Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7].Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl.O>[CH3:39][Si:2]([CH3:38])([CH3:1])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([N:27]=[C:41]=[O:43])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N=C=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (from EXAMPLE 3.2B, 90 mg in a mixture of 1 mL chloroform and 1 mL water containing 47 mg calcium carbonate) at 0° C. was added 46 mg triphosgene and the mixture allowed to warm slowly to room temperature. After 2 hours, the reaction was quenched by the addition of 2N hydrochloric acid, extracted with methylene chloride and the organics dried over sodium sulfate to give the crude title compound (94 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:35][CH:34]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)CCCCCOc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCOc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a mixture of 4-nitrophenol (10.8 g), triethylamine (22 ml) in ethyl acetate (200 ml) at 0° C. was added 6-(4-nitrophenoxy)-hexanoyl chloride (20 g) dropwise, and the mixture was further stirred at room temperature for 16 hours. The reaction mixture was filtered to remove the salts, washed with 5% sodium bicarbonate, water and dried over anhydrous sodium sulphate. The solvent was distilled off under vacuum and the pure compound was precipitated by adding cold methanol. After filtration and drying, the compound was further recrystallized from a mixture of chloroform and methanol (1:1) to give pure 6-(4-nitrophenoxy)-hexanoic acid 4-nitrophenyl ester (15 grams) as white powder with a melting point of 73-76° C. The product was also characterized by 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.85 (m, 6H, CH2X2), 2.70 (t, 2H, CH2), 4.10 (t, 2H, CH2), 6.95 (d, 2H, Ar), 7.30 (d, 2H, Ar), 8.25 (m, 4H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[CH3:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([F:16])[CH:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1F

Procedure:
The title compound, MS: m/e=326.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-fluoro-4-methyl-benzene boronic acid.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7](=[O:16])[N:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].[CH3:21][N:22]=[C:23]=S.CO>CN(C=O)C>[CH3:21][NH:22][C:23]1[C:4]2[C:5](=[O:20])[N:6]([CH2:17][CH2:18][CH3:19])[C:7](=[O:16])[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccncc2)c1=O
Reactant: CN=C=S
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccncc2)c1=O
Reaction time: 14 h

Procedure:
A solution of 6-hydrazino-1-(4-pyridylmethyl)-3-propyluracil (1.5 g, 5.7 mM) and methyl isothiocyanate (1.55 ml, 23 mM) in DMF (15 ml) was heated at 90° C. for 14 hours and then at 110° C. for 14 hours. To the reaction solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/ethanol/water afforded colorless needles (1.02 g, 57%), m.p. >300° C.
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]1([C:2]2[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[N:6]=2)[CH2:26][CH2:25]1
Reactant: Cn1cc(C(=O)OCc2ccccc2)nc1Br
Reactant: OB(O)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)OCc2ccccc2)nc1C1CC1
Temperature: 100 °C

Procedure:
Into a solution of benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (2.8 g, 9.49 mmol) in THF (40 ml) and water (20 ml), cesium carbonate (7.71 g, 23.7 mmol) and cyclopropyl boronic acid (1.22 g, 14.2 mmol) were added under argon atmosphere at RT. The resulting mixture was degassed and purged with argon for 10 min. Pd(PPh3)2Cl2 (0.332 g, 0.04 mmol) was added to the mixture and heated at 100° C. for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography. Yield 1.1 g. 1H-NMR (400 MHz; CDCl3): δ 0.95-1.02 (m, 2H), 1.07-1.11 (m, 2H), 1.72-1.78 (m, 1H), 3.70 (s, 3H), 5.32 (s, 2H), 7.29 (s, 1H), 7.42-7.62 (m, 5H), LC-MS: [M+1]=257.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40].[OH-].[NH4+:43]>C(Cl)(Cl)Cl.ClCCl>[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[C:19]([NH2:43])[C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40]
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reaction time: 0.5 h

Procedure:
Part B of the general methods described for Examples 35-40 was followed using 2.00 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol to provide 2.33 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid. Parts C and D of the general methods described for Examples 35-40 were replaced by the following procedure. mCPBA (0.853 g, 2.97 mmol) was added in one portion to a solution of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline (1.00 g, 2.47 mmol) in chloroform (17 mL), and the reaction was stirred for 30 minutes. Ammonium hydroxide (17 mL) was then added, followed by/7-toluenesulfonyl chloride (0.710 g, 3.70 mmol). The reaction was stirred for 16 hours and then diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic solutions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile to provide 0.680 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a reddish-brown, crystalline solid, mp 209-211° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O-:24])(=[O:23])[CH3:22].[K+].C(C1C=CC=CC=1)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:21]([O:24][CH2:11][C@@H:10]([OH:13])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CCc1ccccc1
Product: CC(=O)OC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 44.7 %

