Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[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:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[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].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH:52]1[CH3:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.CCOC(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[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:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:54]6[CH2:55][CH2:56][N:51]([CH3:50])[CH:52]([CH3:57])[CH2:53]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[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]
Reactant: CC1CNCCN1C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C)C(C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (150 mg, 0.226 mmol), 1,2-dimethylpiperazine (45.7 mg, 0.40 mmol), sodium triacetoxyborohydride (95 mg, 0.45 mmol) and AcOH (18 μl, 0.314 mmol) in 1,2-dichloroethane (DCE) (6 mL) was stirred overnight at room temperature. LC/MS showed that the reaction was complete. The reaction was diluted with EtOAc; the organic layer washed with dilute aq. NaOH, then sat. aq. NaCl and dried [Na2SO4], then concentrated to a viscous taffy. The material was purified on a Gilson HPLC using reverse phase (acetonitrile-water with 0.1% TFA). Fractions containing the desired product were combined, the MeOH removed, the aqueous layer treated with EtOAc and 1N NaOH. The mixture was vigorously extracted with EtOAc (2×), the extract was washed with a small amount of sat. aq. NaCl; dried [Na2SO4], then concentrated to a glassy, creamy tan, coloured foam (0.1002 g). LC-MS m/z 761.5 (M+H)+, 0.76 min (ret time).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5](Cl)=[C:4]([Cl:16])[N:3]=1.CCN(C(C)C)C(C)C.ClC1C(NC2C=C(OC(C)C)NN=2)=NC([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])=NC=1>CCO>[Cl:16][C:4]1[N:3]=[C:2]([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=1
Reactant: Cc1cc(Nc2nc(Cl)nc(Cl)c2Cl)n[nH]1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Temperature: 140 °C
Yield: 26.7 %

Procedure:
To a solution of 2,5,6-trichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 39; 2.0 g, 8.2 mmol) in absolute EtOH (40 ml) were added DIEA (2.5 ml) and (15)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 1.2 g, 8.2 mmol) and the resulting solution was heated to 140° C. for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give an oil which was purified by Gilson (20-75% acetonitrile/H2O, 35 min) to give the titled compound as solid (762 mg). m/z: 383.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:20][CH:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH2:18]2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]1)=[O:2].[O-:24][Mn](=O)(=O)=O.[K+]>>[C:1]([C@@H:3]1[CH2:20][CH:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH2:18]2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]1)([OH:24])=[O:2]
Reactant: C[C@]12CCC(=O)CC1C[C@@H](C=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: C[C@]12CCC(=O)CC1C[C@@H](C(=O)O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a stirred suspension of 7α-formylandrostane-3,17-dione (1.77 g) in t-ButOH (35 mL) and 5% aqueous Na2HPO4 solution (21.5 mL), 1N aqueous KMnO4 (35 mL) was added. After 5 minutes at room temperature, the mixture was quenched by addition of 40% aqueous NaHSO3 solution. The suspension was filtered, washed with H2O and the filtrate was freeze-dried. The residue was taken up with H2O (50 mL) and extracted with EtOAc (4×70 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 7α-carboxyandrostane-3,17-dione (1.80 g, 96%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 12.00 (1H, bb), 2.65 (1H, m), 2.45-0.70 (20H, m), 1.00 (3H, s), 0.79 (3H, s).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[O:24]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25]1>CCO>[O:24]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[CH2:14][C:15]([F:18])([F:16])[F:17])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:25]1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCc1ccoc1
Solvent: CCO
Product: O=C(c1ccc(NCc2ccoc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (103 mg, 0.296 mmol) and 3-furylmethylamine (35 mg, 0.355 mmol) in 3 mL of EtOH containing TEA (0.060 mL, 0.444 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 114 mg (91%); 1H NMR (400 MHz, CHLOROFORM-D) δ 4.26 (q, J=8.40 Hz, 4H), 4.44 (d, J=5.27 Hz, 2H), 6.43 (m, 1H), 7.00 (d, J=8.98 Hz, 1H), 7.46 (m, 2H), 7.55 (dd, J=8.88, 2.05 Hz, 1H), 8.32 (d, J=2.15 Hz, 1H), 8.45 (m, 1H); MS (ESI) 425.72 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:18]([O:20]C)=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:18]([OH:20])=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of methyl 6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylate (13.6 g, 46.3 mmol), and 1N NaOH (92.5 mL, 92.5 mmol) in 225 mL of ethanol is refluxed for 5 h. Water is added to the mixture and the aqueous layer is washed with ether. The aqueous layer is acidified with 1N HCl and extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate/hexanes to yield 6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid melting at 202-203° C. 1HNMR CDCl3: 300 MHz): δ 7.87 (1H, d), 7.65 (2H, d), 7.47 (1H, d), 7.35 (1H, t), 7.25 (2H, d), 2.05 (3H, s). MS m/z 279 (M−1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][C@H:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C@H:19]4[OH:28])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: O=C1NCN(c2ccccc2)C12CCN(C[C@H]1CCc3ccccc3[C@H]1O)CC2
Temperature: -78 °C
Reaction time: 16 h

