Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>CS(C)=O>[C:1]1([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2ccccc12
Solvent: CS(C)=O
Product: c1ccc2c(OCC3CO3)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 1-naphthol (3.0 g, 0.02 mol) in DMSO (10 mL), potassium hydroxy (flakes, 2.0 g, 0.06 mol) was added. The combined mixture was stirred at room temperature for 30 min and then epichlorohydrin (5.6 g, 4.7 mL, 0.06 mol) was added slowly over a period of 45 min and stirring was continued for 16 hours. The reaction was quenched with water (30 mL) and extracted with chloroform (2×50 mL). The combined organic layers were washed with 1N aqueous NaOH (2×50 mL), water (2×100 mL) and brine (2×100 mL) and dried over MgSO4. The solvent was removed under reduced pressure to provide Compound 1 as a yellow liquid (3.26 g, 78%). This product was used without further purification. The structure of Compound 1 is given below:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][N:36]1[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]1)[CH:9]=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)c1
Solvent: CO
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC(O)CN4CCN(c5ccccc5)CC4)cc3o2)c1

Procedure:
3′,5′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 32 (400 mg, 1.13 mmol) and 1-phenyl piperazine (0.17 mL, 1.13 mmol) in dry methanol (100 mL) were reacted in a similar manner to that described under 34 to afford 45. Yield 490 mg (84%); mp 195-196° C.; MS (FAB) 517 (M++1); IR (KBr) 3417, 1633; 1H NMR (200 MHz, DMSO-d6) δ 7.97 (d, J=8.8 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.24 (d, J=1.9 Hz (d, J=7.9 Hz, 2H), 7.12 (dd, J=8.9 Hz, 1.9 Hz, 1H), 7.04 (s, 1H), 6.93 (d, J=8.2 Hz, 2H), 6.80 (d, J=7.1 Hz, 1H), 6.74 (s, 1H), 4.25-4.09 (m, 3H), 3.87 (s, 6H), 3.13 (t, J=6.5 Hz, 4H), 2.63 (d, J=4.5 Hz, 2H), 2.47-2.43 (m, 4H). Analysis Calcd for C30H32N2O6: C, 69.75; H, 6.24; N, 5.42. Found: C, 69.61; H, 6.53; N, 5.61.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].F[C:13]1[C:18]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH:7][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[N:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)F)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cccc(OC(F)F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 3-(difluoromethoxy)aniline (0.038 mL, 0.303 mmol) (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.09 g, 0.202 mmol) in THF (3.0 mL) at 0° C. was treated with LiHMDS 1.0 M in THF (0.606 mL, 0.606 mmol) (Aldrich) dropwise. The solution was stirred at 0° C. for 1.5 h and was then quenched with a saturated solution of NH4Cl at 0° C. The mixture was extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to give 4-(2-(3-(difluoromethoxy)phenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.121 g, 0.207 mmol, 99% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 12.12 (br. s., 1H); 8.84 (d, J=8.2 Hz, 1H); 8.35 (br. s., 1H); 7.72 (br. s., 1H); 7.31 (d, J=8.4 Hz, 1H); 7.20 (d, J=7.8 Hz, 5H); 7.11 (t, J=8.0 Hz, 4H); 6.84-6.90 (m, 4H); 6.80 (d, J=7.8 Hz, 1H); 6.71 (d, J=8.4 Hz, 1H); 6.65 (br. s., 1H); 6.45-6.54 (m, 10H); 6.42 (br. s., 4H); 6.28 (br. s., 1H); 4.84 (br. s., 4H); 3.80 (d, J=3.5 Hz, 7H); 2.60 (br. s., 3H). m/z (ESI, +ve ion) 585.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[NH2:19])(=[O:10])=[O:9])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[NH:19][S:29]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
To a solution of 5-bromo-N-(4-fluoro-2-aminophenyl)-2-methoxybenzenesulfonamide (0.1 mmol) in pyridine (0.5 mL) and DCM (2 mL), 4-chlorobenzenesulfonyl chloride (0.12 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then diluted with ethyl acetate (10 mL). The contents were washed with 10% aqueous HCl (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate (1:1) followed by ethyl acetate to give 43 mg of 5-bromo-N-[2-(4-chlorobenzenesulfonylamino) -4-fluorophenyl]-2-methoxybenzenesulfonamide. LC: Tr 1.10 min, MS: 551.8 (M+1)+
