Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][C:14](=[O:18])[O:15]2)[C@H:11]1/[CH:19]=[C:20](/[Br:30])\[C@H:21](O)[C@@H:22]([CH3:28])[CH2:23][C:24]#[C:25][CH2:26][CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:34])(C)C.O.C(O[C@@H]1C[C@H]2[C@H](CC(=O)O2)[C@H]1/C=C(/Br)\C(=O)[C@@H](C)CC#CCC)(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:9][C@@H:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][C:14](=[O:18])[O:15]2)[C@H:11]1[C:19](=[O:34])/[C:20](/[Br:30])=[CH:21]/[C@@H:22]([CH3:28])[CH2:23][C:24]#[C:25][CH2:26][CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: CCC#CC[C@H](C)[C@@H](O)/C(Br)=C\[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: CCC#CC[C@H](C)C(=O)/C(Br)=C\[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CCC#CC[C@H](C)/C=C(\Br)C(=O)[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
17.6 g (37.1mmol) of (1S,5R,6S,7R)-7-benzoyloxy-6-[(E)-(3R,4S)-2 -bromo-3-hydroxy-4-methyl-1-nonen-6-inyl]-2-oxabicyclo[3.3.0]octan-3-one (for preparation see EP0284547) is dissolved in 260 ml of acetone, cooled under an atmosphere of dry argon to -30° C. and 20 ml of a standardized Jones solution is instilled within 10 minutes. It is stirred for another 1.5 hours at -20° C., excess oxidizing agent is decomposed by adding 25 ml of isopropanol, allowed to heat to 20° C., mixed with 300 ml of water and extracted several times with a total of 600 ml of diethyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution until neutral reaction, dried on magnesium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on about 800 ml of fine silica gel by using an n-hexane/ethyl acetate mixture. In addition to 11.3 g (23.9 mmol, 64%) of (1S,5R,6S,7R)-7-benzoyloxy-6-[(E)-(4S)-2-brom-3-oxo-4-methyl-1-nonen-6-inyl]-2-oxa-bicyclo[3.3.0]octan- 3-one, 3.59 g (7.58 mmol, 26%) of (1S,5R,6R,7R)-7-benzoyloxy-6-[(Z)-(4S)-1-oxo-2-bromo-4-methyl-non-2-en-6-inyl]-2-oxabicyclo[3.3.0]octan-3-one is isolated. The latter compound is dissolved in 45 ml of anhydrous methanol, cooled under an atmosphere of dry argon to -45° C., mixed in portions with a total of 520 mg of sodium borohydride and stirred for 30 more minutes at -45° C. Excess reducing agent is decomposed by adding 0.8 ml of acetone, allowed to heat to 20° C., mixed with water and extracted several times with diethyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution until neutral reaction, dried magnesium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on about 200 ml of fine silica gel by using a dichloromethane/ethyl ether mixture. 1.79 g (3.76 mmol, 50%) of the nonpolar alcohol as well as 528 mg (1.11 mmol, 15%) of the polar alcohol are isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].[Cl-].[Na+]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of (2-aminoethyl)carbamic acid tert-butyl ester (from Step 6 below) (4.2 g, 26.3 mmol) in methylene chloride (50 mL) was added triethylamine (4.4 mL, 31.4 mmol) and methyl bromoacetate (2.4 mL, 26.3 mmol). The reaction was stirred overnight at room temperature. A saturated aqueous solution of sodium chloride (100 mL) was then added, and the organic layer was separated dried over MgSO4, filtered and concentrated. The residue was taken up in diethyl ether, and a saturated solution of HCl in diethyl ether was added to precipitate the product, which was filtered, and dried. It was recrystallized in ethanol/ethyl acetate, to give a white solid; 1.39 g (20% yield). MS-APCI: M+1=233.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4Cl)[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][CH2:41][C@H:42]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=1)[OH:43]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4[NH:40][CH2:41][C@H:42]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=4)[OH:43])[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59-7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H), 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([F:33])[CH:32]=1)[C:27](Cl)=O>>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[C:10]([CH3:11])[C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[N:1]=2)[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: NC(=O)c1ccccc1
Product: COc1ccc2c(O)nc(-c3cc(F)cc(F)c3)nc2c1C
Yield: 85 %