Procedure:
1-Phenyl-8-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one (5.0 g) is dissolved in 60 ml of dry tetrahydrofuran and added, dropwise, to a flask charged with 2.1 equivalents of a 1 molar tetrahydrofuran solution of lithium tri-sec-butylborohydride, previously cooled to -78° C, all under an argon atmosphere. The resulting solution is stirred for 16 hours at room temperature. The reaction mixture is treated at 0° C with 15 ml of 3 molar sodium hydroxide followed by the addition of 15 ml of 30% hydrogen peroxide. The aqueous phase is saturated with potassium carbonate and the organic layer is separated and concentrated. The residue is dissolved in methylene chloride, washed with water, dried and concentrated producing the crude product. Recrystallization of this material from methylene chloride/hexane yields 4.2 g of isomerically pure title compound, melting point 204°-205° C.
Reaction SMILES: [C:1]([C:3](=[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])#[N:2].O.[3H][3H]>O1CCCC1.[Pd]>[C:1]([CH:3]([CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])#[N:2]
Reactant: CCCCC(CC)COC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [3H][3H]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)COC(=O)C(C#N)C(c1ccccc1)c1ccccc1

Procedure:
2-Ethylhexyl 2-cyano-3,3-diphenylacrylate (Eusolex® OCR; Merck) is dissolved in tetrahydrofuran (THF), and 5% Pd/C (56% water; Merck: Art. No. 275175) is added. The hydrogenation is subsequently carried out with hydrogen 3.0 at room temperature and atmospheric pressure. The catalyst is separated off by filtration. The filtrate is freed from solvent in vacuo, and the residue is washed. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuo. The purification is carried out by filtration through silica gel, giving analytically pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[NH:11][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:8]1[N:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:15]2[C:14](=[O:16])[NH:13][C:12](=[O:17])[NH:11][C:10]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccc(Cl)cc2)[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (2.2 g, 7.97 mmol) in THF (30 mL) was added NCS (1.1 g, 8.27 mmol) at 0° C. in portions. Then the resulting mixture was stirred at room temperature until it became a clear solution. The reaction was immediately quenched with ice-water and concentrated. The residue was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to give a crude product. This material was purified by silica gel chromatography eluting with DCM/methanol (50:1 to 20:1) to give 8-chloro-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (450 mg, 18.2% yield) as white solid. LCMS retention time 1.071; LCMS MH+-58 311.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32])#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:14]([NH:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:33])=[O:32])#[N:24]
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: N#Cc1ccccc1S(N)(=O)=O
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccccc1C#N

