Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1cccc2ccc(O)cc12
Yield: 71.8 %

Procedure:
The starting material used in the above example can be prepared as follows: A mixture of 1.93 g (0.01 mol) of 3-nitrophthalic anhydride, 1.59 g (0.01 mol) of 1-amino-7-naphthol and 30 ml of acetic acid is refluxed for 17 hours. The resulting suspension is stirred with 300 ml of water, then filtered and the filter residue is then washed with water and dried. 2.9 g of crude product are obtained and are extracted with chloroform. The chloroform extract is stirred with 4 g of silica gel, filtered with suction whilst hot, and evaporated to dryness. 2.4 g (72% of theory) of 1-(3-nitrophthalimidyl)-7-hydroxynaphthalene are obtained; melting point 136°-7° C.
Reaction SMILES: [CH:1]([O:6][CH3:7])(OC)OC.[C:8]1(=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10](=[O:18])[NH:9]1>C(OC(=O)C)(=O)C.CN(C)C=O>[CH3:7][O:6][CH:1]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:19])[NH:9][C:10]1=[O:18]
Reactant: COC(OC)OC
Reactant: O=C1Cc2ccccc2C(=O)N1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: COC=C1C(=O)NC(=O)c2ccccc21
Temperature: 125 °C

Procedure:
Trimethyl orthoformate (5.648 mL, 51.56 mmol) is added to a solution of 4H-Isoquinoline-1,3-dione (4 g, 24.82 mmol) in acetic anhydride (41.6 mL) and N,N-dimethylformamide (10.4 mL). After it is heated at 125° C. for 50 min, it is cooled and filtered to collected 3.698 g (73%) of the title compound as a yellow solid. mp 260-261° C.; MS (ESI) m/z 204.04 (M+1). Found: C, 58.34; H, 3.63; N, 10.21.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH2:14][C:15]#[N:16])=[N:11][C:10]=2[CH:17]=1)(=[O:5])=[O:4].[C:18]([O:21][C:22](=O)C)(=O)[CH3:19]>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]([C:15]#[N:16])=[C:18]([O:21][CH3:22])[CH3:19])=[N:11][C:10]=2[CH:17]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc2sc(CC#N)nc2c1
Reactant: CC(=O)OC(C)=O
Product: CNS(=O)(=O)c1ccc2sc(C(C#N)=C(C)OC)nc2c1
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 2-cyanomethylbenzothiazole-5-sulfonic acid methylamide (120 mg, 0.45 mmol) and trimethyl orthoracetate (270 mg, 2.2 mmol) in acetic anhydride (2 mL) was heated at 100° C. for 5 hrs. The reaction mixture was cooled to room temperature. The resulting precipitate was isolated by filtration to yield 120 mg (83%) of 2-(1-cyano-2-methoxypropenyl)benzothiazole-5-sulfonic acid methylamide. The product was used in the subsequent step without further purification. MS (m/z, ES+): 324 (M+1, 100%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:54][CH2:55][CH2:56][C:57]([O:59]C)=[O:58].CN1CCOCC1>CN(C)C=O.[Cl-].[NH4+]>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:54][CH2:55][CH2:56][C:57]([OH:59])=[O:58])=[O:24])=[CH:20][N:19]=3)[CH3:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a room temperature solution of 6-(1-(4′-(trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinic acid (60.0 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (118 mg, 0.310 mmol). Methyl 3-aminopropionate hydrochloride (32.4 mg, 0.232 mmol) and N-methylmorpholine (93.9 mg, 0.930 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction was diluted with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (5 mL). 2N LiOH (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was acidified to pH ˜3 with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Kromasil Eternity-5-C18 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 46 to 66% MeCN in water) gave 3-(6-(1-(4′-(trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinamido)propanoic acid (25.3 mg, 34%). 1H NMR (400 MHz, CD3OD, δ): 8.95 (m, 1H), 8.16-8.19 (m, 1H), 7.66-7.72 (m, 4H), 7.60-7.62 (m, 1H), 7.54-7.56 (m, 2H), 6.98-7.00 (m, 2H), 5.55-5.57 (q, 1H), 3.62-3.65 (m, 2H), 2.62-2.64 (m, 2H), 1.70 (d, 3H). MS (M+1): 459.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[N:2]1>C(O)C.[Rh]>[NH:1]1[C:9]2[CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: [Rh]
Solvent: CCO
Product: NC1CCc2cn[nH]c2C1
Yield: 37.4 %

