Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[K])(C)(C)C.[C:7]12([CH2:17][NH:18][C:19]([C:21]3[C:22]4[N:23]([N:27]=[C:28]([CH2:30][OH:31])[CH:29]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.CN(C=O)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:31][CH2:30][C:28]1[CH:29]=[C:22]2[C:21]([C:19](=[O:20])[NH:18][CH2:17][C:7]34[CH2:8][CH:9]5[CH2:10][CH:11]([CH2:12][CH:13]([CH2:15]5)[CH2:14]3)[CH2:16]4)=[CH:26][CH:25]=[CH:24][N:23]2[N:27]=1)[CH3:43]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccn2nc(CO)cc12
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 0.08 h

Procedure:
A 1.0 M solution of tBuOK in THF (0.3 mL) is added to a mixture of 2-hydroxymethyl-pyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)amide (73 mg, 210 μmol) and DMF (1 mL) at 0° C. under N2. After 5 min, ethyl bromoacetate (30 μL, 280 μmol) is added. The cold bath is removed and the mixture is left to stir for 23 h. 50% Sat. aq. NaHCO3 is added and the solution is extracted with EtOAc (20 mL). The organics are dried over Na2SO4, filtered and concentrated. Purification by PTLC (2:1 EtOAc:hexanes) affords the title compound as a pale yellow film. 1H NMR (400 MHz, CDCl3) δ: 8.50 (dd, 1H), 7.57 (d, 1H), 6.88 (s, 1H), 6.81 (dt, 1H), 6.27 (bs, 1H), 4.88 (s, 2H), 4.22 (q, 2H), 4.19 (s, 2H), 3.21 (d, 2H), 1.94-2.04 (m, 3H), 1.56-1.78 (m, 12H), 1.28 (t, 3H). LC-MS m/z (M+H+): 426.3; RT=1.31.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O

Procedure:
p-nitrophenyl ester of tert-butoxycarbonylphenylalanine is reacted with glycine to obtain tert-butoxycarbonylphenylalanylglycine;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1.[CH3:34][O:35][CH2:36][C:37]#[CH:38]>CCN(CC)CC.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>[C:14]([O:13][C:11]([N:10]([C:7]1[O:8][CH2:9][C:5]2([N:6]=1)[C:25]1([CH2:26][O:27][CH2:28]1)[CH2:29][O:30][C:31]1[C:4]2=[CH:3][C:2]([C:38]#[C:37][CH2:36][O:35][CH3:34])=[CH:33][CH:32]=1)[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Reactant: C#CCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc2c(c1)C1(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1)C1(COC1)CO2
Yield: 23.6 %

Procedure:
A mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (150 mg, 0.286 mmol) and 3-methoxyprop-1-yne (0.072 mL, 0.86 mmol) in Et3N (1.5 mL) was purged with argon. To the mixture was added Pd(PPh3)4 (13 mg, 0.011 mmol) and CuBr (4.9 mg, 0.034 mmol), and the mixture was refluxed for 3 hours under an argon atmosphere. The mixture was partitioned between CHCl3 and brine, and filtered through celite. The organic layer of the filtrate was dried over MgSO4, filtered off, and the filtrate was evaporated. Silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 25%) afforded di-tert-butyl[6′-(3-methoxyprop-1-yn-1-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (34.7 mg).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[CH2:18]([NH:25][C:26]([N:4]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH2:1][CH2:2][CH3:3])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C(=O)NCc1ccccc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-(prop-1-yl)amino)-1-tert-butoxycarbonylpiperidine (from Example 17, Step A) with benzyl isocyanate, followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 276.1 (M+H).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.O>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[O:2][CH3:1])[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: CO
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
Methanol (0.462 ml, 11.4 mmol) was added to a stirring suspension of NaH (684 mg, 17.1 mmol) in DMF (10 ml) under an argon atmosphere. The resulting solution was allowed to stir at RT for 20 min. 6-chloro-7-fluoro-8-nitro-9H-β-carboline (500 mg, 1.9 mmol) was added to the stirring solution and the resulting mixture was allowed to stir at RT. Upon addition of H2O, a brown solid precipitated out which was filtered to give the desired 6-chloro-7-methoxy-8-nitro-9H-β-carboline (510 mg, 97% yield). 1H-NMR (300 MHz, DMSO-d6): δ 4.02 (s, 3H), 8.52 (d, 1H), 8.60 (d, 1H), 9.05 (s, 1H), 9.12 (s, 1H), 12.78 (b, 1H). Retention Time (LC, method: ammonium acetate standard): 2.28 min. MS (M+H+): 278.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40].ClCCl>C(O)C>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]([C@H:18]([OH:35])[C@@H:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:40][CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(CN)OC
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc([C@@H](NCC(OC)OC)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 187.2 g (0.4 mol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 210 g (2 mol) of aminoacetaldehyde dimethyl acetal, 5 l of dichloromethane, 3 l of ethanol.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)(=O)=O.[CH2:37]([NH2:39])[CH3:38]>CO>[CH2:37]([NH:39][CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:32])([F:33])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)[CH3:38]
Reactant: CCN
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: CO
Product: CCNCc1cc2ncn(-c3cc(O[C@H](C)c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cn1

