Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@@H:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.CN(C=O)C.[N+](C1C=CC([O:55][C:56](=O)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=CC=1)([O-])=O.C(N(CC)CC)C>C(O)(=O)C>[NH2:37][C:36](=[N:38][C:56](=[O:55])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:35]1[CH:34]=[CH:33][C:32]([NH:31][C@H:18]([C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[C:6]=2[F:5])[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[N:20]=2)=[CH:40][CH:39]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzamidine acetic acid salt [CAS No. 951803-91-1] (5.6 g) and DMF (200 mL), benzoic acid 4-nitrophenyl ester (2.89 g) and triethylamine (4.7 mL) were added, and the resulting mixture was stirred overnight at room temperature. Acetic acid (6.5 mL) was added to the reaction solution, and then the solvent was evaporated under reduced pressure. The residue obtained was crudely purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid), and the crudely purified product obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (4.48 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=O)=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].Cl.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[NH:1]1[C:21](=[O:23])[CH2:20][NH:19][C:17](=[O:18])[CH2:16][NH:15][C:13](=[O:14])[C@@H:11]([CH3:12])[NH:10][C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[CH2:2]1
Reactant: C[C@H](NC(=O)CN)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1NC(=O)CNC(=O)CNC(=O)CNC(=O)[C@@H](C)NC1=O
Temperature: -25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
This compound was synthesized by the method of Veber, D. F. et al, J. Org. Chem., 44, 3101-5 (1979). To a solution of Gly-Ala-DAla-Gly-Gly.HCl prepared as in Example 33D (12.9 g, 35.0 mmol) in anhydrous DMF (4400 ml) was added enough TEA to adjust the pH to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the resulting mixture was cooled to -25° C. To this mixture was added DPPA (9.20 ml, 43.0 mmol) dropwise over 5 min. The reaction was stored at -25° C. (internal temperature) for 48 h thereafter. During this time the pH was monitored periodically (as described above) and maintained at ~8 by the addition of TEA. After this time the reaction mixture was allowed to stand at 0° C. for 48 h. Again the pH was monitored periodically and maintained at ~8 by the addition of TEA. After this time the reaction mixture was diluted with water (4400 ml) and stirred with Bio-Rad AG 501-X8 (mixed-bed) resin (200 g) for 6 h. The resin was separated by filtration and the solution was concentrated to dryness. Trituration of the residue with refluxing THF (250 ml) for 3 h, filtration of the hot THF and drying at high vacuum afforded 6.61 g (60% yield) of the product as a white powder: 1H NMR (DMSO-d6) δ 1.15-1.32 (m, 6 H), 3.45-4.00 (m, 6 H), 4.10-4.38 (m, 2 H), 7.81 (d, J=7.8 Hz, 1 H), 7.97 (t, J=6.6 Hz, 1 H), 8.10 (m, 2 H), 8.18 (d, J=7.5 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:33])[C:7](=[O:32])[N:8](COCC[Si](C)(C)C)[N:9]=1.O=[C:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:33])[C:7](=[O:32])[NH:8][N:9]=2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(OCc4ccccc4)c(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(OCc4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 6-amino-7-benzyloxy-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.065 g, 0.19 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.061 g, 0.36 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated at 70° C. for 14 h. The reaction mixture was cooled to ambient temperature and sodium cyanoborohydride (0.022 g, 0.36 mmol) was added. The reaction mixture was heated at 70° C. for 1 hr then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-(7-benzyloxy-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.028 g, 32%). LC/MS (Table 1, Method 2) Rt=1.205 min; MS m/z: 516 [M+23]+
