Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([NH2:22])[C:4]=2[N:3]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([NH:22][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(NS(C)(=O)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-amine (186 mg), Et3N (0.15 mL) and DCM (20 mL) was added a solution of methanesulfonyl chloride (69 mg) in DCM at 0° C. and then the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with MeOH:DCM=1:30 to afford the desired product as a solid (180 mg, 80%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.40 (s, 3H), 2.98 (t, 4H, J=4.8 Hz), 3.21 (s, 3H), 3.68 (t, 4H, J=4.8 Hz), 5.96 (s, 2H), 6.37 (d, 1H, J=8.1 Hz), 6.80 (s, 2H), 7.35 (t, 1H, J=8.1 Hz), 7.60-7.71 (m, 2H), 7.85 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=8.1 Hz), 8.24 (d, 1H, J=8.1 Hz), 9.49 (br s, 1H); LC-MS: m/e=451 [M+1]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[NH2:17])(=[O:4])=[O:3].N1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:17][S:2]([C:19]1[CH:9]=[CH:10][C:5]2[C:21](=[CH:22][CH:23]=[CH:7][CH:6]=2)[CH:20]=1)(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: c1ccncc1
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (cf. Example 20c, 0.046 g) in pyridine (0.5 ml) was added naphthalene-2-sulfochloride (0.051 g). The reaction mixture was stirred at 70° C. for 6 h, diluted with dichloromethane and chromatographed on silica gel using dichloromethane/methanol/ammonia to obtain the title compound (0.025 g) as an off-white solid. MS (ISP): 439.1 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([NH:6][C:7]1([O:12][CH3:13])[CH2:10][NH:9][C:8]1=[O:11])=[O:5])[CH3:3].C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O.C1COCC1>[C:21]1([CH2:27][C:28]([N:6]([C:7]2([O:12][CH3:13])[CH2:10][NH:9][C:8]2=[O:11])[C:4](=[O:5])[C@@H:2]([CH3:3])[NH2:1])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC1(NC(=O)[C@@H](C)N)CNC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC1(N(C(=O)Cc2ccccc2)C(=O)[C@@H](C)N)CNC1=O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
In 2 ml of DMA is dissolved 0.28 g of the 3-(D-alaninamido)-3-methoxy-2-oxoazetidine obtained in Example 16, and 0.30 g of triethylamine is added. To the solution is added a solution of 0.233 g of phenylacetyl chloride in 2 ml of THF under ice-cooling and the mixture is stirred at room temperature for an hour. The mixture is concentrated under reduced pressure and the residue is extracted with ethyl acetate. The extract is purified by silica gel column chromatography to obtain 0.22 g of 3-(N-phenylacetyl-D-alaninamido)-3-methoxy-2-oxoazetidine.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[S:14][CH:13]=[CH:12][CH:11]=1)=O)C.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17]>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:8]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:19]([O:18][CH2:16][CH3:17])=[O:24])=[C:5]([CH3:4])[NH:23][C:21]=1[NH2:22])=[O:24])[CH3:17]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)CC(=O)C=Cc1cccs1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1Cc1cccs1
Yield: 73 %

Procedure:
Upon heating a solution of 12.2 g of (2-thenylidene)-acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours, 2-amino-6-methyl-4-(2-thenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 170°C (ethanol) is obtained. Yield: 73% of theory.
Reaction SMILES: ClC1C=CC([C@@H]2[C@@H]([C@@H](OC3C=CC(Cl)=C(Cl)C=3)C)CCN(C(C3CCN(C4C=CC(C#N)=CN=4)CC3)=O)C2)=CC=1.N1CCCCC1.C([N:54]1[CH2:59][CH2:58][C@H:57]([C@H:60]([OH:62])[CH3:61])[C@@H:56]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[C:65]([F:70])[CH:64]=2)[CH2:55]1)C1C=CC=CC=1.[Cl:71][C:72]1[CH:73]=[CH:74][C:75](O)=[N:76][CH:77]=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[Cl:71][C:72]1[CH:73]=[CH:74][C:75]([O:62][C@H:60]([C@H:57]2[CH2:58][CH2:59][NH:54][CH2:55][C@@H:56]2[C:63]2[CH:68]=[CH:67][C:66]([F:69])=[C:65]([F:70])[CH:64]=2)[CH3:61])=[N:76][CH:77]=1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)cn1
Agent: CC(Cl)OC(=O)Cl
Agent: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CCNC[C@@H]1c1ccc(F)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethanol and 5-Chloro-2-hydroxy-pyridine via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol to yield 5-Chloro-2-{(S)-1-[(3S,4S)-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethoxy}-pyridine. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as off-white solid. MS (m/e): 566.4 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Br[C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[N:15][N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:17]=1.BrC1C=NN(C2CCCCO2)C=1[N+]([O-])=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[C:14]([N+:24]([O-:26])=[O:25])=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:17]=2)[CH:7]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1c(Br)cnn1C1CCCCO1
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(F)ccc1O
Temperature: 80 °C
Yield: 62 %

