Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:27]=[CH:26][N:25]=[C:24]3[C:15]=2[CH:16]=[CH:17][C:18]2[C:23]3=[N:22][CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:9]=1.O>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([C:21]2[CH:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18]3[C:23](=[C:24]4[C:15](=[CH:16][CH:17]=3)[C:14]([C:11]3[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=3)=[CH:27][C:26]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:25]4)[N:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)cc(-c5ccccc5)nc4c3n2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
Under a nitrogen atmosphere, 15 ml of a 1.6 mol/l phenyllithium solution (24 mmole) was added to a stirred suspension of 2.0 g of bathophenanthroline (6 mmole) in a mixture of 60 ml of toluene and 20 ml of THF, and the resulting mixture was cooled to 0° C. The resulting deep-red solution was stirred overnight at room temperature, and 10 ml of water was then added. The organic layer was separated, and the aqueous layer was extracted with 40 ml of dicholormethane three times. The combined extracts were stirred with 30 g of MnO2 for 2 hours. The mixture was dried over 30 g of anhydrous MgSO4, filtered, and evaporated to give 2.6 g of a light yellow solid in a yield of 90 percent. 1H NMR (500 MHz, CDCl3), ppm: 8.50 (d, J=7.5 Hz, 4H), 8.09 (s, 2H), 7.81 (s, 2H), 7.61-7.57 (m, 8H), 7.55 (dd, J=7.5, 7.5 Hz, 4H), 7.52-7.47 (m, 4H). Analysis for PBP. Found: C, 88.62, H, 4.56, N, 5.82. Calculated: C, 89.23, H, 4.99, N, 5.78.
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1C=CC=CC=1.[C:10]1(=[O:20])[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.OCC(CO)(CO)CO>C1(C)C(C)=CC=CC=1>[CH2:1]1[CH:19]2[CH:18]3[CH:17]=[CH:16][CH:12]([CH:11]2[CH:10]=[CH:2]1)[CH2:13]3.[C:13]([OH:14])(=[O:8])/[CH:12]=[CH:11]/[C:10]([OH:15])=[O:20]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(O)c1ccccc1
Agent: OCC(CO)(CO)CO
Solvent: Cc1ccccc1C
Product: C1=CC2C3C=CC(C3)C2C1
Product: O=C(O)/C=C/C(=O)O

Procedure:
640 T of soya oil fatty acid, 180 T of benzoic acid, 350 T of phthalic anhydride and 335 T of pentaerythritol are condensed at 210° to 230° C, after the addition of 35 T of xylene, in an inert gas atmosphere with distillation of the water formed during esterification, until an acid number of less than 10 is reached. Then 155 T of a copolymer obtained from dicyclopentadiene and fumaric acid in a molar ratio of 5:1 and having an acid number of 30 and a softening temperature of 70 to 80° C are added and condensed at 240° C with the alkyd resin formed beforehand until a viscosity of 10000 mPa.s (55% in a benzinexylene mixture 4:1) and an acid number of less than 15, based on the solid resin, are obtained. The end product is diluted with the above-mentioned mixture of solvents to form a 55% solution.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:28]([Sn:32](I)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCC[Sn](I)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred and cooled (−90° C.) solution of bromide 4 (206 mg, 0.66 mmol) in THF (2.5 mL) was added dropwise 1.5 M solution of tert-butyllithium in pentane (1 mL, 1.51 mmol). After 35 min additional stirring at −90° C., tri-n-butyltin iodide (0.23 mL, 0.79 mmol) was added in one portion. The mixture was stirred at −90° C. for 10 min, −78° C. for 40 min, and then allowed to warm to r.t. The mixture was partitioned between AcOEt-brine. The aqueous layer was extracted with AcOEt (3×) and the combined organic solutions were dried (MgSO4), and concentrated to afford the crude stannane 17, which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([N:22](C)[C:23](=O)OC(C)(C)C)[CH2:17]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][CH3:23])[CH2:17]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N(C)C(=O)OC(C)(C)C)C3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 195.1 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.180 g, 0.413 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50% CH3CN/water). The resulting product was dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(5-chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide hydrochloride (0.150 g, 89% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.13 (s, 1H), 7.28 (s, 1H), 3.87-3.84 (m, 1H), 3.42-3.37 (m, 2H), 3.20-3.14 (m, 2H), 2.59 (s, 3H), 2.42-2.37 (q, 2H), 1.15-2.13 (m, 1H), 1.79-1.75 (m, 1H), 1.65-1.52 (m, 2H), 1.10-1.06 (t, 3H). LCMS (APCI+) m/z 336 (M+H)+.
Reaction SMILES: [Cu][C:2]#[N:3].[CH2:4]1[O:22][C:7]2([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)[O:6][CH2:5]1>CN(C=O)C.O>[CH2:4]1[O:22][C:7]2([CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]([C:2]#[N:3])=[CH:19][CH:20]=3)=[O:14])[CH2:11][CH2:12]2)[O:6][CH2:5]1
Reactant: O=C(c1ccc(Br)nc1)N1CCC2(CC1)OCCO2
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cn1
Temperature: 150 °C
Yield: 52.4 %