Reaction SMILES: [CH3:1][N:2](C)C(Cl)=O.C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[CH2:27]([O:29][C:30](=[O:43])[CH:31]([O:39][CH:40]([CH3:42])[CH3:41])[CH2:32][C:33]1[CH:38]=[CH:37][NH+:36]=[CH:35][CH:34]=1)[CH3:28].C[Si](C#N)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([C:37]1[CH:38]=[C:33]([CH2:32][CH:31]([O:39][CH:40]([CH3:42])[CH3:41])[C:30]([O:29][CH2:27][CH3:28])=[O:43])[CH:34]=[CH:35][N:36]=1)#[N:2]
Reactant: CCOC(=O)C(Cc1cc[nH+]cc1)OC(C)C
Reactant: CN(C)C(=O)Cl
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccnc(C#N)c1)OC(C)C
Reaction time: 11.5 h

Procedure:
2.3 mL dimethyl carbamyl chloride was added dropwise over 40 minutes into a solution of 6.40 g crude 4-(3-ethoxy-2-isopropoxy-3-oxopropyl)-1-pyridinium oleate and 3.3 mL trimethylsilyl cyanide in dichloromethane (60 mL), followed by stirring for 11.5 hours. 10% aqueous potassium carbonate was added to the reaction solution, followed by stirring at room temperature for 30 minutes. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography, to give 3.87 g of ethyl 3-(2-cyano-4-pyridyl)-2-isopropoxypropanoate as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:33][S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])(=[O:31])=[O:32])=[O:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
The carboxylic acid (Example 2) (6.2 g) was stirred at room temperature in dichloromethane (50 ml) with 2-methylbenzene sulphonamide (3.4 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.6 g) and 4-dimethylaminopyridine (0.25 g) for 72 hours. The reaction mixture was diluted with dichloromethane and washed with 0.5N hydrochloric acid, then water. The organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with 0-2% ethyl acetate in dichloromethane, afforded N-[1-(3-nitrobenzyl)indol-5-ylcarbonyl]-2-methylbenzene sulphonamide (m.p. 208°-210° C.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH3:33][C:34]1[O:38][C:37]([C:39](Cl)=[O:40])=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:39]([C:37]3[O:38][C:34]([CH3:33])=[CH:35][CH:36]=3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1ccc(C(=O)Cl)o1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1ccc(C(=O)N2CCN(c3nc4cc(F)cc(F)c4c(Nc4cncc(N5CCOCC5)c4)c3C)CC2)o1

Procedure:
Prepared according to Procedure R using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and 5-methylfuran-2-carbonyl chloride to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(5-methylfuran-2-yl)methanone. 1H NMR (CDCl3) δ ppm 2.11 (br s, 3H), 2.49 (br s, 3H), 3.06 (t, J=5.6 Hz, 4H), 3.30-3.40 (m, 4H), 3.69 (t, J=5.6 Hz, 4H), 3.86 (br s, 4H), 6.27 (br s, 1H), 6.52 (s, 1H), 6.94 (d, J=3.2 Hz, 1H), 7.16 (s, 1H), 7.28-7.31 (m, 1H), 7.53 (br s, 1H,), 7.79 (br s, 1H), 8.37 (s, 1H). Mass Spectrum (ESI) m/e=549.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:18][CH2:17][C:10]2([NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]1[N:37]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:30]2[N:31]=[C:32]([C:35]#[N:36])[N:33]=[CH:34][C:29]=2[CH:28]=1>CN(C=O)C>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][N:37]1[C:30]2[N:31]=[C:32]([C:35]#[N:36])[N:33]=[CH:34][C:29]=2[CH:28]=[C:27]1[CH2:26][N:12]1[C:11](=[O:16])[C:10]2([CH2:9][CH2:8][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:18][CH2:17]2)[NH:14][C:13]1=[O:15]
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: O=C1NC(=O)C2(CCN(c3ncccn3)CC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)NC3(CCN(c4ncccn4)CC3)C2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a solution of 180.0 mg (0.728 mmoles) of 8-pyrimidin-2-yl-1,3,8-triaza-spiro[4.5]decane-2,4-dione in 2.0 ml of DMF, 99.4 mg (0.719 mmoles) of K2CO3 and 170.0 mg (0.553 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added at ambient temperature. The mixture is stirred for 5 hours at ambient temperature and filtered. The mixture is diluted with AcOEt and H2O, and then extracted with AcOEt. The combined extracts are washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 151.5 mg of desired 7-(2,2-dimethyl-propyl)-6-(2,4-dioxo-8-pyrimidin-2-yl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 58% yield.