Procedure:
The general procedure described above was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and 3,5-difluoro-benzoyl chloride as acid chloride [B], which gave the title compound (2.1 g, 85%), [M+H]=303.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[CH3:12][S:13]([NH:16][CH2:17][CH2:18][O:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])(=[O:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N+:7]([CH2:18][CH2:17][NH:16][S:13]([CH3:12])(=[O:15])=[O:14])[C:6]=2[CH:11]=1.[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([O-:22])(=[O:19])=[O:21])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)NCCOS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1nc2cc(Cl)ccc2o1
Product: Cc1oc2ccc(Cl)cc2[n+]1CCNS(C)(=O)=O
Product: O=S(=O)([O-])c1ccc(Cl)cc1

Procedure:
The desired crystal was obtained by carrying out the same synthesis as used in Synthesis Example 1 using 4.2 g (25 mmols) of 5-chloro-2-methylbenzoxazole and 15.7 g (50 mmols) of 2-methanesulfonylaminoethyl-4-chlorobenzenesulfonate. Yield: 7.3 g (60.8%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[NH2:14][OH:15]>>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12](=[NH:13])[NH:14][OH:15])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: N#CC1(COCCCl)CCOCC1
Reactant: NO
Product: N=C(NO)C1(COCCCl)CCOCC1
Yield: 84 %

Procedure:
Reaction of 4-((2-chloroethoxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (10.78 g, 52.9 mmol) with hydroxylamine gave 10.59 g (84% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.60 (2H, m, CH2), 2.04 (2H, m, CH2), 3.52 (2H, s, CH2), 3.55-3.85 (8H, m, 4×CH2), 5.01 (2H, broad s). MS (ESI+) m/e 237 [M+H+].
Reaction SMILES: C[CH2:2][S:3]([NH2:6])(=[O:5])=[O:4].[H-].[Na+].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[CH:21]1[O:29][CH:20]21)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[CH3:31]S(C)=O>>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[CH:21]([OH:29])[CH:20]2[N:6]([CH3:31])[S:3]([CH3:2])(=[O:5])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCS(N)(=O)=O
Reactant: CS(C)=O
Reactant: CC1(C)Oc2ccc(OCc3ccccc3)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C1c2cc(OCc3ccccc3)ccc2OC(C)(C)C1O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.25 g (39 mmol) of methyl-methanesulfonamide in 7.5 ml of DMSO were added dropwise to a suspension of 0.21 g (7 mmol) of 80 percent sodium hydride in 15 ml of DMSO, and the mixture was stirred at RT for 30 min. 8.2 g (29 mmol) of 6-benzyloxy-2,2-dimethyl-3,4-epoxychroman, dissolved in 18 ml of DMSO were then added dropwise, and the batch was heated at 50° C. for 2 days. The mixture was subsequently poured into water and the precipitate was filtered off with suction and dried well under reduced pressure, giving 8.8 g of N-(6-benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide, m.p. 162-164° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[OH-].[K+:34].CO>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([O-:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[K+:34]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2-[2-[4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid (0.20 g) was added to a mixture of a 1N aqueous potassium hydroxide solution (0.46 mL), methanol (5 mL) and tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give crystals (0.19 g, yield 86%) of potassium 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate. Recrystallization from methanol-diethyl ether gave colorless prism crystals. melting point: 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C([NH:30][CH2:31][C:32]([OH:34])=[O:33])(C)(C)C>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:30][CH2:31][C:32]([O:34][C:3]([CH3:18])([CH3:4])[CH3:2])=[O:33])=[CH:18][C:3]=1[C:4](=[O:5])[NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: CC(C)(C)NCC(=O)O
Product: CC(C)(C)OC(=O)CNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 80.1 %

Procedure:
Prepared according to the method of Example 1 using 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.2 g) and tertbutyl glycine (0.26 g) to deliver the sub-title compound as a brown foam (0.10 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:20]=[CH:21]/[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[NH:4][N:3]=1.CO.C1COCC1.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:20]=[CH:21]/[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: CN(C)C(=O)/C=C/c1ccc(-c2ccc([N+](=O)[O-])cc2)c2c(N)n[nH]c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)/C=C/c1ccc(-c2ccc(N)cc2)c2c(N)n[nH]c12
Temperature: 85 °C
Yield: 72.9 %

