Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH3:24])[C:17]=1[CH:25]=[O:26].S(=O)(=O)([OH:30])N.[O-]Cl=O.[Na+]>O.C1COCC1.CS(C)=O.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH3:24])[C:17]=1[C:25]([OH:30])=[O:26]
Reactant: NS(=O)(=O)O
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(OC)cc(C)c1C=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(OC)cc(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A solution of 2-(3-methyl-2-Formyl-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (1 mmol) and sulfamic acid (3 mmol) in 7 mL of H2O:THF:DMSO (20:10:1) at 0° C. was treated with NaClO2 (3 mmol) in 1 mL of H2O. The reaction mixture was stirred for 20 min at 0° C. The reaction was diluted with EtOAc (30 mL), washed with saturated aqueous NH4Cl (2×15 mL) and saturated brine, and dried (Na2SO4). Evaporation of the solvents under reduced pressure and further purification by column chromatography gave 2-(3-methyl-2-carboxy-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (85%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]#[C:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[C:5]([F:18])=[C:4]([F:19])[N:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]#[C:10][C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:20](=[O:22])[CH3:21])=[CH:13][CH:12]=2)[C:5]([F:18])=[C:4]([F:19])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Into the solution of 4-((Perfluoropyridin-4-yl)ethynyl)aniline, (13a) (0.158 g, 0.59 mmol) in 3 mL of CH2Cl2 were added acetic anhydride (0.134 g, 1.26 mmol) and Et3N (0.128 g, 1.26 mmol). The reaction mixture was stirred at room temperature overnight. After concentrating the solution in vacuo, the product was isolated by column chromatography (EtOAc:Hexane=1:2 to 1:1) with 85% yield: 1H-NMR (400 MHz, CD3OD) δ 7.70 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 2.15 (s, 3H); 13C-NMR (150 MHz, CD3CN) δ 170.1, 144.5 (dm, J=237 Hz), 143.1 (dm, J=259 Hz), 142.7, 134.2, 120.0, 115.4, 107.5 (t, J=3.4 Hz), 73.6 (t, J=4.3 Hz), 24.5; HRMS (ESI+): calcd for C15H9F4N2O1 [M+H]+ 309.06510, found 309.06678; m.p. 189-190° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22](=O)[CH3:23])=[C:6]([CH3:21])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][C:11]=2[O:19][CH3:20])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:25][NH2:26]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:22]([CH3:23])=[N:25][N:26]=[C:1]3[CH3:2])=[C:6]2[CH3:21])=[C:11]([O:19][CH3:20])[CH:12]=1)[CH3:18]
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1
Reactant: NN
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (60 mg) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.06 (d, 1H), 6.66 (m, 2H), 4.05 (q, 2H), 3.86 (s, 3H), 2.84 (s, 6H), 2.41 (s, 6H), 1.25 (t, 3H); MS (ESI) 326 (M+H)+
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[N:4][CH:3]=1.[N:21]([O-])=O.[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>O.CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a 6° C. mixture of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (16 g, 48 mmol), AcOH (97 mL) and H2O (97 mL) was added NaNO2 (4.0 g, 58 mmol) in H2O (12 mL) dropwise over 15 min. After 1.5 hours, a 1:1 mixture of concentrated sulfuric acid and water (6 mL) was added dropwise. After 1.5 hours, NaNO2 (0.5 g, 7 mmol) in H2O (2 mL) and a 1:1 mixture of concentrated sulfuric acid and water (5 mL) were added. The reaction was allowed to warm to room temperature overnight. The reaction was re-cooled in an ice bath and over a period of 1.5 hours, a 1:1 mixture of concentrated sulfuric acid and water (30 mL) and NaNO2 (1.5 g, 22 mmol) in H2O (5 mL) was added. Aqueous 3.75 M NaOH (210 mL) was added dropwise and the resulting suspension was filtered. The precipitate was washed sequentially with water and ether, then suspended in dichloromethane:ethanol (1:1) and filtered. The filtrate was washed sequentially with 1M aqueous Na2CO3 and brine, dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (9.6 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(OCC=C)=O)[CH2:14][CH2:13]3)[N:11]=2)=[CH:4][CH:3]=1.CC1(C)CC(=O)CC(=O)C1>C1COCC1.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[N:11]=2)=[CH:24][CH:25]=1