Reaction SMILES: [NH2:1][C:2](C(O)=O)([CH2:6][CH2:7][CH:8]([F:13])[CH:9]([NH2:12])[CH:10]=[CH2:11])[C:3]([OH:5])=[O:4].Cl>C(O)(=O)C>[F:13][CH:8]([CH:9]([CH:10]=[CH2:11])[NH2:12])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: C=CC(N)C(F)CCC(N)(C(=O)O)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: C=CC(N)C(F)CC[C@H](N)C(=O)O

Procedure:
Reaction of the iodide 21 with diethylphthalimidomalonate yields ethyl 2,6-diphthalimido-2-ethoxycarbonyl-5-fluoro-7-octenoate, 22. Removal of the amino-protecting groups leads to ethyl 2,6-diamino-2-ethoxycarbonyl-5-fluoro-7-octenoate, 23. Acid hydrolysis of 23 yields 2,6-diamino-2-carboxy-5-fluoro-7-octenoic acid 24, which is decarboxylated by heating with acetic acid in the presence of hydrochloric acid to yield δ-fluoro-ε-vinyllysine, 25. Protection of the amino groups wih di-tert-butyl dicarbonate and triethylamine results in the preparation of Nα,Nε -di-tert-butoxycarbonylamino-δ-fluoro-ε-vinyllysine, 26, which upon oxidation with potassium permanganate yields Nα,Nε -di-tert-butoxycarbonylamino-δ-fluoro-ε-carboxylysine, 27. Removal of the protecting group with HCl results in the desired δ-fluoro-ε-carboxylysine, 2.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:32][CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:27][N:28]=[C:29]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH2:37])(=[O:38])=[O:39])=[CH:32][CH:31]=4)[N:40]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)n2)cc1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.31) (188 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/dichloromethane) as a yellow solid (220 mg, 79%). MS (ISP) 555.3 [(M+H)+]; mp 300° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9].CCO.Cl>O>[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)COc1ccc(-c2cccnc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(-c2cccnc2)cc1Cl

Procedure:
250 mg (6.250 mmol) NaOH in 10 mL water was added to a solution of 0.400 g (1.371 mmol) ethyl (2-chloro-4-pyridin-3-yl-phenoxy)-acetate in 40 mL abs. EtOH and the mixture was stirred for 1 h at RT. The reaction mixture was acidified with aqueous HCl (1 M) to pH 7.5, the precipitate was filtered off and washed with water.
Reaction SMILES: CC(C)N=C=NC(C)C.O[CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14].[CH3:20][CH2:21][N:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:45][CH2:44][N:43]([C:46]4[CH:51]=[CH:50][C:49]([NH:52][S:53]([C:56]5[CH:61]=[CH:60][C:59]([NH:62][C@@H:63]([CH2:73][S:74][C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH2:64][CH2:65][N:66]6[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68][CH2:67]6)=[C:58]([S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH:57]=5)(=[O:55])=[O:54])=[CH:48][CH:47]=4)[CH2:42][CH2:41]3)[CH:35]=2)[C:24]([C:88]([OH:90])=[O:89])=[C:23]1[CH3:91]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:22]([CH2:21][CH3:20])[C:23]([CH3:91])=[C:24]([C:88]([O:90][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:89])[C:25]=2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][N:43]([C:46]4[CH:47]=[CH:48][C:49]([NH:52][S:53]([C:56]5[CH:61]=[CH:60][C:59]([NH:62][C@H:63]([CH2:64][CH2:65][N:66]6[CH2:67][CH2:68][CH:69]([OH:72])[CH2:70][CH2:71]6)[CH2:73][S:74][C:75]6[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=6)=[C:58]([S:81]([C:84]([F:85])([F:86])[F:87])(=[O:82])=[O:83])[CH:57]=5)(=[O:55])=[O:54])=[CH:50][CH:51]=4)[CH2:44][CH2:45]3)[CH:35]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CCO
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCn1c(C)c(C(=O)OCCC(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 957 (100 mg, 0.09 mmol), DIC (18 mg, 0.14 mmol) and DMAP (20 mg, 0.14 mmol) in DCM (2 mL) was added tert-butyl 3-hydroxypropanoate (41 mg, 0.28 mmol). The solution was stirred for 6 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in DCM (5 mL) and followed by adding TFA (2.5 mL). The solution was stirred at room temperature for 3 h until no starting material was observed by TLC. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 5 (salt with TFA, 75 mg, yield 70% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. MS (ESI): m/z 1238.17 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17].[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CC(C)=O.O>[C:18]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17])(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(=O)O)ccc1NC(=O)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