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[C:8](=O)[C:9](=[O:13])[NH:10][C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[O:13]=[C:9]1[C:8](=[N:22][NH:21][C:20]2[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=2)[C:7]2[CH:6]=[C:5]3[O:1][CH2:2][O:3][C:4]3=[CH:12][C:11]=2[NH:10]1
Reactant: O=C1Nc2cc3c(cc2C1=O)OCO3
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc4c(cc32)OCO4)cc1
Yield: 55 %

Procedure:
The title compound was prepared from 5H-[1,3]dioxolo[4,5-f]indole-6,7-dione (Lackey and Stembach, Synthesis 1993, 993-7) and 4-sulfonamidophenylhydrazine hydrochloride in 55% yield as an orange crystalline solid following Procedure G: mp>220° C.; 1H NMR (DMSO-d6): δ 12.63 (s, 1H), 10.89 (s, 1H), 7.73 (d, J=7 Hz, 2H), 7.50 (d, J=7 Hz, 2H), 7.22 (s, 2H), 7.13 (s, 1H), 6.56 (s, 1H), 6.00 (s, 2H), Anal. Calcd for C15H12N4O5S: C, 50.00; H, 3.36; N, 15.55. Found: C, 50.08; H, 3.35; N, 15.49.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH2:22]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([C:17]1[CH:18]=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1)[CH:21]=[CH2:20]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.8 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7) (10 g, 29.7 mmol) in N,N-dimethylformamide (20 mL) was added allyltributylstannane (14 mL, 44.51 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.72 g, 1.49 mmol) at room temperature and then stirred at 80° C. for 12 h. The mixture was cooled to room temperature and extracted with ethyl acetate (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 5-allyl-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine as a white solid (5.3 g, 60%): LC/MS m/e calcd for C16H14N2O2S [M+H]+ 299.37, observed 299.1.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][N:3]1[CH2:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][N:3]1[CH2:13][C:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2)=[O:16]
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)CN1CCN(c2ccccn2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)C1=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of (2-oxo-3-pyridin-2-ylimidazolidin-1-yl)acetic acid (22 mg, 0.10 mmol, described in Intermediate 14), (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (25 mg, 0.10 mmol, described in Intermediate 4), EDC (19 mg, 0.10 mmol), HOBT (15 mg, 0.10 mmol), and N,N-diisopropylethylamine (0.0138 mL, 0.10 mmol) is stirred in DMF (0.5 mL) at ambient temperature for 18 h. The crude mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provides the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14](Br)[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1.[CH3:24][Sn](C)(C)C.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14]([CH3:24])[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1
Reactant: Cc1c(Br)c(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: C[Sn](C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1c(C)c(-c2ccc3c(c2)C(C)(C)OC(=O)N3)n(C)c1C#N
Yield: 85.8 %

Procedure:
A solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile (0.11 g, 0.29 mmol), PhCNPdCl(PPh3)2 (cat., 11 mg) and tetramethyltin (10 eq, 0.53 g, 2.9 mmol) in HMPA (3 mL) was heated to 110° C. for 5d. The solution was allowed to cool, poured into water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile (77 mg, 85%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.63 (s, 6H), 1.87 (s, 3H), 2.49 (s, 3H), 3.50 (s, 3H), 6.99 (d, 1H, J=8.2 Hz), 7.25 (dd, 1H, J=8.2, 1.4 Hz), 7.29 (s, 1H), 10.39 (s, 1H). MS (ESI (−)) 308 (M−H)−. Anal. calcd for C18H19N3O4, C, 69.9, H, 6.19, N, 13.6. Found, C, 68.8, H, 6.22, N, 12.9.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])([CH2:10][OH:11])[CH2:8][OH:9].C([O-])([O-])=O.[K+].[K+].CO>C(#N)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])([CH2:8][OH:9])[CH2:10][OH:11])[CH:17]=1
Reactant: NC(CO)(CO)c1cc(Br)ccc1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=C(CCl)NC(CO)(CO)c1cc(Br)ccc1F
Reaction time: 2 h

Procedure:
A solution of chloro-acetyl chloride (6.39 ml, 80 mmol) in 10 ml ACN was added dropwise to a mixture of 2-amino-2-(5-bromo-2-fluoro-phenyl)-propane-1,3-diol (5.3 g, 20 mmol) and K2CO3 (11.1 g, 80 mmol) in 90 ml ACN while the temperature did not rise above 35° C. The mixture was stirred for 2 h. MeOH (40 ml, 99 mmol) were added and after 5 min stirring the mixture was filtered over celite and washed with MeOH. The filtrate was acidified with citric acid solution (10%, aqueous) (pH 4-5) and partly evaporated. The remaining aqueous layer was extracted with EtOAc. The organic layer was washed with NaHCO3 solution (10%, aqueous) and brine, dried with Na2SO4 and evaporated to provide the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4](=O)[C:5]2=O.COP([CH2:18][C:19](=O)[CH2:20][C:21]1([CH3:24])[CH2:23][CH2:22]1)(=O)OC.O.[NH2:27][NH2:28]>>[CH3:1][C:2]1([CH3:11])[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[CH:18]=[C:19]([CH2:20][C:21]3([CH3:24])[CH2:23][CH2:22]3)[N:27]=[N:28][C:5]=12
Reactant: COP(=O)(CC(=O)CC1(C)CC1)OC
Reactant: CC1(C)C2CCC1C(=O)C2=O
Reactant: NN
Solvent: O
Product: CC1(Cc2cc3c(nn2)C2CCC3C2(C)C)CC1

Procedure:
Light-yellow solid MS (ESI): 243.1 (MH+). Prepared from 7,7-dimethyl-bicyclo[2.2.1]heptane-2,3-dione (R. F. Childs et al., J. Am. Chem. Soc.; 1980; 102; 4159), [3-(1-methyl-cyclopropyl)-2-oxo-propyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]1([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:12][CH2:13][C:14]([C:4]1[CH:3]=[CH:2][C:1]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CS(=O)(=O)Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)CCl)cc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
In a flask containing 128.4 g (0.75 mole) of N-phenylmethanesulfonamide, 169.5 g (1.50 mole) of chloroacetyl chloride in 1 L of methylene chloride under an atmosphere of nitrogen and cooled to about -10° C. add 300 g (2.25 mole) of aluminum chloride. Stir the resulting mixture for about 16 hours. Pour the reaction mixture onto 2 Kg of ice containing 600 mL of concentrated hydrochloric acid. Collect the precipitate and wash with methanol (3×300 mL) and dry in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:19]([O-])([O-])=O.[Na+].[Na+].O>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: O=C(O)c1cc(O)cc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 3-hydroxy-5-nitrobenzoic acid (2.00 g, 11 mmol) and concentrated sulfuric acid (0.5 mL) in MeOH (15 mL) was refluxed overnight, cooled to room temperature, and poured into mixture of Na2CO3 (saturated solution, 25 mL), water (150 mL), and ice (50 g). Resulting precipitate was filtered, washed with water (3×30 mL), and air-dried. Yellow microcrystals, yield 1.37 g (63%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.94 (s, 1H); 8.09 (s, 1H); 7.78 (s, 1H); 7.71 (s, 1H); 3.90 (s, 3H).
Reaction SMILES: O=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:19]>CO>[NH2:19][C@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)Cc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C[C@H](N)Cc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ru(OAc)2((R)-dm-binap) (0.248 g, 0.260 mmol), methyl 3-oxo-4-phenylbutanoate (10.00 g, 52.0 mmol), ammonium acetate (4.01 g, 52.0 mmol) and methanol (50 mL) were placed in a 200 mL stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 14 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R)-3-amino-4-phenylbutanoate as a crude material (13.01 g). The enantiomeric excess of methyl (3R)-3-amino-4-phenylbutanoate in the crude product was determined to be 94.7% ee by HPLC analysis using a SUMICHIRAL OA-4100R column after conversion into methyl (3R)-3-(4-nitrobenzoylamino)-4-phenylbutanoate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[ClH:15]>S(Cl)(Cl)=O.O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Br
Reactant: Cl
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Br

Procedure:
10 g of 4-bromo-3-sulfamoylbenzoic acid were heated under reflux in a mixture of 80 ml of thionyl chloride and 50 ml of dioxane until HCl had completely developped. Then, the reaction mixture was concentrated under reduced pressure to 40 ml, 200 ml of petroleum ether were added and the crystals were filtered off. Melting point: 138° C (decomposition).