Procedure:
A mixture composed of 2.0 mmol (0.599 g) of (2S,3S)-3-(t-butoxycarbonylamino)-1-chloro-2-hydroxy-4-phenylbutane, 0.1 mmol (0.032 g) of tetrabutylammoniumbromide, 5.0 mmol (0.49 g) of potassium acetate and 10 ml of acetonitrile was stirred under reflux for 50 hours. Thereafter, the solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. Quantitative analysis was curried out by high performance liquid chromatography using ethylbenzene as an internal standard. Thus was obtained 0.289 g (45%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[CH3:19])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2C)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: COc1ccc(F)c(C)c1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(3-fluoro-6-methoxy-2-methyl-phenyl)-methanone (Example 350) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(3-fluoro-6-methoxy-2-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 402.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1>CC(O)=O.C1COCC1.[OH-].[Na+]>[CH:23]1([CH2:24][N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)[CH2:21][CH2:22]1
Reactant: N#CC(O)C1CC1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC1CCN(CC2CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
3-Hydroxy-pyrrolidine (5.65 g, 65 mmol, 1.0 equiv) was dissolved in 100 mL of 1% AcOH in THF and cooled to 0° C. Na(OAc)3BH (24 g, 114 mmol, 1.75 equiv) and cyclopropylcarboxaldehyde (5.0 g, 71 mmol, 1.1 equiv) were added and the resulting mixture was stirred at 0° C. for 1 h and room temperature overnight (16 h). The reaction was diluted with 200 mL of 2 N NaOH, and the product was extracted 3×200 mL of CH2Cl2. The organic extracts were combined, dried over Na2SO4, decanted and concentrated to yield the desired product as a free-flowing oil (7.26 g, 79%) which was used without further purification; MS, m/z 142=M+1.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.[CH3:55][C:56]1[O:60][C:59](=[O:61])[O:58][C:57]=1[CH2:62][O:63][C:64](=[O:84])[C@H:65]([OH:83])[CH2:66][C@H:67]([NH2:82])[CH2:68][C:69]1[CH:74]=[CH:73][C:72]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([Cl:81])[CH:76]=2)=[CH:71][CH:70]=1>>[CH3:55][C:56]1[O:60][C:59](=[O:61])[O:58][C:57]=1[CH2:62][O:63][C:64](=[O:84])[C@H:65]([OH:83])[CH2:66][C@H:67]([NH:82][C:13]([C:4]1[CH:3]=[C:2]([OH:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=1)=[O:15])[CH2:68][C:69]1[CH:74]=[CH:73][C:72]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([Cl:81])[CH:76]=2)=[CH:71][CH:70]=1
Reactant: O=C(O)c1cc(O)n(-c2ccccn2)n1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
5-Hydroxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid (8.1 mg, 39 μmol) and HCTU (16.2 mg, 39 μmol) were combined in DMF (166 μL, 2.1 mmol) and stirred at room temperature for 15 minutes. DIPEA (19 μL, 0.1 mmol) and (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (15.4 mg, 36 μmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to yield the title compound (18 mg). MS m/z [M+H]+ calc'd for C31H27ClN4O8, 619.15. found 619.1.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=S)[N:18]([CH:23]([C:25](OCC)=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:30]=[C:17]3[C:16](=[CH:15][CH:14]=2)[O:21][CH2:20][C:19]2[N:18]3[CH:23]([CH3:24])[C:25](=[O:26])[NH:32][N:33]=2)[CH2:11]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.530 g, 1.22 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.486 g, 9.72 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.234 g, 52%) as a white solid. LC/MS (Table 1, Method 3) Rt=1.332 min.; MS m/z: 389 [M+H]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([OH:45])=O)[CH:41]=2)[CH:36]=[CH:35]1.[CH3:46][O:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][C:50]=1[Cl:56]>O1CCCC1>[CH3:46][O:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:43]([C:40]2[CH:41]=[C:42]3[C:37]([CH:36]=[CH:35][NH:34]3)=[CH:38][CH:39]=2)=[O:45])=[CH:51][C:50]=1[Cl:56]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26 %

Procedure:
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (8.3 g, 17.8 mmol, 1.1 equiv.) and diisopropyl ethyl amine (4.4 ml, 33.9 mmol, 2.1 equiv.) were added to 1H-indole-6-carboxylic acid (2.6 g, 16.2 mmol, 1 equiv.) in tetrahydrofuran (30 mL) and the mixture was shaken for 5 minutes at room temperature. 4-Amino-2-chlorobenzoic acid methyl ester (3.3 g, 17.9 mmol, 1.1 equiv.) was added and the resultant mixture was shaken at room temperature for 16 hours. The solvent was removed under vacuum and the residue triturated with dichloromethane (10 mL). The solid was filtered to afford 2-chloro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester, 1.4 g (26% yield). LC @215 nm; Rt 1.36: 90%, m/z (ES+): 329 (M+H+.); δH (400 MHz; d6-DMSO) 11.65 (1H, s), 10.59 (1H, s), 8.16 (1H, s), 8.10 (1H, s), 7.93 (2H, m), 7.65 (2H, s), 7.59 (1H, m), 6.62 (1H, s), 3.85 (3H, s).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CNCc1ccc(Cl)cc1