Procedure:
In a similar manner as described for example 116, 200 mg of crude [3-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (example 49, step 1) and 0.925 ml ethylamine (2 M solution in THF) in 4 ml methanol give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:19][C:20]([O:22][CH2:23]C)=[O:21])(C(OCC)=O)[C:8]2=[O:25])=[O:4].Cl.C(O)(=O)C.C(CC1C(=O)C2C(=CC=C(C(O)=O)C=2)C1)(O)=O.S(=O)(=O)(O)O>CO>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH:9]1[C:8](=[O:25])[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[CH2:10]1
Reactant: CCOC(=O)CC1(C(=O)OCC)Cc2ccc(C(=O)OC)cc2C1=O
Agent: Cl
Agent: O=C(O)CC1Cc2ccc(C(=O)O)cc2C1=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC1Cc2ccc(C(=O)OC)cc2C1=O
Temperature: 25 °C
Yield: 686.3 %

Procedure:
2-Ethoxycarbonylmethyl-3-oxo-indan-2,5-dicarboxylic acid-2-ethyl ester-5-methyl ester (Step 2, 530 mg, 1.5 mmol) in 1.3 ml mixture of 6 N HCl: acetic acid (1:1) was heated to reflux for 3 h. The reaction mixture was evaporated to dryness, 10 ml water was added and extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulphate and then concentrated. The crude product was washed with hexane and precede next step without further purification (530 mg). To a stirred solution of 2-carboxymethyl-3-oxo-indan-5-carboxylic acid (3.5 g, 14.9 mmol) in methanol (53 ml) was added concentrated sulphuric acid (5.6 ml) at 0° C. After addition temperature of the reaction mixture was slowly raised to room temperature and then heated to reflux for 5 h. The reaction mixture was evaporated. Water was added and extracted with ethyl acetate. Ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, brine, dried and concentrated under reduced pressure. Crude was purified by column chromatography using acetone/hexane (25%) to yield a desired product (2.7 g). 1H NMR (400 MHz, CDCl3) d 8.44 (1H, s), 8.30 (1H, d), 7.57 (1H, d), 3.95 (3H, s), 3.78 (3H, s), 3.53 (1H, dd), 3.09-2.93 (3H, m), 2.71 (1H, dd) ppm.
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCCCCCCCN1.[CH2:23]([O:30][C:31]([CH:33]1[NH:36][C:35](=[O:37])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>C(Cl)Cl>[N+:38]([C:41]1[CH:42]=[CH:43][C:44]([S:47]([N:36]2[CH:33]([C:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:32])[CH2:34][C:35]2=[O:37])(=[O:49])=[O:48])=[CH:45][CH:46]=1)([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC(C(=O)OCc2ccccc2)N1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CC(=O)N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 20.1 %

Procedure:
Diazabicycloundecane (152 mg, 1 mM) was added to a mixture of 205 mg (1 mM) 4-benzyloxycarbonyl azetidin-2-one and 181 mg (1 mM) p-nitrobenzenesulfonyl chloride in 10 ml methylene chloride at room temperature. After stirring 21/2 hours, the orange solution was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel in hexane/ethyl acetate to yield 64 mg (17%) of 1-p-nitrophenylsulfonyl-4-benzyloxycarbonyl azetidin-2-one.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]([C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])=[C:12]([O:29][CH3:30])[CH:11]=1)=O.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:7]=[C:2]1[NH:3][C:4](=[O:6])[C:5](=[CH:8][C:10]2[CH:28]=[CH:27][C:13]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[C:23]([F:24])([F:25])[F:26])=[C:12]([O:29][CH3:30])[CH:11]=2)[S:1]1
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(C=C2SC(=O)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 130 °C

