Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1.Br[CH2:20][CH2:21][CH2:22][Cl:23]>C1COCC1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][N:13]1[CH2:12][CH2:11][C:10]2[CH:16]=[CH:17][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[CH:5]=3)=[CH:8][C:9]=2[CH2:15][CH2:14]1
Reactant: ClCCCBr
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc3c(c2)CCN(CCCCl)CC3)n(C)n1
Temperature: 25 °C

Procedure:
To a solution of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (0.5 g) in dry THF (10 ml), diisopropylethylamine (0.85 ml) and 1-bromo-3-chloropropane (0.47 mL) were added and the resulting mixture was refluxed for 7 hours. After cooling at room temperature it was diluted with ethyl acetate (30 ml) washed twice with a saturated solution of NaHCO3 in water (20 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by biotage chromatography using a silica 25 M+ cartridge and eluting with cHex/EtOAc 8:2 to give the title compound as a colourless oil (0.57 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]([C:17](C)([CH3:26])[C:18](=[O:25])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:12]3[CH2:28][CH2:29][N:30]([CH:32]=O)[CH2:31][C:11]=3[C:10]=2[CH:9]=1.[CH2:34]1COCC1>>[CH3:34][O:25]/[C:18](/[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[C:17](\[N:13]1[C:14]2[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=2[C:11]2[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][C:12]1=2)/[CH3:26]
Reactant: Cc1ccc2c(c1)c1c(n2C(C)(C)C(=O)c2ccncc2)CCN(C=O)C1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CO/C(=C(/C)n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Reaction time: 0.17 h

Procedure:
LAH (87 mg, 52.63 mmol) was taken in dry THF (10 mL) under inert atmosphere stirred for 10 min, 8-methyl-5-(2-methyl-1-oxo-1-(pyridin-4-yl)propan-2-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carbaldehyde (0.33 g, 0.914 mmol) was added portionwise and stirred at RT for 1 h. The reaction was monitored by TLC. LAH was quenched with sat. sodium sulfate (aqueous) at 0° C., filtered the reaction mass. The filtrate was extracted with EtOAc, dried over anhydrous sodium sulfate and evaporated to dryness to afford 0.24 g of the title compound as a yellow sticky solid. 1H NMR (CDCl3, free base) δ (ppm): 8.36 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.78 (d, 2H), 3.78 (s, 2H), 3.60 (s, 3H), 2.82 (m, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.30 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:56][O:57][C:58](=[O:63])[C:59]([NH2:62])([CH3:61])[CH3:60]>CN(C=O)C>[CH3:56][O:57][C:58](=[O:63])[C:59]([CH3:61])([NH:62][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])[CH3:60]
Reactant: O=C(O)c1ccc2ccccc2c1NCCCc1ccccc1
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1NCCCc1ccccc1
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
Under argon atmosphere 16 mg 1-(3-phenyl-propylamino)-naphthalene-2-carboxylic acid, 10 mg 1-hydroxybenzotriazole, 12 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 18 μl of N,N-diisopropylethylamine in 1 ml of dry DMF were stirred at 0° C. After 30 minutes at 0° C. 8 mg of 2-aminoisobutyric acid methyl ester hydrochloride, followed by 18 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, and the residue was purified by RP-HPLC to yield 7 mg of 2-methyl-2-{[1-(3-phenyl-propylamino)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[H][H]>CO.[Pd]>[F:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c2cnccc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c2cnccc12
Yield: 40.2 %

Procedure:
To a nitrogen flushed solution of 8-fluoro-5-nitroisoquinoline (Description 42; 1.33 g, 6.9 mmol) in methanol (100 ml) was added 10% palladium on carbon (500 mg) and the resulting mixture stirred under a balloon of hydrogen for 3.5 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was purifted by MPLC (Biotage Flash™ 40) eluting with 2% MeOH in dichloromethane to give the title compound (450 mg, 40%) as a yellow solid.
Reaction SMILES: [C:1]1([OH:14])[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H][H]>[Pd].C(O)C>[C:1]1([OH:14])[N:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: [H][H]
Reactant: Oc1nnc2ccc3ccccc3n12
Agent: [Pd]
Solvent: CCO
Product: Oc1nnc2n1-c1ccccc1CC2
Reaction time: 6 h

Procedure:
s-Triazolo(4,3-a)quinolin-1-ol (2.0 grams) was mixed with 125 milliliters of ethanol, and 1.0 gram of 5 percent palladium on carbon was added. The resulting mixture was hydrogenated at 50 psi hydrogen pressure and a temperature of 50°C., for 6 hours. The mixture was then filtered to remove catalyst, and the filtrate was evaporated to yield the desired 4,5-dihydro-s-triazolo(4,3-a)quinolin-1-ol product, m.p., 181°-2.5°C. Its identity was confirmed by NMR and by microanalysis.
Reaction SMILES: [NH:1]([C:18]([O:20]C(C)(C)C)=O)[C@@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)[C:27]([OH:29])=[O:28].ClCCl>>[NH:1]([C:27]([O:29][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:28])[C@H:2]([C:18]([NH:1][C@@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:20])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 1 h