Procedure:
Combine 1H-indazol-6-ylamine (12.45 g, 93.6 mmol) and 5% Rh/C (6.13 g) in ethanol (300 mL) and heat at 120° C. for 72 hours under ˜1000 psi H2. Cool the reaction and filter through hyflo. Remove the solvent in vacuo and purify the crude product with 10% 2 M NH3 in MeOH in CH2Cl2 and re-purify mixed fractions with 15% 2 M NH3 in MeOH in CH2Cl2 to afford 4.80 g (37%) of the titled product. MS (m/z): 138 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)C.[N+]([O-])([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 84 %

Procedure:
An article in Journal of the American Chemical Society, 72 (1950), 798, discloses that 2,6-dichloro-4-nitroaniline, ethanol and sodium nitrate can be reacted at the boil, in the absence of water and in the presence of concentrated sulfuric acid, to give an 84% yield of 3,5-dichloronitrobenzene. A corresponding reaction to form the 3,5-dibromonitrobenzene proceeds with a yield of 91%. The process is unsatisfactory in respect of the yield and purity of the end product and in respect of simple, reliable and economical operation, particularly on an industrial scale.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][C@@H:52]1[CH2:57][NH:56][CH2:55][C@H:54]([CH3:58])[NH:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:56]6[CH2:55][C@H:54]([CH3:58])[NH:53][C@H:52]([CH3:51])[CH2:57]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)ccc2OC)c1
Yield: 67.6 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, (2R,6S)-2,6-dimethylpiperazine (13.7 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 uL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [41.8 mg (67.6%)]. LC-MS m/z 773 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[C:51]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O-:58])=O.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:61]([O:60][C:51](=[O:59])[CH2:52][CH2:53][CH2:54][CH2:55][C:56]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:7][CH3:8])[CH2:9][CH3:10])=[O:58])[CH3:62]
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCC(=O)N(C)CCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C(CC)CC
Yield: 81.6 %

Procedure:
By using 200 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 60 mg of monoethyl adipate, and 0.10 mL of N-ethyl-N-isopropylpropan-2-amine as starting materials, and using 142 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as a condensing agent, the reaction similar to Preparation Example 27 was performed, thereby obtaining 200 mg of methyl 4-(2-{4-[({2-[(3-{[{2-[(6-ethoxy-6-oxohexanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:24])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29].CO>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:24])[C:11]1=[CH:27][N:28]([CH3:30])[CH3:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)CC2=O)c(=O)[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)C(=CN(C)C)C2=O)c(=O)[nH]c1=O
Temperature: 50 °C
Yield: 56.3 %