Procedure:
To a mixture of (5-fluoro-2-hydroxyphenyl)boronic acid (225 mg, 1.44 mmol) and 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole or 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 22, 498 mg, 1.80 mmol) in 1,2-dimethoxyethane (4.5 mL) and 2 M solution of potassium carbonate in water (2.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (86.71 mg, 0.08 mmol). The mixture was sparged with argon (×3) and heated at 80° C. for 4 hours. Additional 5-fluoro-2-hydroxyphenyl)boronic acid (56 mg) was added and the reaction mixture stirred with heating for 18 additional hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and filtered through diatomaceous earth. The layers were separated and the organic layer washed with water and brine, dried over anhydrous magnesium sulfate, filtered, then concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (100% hexanes to 50% ethyl acetate in hexanes gradient elution) to afford the title compound as a light yellow solid (275 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1Cl)=[O:4].[CH:15]1([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:20][C:21]=1[F:26])=[O:4]
Reactant: Nc1ccc(C2CCC2)cc1F
Reactant: COC(=O)c1ccn2cncc2c1Cl
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 100 °C
Yield: 36.8 %

Procedure:
A suspension of 8-chloro-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (250 mg, 1.2 mmol), 4-cyclobutyl-2-fluoroaniline (230 mg, 1.4 mmol), Pd2dba3 (43 mg, 0.047 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (80 mg, 0.19 mmol) and K3PO4 (350 mg, 1.7 mmol) in toluene (5 ml) was degassed with argon for 10 minutes and then heated at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered through hyflo®. The filtrate was concentrated in vacuo, and the resultant gum was subjected to flash chromatography (Si-PPC, eluting with 5% ethyl acetate in DCM) to afford the title compound as a yellow oil (150 mg, 38%). 1H NMR (CDC13): 7.95 (1H, s), 7.73 (1H, d, J=7.4 Hz), 7.23 (1H, t, J=8.6 Hz), 7.07 (1H, d, J=7.3 Hz), 7.01 (2H, m), 6.50 (1H, s), 3.90 (3H, s), 3.59 (1H, m), 2.39 (2H, m), 2.17 (2H, m), 2.06 (1H, m), 1.93 (1H, m).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>C1COCC1>[CH3:10][C:8]1[CH:9]=[C:4]([B:12]([OH:17])[OH:13])[CH:5]=[C:6]([CH3:11])[CH:7]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: Cc1cc(C)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mg turnings (1.44 g, 59.43 mmol) were covered with dry THF (18.8 ml) in a dried, N2 filled flask fitted with an addition funnel and reflux condenser. To this was added 5-bromo-m-xylene (10 g, 54.03 mmol) in THF (15 ml) after initiation of the Grignard reaction. The addition was carried out over several minutes and the reaction mixture was heated at reflux for 1-2 h until most of the Mg had reacted. The reaction mixture was then cooled and transferred to an addition funnel fitted to a N2 filled flask containing triisopropyl borate (24.9 ml) at -70° C. The dropwise addition was carried out over several minutes and the mixture warmed to room temperature and stirred overnight. The grey solution was poured onto 2 M HCl and immediately turned yellow. The solution was extracted into Et2O and the Et2O fractions were combined, dried over MgSO4 and the solvent was removed in vacuo to yield 2.41 g (29.7%). mp 249-251° C.; 1H NMR (CDCl3) 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD3OD) 21.36, 133.28, 134.39, 137.48.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][N:7]([CH3:8])[C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CN(Cc1cccc(CO)c1)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(Cc1cccc(CBr)c1)C(=O)OC(C)(C)C
Reaction time: 96 h
Yield: 63.3 %