Procedure:
30 g (1.0 eq) Boc-D-Glu(OBzl)-NH2 was dissolved in 100 mL trifluoroacetic acid-dichloromethane (v/v=1:1), and the solution was stirred for 1 hour at r.t to remove Boc group. After the completion of the reaction, the TFA was removed under vacuum; the residue was repeatedly grinded and washed in anhydrous ether, and evaporated to dryness, and re-dissolved in tetrahydrofuran. The pH of the solution was adjusted to 7˜8 with N-methyl morpholine (NMM) in ice bath. The Boc-Ala-OSu solution was sparingly added to the solution in a few portions. The mixture was stirred for 5 hours in ice bath, and continued for 24 hours at r.t. After the completion of the reaction, the mixture was evaporated to dryness. The residue was dissolved in proper amount AcOEt and successively washed with diluted hydrochloric acid, saturated sodium bicarbonate aqueous solution and water. The AcOEt layer was separated, and dried with MgSO4 overnight. The mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from methanol and water, the crystal was washed with a big amount of ether to obtained 29.4 g target compound. Yield: 81%, m.p.=134˜135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](O)[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: OC1Cc2ccccc2Sc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)Sc1ccccc1C=C2

Procedure:
17 G. 3-bromo-11-hydroxy-10,11-dihydrodibenzo[b,f]thiepin are dissolved in 600 cc. benzene; 1 gram p-toluene sulfonic acid is added and the mixture is refluxed with elimination of water for two hours. The solution is cooled and washed with aqueous sodium bicarbonate solution and water, dried and stripped to a solid residue. 16 G. of 3-bromodibenzo[b,f]thiepin are obtained.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:36])[C@H:11]([N:17]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:36])[C@H:11]([N:17]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H](C(=O)NOCc2ccccc2)C(O)C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H](C(=O)NO)C(O)C(C)C)cc1

Procedure:
A solution of N-benzyloxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-hydroxy-4-methylpentanamide (125 mg) in ethanol (100 ml) is hydrogenated in the presence of 5% palladium on charcoal (100 mg) at room temperature and atmospheric pressure to yield N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-hydroxy-4-methyl-pentanamide, m.p. 81°-82° C.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:13]=[CH:14][C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])O>>[CH:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:12][C@H:23]2[O:24][C@H:15]([CH2:14][OH:13])[C@@H:17]([OH:18])[C@H:19]([OH:20])[C@H:21]2[OH:22])=[CH:7][CH:8]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OCc1ccccc1
Solvent: CC(=O)Cl
Product: OC[C@H]1O[C@H](OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Acetyl chloride, 80 mL, was added carefully to 1.75 L benzyl alcohol. This was followed by the addition of 180 g glucose. The mixture was heated, with stirring, at 80° C. overnight; then cooled, and poured into a plastic bucket. The product was precipitated as an oil by the addition of ether (3 L) and hexane (15 L). The supernatant liquid was decanted, and the residual oil washed with ether-hexane 1:1 (10 L), then ether. This afforded benzyl-alpha-D-glucopyranoside as a semisolid which was filtered, crushed, and washed with ether, then hexane to afford 237.3 g (0.88 mole; 88%) white solid.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]3[N:26]=[C:25]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH:24]=[CH:23][CH:22]=3)=[CH:19][N:20]=[C:14]2[N:13]=1)([O:4][Si](CC)(CC)CC)[CH3:3]>C(O)C.Cl>[OH:4][C:2]([C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]3[N:26]=[C:25]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH:24]=[CH:23][CH:22]=3)=[CH:19][N:20]=[C:14]2[N:13]=1)([CH3:1])[CH3:3]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(-c4ccccc4C#N)n3)cnc2n1
Agent: Cl
Solvent: CCO
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccccc4C#N)n3)cnc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of crude 2-{6-[7-(1-methyl-1-triethylsilanyloxy-ethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile in ethanol (3 ml) was added 3 drops of concentrated hydrochloric acid and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue made basic by the addition of saturated aqueous sodium hydrogencarbonate. The aqueous phase was diluted with water (30 ml) and extracted with ethyl acetate (2×75 ml). The combined organic phase was washed with water (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give an orange oil. This oil was purified on silica eluting with dichloromethane (+1% 0.880 ammonia) on a gradient of methanol (1-3%). Collecting the appropriate fractions followed by recrystallisation from ethyl acetate/isohexane gave 2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile as a white solid: δH (360 MHz, CDCl3) 1.63 (6H, s), 4.52 (1H, s), 7.16 (1H, d, J 7), 7.55-7.62 (2H, m), 7.74-7.96 (5H, m), 8.36 (1H, s), 10.37 (1H, d, J 7); m/z (ES+) 356 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>C(Cl)Cl>[CH3:12][C:3]1[C:2]([NH:1][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nc2ccccc2cc1N
Solvent: ClCCl
Product: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-amino-2-methylquinoline(4 g, 25 mmol) and phenyl chloroformate(4.04 g, 25 mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2 hrs. The mixture solution was concentrated under the reduced pressure to remove methylene chloride and purified by column chromatography(ethylacetate:hexane=1:10) to obtain the titled compound.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NS(C)(=O)=O)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NS(C)(=O)=O)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)Nc1cccc(N)c1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CS(=O)(=O)Nc1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methanesulfonylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-Amino-phenyl)-methanesulfonamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: S(O)(O)(=O)=O.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])=[CH:15][CH:14]=1.N12CCCN=C1CCCCC2.Cl>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:25]([OH:26])=[N:11][C:7]3[N:6]([CH:10]=[CH:9][N:8]=3)[C:20]=2[OH:21])=[CH:17][CH:18]=1
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Oc1nc2nccn2c(O)c1-c1ccc(F)cc1
Temperature: 100 °C

