=O)[CH:4]([C:16]#[N:17])[C:5]1([CH3:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6]1.[Cl-].[Na+]>CS(C)=O.O>[CH3:15][C:5]1([CH2:4][C:16]#[N:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C(C#N)C1(C)CCOc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(CC#N)CCOc2ccccc21
Reaction time: 4 h
Yield: 69.7 %

Procedure:
A mixture of 6 g (23 mmol) of cyano(4-methylchroman-4-yl)acetic acid methyl ester and 7.25 g (124 mmol) of sodium chloride in 40 mL of wet DMSO was warmed to reflux. The reaction was monitored by TLC. After 4 hours, the reaction was cooled and diluted with water and extracted with diethyl ether. The combined organic layers were washed with four portions of water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3 g (68%) of (4-methylchroman-4-yl)acetonitrile as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6][C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:24][N:2]([CH3:1])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6]([C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1)=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc2nc(C)c(SCc3ccccc3N(C)C)nc2cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc(C)c(S(=O)Cc3ccccc3N(C)C)nc2cc1C
Yield: 28.8 %

Procedure:
In a mixture of 35 ml of chloroform and 3 ml of methanol was dissolved 3.71 g of 2-(2-dimethylaminobenzylthio)-3,6,7-trimethylquinoxaline. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was slowly added 2.45 g of m-chloroperbenzoic acid (purity: 80%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (acetone/hexane). The eluate was concentrated and the resulting residue was crystallized from ether/hexane to give 1.12 g of 2-(2-dimethylaminobenzylsulfinyl)-3,6,7-trimethylquinoxaline as a yellow crystalline powder, m.p. 83°-88° C. (decompn.).
Reaction SMILES: COC1C=C(N[N:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C=C(C(F)(F)F)C=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[NH2:25].C(#N)CC#N.O.[NH2:39][NH2:40]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][N:14]=[C:15]2[C:16]([NH2:17])=[N:40][N:39]=[C:18]2[NH2:19])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: COc1cc(NN=C(C#N)C#N)cc(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: N#CCC#N
Product: COc1cc(NN=C2C(N)=NN=C2N)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4-[(3-methoxy-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 134 mg (0.5 mmol) of 2-[(3-methoxy-5-trifluoromethylphenyl)hydrazono]malononitrile, which was derived from 3-methoxy-5-trifluoromethylaniline (191 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 10 mg (7%) of the compound as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C(C(C)=O)C>[F:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:25][C:26](=[O:28])[CH3:27])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)COc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
83 g of pulverised potassium carbonate and 4 g of of finely powdered potassium iodide are added to a solution of 94.1 g of 4-(4-fluorophenoxy)phenol in 400 ml of methyl ethyl ketone, and the mixture is heated to reflux temperature. With stirring, 64 g of freshly distilled chloroacetone are added dropwise over 1 hour, and the reaction mixture is stirred for a further 2 hours at reflux temperature. After cooling, the reaction mixture is filtered and the solvent is removed by vacuum distillation. The crude product is recrystallised from n-hexane/diethyl ether (5:1), to give the pure, colourless 1-[4-(4-fluorophenoxy)phenoxy]-2-propanone which melts at 56°-57° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH2:9][CH2:10][OH:11])=[N+:7]=[N-:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:11][CH2:10][CH2:9][N:6]=[N+:7]=[N-:8])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=NCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonyl chloride (5.7 g) in methylene chloride (20 ml) was added dropwise to a stirred solution of 2-azidoethanol (4.3 g) and triethylamine (5.0 g) in methylene chloride (80 ml). After 2 hours stirring at room temperature the reaction mixture was washed with water, dried (MgSO4) and evaporated to dryness in vacuo to give the title compound as a yellow oil, yield 7 g, which was used directly without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][N:36]=3)[CH2:12]1)[C:8](=[O:45])[NH:7]2)=[O:5])C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:29]([O:28][C:26]([NH:25][CH:15]1[C:14](=[O:33])[N:13]2[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][N:36]=3)[CH2:12]2)[C:8](=[O:45])[NH:7][C:6]2([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3nccc4ccccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid ethyl ester (1.10 g, 1.77 mmol) was dissolved in the mixed solvent system; THF (18 mL), methanol (8 mL), and water (2 mL). Powdered lithium hydroxide hydrate (744 mg, 17.7 mmol) was added. The light yellow slurry was stirred at rt under N2 for 24 h, and then concentrated in vacuo. The residue was partitioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 4N HCl until the pH was 4. This acidic solution was extracted with ether four times. The combined ether extracts were dried (MgSO4) and concentrated in vacuo to give 0.95 g (90%) of 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid as a white solid: 1H NMR (300 MHz, CD3Cl3) δ 1.30 (s, 9H), 1.34–1.46 (m, 4H), 1.52–1.68 (m, 2H), 1.84 (m, 2H), 2.08–2.58 (m, 6H), 2.78–2.87 (m, 1H), 4.07 (m, 1H), 4.32 (d, J=11.3 Hz, 1H), 4.41 (m, 1H), 4.79 (t, J=7.3 Hz, 1H), 5.14 (t, J=9.5 Hz, 1H), 5.23 (d, J=7.3 Hz, 1H), 5.60 (q, J=8.8 Hz, 1H), 5.86 (s, 1H), 7.08 (s, 1H), 7.22 (d, J=6.2 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.94 (d, J=5.9 Hz, 1H), 8.17 (s, J=8.4 Hz, 1H). LC-MS (Method A, retention time: 3.32 min), MS m/z 593 (M++1)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ONC(=O)[C@@H](O)[C@@H](C([N:61]1[CH2:66][CH2:65][N:64]([C:67]2[CH:72]=[C:71](C(F)(F)F)[CH:70]=[CH:69][N:68]=2)[CH2:63][C@H:62]1[CH3:77])=O)CC(C)C>CN(C=O)C.O>[CH3:16][C:2]1([CH3:1])[O:3][C:4](=[O:15])[C@H:5]([C@@H:7]([C:8]([N:61]2[CH2:66][CH2:65][N:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=3)[CH2:63][C@H:62]2[CH3:77])=[O:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[O:6]1
Reactant: CC(C)C[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@H](O)C(=O)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 49 %

Procedure:
To a cold (0° C.) solution of (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid (prepared according to WO 94/0244 or similarly to Seebach et al., 1990, Org. Syntheses, Coll. Vol. III, p 153-159; 7; 755.0 mg; 3.28 mmol; 1.0 eq.) and DIEA (1.18 mL; 6.89 mmol; 2.1 eq.) in DMF (4 mL) was added HATU (1.37 g; 3.61 mmol; 1.1 eq.) and the resulting reaction mixture was stirred for 2 min at 0° C. (3R)-3-methyl-1-pyridin-2-ylpiperazine (Intermediate 3, 639.3 mg; 3.61 mmol; 1.1 eq.) was then added and the resulting reaction mixture was stirred for 14 h at RT. Water was added and the mixture was extracted with Et2O (3×). The combined organic layers were washed with an aqueous saturated solution of NaCl, dried over MgSO4, filtered and evaporated to give an oil. This residue was purified by chromatography (gradient from 33% EtOAc in c-hex up to 50% EtOAc in c-hex in about 30 min) to give the title product as a white solid (625 mg, 49%) as a mixture of 2 diastereoisomers (HPLC (Condition D): Rt major: 13.7 min; Rt minor: 13.8 min.; major/minor: 55/45). M+(ESI): 390.3. HPLC (Condition A), Rt: 2.3 min (HPLC purity: 97.4%).