Procedure:
Thiazolidine-2,4-dione (2.55 g, 21.79 mmol) and 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile (21.79 mmol) were dissolved in toluene (150 mL) and treated with benzoic acid (3.27 mmol) and piperidine (2.83 mmol). The flask was equipped with a Dean-Stark trap, and the reaction was refluxed in a 130° C. oil bath for 12 h. After cooling to RT, the product was collected by filtration and triturated with hexanes to afford the title compound. 1H NMR (400 Hz, DMSO-d6) δ 12.68 (NH), 8.32 (d, 1H), 8.00 (dd, 1H), 7.83 (s, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 7.26 (dd, 1H), 6.90 (d, 1H), 3.77 (s, 3H); LC/MS (m/z) [M+1]+ 421.0 (calculated for C19H12F3N2O4S, 421.04).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([NH:9][C:10](=[O:21])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14][CH2:13]2)=[C:7]([S:22][CH3:23])[CH:6]=[C:5]([CH3:24])[N:4]=1.[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:36]2[N:37]=[C:38]([SH:40])[NH:39][C:35]=2[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:36]2[N:37]=[C:38]([S:40][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][N:12]([CH2:11][C:10]([NH:9][C:8]4[C:3]([S:2][CH3:1])=[N:4][C:5]([CH3:24])=[CH:6][C:7]=4[S:22][CH3:23])=[O:21])[CH2:13][CH2:14]3)[NH:39][C:35]=2[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Sc1nc2ccc(OCc3ccccc3)cc2[nH]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccc(OCc4ccccc4)cc3[nH]2)CC1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Under argon, N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (1.00 g, 2.70 mmol), 5-benzyloxy-2-mercaptobenzimidazole (2.57 g, 10.0 mmol), and triphenylphosphine (2.50 g, 9.53 mmol) were dissolved in N,N-dimethylformamide (30 mL). To the solution, under cooling with ice, diethyl azodicarboxylate (1.27 mL, 8.07 mmol) was added dropwise, followed by stirring for one hour at the same temperature. Ethyl acetate and 1 mol/L hydrochloric acid were added to the reaction mixture. The aqueous layer was separated from the mixture, and the organic layer was further extracted with 1 mol/L hydrochloric acid. The obtained aqueous layers were combined and adjusted to basic conditions with a 1 mol/L aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The thus-obtained residue was purified through silica gel column chromatography (chloroform : saturated ammonia-methanol=20:1), to thereby yield 1.56 g of 2-[4-[2-(5-benzyloxybenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as a colorless amorphous product (yield 94.9%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][C:15]2[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:14]1=2.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[C:22]([C:18]1[C:15]2[CH:16]=[C:17]([B:25]([OH:30])[OH:26])[S:13][C:14]=2[CH:21]=[CH:20][CH:19]=1)([OH:24])=[O:23]
Reactant: O=C(O)c1cccc2sccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cccc2sc(B(O)O)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
n-Butyllithium (2.5 M, 94 mL) is added dropwise to a stirred solution of diisopropylamine (33.0 mL, 235 mmol) in anhydrous THF (300 mL) at −78° C. under nitrogen atmosphere. After 30 minutes, a solution of benzo[b]thiophene-4-carboxylic acid (20.0 g, 112 mmol) in anhydrous THF (300 mL) is added. Upon the completion of addition, the reaction mixture is allowed to warm up to 0° C. where it is stirred for another 2 hours. The reaction mixture is cooled to −30° C. before it is treated with triisopropyl borate (65.0 mL, 282 mmol). The cooling bath is then removed and the reaction is allowed to reach ambient temperature where it is carefully quenched with concentrated HCl (200 mL). After evaporation of THF a suspension is formed, the solid is collected by filtration, washed twice with water (150 mL×2) and dried to provide the title compound as a white solid (20.0 g, 80% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[CH:6]=1)=O.O.[NH2:16][NH2:17]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]=2[CH:13]=1
Reactant: NN
Reactant: COC(=O)c1cc2cc(Cl)ccc2s1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc2cc(Cl)ccc2s1
Temperature: 0 °C