Procedure:
5'-O-(t-Butyldimethylsilyl)-2',3'-dideoxy-5-methyl-2'-oxo-uridine (3.854 g, 10.9 mmol) from Step 3 was dissolved in 50 mL of dry dimethylformamide (DMF) and 1.74 mL (1.56 g, 13.1 mmol) of N,N-dimethylformamide dimethylacetal was added. The reaction mixture was heated in an oil bath at 50° C. for 40 min. The solvent was evaporated in vacuo and the residue purified on a silica gel column, the product eluting with 5% methanol in methylene chloride to give 2.512 g (56.3% yield) of the title compound, [α]D23 =-84.2° (C, 1.44, MeOH). DCI MS M/Z: (M+H)+ 410.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:28]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:33]4[S:34][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(C=O)s4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 5-formyl-2-thiopheneboronic acid in General Procedure A. Purification on silica yielded 5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-thiophene-2-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[OH:21][CH2:22][CH:23](CO)[OH:24].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH:22]([CH2:23][OH:24])[OH:21])=[O:7]
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCCC(=O)OCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1.0 g (3.5 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate was slowly added dropwise to a solution of 0.65 g (7.1 mmol) of glycerol and 0.59 g (4.3 mmol) of potassium carbonate in dry N,N-dimethylformamide (3.5 mL) at 80° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[O:29][C:28]4=[O:38])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[O:29][C:28]4=[O:38])=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3)cc2)=NO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
(5R)-3-{4′-[5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (0.24 g, 0.45 mmol) was dissolved in THF (5 ml) at 25° C. Tetrabutylammoniumfluoride.3H2O (0.138 g, 0.495 mmol) was added as a solid and the reaction was stirred at 25° C. for 1.5 hours. The mixture was then diluted with ethyl acetate (50 ml) and poured into water. The layers were separated and the aqueous layer was extracted three times with ethyl acetate (3×50 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent, giving 0.05 g desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 226a (279 mg, 0.80 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 199e (1.53 g, 3.2 mmol), Pd2(dba)3 (73.2 mg, 0.080 mmol), tricyclohexyl-phospine (44.6 mg, 0.16 mmol), cesium carbonate (521.6 mg, 1.6 mmol), 1,4-dioxane (10 mL), and water (8 drops). After three cycles of vacuum/argon flush, the mixture was stirred at 110° C. for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 40:1 ethyl acetate/methanol to afford 226b as a yellow solid (120 mg, 23%). MS-ESI: [M+H]+ 667.3
Reaction SMILES: [NH2:1][C@@H:2]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C@@H:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[CH:31]1([CH2:37][C:38](O)=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH:31]1([CH2:37][C:38]([NH:1][C@@H:2]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:3]([NH:5][C@@H:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][C@@H:7]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:4])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Reactant: O=C(O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CC1CCCCC1)N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To a stirred solution of (2S)-2-amino-2-(4-fluorophenyl)-N-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]acetamide (65b) (81 mg, 0.199 mmol) in dichloromethane (2 mL) under nitrogen was added cyclohexylacetic acid (35 mg, 0.246 mmol), HOBt (35 mg, 0.259 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (50 mg, 0.261 mmol). The mixture was stirred 5 h at ambient temperature then evaporated. The residue was dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, 1N aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane:ethyl acetate to afford the title compound (89 mg, 84%) as a white solid. TLC Rf=0.42 (6:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.81-1.37 (m, 5H), 1.59-1.87 (m, 6H), 2.09 (d, 2H, J=6.5 Hz), 5.09 (t, 1H, J=7.0 Hz), 5.26 (d, 1H, J=7.0 Hz), 5.83 (d, 1H, J=7.0 Hz), 6.24 (br d, 1H, J=6.5 Hz), 6.48 (br d, 1H, J=6.5 Hz), 6.88-7.05 (m, 3H), 7.12-7.30 (m, 5H), 7.36 (s, 5H), 7.56 (br s, 1H). MS APCI, m/z=530 (M+1). LC/MS: 2.69 min.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].C(O[C:20]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)(C)(C)C>[OH-].[K+].CO>[C:26]([O:25][C:23]([O:22][C:20]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 12 °C
Yield: 83.2 %

Procedure:
A solution comprising 2.4 grams of potassium hydroxide, 201 grams 4-acetoxystyrene and 500 grams of methanol was heated at reflux for 2.2 hours. The reaction was cooled to 12° C. and 64 grams potassium hydroxide pellets were added over a period of 10 minutes. After warming to 25° C., 314 grams di-tertiary-butyl-dicarbonate was introduced over a period of one hour. After an additional 2.3 hours of reaction time, the reaction slurry was washed with water and extracted with ethyl acetate. The ethyl acetate was stripped from the extraction mixture using a rotary evaporator, and the residual oil was charged with 0.26 grams phenothiazine inhibitor. Distillation at 0.1 mm Hg yielded 227.2 grams (85% yield) 4-tertiary-butoxycarbonyloxystyrene.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1C[CH2:10]1)=[O:7].[N+](CC)#[C-]>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH2:9][CH3:10])=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Agent: [C-]#[N+]CC
Product: CCNC(=O)[C@@H](O)[C@@H](N)CC

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, using isocyanoethane in the third step (A3).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[Cl-].[NH4+]>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:10](=[O:11])[CH2:9][Cl:8])=[CH:26][CH:25]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 1 h
Yield: 65.5 %

Procedure:
0.24 ml of triethylamine and 0.17 ml of chloroacetyl chloride were added to a solution of 300 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in step (b) above] in 6 ml of methylene chloride cooled in an ice-water bath, and the resulting mixture was stirred for 1 hour. After this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water, dried over anhydrous sodium sulfate and the solvent was then removed by evaporation under reduced pressure. The resulting residue was recrystallized from a mixed solvent of methylene chloride and hexane to obtain 259.4 mg (yield 65.5%) of the title compound as a solid having a melting point of 196° to 197° C.