Procedure:
A solution of Example 84C (113 mg, 0.32 mmol) in a mixture of ethanol (1 mL), methanol (1 mL), and THF (1 mL) was treated with iron powder (144 mg) and NH4Cl (17 mg), heated to 85° C. for 4 hours, cooled to room temperature, and filtered. The filtrate was partitioned between water and ethyl acetate and the organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 75 mg of the desired product. MS (ESI(+)) m/e 322 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:14]([CH2:17][CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])=[N+:15]=[N-:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[N:14]([CH2:17][CH2:18][CH:19]([C:20]([F:21])([F:23])[F:22])[O:24][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=NCCC(O)C(F)(F)F
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)nc1OC(CCN=[N+]=[N-])C(F)(F)F
Reaction time: 20 h
Yield: 91.3 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinonitrile (0.675 g, 3.27 mmol) and 4-azido-1,1,1-trifluoro-2-butanol (0.552 g, 3.26 mmol) in DMF (8.5 mL) was treated with caesium carbonate (2.18 g, 6.69 mmol) at ambient temperature. After 20 h, the mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed (water, brine), dried, and-evaporated to give the product as a brown oil (1.01 g, 90%).
Reaction SMILES: COC1C=CC(N(OC(C)C(O)C)OC(C)C(O)C)=C(CCC)C=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)Cl)C=CC=CC=1.[CH2:49]([O:53][CH2:54][CH:55]1[CH2:62][N:61]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70]CCCCCCCCCCC)=[CH:65][CH:64]=2)[CH2:60][CH:59]([CH2:82][O:83][CH2:84][CH2:85][CH2:86][CH3:87])[O:58][P:57](=[O:94])([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[O:56]1)[CH2:50][CH2:51][CH3:52]>ClCCl>[CH2:84]([O:83][CH2:82][CH:59]1[CH2:60][N:61]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=2)[CH2:62][CH:55]([CH2:54][O:53][CH2:49][CH2:50][CH2:51][CH3:52])[O:56][P:57](=[O:94])([C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[O:58]1)[CH2:85][CH2:86][CH3:87]
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Agent: CCCc1cc(OC)ccc1N(OC(C)C(C)O)OC(C)C(C)O
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOCC1CN(c2ccc(OC)cc2)CC(COCCCC)OP(=O)(c2ccccc2)O1
Yield: 24 %

Procedure:
It is prepared from 4-methoxy-N,N-di(2-hydroxy-3-butoxy)-propyl aniline (1.91 g, 5 mmol), pyridine (1.2 g, 15 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonous dichloride (1 g, 5.1 mmol) in dichloromethane as described for compound 200 to obtain a colourless liquid 0.6 g (24%) and its isomer 0.6 g (24% a colourless liquid).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[CH:9][CH2:8][N:7]1S(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C)=CCN1S(=O)(=O)c1ccc(C)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]ccc1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
Pyrroline 83 (8.80 g, 28.48 mmol) was dissolved in THF (70 mL). DBU (9.78 mL, 65.50 mmol) was added dropwise and the resulting solution stirred under reflux overnight. The mixture was cooled to room temperature, diluted with ether and washed with 5% aq. HCl, 5% sodium bicarbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the crude solid 84 (4.30 g, 98%). 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.35 (s, 3H), 4.31 (q, 2H), 6.08 (d, 1H), 6.81 (d, 1H), 8.90 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ □ 12.76, 14.53, 59.96, 112.58□, 119.35, 121.53, 127.96, 162.01 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 12.76, 14.53; CH2 carbons: 59.96; CH carbons: 112.58, 121.53 ppm. LC/MS: 90.74%, m/z=153.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH2:19]([N:21](CC)CC)[CH3:20].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:21][CH2:19][CH3:20])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CCN
Solvent: CC(=O)CC(C)=O
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
First, 320 g (1.983 mol) of L-glutamic acid-γ-methyl ester was suspended in 500 g of methanol. To this, 219 g (2.186 mol, 1.1 eq.) of acetylacetone and 200 g (1.983 mol, 1 eq.) of triethylamine were added. The mixture was stirred at 60° C. for one hour. Subsequently, 1,277 g (19.8 mol) of 70% ethylamine was added to the mixture. After the mixture was allowed to react for 6 hours, the reaction solution was heated under normal pressure. In this manner, 667 g of excessive ethylamine was recovered and deprotection was performed at the same time. To the slurry of the theanine precipitated, 1 L of 2-propanol was added. The crystal was filtrated by suction and washed with 200 mL of 99.5% ethanol to obtain theanine (314.3 g) as a white crystal substance (yield: 91%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:63]([O-:65])=[O:64])=[C:47]([C:49]2[C:54]([O:55][CH3:56])=[CH:53][N:52]([CH:57]([CH3:61])[C:58](O)=[O:59])[C:51](=[O:62])[CH:50]=2)[CH:48]=1>CN(C=O)C>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:63]([O-:65])=[O:64])=[C:47]([C:49]2[C:54]([O:55][CH3:56])=[CH:53][N:52]([CH:57]([CH3:61])[C:58]([NH:1][C:2]3[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=3)=[O:59])[C:51](=[O:62])[CH:50]=2)[CH:48]=1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon and at RT, 25 mg (0.13 mmol) of tert-butyl 4-aminobenzoate, 44 μl (0.26 mmol) of N,N-diisopropylethylamine and 74 μl (50% strength in DMF, 0.13 mmol) of T3P were added to a solution of 30 mg (0.09 mmol) of 2-[4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) in 2 ml of DMF, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (71% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 170 °C
Yield: 26.1 %