Procedure:
8.00 g (35.3 mmols) of 5-chloro-2-benzo[b]thiophenecarboxylic acid methyl ester and 10 ml of hydrazine hydrate in 100 ml of absolute ethanol are boiled under reflux for 45 minutes. The cooled suspension is diluted with 100 ml of ice water and the product is filtered off. It is washed with two 40 ml portions of methanol and dried in vacuo. 5-Chloro-2-benzo[b]thiophene-carboxylic acid hydrazide with a melting point of 254°-255° is obtained.
Reaction SMILES: N[CH:2]1[CH2:6][C@@:5]([CH:26]([CH3:28])[CH3:27])([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])[CH:4]=[CH:3]1.[O:29]=C(C(OCC)=O)C(OCC)=O.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:22]([O:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[CH2:10][NH:9][C:7]([C@:5]1([CH:26]([CH3:28])[CH3:27])[CH2:6][C:2](=[O:29])[CH:3]=[CH:4]1)=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of (1S)-4-amino-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]1-isopropylcyclopent-2-ene-1-carboxamide (35 g, 88 mmol) and diethyl oxomalonate (31 g, 176 mmol) in toluene (350 mL) was refluxed until no more starting material left as judged by HPLC. The reaction mixture was cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (27 g, 176 mmol) was added. The reaction mixture was then warmed to r.t. and stirred at this temperature for 1 hr before being quenched with 1M HCl and vigorously stirred for 1 hr. The reaction mixture was diluted with EtOAc and the two layers were separated. The aqueous phase was then extracted with EtOAc (5×). The organics were combined, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography on silica gel eluting with hexane:EtOAc (11:1) to yield 32 g of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide as a pale yellow solid.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[Cl:8][CH:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1>CO.ClCCl>[Cl:8][CH:9]1[CH2:12][CH:11]([C:13]([O:15][CH3:2])=[O:14])[CH2:10]1
Reactant: O=C(O)C1CC(Cl)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(Cl)C1

Procedure:
TMS-diazomethane (2.0 M in diethyl ether, 2.2 ml, 4.4 mmol) was added dropwise to a solution of 3-chlorocyclobutanecarboxylic acid (540 mg, 4.0 mmol) in methanol (5.0 mL) and dichloromethane (5.0 mL) at 0° C. The reaction mixture was concentrated under reduced pressure to afford methyl 3-chlorocyclobutanecarboxylate. The material was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5](O)[N:4]=1.O.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][C:5]1[N:4]=[C:3]([CH:2]([F:10])[F:1])[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc(C(F)F)n1
Solvent: ClCCl
Solvent: O
Product: FC(F)c1ccnc(Cl)n1
Temperature: 85 °C

Procedure:
4-(difluoromethyl)pyrimidin-2-ol was diluted with phosphorus oxychloride (80 mL) then heated at 85° C. for 3 hours with periodic venting of the reaction mixture. The mixture was cooled to rt, diluted with DCM (500 mL) and poured into water (˜1 L) cooled in an ice bath at such a rate the exotherm was maintained at ˜30° C. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2×500 mL) and the organics were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-4-(difluoromethyl) as a light yellow oil. MS ESI calcd. for C5H4ClF2N2 [M+H]+ 165. found 165. 1H NMR δ ppm DMSO-d6): 8.18 (1H, d, J=6.25 Hz), 6.63 (1H, t, J=54.22 Hz). 6.57 (2H, d, J=6.26 Hz).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([N:26]1[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]1)=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine (10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1 mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA (12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL). The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL), dried (MgSO4) and concentrated in vacuo. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid. m/z (ES+)=367 [M+H]+; RT=3.28 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13]OC1C=CC(B(O)O)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:24]([C:27]1[CH:32]=[CH:31][C:30](CCCC(O)=O)=[CH:29][CH:28]=1)([OH:26])[OH:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C:30]1[CH:31]=[CH:32][C:27]([B:24]([OH:26])[OH:25])=[CH:28][CH:29]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(B(O)O)cc1
Reactant: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Agent: BrCc1ccccc1
Product: O=C(CCCc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 69 %

Procedure:
Using a procedure analogous to that used to prepare 1B, 2B (212 mg, 1:1 mixture of 2B and 2A) was reacted with benzyl bromide to afford 2C (90 mg, 69%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.92 (m, 2H), 2.33 (t, J=7.0 Hz, 2H), 2.62 (t, 2H), 5.08 (s, 2H), 7.11 (d, 2H), 7.25-7.35 (m, 5H), 7.69 (d, 2H).