Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]>C(OCC)(=O)C>[F:35][C:36]1[C:41]([O:17][C:16](=[O:18])[C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:5]([O:4][C:2]([CH3:19])([CH3:1])[CH3:3])=[O:6])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2.75 h
Yield: 99.7 %

Procedure:
N-(1,1-Dimethylethoxycarbonyl)phenylalanine (6.36 g, 24 mmol) in ethyl acetate (50 mL) at 0° C. was added to dicyclohexylcarbodiimide (4.95 g, 24 mmol) and pentafluorophenol (4.42 g, 24 mmol) in ethyl acetate (50 mL) at 0° C. The mixture was stirred for 2.75 h at 0° C. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate. The residue was dissolved in ethyl acetate. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate to give N-(1,1-dimethylethoxycarbonyl)phenylalanine pentafluorophenyl ester (10.32 g, quantitative).
Reaction SMILES: C(O[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9][CH2:8]2)(=O)C.C([OH:24])(CC)C.C(OC1C=C2C(=CC=1)[C@](C)(C(F)(F)F)OCC2)(=O)C>CCCCCC>[OH:24][CH:8]1[C:7]2[C:12](=[CH:13][CH:14]=[CH:5][CH:6]=2)[C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9]1
Reactant: CCC(C)O
Reactant: CC(=O)Oc1ccc2c(c1)CCOC2(C)C(F)(F)F
Agent: CC(=O)Oc1ccc2c(c1)CCO[C@@]2(C)C(F)(F)F
Solvent: CCCCCC
Product: C[C@]1(C(F)(F)F)OCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of racemic 6-acetoxy-1-methyl-1-trifluoromethylisochroman (38.4 g, 0.140 mol), 10% sec-butanol solution in hexane (1.3 L), and lipase PS (35 g) was stirred vigorously at room temperature for 23 hr. After filtration, the filtrate was concentrated under reduced pressure to give a mixture. This was purified by silica-gel column chromatography eluted with gradient of hexane and ethyl acetate (15:1,5:1,2:1) to give, first, (1R)6-acetoxy-1-methyl-1-trifluoromethyl-isochroman as a colorless oil (17.3 g, 45%, 94%ee). The 1H-NMR spectra of this compound was identical with that of racemate. The second fraction gave (1S)-4-hydroxy-1-methyl-1-trifluoromethyl-isochroman as crystals (16.9 g, 52%, 83%ee). The 1H-NMR spectra of this material was identical with that of racemate.
Reaction SMILES: [Na].CO.[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH2:14]>CCOC(C)=O>[CH3:9][O:8][C:6]([CH:5]([CH2:14][CH2:13][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]([O:11][CH3:12])=[O:10])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: C=Cc1ccncc1
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(CCc1ccncc1)C(=O)OC
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a stirred solution of elemental sodium (20 g, 840 mmol) and CH3OH (600 ml) was added dimethyl malonate 10-1 (135 ml, 1120 mmol). After 5 minutes, 4-vinyl pyridine 10-2 (15.3 ml, 140 mmoles) was added and the solution was heated to 50° C. for 18 h. The reaction was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatoraphy (silica, 60% EtOAc/hexanes) furnished the diether 10-3 (19.1 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:4][C:3]=1[F:9]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)c(F)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
step 1—To a solution of 4-bromo-3-fluoro-aniline (1.00 g, 5.263 mmol) in pyridine (5 mL) at 0° C. was added methanesulfonyl chloride (0.500 mL, 6.424 mmol). The reaction was gradually warmed to RT and stirred overnight then diluted with EtOAc. The organic layer was washed successively with saturated aqueous CuSO4 solution, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 20% EtOAc) to afford 1.235 g (88%) of N-(4-bromo-3-fluoro-phenyl)-methanesulfonamide (72) as a white solid.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[C:67]1[CH:79]=[CH:78][C:77]2[C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[C:70](=[O:80])[C:69]=2[CH:68]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:67]2[CH:79]=[CH:78][C:77]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[C:70](=[O:80])[C:69]=3[CH:68]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(=O)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
(3,4,5-Tris(octadecyloxy)-cyclohexyl)-methanol (82.5 mg, 89.7 μmol), 2-hydroxy-9-fluorenone (26.4 mg, 135 μmol) and triphenylphosphine (35.3 mg, 135 μmol) were dissolved in dehydrated THF (1.6 mL), DIED (27 μL, 137 μmol) was added, and the mixture was stirred for 1.5 hours. THF was evaporated, and 90% aqueous acetonitrile (10 mL) was added to the residue to allow crystallization. The crystals were filtered, and the obtained crystals were washed well with acetonitrile (10 mL) to give 2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenone (91.2 mg, 83.1 μmol, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4.[Na].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.C1(C=CC(O)=CC=1)O>CS(C)=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCC3C1
Reactant: C=Cc1ccc(C)nc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C2CCCN(C1)C2
Temperature: 100 °C