Reactant: C=CCOC(=O)N1CCC(c2csc(Cc3ccc(Cl)cc3)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: C1CCOC1
Product: Clc1ccc(Cc2nc(C3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of allyl 4-[2-(4-chlorobenzyl)-1,3-thiazol-4-yl]piperidine-1-carboxylate (692 mg) in anhydrous THF (20 ml) was added dimedone (2.06 g) followed by Pd(PPh3)4 (201 mg) and the resulting mixture was stirred at room temperature for 4 hours. A further portion of dimedone (1.03 g) and Pd(PPh3)4 (100 Mg) was added and the mixture was stirred for a further 18 hours. The reaction mixture was partitioned between 1N sodium hydroxide (50 ml) and ethyl acetate (100 ml). The organics were separated, dried and evaporated to dryness. The residue was purified by column chromatography on SCX-2 stationary phase using a gradient of DCM up to 50% 7N NH3 in MeOH in dichloromethane as eluent to give 4-[2-(4-chlorobenzyl)-1,3-thiazol-4-yl]piperidine as a solid. Yield 162 mg). NMR (CDCl3): 1.8 (m, 2H), 2.2 (m, 2H), 2.4 (bs, 1H), 2.8-3.0 (m, 3H), 3.3 (m, 2H), 4.4 (s, 2H), 7.4 (m, 5H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1>>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCC=CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Reaction time: 72 h
Yield: 56.9 %

Procedure:
Diethyl ethoxymethyleneoxalacetate (3.17 g, 0.013 mol) is added to a solution of 1-morpholinobutene (1.84 g, 0,013 mol) dissolved in CH2C12 (40 mL) at 0°. The solution is concentrated in vacuo, and ammonium acetate (50 g), ammonium hydroxide (10 mL), tetrahydrofuran (20 mL) and 95% ethanol (20 mL) are added. The solution is heated to reflux for 30 minutes, then held at 3° for 72 hours. The reaction solution is then partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give the product (1.85 g, 0.0074 mol, 57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([N:15]2[CH:19]=[CH:18][N:17]=C2)=[O:14])[CH2:8]1>C(Cl)Cl.C(O)(C)C>[NH2:17][CH2:18][CH2:19][NH:15][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8]1)=[O:14]
Reactant: O=C(N[C@H]1CCN(c2ccccn2)C1)n1ccnc1
Solvent: CC(C)O
Solvent: ClCCl
Product: NCCNC(=O)N[C@H]1CCN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of imidazole-1-carboxylic acid ((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-amide (9.9 ml of a 0.1 M solution in DCM, 0.99 mmol) in iso-propanol (1 ml) is added ethyl-1,2-diamine (2 ml, 37 mmol). The reaction mixture is stirred at room temperature for 4 hours and then extracted with DCM using a continuous liquid-liquid extraction system to yield the titled compound as 1:4 mole ratio mixture with imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7].C(N(CC)CC)C.[O:35]=[C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:45])[N:37]1[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH3:22])=[O:7])=[C:2]([NH:1][S:48]([CH2:47][CH2:46][N:37]2[C:36](=[O:35])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]2=[O:45])(=[O:49])=[O:50])[CH:26]=1
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a solution of of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone (0.050 g, 0.13 mmol) in methylene chloride (1 mL) at ambient temperature was added triethylamine (0.027 mL, 0.19 mmol) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045 g, 0.17 mmol). The reaction was stirred overnight at ambient temperature. Additional triethylamine ((0.027 mL, 0.19 mmol) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045 g, 0.17 mmol) was added. The reaction was stirred one hour, then additional triethylamine (0.055 mL, 0.34 mmol) was added. The reaction was stirred and hour, then additional 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.090 g, 0.34 mmol) was added. After stirring an additional 1 hour, the reaction was treated with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via radial chromatography (2 mm plate) gave the title compound (0.030 g).