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 2-cyanobenzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-(2-cyanobenzenesulfonyl)-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 1.52 g (3.73 mmol) of N-(2-cyanobenzenesulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 810 mg of the above-identified compound (yield 60.1%). Properties: colorless crystal, Melting point: 160°-161° C., PMR (δppm, DMSO-d6):3.71 (3H,s), 6.61 (1H,s), 6.90 (1H,s), 7.12 (1H,s), 7.23 (1H,d), 7.72 (1H,s), 7.86 (1H,d), 11.59 (1H,br).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: BrC1CCCC1
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ncccc1OC1CCCC1
Yield: 60 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, bromocyclopentane (0.63 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-cyclopentyloxy pyridine (480 mg, yield: 60%) was obtained as an oil phase.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][C:25]=3[CH3:32])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(O)(C)C.CCOC(C)=O>CS(C)=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][C:25]=3[CH3:32])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cc(CO)ccc2C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cc(C=O)ccc2C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
The {[4-(5′-hydroxymethyl-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 7: step b) 30 mg, 0.056 mmol) was dissolved in a mixture of DMSO (1 mL) and DCM (1 mL) and cooled to 0° C. Triethylamine (12 μL, 0.084 mmol) and sulfur trioxide-pyridine complex (11 mg, 0.068 mmol) were added and the solution was stirred for 1 h at 0° C. Partial conversion was evident by TLC. Additional triethylamine (20 μL, 0.14 μL) and sulfur trioxide-pyridine complex (18 mg, 0.11 mmol) were added and the solution was stirred for 3 h at rt. Isopropanol (250 μL) was added, the reaction was stirred for 15 min, and EtOAc (40 mL) was added. The EtOAc solution was extracted with citric acid (2×10 mL), NaHCO3 (2×10 mL), water (5×10 mL), and brine (20 mL), and was dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (26 mg, 87%) which was used without further purification. 1H-NMR (CD3OD): δ 10.00 (s, 1H), 7.99 (m, 3H), 7.81 (dd, 1H, J=1.6 7.7 Hz), 7.72 (d, 1H, J=7.7 Hz), 7.59 (m, 2H), 7.46 (d, 1H, J=7.7 Hz), 2.58 (s, 3H), 2.30 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [O:1]=[CH:2][CH:3]=[C:4]1[O:10][CH:9]2[N:6]([C:7](=[O:11])[CH2:8]2)[CH:5]1[C:12]([O:14][CH2:15]C1C=CC=CC=1)=[O:13]>C(Cl)(Cl)Cl>[O:1]=[CH:2][CH:3]=[C:4]1[O:10][CH:9]2[N:6]([C:7](=[O:11])[CH2:8]2)[CH:5]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=CC=C1OC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C(=CC=O)OC2CC(=O)N21
Reaction time: 72 h

Procedure:
Racemisation of benzyl 3-oxoethylidene-7-oxo4-oxa-1-azabicyclo[3.2.0] heptane-2-carboxylate (II):- A solution of the title compound (II) as a mixture of geometrical isomers E-Z (2:1) (162 mg, 0.56mmol) in chloroform (8 ml) was allowed to stand at ambient temperature away from strong light for three days. The solution was evaporated to dryness, chromatographed over silica gel in ethyl acetate-hexane (1:1), and, on evaporation, gave the title compound in the ratio of geometric isomers E-Z (1.7:1) (53 mg, 33%), [α]20+16.4° (c=2% in dichloromethane); addition of R-2,2,2-trifluoro-1-(9-anthryl)ethanol (1000% by weight) to the nmr solution (250 MHz, CDCl3) caused two sets of signals to appear for the 6b, 6a and 8 protons of both the E and Z isomers and for the 2 proton of the E isomer. Irradiation of specific protons demonstrated coupling between the 5 and 6 and the 8 and 9 protons for all these signals. The intensity of the signals indicated a 65:35 mixture of enantiomers. When the title compound was freshly prepared the geometric isomer ratio was E-Z (1.6:1), [α]20+53.9° (c=2% in dichloromethane); and addition of R-2,2,2 trifluro- 1-(9-antreyl)ethanol to the nmr solution showed a 93:7 mixture of enantiomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7]2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]2([C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1)=[O:27]
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N1CCC2(CC1)OCc1ccccc12
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
3H-spiro[2-benzofuran-1,4′-piperidine] (5 g, 26 mmol) was dissolved in THF (100 mL) and cooled in ice. Then N-ethyldiisopropylamine (4.94 mL, 29 mmol) and chloroacetyl chloride (2.31 mL, 29 mmol) were added. The mixture was stirred at 20° C. for 15 min. The solid was filtered off and washed with THF. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica gel with heptane/AcOEt 70:30. One obtained light yellow crystals (6.5 g, 92%). MS: m/z=266 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:18])=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1]([C:3]1[C:4]([I:18])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.2 %