Procedure:
A solution of 10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (173.8 mg, 0.768 mmol; Example 201) in dimethyl sulfoxide (3 mL) was treated with sodium (30% dispersion in paraffin; 87.7 mg, 1.144 mmol; Aldrich), 2-methyl-5-vinylpyridine (204.6 mg, 1.717 mmol; prepared as described in International Publication No. WO 2001017968) and hydroquinone (28.6 mg, 0.260 mmol; Aldrich). The reaction was purged with nitrogen for 15 minutes, then heated to 100° C. for 17 hours. After cooling, the reaction was partitioned between 1 M K2CO3 (35 mL) and chloroform (3×35 mL). The combined organic layers were washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated. Methanol (10 mL) was added to the residue and the resulting suspension was filtered through diatomaceous earth, then purified by preparative HPLC (Phenomenex® Luna® Combi-HTS™ C8(2) 5 μm 100 Å AXIA™ 30×75 mm column, gradient of 10-100% acetonitrile in 0.1% trifluoroacetic acid, flow rate 50 mL/minute) to afford the title compound as the bis trifluoroacetic acid salt: 1H NMR (300 MHz, methanol-d4) δ ppm 1.54-1.78 (m, 3H), 1.95-2.05 (m, 1H), 2.41 (s, 3H), 2.67 (s, 3H), 3.42-3.55 (m, 4H), 3.68-3.72 (m, 1H), 4.34-4.41 (m, 1H), 4.48-4.57 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.27 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 8.03 (dd, J=8.3, 2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH2:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1>C1COCC1.C(N(CC)CC)C>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.5 %

Procedure:
4-(4-Biphenylylmethoxy)phenylacetic acid (1.51 g), tert-butyl 2-aminoethyl(methyl)carbamate (826 mg), WSC (1 g), 1-hydroxybenzotriazole (798 mg), and triethylamine (2.2 ml) were added to THF (90 ml). The reaction mixture was stirred at room temperature for 20 hr and poured onto water, followed by extraction with ethyl acetate-THF (1:1). The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride sequentially, dried with sodium sulfate, and concentrated. The residue was purified by alumina column chromatography (eluent; methanol:THF=1:1) followed by recrystallization from THF-IPE gave the titled compound (888 mg).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CO>[CH3:1][O:20][C:19](=[O:21])[CH2:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]=[CH:9][CH:10]=[N:11]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc2nccnc2c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc2nccnc2c1

Procedure:
Trimethylsilyldiazomethane [2.0M in hexanes] (0.08 mL) was added dropwise to a solution of quinoxalin-6-yl-acetic acid (0.030 g, 0.159 mmol) in toluene/methanol [8/1] (0.5 mL) and stirred until the bubbling stopped. The reaction was then evaporated and the crude product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 0.013 g of quinoxalin-6-yl-acetic acid methyl ester. This was added to a solution of hydrazine (0.10 mL) in methanol and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo to give 0.019 g of quinoxalin-6-yl-acetic acid hydrazide. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (bs, 1H), 9.35 (m, 2H), 8.46 (d, 1H, J=8.8 Hz), 8.39 (m, 1H), 8.19 (dd, 1H, J=2.0, 8.8 Hz), 4.68 (bs, 2H), 4.07 (s, 2H).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH2:24][C@H:25]([C:27]([NH:29][C@H:30]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@H:55]([C:65]([NH:67][C@H:68]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:69][O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:66])[CH2:56][CH2:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:53])[CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:41])[CH2:31][CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:28])[CH3:26].FC1C(O)=C(F)C(F)=C(F)C=1F.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@H:55]([C:65]([NH:67][C@H:68]([C:75]([O:77][C:78]([CH3:79])([CH3:81])[CH3:80])=[O:76])[CH2:69][O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:66])[CH2:56][CH2:57][C:58](=[O:64])[O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:53])[CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:41])[CH2:31][CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:28])[CH3:26])=[O:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
2.59 g. (8 mmoles) of Z-Asn-Gly-OH, 6.65 g. (8 mmoles) of H-Ala-Glu(OtBu)-Asp(OtBu)-Glu(OtBu)-Ser(tBu)-OtBu and 4.86 g. of pentafluorophenol are dissolved in 28 ml. of DMF. The solution is cooled to 0° C, and 1.81 g. (8.8 mmoles) of DCC are added to it. The reaction mixture is stirred at 0° C for 0.5 hours, and stirring is continued at room temperature for 2.5 hours. The separated DCU is removed by filtration; the filtrate is evaporated to dryness, and the residue is triturated with ethyl acetate. 7.3 g. (80.5 %) of Z-25-31-OtBu are obtained. M.p.: 194° C (under decomposition), Rf3 = 0.6.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][N:8]2[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]4[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[CH:21]4)[CH:14]=[C:9]23)[CH2:3][CH2:2]1.CC1(C)C2C=CC=CC=2I([C:37]([F:40])([F:39])[F:38])O1>C(Cl)(Cl)Cl.[Zn](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>[CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][N:8]2[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]4[CH:24]=[C:23]([CH2:25][O:26][C:37]([F:40])([F:39])[F:38])[N:22]=[CH:21]4)[CH:14]=[C:9]23)[CH2:3][CH2:2]1
Reactant: O=C1CN=C(n2cnc(CO)c2)C=C2c3cccc(C4CC4)c3CCN12
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Agent: O=S(=O)(N([Zn]N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1CN=C(n2cnc(COC(F)(F)F)c2)C=C2c3cccc(C4CC4)c3CCN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.9 %