Reaction SMILES: C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]([C:58](=[O:69])[C:59]([O:61]CC1C=CC=CC=1)=[O:60])[C:24]1[CH:57]=[CH:56][C:27]([CH2:28][C@@H:29]([C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([OH:55])[C:44]=2[C:45]([O:47][CH3:48])=[O:46])=[O:36])[NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[C:59]([C:58]([N:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([OH:16])=[O:14])[C:24]1[CH:57]=[CH:56][C:27]([CH2:28][C@@H:29]([C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([OH:55])[C:44]=2[C:45]([O:47][CH3:48])=[O:46])=[O:36])[NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1)=[O:69])([OH:61])=[O:60]
Reactant: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cc(OC)cc(O)c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)O)c2ccccc2C(=O)O)cc1)C(=O)NCCCCOc1cc(OC)cc(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 2-(4-{[4-{{2-[(benzhydryloxy)carbonyl]phenyl}[(benzyloxy)(oxo)acetyl]amino}-N-(methoxycarbonyl)-L-phenylalanyl]amino}butoxy)-6-hydroxy-4-methoxybenzoate and 10% Pd—C (0.1 g) in methanol (25 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 16 hours. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to provide the titled compound. MS (ESI(+)) m/e 682 (M+H)+; 1H NMR (500 MHz, DMSO-d6) 10.66, 10.67 (s, s, 1H), 8.03-7.96 (m, 1H), 7.90-7.83 (m, 1H), 7.63-7.15 (m, 8H), 6.07-6.05 (m, 2H), 4.18-4.10 (m, 1H), 3.95-3.89 (m, 2H), 3.73 (s, 3H), 3.43 (s, 3H), 3.15-3.02 (m, 2H), 2.95-2.86 (m, 1H), 2.78-2.68 (m, 1H), 1.68-1.56 (m, 2H), 1.54-1.47 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(Cl)coc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(Cl)coc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
Ethyl 3-chloro-1-benzofuran-6-carboxylate (110 mg, 0.49 mmol) is dissolved in MeOH (3 ml) and water (0.75 ml), treated drop-wise with 2N NaOH (0.27 ml, 0.54 mmol) and stirred overnight at RT. The volatiles are removed in vacuo, the residue is dissolved in water (3 ml) and the pH is adjusted to 3 with concentrated HCl. The resulting solid is filtered and dried overnight in a vacuum oven to afford 88 mg (92%) of 3-chloro-1-benzofuran-6-carboxylic acid as a white solid. MS for C9H5ClO3 (EI) m/z: 196(M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)c1ccccc1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 14.8 %

Procedure:
4-nitrophthalic anhydride (0.5g, 0.0026 mol) and o-aminobenzoic acid (0.36 g, 0.0026 mol) were refluxed as above for four days. The clear solution was purified as per 120 with an additional final crystallisation from acetone/H2O to yield 0.12 g (15%) 147 as a very pale dull yellow powder: mp=242-243 ° C.; Rf0.80 (A): Rf0.88 (C): Rf0.49 (D): IR (cm−1): 2725-3100 (OH), 3071 (C═CH), 2646 (C—H), 1786 (C═O), 1730 (C═O), 1693 (C═O), 1620 (C═C), 1601 (C═C), 1538 (N═O), 1491 (C═C), 1452 (C═C), 1383 (C—O), 1345 (N═O), 1123 (C—C), 723 (C═CH); MS m/z (rel intensity) 311 (33), 267 (76), 241 (54), 136 (100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])#[N:2].[C:23]([CH:26]=[C:27]=[O:28])(=[O:25])[CH3:24]>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[C:7]([NH:9][C:27](=[O:28])[CH2:26][C:23](=[O:25])[CH3:24])[CH:6]=[CH:5][C:4]=1[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])#[N:2]
Reactant: CC(=O)C=C=O
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1C#N
Solvent: CCOC(C)=O
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1C#N
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 2-cyano-N1,N1-dihexylbenzene-1,4-diamine (1.55 g, 5.14 mmol) in EtOAc (30 mL) was added acetyl ketene (0.52 g, 6.19 mmol) with stirring and the mixture was stirred at 80° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as yellow oil (1.47 g, 74%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:37])/[C:13](=[N:27]\[O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:38])[N:8]2[S:39]([OH:42])(=[O:41])=[O:40])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:37])/[C:13](=[N:27]\[O:28][CH2:29][C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:38])[N:8]2[S:39]([OH:42])(=[O:40])=[O:41])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Yield: 31.1 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (97 mg, 0.154 mmol), DCM (1.54 mL) and TFA (711 μl, 9.23 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (22.7 mg, 22%) as a white powder. LCMS: Rt=0.28 min, m/z=475.0 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (d, J=9.0 Hz, 1H), 8.56 (s, 1H), 8.07 (s, 1H), 6.80 (s, 1H), 5.25 (dd, J=9.0, 5.9 Hz, 1H), 4.69-4.49 (m, 4H), 4.36 (dt, J=7.4, 4.9 Hz, 1H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][C:28]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:27][N:26]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1>[F:31][C:30]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=2)=[N:26][CH:27]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:29]=1