Procedure:
A stirred suspension of copper (I) cyanide (0.66 g, 7.4 mmol) and 1-(6-bromo-3-pyridyl)carbonyl-4-piperidone ethylene ketal (2.2 g, 6.7 mmol, prepared as in Example V from 6-bromo-3-pyridinecarboxylic acid) in DMF (30 ml) was heated at 150° C. for 3 h. The mixture was cooled, diluted with water, extracted with ethyl acetate, dried over sodium sulphate and evaporated. Purification by flash chromatography on silica, eluting with 20% ethyl acetate/hexane, gave a white crystalline solid (0.96 g, 52%), m.p. 133°-135° C.
Reaction SMILES: [OH2:1].Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:29][CH2:30][CH:31]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:33][CH2:32]2)(=O)=O)=CC=1>CN(C)C=O>[O:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:40][CH:31]([CH2:30][CH2:29][N:3]2[CH2:8][CH2:7][C:6](=[O:1])[CH2:5][CH2:4]2)[CH2:32]1
Reactant: O=C1CCCCN1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(CCC2COc3ccccc3C2)CC1
Reaction time: 18 h

Procedure:
First 8.45 g (55 mmol) of piperidone hydrochloride monohydrate and then 22.62 g (175 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 16.62 g (50 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 100 ml of dimethylformamide. The mixture is stirred for 18 hours at 80° and, after cooling, is concentrated to dryness by evaporation under reduced pressure. The residue is dissolved in diethyl ether and washed with water. The organic phase is separated off and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline, while cold, with concentrated sodium hydroxide solution and extracted with dichloromethane. The dichloromethane phases are combined, dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. A dark brown resin is obtained which is purified by chromatography on 350 g of silica gel (0.040-0.063 mm) using toluene/ethyl acetate (1:1) as the eluant. 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine is obtained in the form of a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)[CH2:2]1.[CH3:32][C:33]([CH3:47])([O:35][C:36]([NH:38][C@@H:39]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:40]([OH:42])=[O:41])=[O:37])[CH3:34].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[OH2:18].[CH3:34][C:33]([CH3:47])([O:35][C:36]([NH:38][C@@H:39]([CH2:43][CH:44]([CH3:45])[CH3:46])[C:40]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)[CH2:2]1)=[O:41])=[O:37])[CH3:32].[CH3:47][C:33]([CH3:32])([O:35][C:36]([NH:38][C@@H:39]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:40]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)[CH2:2]1)=[O:42])=[O:37])[CH3:34]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C1NC(CC2CNc3ccccc32)c2nc3ccccc3c(=O)n2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(CC2NC(=O)c3ccccc3-n3c2nc2ccccc2c3=O)c2ccccc21
Product: O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(2,3-Dihydro-1H-indol-3-yl)methyl]-quinazolino(3,2-A)-1,4-benzodiazepin-5,13-(6H,7H)-dione (50 mg, 0.122 mmole) was dissolved in 2 ml of dry dimethylformamide under nitrogen and treated at room temperature with 2-(S)-(1,1-dimethylethoxycarbonyl)amino-4-methylpentanoic acid (34 mg, 0.146 mmole), 1-hydroxybenzotriazole (20 mg, 0.146 mmole), and dicyclohexylcarbodiimide (30 mg, 0.146 mmole), respectively. The pH of the reaction mixture was adjusted to approximately 8 with triethylamine (20 μl) and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with 10% citric acid and brine, then dried and concentrated. Silica gel chromatography (95:5 chloroform-methanol) afforded 23 mg of the analytical sample along with 19 mg recovered starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)C1CCCC1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)C2CCCC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)cyclopentanecarboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and cyclopentanecarboxylic acid using method D. NMR; δH [2H6]—DMSO 9.85,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.52-7.49,(2H, m), 7.40,(2H, d), 7.20,(1H, d), 3.16,(2H, t), 2.74,(1H, m), 2.15,(3H, s), 1.83-1.51,(8H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.42 min, MH+377.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([OH:12])=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CCO>[Br:11][C:9]1[CH:10]=[C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:2]=2)[C:6]([OH:12])=[N:7][CH:8]=1
Reactant: O=C(CBr)c1cc(Br)cnc1O
Reactant: Nc1ccccn1
Solvent: CCO
Product: Oc1ncc(Br)cc1-c1cn2ccccc2n1
Yield: 67.6 %