Procedure:
A stirred solution of tert-butyl-N-[3-(hydroxymethyl)benzyl]-N-methylcarbamate (4.2 g, 16.7 mmol) in CH2Cl2 (150 ml) at 0° C., was treated with carbon tetrabromide (8.0 g, 24.1 mmol) and triphenyl phosphine (6.35 g, 24.21 mmol). The resultant solution was warmed to room temperature and stirred for 4 days. The resultant mixture was evaporated to dryness and the residue purified by chromatography (SiO2, gradient elution with 100% hexane; 99:1 hexane:ethyl acetate; 95:5 hexane: ethyl acetate) to give the desired product (3.32 g, 60%). 1H NMR (CDCl3) δ 1.50 (s, 9H), 2.80 (s, br, 3H), 4.20 (s, 2H), 4.30 (s, 2H), 7.15 (m, 1H), 7.25 (m, 1H), 7.30 (m, 2H). LRMS m/z=333.2 (M+18)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[N:16]=[N:17][N:18](CCC#N)[N:19]=2)[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2nnn(CCC#N)n2)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)cc(-c2nn[nH]n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 3-tert-butyl-5-(2-(2-cyanoethyl)-2H-tetrazol-5-yl)benzoate (500 mg) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (76 mg) in 5.0 mL of water. The reaction mixture was stirred at RT for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 3-tert-butyl-5-(2H-tetrazol-5-yl)benzoic acid. MS found: (M+H)+=247.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[C:19]([O:29][CH3:30])[CH:18]=2)[C:13](=[O:31])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([OH:28])([CH3:26])[CH3:27])=[C:19]([O:29][CH3:30])[CH:18]=3)[C:13](=[O:31])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1cc(-n2ccc(O)cc2=O)ccc1OCC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-chloro-4-(chloromethyl)benzene (26.4 mg, 0.16 mmol), 4-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part C (50 mg, 0.16 mmol) and K2CO3 (67.9 mg, 0.49 mmol) in DMF (1.0 mL) was stirred at 100° C. for 90 min The mixture was cooled to RT, filtered and the filtrate was concentrated. The crude product was purified by prep-HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) yielding the title compound D-2-4-(4-chlorobenzyloxy)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one D-2 (30 mg, 41.2% yield) as white solid. LC/MS 430 (M+H)+, tR 0.93 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ ppm 7.32-7.44 (4H, m), 7.24-7.28 (1H, m), 6.96 (1H, d, J=8.53 Hz), 6.80-6.91 (2H, m), 6.06-6.18 (2H, m), 5.03 (2H, s), 3.85 (5H, d, J=1.76 Hz), 1.35 (6H, s).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[OH:1])[CH3:16]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid 10.0 g (55 mmol) in ethanol 100 mL was added dropwise 2 mL of conc. HCl, followed by stirring for 24 hrs under reflex. The mixture was cooled to room temperature, concentrated in a vacuum, and diluted with ethyl acetate. This dilution was washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated NaCl solution, dried over magnesium sulfate and concentrated in a vacuum. The concentrate was purified using column chromatography (developing solvent: ethylacetate/hexane=1/4) to afford the title compound 10.0 g (yield 86%).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].FC(F)(F)C(O)=O.[CH3:12][C:13]([C:15]1([CH2:22][OH:23])[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)=[O:14]>C(Cl)Cl.O>[CH3:12][C:13]([C:15]1([CH2:22][O:23][C:2](=[O:1])[NH2:3])[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)=[O:14]
Reactant: N#C[O-]
Reactant: CC(=O)C1(CO)CC2C=CC1C2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(=O)C1(COC(N)=O)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.7 %

Procedure:
52 g (0.8 mole) of sodium cyanate, followed dropwise by 95.8 g (0.84 mole) of trifluoroacetic acid, are added to a solution of 66.4 g (0.4 mole) of 2-hydroxymethylnorborn-5-en-2-yl methyl ketone in 120 ml of methylene chloride at 20° C., with slow stirring. The mixture is then stirred for 5 hours at room temperature, after which it is diluted with water. It is then repeatedly extracted with methylene chloride and the organic phases are combined and dried over sodium sulfate. After distilling off the solvent, a crystalline residue (83.1 g=99%) is obtained, and this is recrystallized from ethyl acetate. 45.8 g of 2-carbamyloxymethylnorborn-5-en-2-yl methyl ketone, of melting point 118°-119° C., are obtained.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][O:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]=[O:17])=[C:11]([O:18][CH3:19])[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(OCC)(=O)C.O.CN(C=O)C>[CH3:6][O:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH:16]=[O:17])[CH2:2][C:3](=[O:5])[CH3:4])=[C:11]([O:18][CH3:19])[CH:10]=1
Reactant: CC(=O)CCl
Reactant: COC(=O)c1ccc(NC=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Reaction time: 3 h