Reactant: CCCCCCCCOc1cnc(-c2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCCOc1cnc(-c2ccc(O)cc2)c(F)c1
Yield: 85.1 %

Procedure:
4.30 g (8.00 mmol) of 2-(4-tert-butyldiphenylsilyloxyphenyl)-3-fluoro-5-octyloxypyridine are stirred for 2 hours at room temperature with 16 ml of a 1-molar tetrabutylammonium fluoride solution in tetrahydrofuran in 50 ml of tetrahydrofuran. Aqueous sodium chloride solution is then added, the reaction mixture is extracted with ether, and the ether phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, evaporated to dryness and purified by chromatography (silica gel/hexane: ethyl acetate 8:2), giving 2.16 g of 3-fluoro-2-(4-hydroxyphenyl)-5-octyloxypyridine. ##STR33##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.B(O)O.C([O-])([O-])=O.[K+].[K+].O>CC#N.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>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)cc1
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: OBO
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2ccccc2)cc1

Procedure:
A solution of tert-butyl(trans)-2-(4-bromophenyl)cyclopropylcarbamate (Intermediate F; 1 equiv), 1.2 equiv of the boronic acid, 3.0 equiv of K2CO3 in CH3CN+H2O (4:1) was degassed for 30 mins with Argon gas, added 0.01 equiv of Pd (PPh3)4, heated the reaction mixture at reflux temp for 4 h. The progress of the reaction was monitored by TLC, after completion, poured the reaction mixture into water, extracted with EtOAc. The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography to get tert-butyl(trans)-2-(1,1′-biphenyl-4-yl)cyclopropylcarbamate derivative
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[OH:12][CH:13]([N:26]1[C:32](=[O:33])[C@@H:31]2[C@H:27]1[S:28][C:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[N:30]2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15]>O.ClCCl.CC(C)=O>[OH:12][CH:13]([N:26]1[C@H:27]([SH:28])[C@H:31]([NH:30][C:29](=[O:8])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@H]3N=C(Cc4ccccc4)S[C@H]32)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Toluene-4-sulphonic acid (3.42 g, 17.98 mmol) in water (8 ml) was added to a solution of 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (4.12 g, 10.0 mmol) in dichloromethane (20 ml) and acetone (20 ml). After stirring for 2.5 h at room temperature, the reaction mixture was diluted with dichloromethane, washed with water (×2), dried and concentrated in vacuo to yield crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate as a colourless foam. The crude thiol was dissolved in acetone (50 ml) and treated with a solution of 2-bromoacetyl-5-methyltetrahydrofuran (1.67 g, 8.1 mmol) in acetone (5 ml). After 10 min., potassium carbonate (687 mg, 5.0 mmol) was added, and the mixture stirred for a further 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with water (×2) and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane to yield the title compound as a colourless foam (2.68 g, 60%); νmax (CH2Cl2) 3412, 1781, 1744, 1685 and 1515 cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)].
Reaction SMILES: [OH:1][C:2]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=O)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:1][C:2]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:5]([C:6](=[N:21][OH:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCCc1cc(C(=O)c2ccccc2F)ccc1O
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1cc(C(=NO)c2ccccc2F)ccc1O

Procedure:
A solution of 4-hydroxy-5-propyl-2'-fluorobenzophenone (Step A; 1.35 g, 5.23 mmol) in 15 mL of pyridine was treated with hydroxylamine hydrochloride (1.82 g, 26.15 mmol). The mixture was refluxed for 24 hours, cooled and the pyridine removed in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (20% ethyl acetate/hexane eluent) to yield the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[N:18]([CH3:23])[N:19]=[C:20]([CH3:22])[CH:21]=2)[C:8]=1[CH3:24]>C1COCC1.CO>[CH3:23][N:18]1[C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:25])=[O:4])=[C:8]2[CH3:24])=[CH:21][C:20]([CH3:22])=[N:19]1
Reactant: COC(=O)Cc1c(C)n(Cc2cc(C)nn2C)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cn2c(C)c(CC(=O)O)c3cccnc32)n(C)n1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (0.5 mL) is added to a stirring solution of [1-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (29 mg, 0.09 mmol) in 1:1 THF/MeOH (2 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and the resulting precipitate collected by filtration to furnish [1-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=299.