Procedure:
A mixture of 266 (180 mg, 1.18 mmol), 2-fluoro-4-nitrophenol (558 mg, 3.55 mmol) and K2CO3(981 mg, 7.10 mmol) in Ph2O (4 mL) was heated at 170° C. for 8 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography with gradient elution of hexane, to hexane/EtOAc (1:1), to afford the title compound 267 (84 mg, 26% yield) as a yellowish solid. MS (m/z): 274. 1 (M+H) (found).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.C(O)(=O)C.C(O)(=O)C.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].C1C2=C3C(=CC=C2C=CC=1)N=C1C(C=CC=C1C(O)=O)=N3>C(O)(=O)C>[CH:9]1[C:10]2=[C:1]3[C:2](=[CH:3][CH:4]=[C:5]2[CH:6]=[CH:7][CH:8]=1)[N:31]=[C:30]1[C:22]([C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=[CH:29]1)=[N:21]3
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: Nc1cccc(C(=O)O)c1N
Agent: O=C(O)c1cccc2nc3c(ccc4ccccc43)nc12
Solvent: CC(=O)O
Product: O=C(O)c1cccc2nc3ccc4ccccc4c3nc12

Procedure:
A mixture of 1,2-naphthoquinone (commercially available, 2.0 g) and 2,3-diamino-benzoic acid, diacetate salt, (3.79 g) was heated to reflux in acetic acid (30 mL) for 2 hours. The reaction mixture was cooled and the solvent removed in vacuo to yield a gum. This was purified using flash chromatography to yield a 2:1 mixture of the desired title compound to the undesired benzo[a]phenazine-8-carboxylic acid (840 mg). The two isomers were separated after further modification (see Reference Example 3B below).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]([CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[SH:19](=[O:21])=[O:20])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>Cl.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[NH:14]1[CH2:17][CH:16]([N:18]([CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[SH:19](=[O:20])=[O:21])[CH2:15]1
Reactant: [H][H]
Reactant: O=[SH](=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[SH](=O)N(Cc1cc(F)cc(F)c1)C1CNC1
Yield: 102.9 %

Procedure:
N-Azetidin-3-yl-N-(3,5-difluorophenyl)methylsulfonamide hydrochloride is obtained in the following manner: in a 500-cm3 hydrogenator, a solution of 1 g of N-(1-benzhydrylazetidin-3-yl)-N-(3,5-difluorophenyl)methylsulfonamide in a mixture of 2.5 cm3 of 1M hydrochloric acid and 0.41 cm3 of acetic acid is hydrogenated in the presence of 0.161 g of palladium hydroxide at a hydrogen pressure of 30 bar for 4 hours. The catalyst is removed by filtration on a celite bed and then the filtrate is concentrated to dryness at 40° C. under 2.7 kPa to give 630 mg of N-azetidin-3-yl-N-(3,5-difluorophenyl)methylsulfonamide, melting at 216° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CCNCC
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)[C@@H](O)CC[C@@H]12)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL CH2Cl2 is added 22.5 mL (0.217 mmol) diethylamine. The reaction mixture is stirred at room temperature for 2 hours 30 minutes and then concentrated in vacuo to give an orange paste. The residue is dissolved in ethyl actate (EtOAc) and precipitated with hexane. The precipitate is washed two times with hexane to give 45 mg (77%) product as an orange solid. HRMS (ESI) m/z calcd for C27 H37NO8 503.25206, found: 504.25747 (M+H)+1.