Procedure:
To a solution of methyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (1.5 g, 40.1 mmol) in THF (110 mL) was added a 1.0 M solution of sodium hydroxide in water (50 mL). The reaction mixture was allowed to stir at rt overnight and was then allowed to settle. The two layers were separated and the aqueous solution was washed with EtOAc and acidified with 1 N HCl. A precipitate formed and was filtered to give 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylic acid (1.2 g, 82%). LCMS: (FA) ES+ 365.0, ES− 363.1. 1H NMR (400 MHz, d6-DMSO) δ: 3.71-3.78 (m, 4H) and 3.51-3.58 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:13][CH:12]=2)[C:3]([OH:26])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.8 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid methyl ester (753 mg, 2.0 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (1.02 g, 24.3 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid (727 mg, quant.) as an amber foam: EI-HRMS m/e calcd for C22H28O3 (M+) 340.2038, found 340.2037.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1ccc(-c2ccoc2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(-c2ccoc2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([4-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 84%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][O:13][CH3:12])[N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COCc1ccccc1B(O)O
Product: COCc1ccccc1-c1cccc2nc(Cl)nn12

Procedure:
226 a) 2-Chloro-5-(2-methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (546.0 mg, 2.35 mmol) and 2-(methoxymethyl)phenylboronic acid (545.0 mg, 3.29 mmol) in a manner analogous to Example 2c. Product was isolated as a white solid (0.384 g, 60%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72-7.41 (m, 6H), 7.09-7.05 (m, 1H), 4.30 (br s, 2H), 3.16 (s, 3H). MS=274 (MH)+. 226 b) N7-[5-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-(2-methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (365.0 mg, 1.33 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (350.0 mg, 1.33 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (226.0 mg, 0.41 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a white foam (0.115 g, 17%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.64 (d, J=7.7 Hz, 1H), 7.59-7.42 (m, 5H), 7.39-7.13 (m, 3H), 7.00 (d, J=7.5 Hz, 1H), 6.92-6.88 (m, 1H), 4.35 (br s, 2H), 3.57-3.47 (m, 4H), 3.20 (s, 3H), 2.85-2.78 (m, 4H), 1.49 (s, 9H). MS=500, 501 (MH)+.
Reaction SMILES: [ClH:1].[CH2:2]([NH:6][CH:7]1[CH2:13][CH:12](O)[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9][CH2:8]1)[CH2:3][CH2:4][CH3:5].P(=O)(O)(O)O>>[ClH:1].[CH2:2]([NH:6][CH:7]1[CH:13]=[CH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9][CH2:8]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC1COc2ccccc2C(O)C1
Agent: Cl
Agent: O=P(O)(O)O
Product: CCCCNC1C=Cc2ccccc2OC1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
15.3 g 3-butylamino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol hydrochloride were stirred for four hours at room temperature in 80 ml of an 85 percent aqueous phosphoric acid solution. Subsequently, the solution was poured over 100 g of ice, and the mixture was worked up as described in Example 1. 12.1 g of 3-butylamino-2,3-dihydro-1-benzoxepine hydrochloride were obtained. Melting point: 138 degrees C.