Procedure:
A solution of 9-cyclopropyl-2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (135 mg, 0.38 mmol) in CHCl3 (50 mL) under Ar, was treated with 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol) and Zn(NTf2)2 (242 mg, 0.39 mmol). The mixture was stirred at RT for 16 h, and then treated again with 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol) and Zn(NTf2)2 (242 mg, 0.39 mmol). After 24 h, the mixture was poured onto H2O and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 100:0 to 95:5) and by SFC (column: PPU 5 m, 250×30 mm, 60 A, Princeton; eluent: isocratic 20% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (3 mg). UPLC-MS: MS 417.2 (M+H+); UPLC rt 1.15 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.56-0.71 (m, 2H); 0.93-1.05 (m, 2H); 1.91-2.04 (m, 1H); 3.14-3.20 (m, 2H); 3.89-4.01 (m, 2H); 4.34 (br s, 2H); 5.00 (s, 2H); 7.03 (s, 1H); 7.18-7.26 (m, 1H); 7.26-7.34 (m, 1H); 7.69-7.85 (m, 2H); 8.25 (s, 1H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH:13]=C)[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8](=[O:11])[CH2:9][CH3:10])[CH2:12][CH:13]=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(C(=O)CC)(c1ccccc1)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 17.2 %

Procedure:
4,4-diphenyl-6-hepten-3-one (144 mg) was dissolved in a mixture of dioxane and water (3:1, 11 ml). A 10% aqueous osmium tetroxide solution (0.5 ml) was added. The resultant solution was stirred at room temperature for 5 min. A solution of sodium periodate (550 mg) in water was then added dropwise. The reaction mixture was allowed to stir for 16 hours. Water was added, and the aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water (once) and dried (MgSO4). Rotary evaporation of the solution gave a crude product which was purified by preparative thin layer chromatography (PTLC) on silica gel. Development with hexane/ethyl acetate (2:1) produced three bands. The lowest band (Rf 0.66) was scraped off the plate and eluted with methanol to yield 25 mg of 3,3-diphenyl-4-oxo-hexanal.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CC)=O.[NH2:20][C:21]1[C:26]([Mg]Br)=[CH:25][CH:24]=[CH:23][N:22]=1>>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:17]
Reactant: Nc1ncccc1[Mg]Br
Reactant: CCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O

Procedure:
The process of claim 1, wherein ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide of formula (V) is reacted with 2-amino-pyridyl-magnesium bromide of formula (VI) to give 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=O)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]1[NH:51][CH2:50][CH2:49][N:48]2[CH2:52][CH2:53][CH2:54][C@H:47]12>CN(C)C(=O)C.CC1CCCO1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][S:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:51]2[CH2:50][CH2:49][N:48]3[CH2:52][CH2:53][CH2:54][C@@H:47]3[CH2:46]2)=[O:18])[CH:14]=1)(=[O:12])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid (0.96 g, 3.06 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.28 g, 3.37 mmol) in N,N-dimethylacetamide (7.4 mL) and 2-methyltetrahydrofuran (22 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (0.54 g, 4.28 mmol). The reaction was stirred at ambient temperature for 5.5 hours, and then it was diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (35 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCO3/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×15 mL), and then it was concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2s1
Yield: 64 %

Procedure:
Prepared from VII and 3-chloro-4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 64%; yellow solid; mp 252° C.; IR (KBr) νmax/cm−1 3456, 3015, 2970, 2946, 2229, 1642, 1441, 1153, 1129, 1051, 968, 903, 817, 774, 695; 19F NMR (282 MHz, DMSO-d6) δ −123.8; 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, 1H, J=9.0 Hz), 8.30 (s, 1H), 7.62 (m, 2H), 7.34 (m, 2H); HRMS calcd for C16H7N5SClF (M+H+): 356.0156, found 356.0167.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)(=[O:23])[CH3:22]>C(N(CC)CC)C>[C:21]([NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:27]1)(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(=O)NCC1CCCNC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 6 h
Yield: 83.5 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(2.83 g), 3-acetamidomethylpiperidine (1.87 g) and triethylamine (1.5 g) inacetonitrile (60 ml) was refluxed with stirring for 6 hours. The precipitate was filtered to give 7-(3-acetamidomethylpiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.5 g). The product (3.0 g) was suspended in 6N hydrochloric acid (50 ml) and heated at 100° C. with stirring for 5 hours. The reaction mixture was concentrated in vacuum, and the crude material was dissolved in 20 ml of aqueous ammonium hydroxide under ice-cooling. Removal of the solvent followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave 7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.6 g), which was recrystallized from methanol-water to afford colorless prisms. m.p. 242°-243° C.