8.2 g of potassium carbonate was added to a suspension of 3.0 g of 4-amino-3-methylbenzoic acid in 60 ml of acetone and 60 ml of water. Thereto was dropwise added, with ice-cooling, a solution of 4.0 g of cinnamoyl chloride in 30 ml of acetone. The mixture was stirred at the same temperature for 30 minutes to give rise to a reaction. The reaction mixture was poured into ice water, and the mixture was made acidic with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 2.9 g of 4-cinnamoylamino-3-methylbenzoic acid as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][C:22]=2[N:23]=1.[C:34](Cl)(=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:12]=[CH:11][C:10]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:43])[CH2:30][CH2:29]3)=[CH:24][C:22]=2[N:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCNCC4)ccc3o2)c(F)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCN(C(=O)OCc5ccccc5)CC4)ccc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (Example 61) (70 mg, 0.14 mmol) dissolved in DCM (10 ml) and added TEA (0.1 ml, 0.72 mmol). This mixture stirred at rt for 30 mins and added benzyl carbonochloridate in toluene (48 mg, 0.28 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (1:2) as eluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 172-175° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.49-8.43 (m, 1H), 7.90-7.84 (m, 2H), 7.68 (d, J 1.4, 1H), 7.57 (d, J 8.5, 1H), 7.42-7.22 (m, 6H), 5.17 (s, 2H), 4.42-4.25 (bs, 2H), 3.13 (s, 3H), 3.00-2.78 (m, 3H), 2.00-1.88 (m, 2H), 1.80-1.65 (m, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[C:14]2[CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=3)(=[O:25])=[O:24])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][N:9]1C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[K+].C(O)C.[Cl-].[Na+].O>[CH2:1]([CH:8]1[C:14]2[CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=3)(=[O:25])=[O:24])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)NCCC3)c1
Temperature: 100 °C
Yield: 76.3 %

Procedure:
0.11 mmol of ethyl 1-benzyl-8-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate were dissolved in a solution of potassium hydroxide in ethanol (20%). The solution was heated in the microwave at 100° C. for 3 h. The mixture was diluted with brine and extracted with ethyl acetate (3×). The combined organic layers were concentrated in vacuo to give 96 mg of crude material that was purified by flash chromatography to yield 37 mg of N-(2-(1-benzyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (77%).
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:21][CH2:22][CH3:23])=[C:15](B(O)O)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C(O)C.O.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].CCCCCCC>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH2:22][CH3:23])=[C:13]([C:2]2[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: CCCOc1ccc(F)cc1B(O)O
Reactant: Nc1ccc(I)c(N)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CCCCCCC
Solvent: CCO
Product: CCCOc1ccc(F)cc1-c1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
To a suspension of 3-iodopyridine-2,6-diamine (Preparation 44, 1.5 g, 6.38 mmol) in ethanol (5 ml) and water (5 ml) was added 5-fluoro-2-propoxyphenyl boronic acid (1.6 g, 8.10 mmol) and sodium carbonate (744 mg, 7.02 mmol), then the slurry was stirred for 10 minutes at room temperature under nitrogen. Palladium (0) bis(dibenzylideneacetone) (0.088 g, 0.153 mmol) and tri-tert-butyl phosphine (1M solution in toluene, 1.28 ml, 1.28 mmol) were added and the reaction was heated at 80° C. for 6 hours before concentrating in vacuo. The residue was taken up in ethyl acetate (100 ml) and washed with water (3×50 ml) then brine (50 ml) before drying over anhydrous MgSO4, filtering and concentrating in vacuo. The residue was purified by column chromatography eluting with 1:9 to 8:2 ethyl acetate:heptane to afford the title compound as a yellow foam (0.591 g, 35% yield).
Reaction SMILES: O[CH2:2][C@H:3]1[C@H:5]([C:6]([OH:8])=[O:7])[C:4]1([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[CH3:9][C:4]1([CH3:10])[C@H:5]2[C@@H:3]1[CH2:2][O:7][C:6]2=[O:8]
Reactant: CC1(C)[C@@H](CO)[C@@H]1C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2C(=O)OC[C@@H]21

Procedure:
From 4041 g of the resultant solution, 20.1 g of that was used, and the subsequent cis body/trans body separation operation was carried out. Into 20.1 g of this solution, a 20% sodium hydroxide aqueous solution was dropped, to adjust pH of the solution to 3. An extraction operation was repeated three times from this solution with 7.8 kg of toluene, and the resultant organic layers were combined. Then, toluene was distilled off, then, 1.49 g of a solution containing 1.17 g of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (9.27 mmol, yield based on ethyl cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate: 97.2%, (1R, 5S)-body had an optical purity of 92.8% ee) was obtained. In this toluene solution, 0.057 g (0.39 mmol) of trans-3-hydroxymethyl-2, 2-dimethylcyclopropanecarboxylic acid was present.