Procedure:
A mixture of 2-bromo-1-(5-bromo-2-hydroxypyridin-3-yl)ethanone (300 mg, 1.02 mmol) and 2-aminopyridine (100 mg, 1.06 mmol) in EtOH (10 mL) was stirred at reflux overnight. The reaction mixture was cooled and filtered to provide 5-bromo-3-(imidazo[1,2-a]pyridin-2-yl)pyridin-2-ol (200 mg, yield: 67%). 1H-NMR (DMSO, 400 MHz) δ 12.75 (br s, 1H), 9.02 (s, 1H), 8.94 (d, J=6.8 Hz, 1H), 8.42 (d, J=2.8 Hz, 1H), 7.89˜7.96 (m, 3H), 7.45 (d, J=4.8 Hz, 1H). MS (M+H)+: 290/292.
Reaction SMILES: N1CC[CH2:3][CH2:2]1.C1(=O)CCCC1.[C-]#N.[K+].[CH3:15][C:16]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:19])[C:17]#[N:18]>O>[N:20]1([C:16]2([C:17]#[N:18])[CH2:19][CH2:3][CH2:2][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C#N)N1CCCC1
Reactant: C1CCNC1
Agent: [C-]#N
Agent: [K+]
Solvent: O=C1CCCC1
Solvent: O
Product: N#CC1(N2CCCC2)CCCC1
Yield: 76 %

Procedure:
The title compound (2.50 g, 76%) was prepared from pyrrolidine (1.42 g, 20 mmol), cyclopentanone (1.68 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.80-1.90 (10H, m), 2.15 (2H, m), 2.71 (4H, m).
Reaction SMILES: [OH:1][C@:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]([CH2:28][OH:29])[CH:20]=3)=[CH:17][N:18]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C>ClCCl>[C:30]([O:29][CH2:28][C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C@@:2]3([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]3)=[N:18][CH:17]=2)[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc([N+](=O)[O-])c3)s2)CC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COC(C)=O)cc([N+](=O)[O-])c3)s2)CC1(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
To a solution of the product of Step 4 (194 mg, 0.46 mmol) dissolved in dichloromethane (1.8 mL) at −20° C. was added acetyl chloride (34 μL, 0.48 mmol) and triethylamine (129 μL, 0.92 mmol). The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was quenched with saturated aqueous sodium bicarbonate, and extracted with dichloromethane (3×). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated to afford methyl (1S,4R)-4-(5-{3-[(acetyloxy)methyl]-5-nitrophenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (203 mg, 0.39 mmol, 86% yield) as a yellow foam. MS ESI: [M+H]+ m/z 463.1.
Reaction SMILES: C(O[C:6]([C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[C:10]([C:15]([O:17]CCCC)=O)[CH:9]=1)=[O:7])CCC.[CH3:22][O-:23].[Na+].[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28]>CO>[NH2:14][C:12]1[CH:13]=[C:8]([C:6]([NH:25][CH:26]([CH2:27][OH:28])[CH2:22][OH:23])=[O:7])[CH:9]=[C:10]([C:15]([NH:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28])=[O:17])[CH:11]=1
Reactant: C[O-]
Reactant: CCCCOC(=O)c1cc(N)cc(C(=O)OCCCC)c1
Reactant: NC(CO)CO
Agent: [Na+]
Solvent: CO
Product: Nc1cc(C(=O)NC(CO)CO)cc(C(=O)NC(CO)CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
5-Amino-1,3-benzenedicarboxylic acid di-n-butyl ester (1148 g, 3.91 mol) is loaded into a 10 L reaction vessel containing methanol (7.5 L) and a 1.5M solution of sodium methylate in methanol (0.39 L, 0.59 mol) and 2-amino-1,3-dihydroxypropane (820 g, 9.0 mol) are added thereto. The reaction mixture is then heated to the reflux temperature and kept at this temperature for 4 hours. The mixture is then concentrated to 4 L, cooled to 25° C. and after one night at room temperature it is filtered. The solid on filter is washed with methanol (2×1.3 L) and dried yielding the compound of the title (1215 g, 3.71 mol, yield: 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:11])[NH:9][OH:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:20][C:19]=1[O:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:14])=[O:13].[CH2:39](O)[CH2:40][CH2:41][CH3:42].[ClH:44]>>[ClH:44].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:11])[NH:9][OH:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:20][C:19]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:37])(=[O:13])=[O:14]
Reactant: CCCCO
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)NO)ccc2O)c(OCC(=O)O)c1
Agent: Cl
Product: CCCCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)NO)ccc1O