Procedure:
Chloroacetone (84.5 mL) was added dropwise to the DMF (497 mL) mixture of 4-formylamino-3-methoxybenzoic acid methyl ester (111 g), cesium carbonate (346 g), and potassium iodide (8.78 g) at room temperature, and the reaction mixture was agitated for 3 hours. Cesium carbonate (173 g) and chloroacetone (42.0 mL) were added to the reaction mixture, and the reaction mixture was agitated at room temperature for 2 hours. Iced water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. Ethyl acetate was added to the aqueous layer and the organic layer was partitioned. The organic layers were combined, washed with water and a saturated saline solution in this order, and the obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with toluene and the solution was concentrated under reduced pressure. Tert-butylmethyl ether and heptane were added to the resulted residue and the deposited solids were separated by filtering and washed with a 50% heptane solution of tert-butylmethyl ether. 118 g of the title compound was obtained by air-drying the obtained solids overnight.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:7][CH:8]=1)=[O:1]
Reactant: O=S(=O)(Nc1ccc(CO)cc1)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1ccc(NS(=O)(=O)c2ccccn2)cc1
Yield: 60.2 %

Procedure:
To a stirred solution of pyridine-2-sulfonic acid (4-hydroxymethyl-phenyl)-amide (200 mg, 0.76 mmol), and pyridine (612 μL) in anhydrous CH2Cl2 (3mL) was added Dess-Martin periodiane (450 mg, 1.06 mmol). The resultant solution was stirred at room temperature for 1 h. The mixture was diluted with 100 mL CH2Cl2, filtered through celite, and concentrated. The crude material was purified by recrystallisation from cold CH2Cl2 to give the title compound (120 mg, 60%) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 7.34 (d, 2H, J=8.4 Hz), 7.49-7.50 (m, 1H), 7.74 (br s, 1H), 7.75 (d, 2H, J=8.4 Hz), 7.89-7.70 (m, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70 (d, 1H, J=4.2 Hz), 9.87 (s, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4]C(O)=O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C:63]1[CH:64]=[C:65]([CH:67]=[CH:68][CH:69]=1)[NH2:66]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:66][C:65]1[CH:64]=[C:63]([C:4]#[C:3][C:2]([CH3:9])([OH:1])[CH3:8])[CH:69]=[CH:68][CH:67]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)(O)C#CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1cccc(N)c1

Procedure:
In a 3-liter 4-neck flask provided with a mechanical stirrer there are introduced—in the order—64.0 g (0.50 mol, 1.0 eq.) of 4-hydroxy-4-methyl-2-pentinoic acid, 5.7 g of Pd(OAc)2 (5% mol), 24 g of XPhos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; 10% mol) and 378 g (1.5 mol, 3 eq. mol.) of TBAF (Tetra-n-butylammonium fluoride). The mixture is dissolved, under Argon atmosphere, in 2 L of distilled anhydrous THF. 55 ml of 3-Bromoaniline (d=1.585 g/mL, 0.5 mol, 1.0 eq. mol.) are added to this solution.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45](O)=[O:46].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:46]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-80% ethyl acetate/chloroform to give the title compound (0.016 g, 61% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.86 (s, 9 H), 1.63 (m, 2 H), 2.07 (s, 6 H), 2.78 (m, 4 H), 3.51 (s, 3 H), 3.62 (m, 1 H), 3.94 (m, 3 H), 4.25 (m, 2 H), 4.87 (d, J=5.15 Hz, 1 H), 6.89 (m, 4 H), 7.19 (m, 5 H), 7.31 (m, 3 H), 7.61 (d, *8.46 Hz, 1 H), 7.84 (m, 5 H), 8.62 (d, J=4.41 Hz, 1 H).