Reaction SMILES: CC1C=CC(C(C)C)=CC=1.[CH3:11][C:12]1[CH:17]=[C:16]([P:18]([C:56]2[CH:61]=[C:60]([CH3:62])[CH:59]=[C:58]([CH3:63])[CH:57]=2)[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[P:39]([C:48]2[CH:53]=[C:52]([CH3:54])[CH:51]=[C:50]([CH3:55])[CH:49]=2)[C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=2)[CH:15]=[C:14]([CH3:64])[CH:13]=1.[Cl:65][Ru:66]Cl.C(NCC)C.[CH3:73][CH:74]([C@H:76]([NH2:95])[C:77]([NH2:94])([C:86]1[CH:91]=[CH:90][C:89]([O:92][CH3:93])=[CH:88][CH:87]=1)[C:78]1[CH:83]=[CH:82][C:81]([O:84][CH3:85])=[CH:80][CH:79]=1)[CH3:75]>CO>[CH3:63][C:58]1[CH:57]=[C:56]([P:18]([C:16]2[CH:15]=[C:14]([CH3:64])[CH:13]=[C:12]([CH3:11])[CH:17]=2)[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[P:39]([C:48]2[CH:49]=[C:50]([CH3:55])[CH:51]=[C:52]([CH3:54])[CH:53]=2)[C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=2)[CH:61]=[C:60]([CH3:62])[CH:59]=1.[CH3:75][CH:74]([C@H:76]([NH2:95])[C:77]([NH2:94])([C:78]1[CH:79]=[CH:80][C:81]([O:84][CH3:85])=[CH:82][CH:83]=1)[C:86]1[CH:87]=[CH:88][C:89]([O:92][CH3:93])=[CH:90][CH:91]=1)[CH3:73].[Cl-:65].[Ru+:66]
Reactant: Cl[Ru]Cl
Agent: COc1ccc(C(N)(c2ccc(OC)cc2)[C@@H](N)C(C)C)cc1
Agent: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccc3ccccc3c2-c2c(P(c3cc(C)cc(C)c3)c3cc(C)cc(C)c3)ccc3ccccc23)c1
Solvent: CO
Solvent: CCNCC
Solvent: Cc1ccc(C(C)C)cc1
Product: [Cl-]
Product: [Ru+]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under a nitrogen gas, [RuCl2(p-cymene)]2 3.07 g (5.0 mmol), (S)-XylBINAP 7.35 g (10.0 mmol) and methanol 110 mL were added to a 200 mL 4-neck flask. The mixture was heated to 50° C. and stirred for 2 hours to prepare [RuCl(p-cymene)((S)-xylbinap)]Cl. The reaction solution was cooling down to room temperature, then diethylamine 736 mg (10 mmol) and (S)-DAIPEN 3.48 g (11.1 mmol) were added to the reaction solution, and stirred for 3 hours at 60° C. After concentration, the residue was dissolved in butyl acetate and the precipitated salts were separated by filtration. The filtrate was concentrated and the mixture added with heptane (110 mL) was cooling down to −10° C. The precipitated crystals were filtered to obtain the title compound (11.62 g) with yield of 98%.
Reaction SMILES: [OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][NH:20]C)[CH2:13][CH2:12]2)[CH2:6][C:5]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:4]=2[O:3]1.C1COCC1.C([O-])(O)=O.[Na+].Cl[C:41]([O:43][CH3:44])=[O:42]>O.CO>[OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][NH:20][C:41]([O:43][CH3:44])=[O:42])[CH2:13][CH2:12]2)[CH2:6][C:5]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:4]=2[O:3]1
Reactant: CNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-2-hydroxy-3-(2-(trans-4-(2-(methylamino)ethylamino)cyclohexyl)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 51 (39 mg) in a mixture of H2O (1 mL), THF (1 mL) and MeOH (1 mL) was added NaHCO3 (200 mg), followed by methyl chloroformate (1.2 eq). The reaction mixture was stirred at RT overnight. The solvent was then removed in vacuo and the crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 448 (MH)+.
Reaction SMILES: [CH2:1]1[C:3]([NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])([C:4]([OH:6])=O)[CH2:2]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.[O:51]1[CH:55]=[C:54]([C:56]2([NH2:59])[CH2:58][CH2:57]2)[N:53]=[CH:52]1>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C:3]1([C:4](=[O:6])[NH:59][C:56]2([C:54]3[N:53]=[CH:52][O:51][CH:55]=3)[CH2:58][CH2:57]2)[CH2:2][CH2:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1(c2cocn2)CC1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
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: CN(C)C=O
Product: O=C(NC1(C(=O)NC2(c3cocn3)CC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
To a round bottom flask was added Z-1-aminocyclopropane-1-carboxylic acid (150 mg, 0.638 mmol) in DMF (10 ml), followed by the addition of Hunig's base (207 mg, 1.6 mmol) and HATU (270 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of 1-Oxazol-4-yl-cyclopropylamine (200 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC to afford 70 mg of [1-(1-oxazol-4-yl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid benzyl ester, m/z 343 [M+1]+.