Procedure:
A mixture of 2.76 g of (2R)-3-chloro-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester, 3.54 g of p-chlorobenzylamine, 3.25 g of N-ethyl-N,N-diisopropylamine and 20 ml of ethanol is heated under reflux for 48 hours. Removal of the solvent and chromatography yield (2S)-3-(p-chlorobenzylamino)-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=7.4-7.17 (9H,m); 4.14-3.83 (3H,m); 3.71 (2H, ABq); 3.20 (2H,d): 2.6-2.5 (2H,m); 1.96-1.62 (2H,m); 1.25 (3H,t); 31P-NMR spectrum (in CDCl3): δ=53.9; 52.7.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:15])(=O)=O.O.[Cl-].[Na+]>C(Cl)(Cl)Cl>[OH:1][N:2]=[C:3]([C:9](=[O:11])[CH2:10][Cl:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CCl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 31.83 g) in chloroform (70 ml) was added dropwise sulfuryl chloride (29.7 g) over 6 minutes under ice-cooling, and the mixture was stirred for 4.5 hours at ambient temperature. The mixture was cooled to 7° C., and sulfuryl chloride (13.498 g) was further added thereto. The mixture was stirred at ambient temperature for overnight. After the reaction mixture was cooled with ice-water, chloroform (50 ml) and water (40 ml) were added thereto with stirring. The mixture was saturated with sodium chloride, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (40 ml×2), dried over magnesium sulfate and then filtered. The filtrate was evaporated to give ethyl 2-hydroxyimino-3-oxo-4-chlorobutyrate (syn isomer), quantitatively.
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C([O-])(=O)C.[NH4+:33].N>CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH:3]=[C:4]([NH2:33])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: [NH4+]
Reactant: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CC(=O)[O-]
Agent: N
Solvent: CO
Product: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 55 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
A mixture of 7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (22.1 g), ammonium acetate (25 g), methanol (220 mL), and aqueous ammonia (22 mL) are heated to about 55° C. and stirred for about 6 hours. The reaction mass is then cooled to 30° C. and the undissolved particles are filtered off. The filterate is distilled off completely under vacuum. To the residue, ethanol (25 mL) is charged and the mixture is stirred at about 30° C. for about 30 minutes. The solid is filtered, washed with ethanol (5 mL), and dried to afford the title compound. (Yield: 75%; purity by HPLC: 96.7%)
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[O:21]1[C:2]2([CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:1]1
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2(CO2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.1 %

Procedure:
To a 0° C. solution of tert-butyl 3-methyleneazetidine-1-carboxylate (3.50 g, 20.7 mmol) in 115 ml, CHCl3 was added 77% mCPBA (13.9 g, 62.0 mmol) in 3 batches. Isopropyl alcohol (2 mL) was added. The reaction mixture was stirred for 10 minutes, then warmed to ambient temperature and stirred. After 19 hours, the milky reaction mixture was cooled to 0° C., 10 mL isopropyl alcohol was added (reaction mixture clarified), and another 1 equivalent of mCPBA was added. The reaction mixture was warmed to ambient temperature and stirred 2 hours, then another 1 equivalent mCPBA was added portionwise. After a total of 40 hours, the reaction mixture was cooled to 0° C., and 200 mL of 1:1 saturated Na2S2O3/saturated NaHCO3 was added slowly by pouring portionwise through ice (internal temperature was monitored; an initial 10° C. exotherm was observed). The mixture was stirred for 30 minutes, then extracted with CHCl3, and combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (5-50% ethyl acetate in hexanes gradient) to give the desired product (1.0 g, 26.1% yield) as a clear colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])C.CC(C)=O.N1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH2:15]([C:8]1[CH:7]=[CH:6][C:5](=[C:1]([CH3:3])[CH3:4])[CH:9]=1)[CH2:16][CH2:17][CH3:18]
Reactant: C1CCNC1
Reactant: CC(C)(C)C1=CC=CC1
Solvent: CC(C)=O
Solvent: CO
Product: CCCCC1=CC(=C(C)C)C=C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
A mixture of t-butylcyclopentadiene (15 g, 123 mmol), acetone (9.0 mL, 135.2 mmol), pyrrolidine (11.7 mL, 135.3 mmol) and methanol (100 mL) was stirred at 0° C., for 30 minutes, and then at room temperature overnight. The reaction mixture was quenched with acetic acid (7.38 g) and with water (100 mL) at 0° C. The mixture was extracted with Et2O (3×200 mL); the organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous magnesium sulphate, filtered and finally concentrated, thus yielding 2-butyl-6,6-dimethylfulvene in the form of a yellow liquid (18.24 g, 92% yield).