Procedure:
Method 2) A solution of 110 g of [4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid in 1.00 L of 14% hydrogen chloride n-butanol solution was stirred at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give 111 g of crude crystal. The crude crystal was recrystallized from n-butanol-diisopropyl ether to give 83.3 g of n-butyl [4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:34]2[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]2)=[O:18])=[N:14][CH:15]=1
Reactant: OC1CCNCC1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC(O)CC2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (94 mg, 0.223 mmol) obtained in Example 12 in methylene chloride (3 ml), 4-hydroxypiperidine (27 mg, 0.268 mmol), 1-hydroxybenzotriazole (30 mg, 0.223 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.268 mmol) and 4-methylmorpholine (29 μl, 0.268 mmol) were added, and the resulting mixture was stirred for 18 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with an aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:30) was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (76 mg, 0.151 mmol, 68%) as a white powder.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=O)[CH2:2][CH3:3].C[Si](C)(C)[C:12]#[C:13][C:14](=O)[CH3:15].C([O-])(=O)C.[NH4+:23]>CO>[CH2:2]([C:1]1[N:23]=[C:14]([CH3:15])[CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:3]
Reactant: CC(=O)C#C[Si](C)(C)C
Reactant: [NH4+]
Reactant: CCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Solvent: CO
Product: CCc1nc(C)ccc1C(=O)OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl propionylacetate (1.93 mL), 4-trimethylsilyl-3-butyn-2-one (2.65 mL) in MeOH (100 mL) was added ammonium acetate (3.55 g) at room temperature. The mixture was stirred at 60° C. overnight. After cooling, the mixture was concentrated. The residue was diluted with water, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in EtOAc and the insoluble material was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (1.56 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Cu][C:10]#[N:11]>CN(C=O)C>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[N:11]
Reactant: N#C[Cu]
Reactant: O=Cc1cc(Br)cs1
Solvent: CN(C)C=O
Product: N#Cc1csc(C=O)c1
Yield: 71.5 %

Procedure:
49.3 g (258.05 mmol) of 4-bromothiophene-2-carbaldehyde and 27.8 g (310.41 mmol) of copper(I) cyanide were suspended in 130 ml of absolute DMF and refluxed for 8 h. The solvent was removed in a rotary evaporator at 40° C., and the residue was suspended in ethyl acetate and transferred into a Soxleth [sic] apparatus. The residue was extracted overnight, the yellow solution was dried over sodium sulfate and concentrated in a rotary evaporator, and the resulting yellow solid was recrystallized from ether to result in 25.3 g of product (80% of theory).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:20])=[CH:7][CH:6]=1)[CH3:3].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[O-:32][CH2:33][CH3:34].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]2[CH:23]([C:24]3[CH:31]=[CH:30][C:27]([CH3:28])=[CH:26][CH:25]=3)[C:13](=[O:14])[C:12]3[C:16]([C:15]([O:32][CH2:33][CH3:34])=[O:20])=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10]2)=[CH:21][CH:22]=1)[CH3:1]
Reactant: Cc1ccc(C=O)cc1
Reactant: CN(C)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (500 mg, 1.7 mmol) and 4-methylbenzaldehyde (204 mg, 1.7 mmol) in ethyl propionate (30 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (156 mg, 6.8 mmol) in ethanol (30 mL)) was added dropwise. After the addition, the mixture was stirred at 10° C. for 1 hr, then at 30° C. for 3 hr. The mixture was quenched with water (30 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (30 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by chromatography (silica gel, dichloromethane/methanol=100:1 to 10:1) to give the title compound (110 mg, yield: 15%). LC-MS (ESI) m/z: 443 (M+1)+.