Procedure:
7.2 g (39.3 mmol) 1H-Imidazol-2-ylamine sulfate are dissolved in 45 mL DMF. 10 g (39.3 mmol) diethyl (4-fluorophenyl)malonate is added. After dropwise addition of 17.6 mL (118 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. over night. The DMF has been removed and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (60 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (5.78 g=53.9%), which is used without further purification. Another crop of 0.48 g (4.5%) is obtained by treating the solid residue in the flask with water and 2M HCl. After stirring for one hour the crystals are collected.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 63 %

Procedure:
1,1-Cyclopropanedicarboxylic acid (2.5 g) was dissolved in tetrahydrofuran (25 ml) under a nitrogen atmosphere, and triethylamine (2.68 ml) was added dropwise thereto while stirring in an ice water bath. After stirring at the same temperature for 30 min, thionyl chloride (1.4 ml) was added dropwise while stirring in an ice water bath. After stirring at the same temperature for 30 min, a solution of 2,4-difluoroaniline (2.15 ml) in tetrahydrofuran (15 ml) was added while stirring in an ice water bath, and the reaction mixture was allowed to gradually warm up to room temperature and stirred overnight. After addition of a 2N aqueous solution of sodium hydroxide (75 ml) to the reaction mixture, tetrahydrofuran was removed under reduced pressure. To the resultant solution was added tert-butyl methyl ether (25 ml), followed by stirring. The organic layer and the aqueous layer were separated. The aqueous layer was cooled in an ice water bath, 5N hydrochloric acid (30 ml) was added and stirred. The precipitated solid was collected by filtration, and washed with water. Drying under aeration and hot-air drying at 60° C. for 8 hr provided the titled compound as white powder (2.918 g, 63%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-3-trifluoromethylbenzoic acid (395 mg) in methanol (5 mL) was added conc. sulfuric acid (0.4 mL), and the mixture was heated for 6 hours under reflux. The reaction mixture was allowed to stand for cooling down to room temperature, and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine, and concentrated to give the title compound (403 mg).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][C:14]1[N:15]=[N:16][NH:17][CH:18]=1)[CH2:2]2.[C:20](Cl)(=[O:31])[O:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1.[OH-].[Na+]>C(Cl)Cl>[NH:17]1[CH:18]=[C:14]([CH2:13][CH2:12][CH2:11][C:10]([NH:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:20]([O:21][CH2:22][C:23]4[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=4)=[O:31])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)=[O:19])[N:15]=[N:16]1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(CCCc1c[nH]nn1)NC1CC2CCC(C1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCCc1c[nH]nn1)NC1CC2CCC(C1)N2C(=O)OCc1cc(Cl)cc(Cl)c1

Procedure:
A reaction mixture comprising of N-(8-azabicyclo[3.2.1]octan-3-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide (294 mg, 1.116 mmol), 3,5-dichlorobenzyl carbonochloridate (267 mg, 1.116 mmol) and sodium hydroxide (5.58 ml, 112 mmol) in DCM (3.7 ml) was stirred at room temperature for 18 hours. The reaction mixture was separated and the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS and the resulting product fractions were concentrated under reduced pressure to give aqueous solutions which were extracted with ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O-:15].[Na+]>CO.O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[O:15][CH3:14])([O-:13])=[O:12]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 95 %

Procedure:
0.200 g (1.00 mmol) of commercially available 2-chloro-1,3-dinitrobenzene was dissolved in a warm solution of 15 ml methanol and 0.223 g (4.13 mmol) of NaOMe. The reaction was stirred overnight with continued warming. The residue was dissolved in water after evaporation of the solvent. The aqueous solution was extracted with dichloromethane, dried and evaporated under reduced pressure to give 0.187 g of 2,6-dinitroanisole (95%) as yellow flakes. 1H NMR (CDCl3) δ 8.06 (d, J=8.2 Hz, 2H, Ar—H), 7.38 (t, J=8.2 Hz, 1H, Ar—H), 4.09 (s, 3H, O—CH3). 13C NMR (CDCl3) δ 148.0, 129.4, 124.2, 65.1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.CS(O[CH2:17][CH:18]1[CH2:20][CH2:19]1)(=O)=O.C(N(CCCC)CCCC)CCC>C(OCC)C>[CH:18]1([CH2:17][N:4]2[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][C:2]([CH3:1])=[N:3]2)[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)OCC1CC1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Solvent: CCOCC
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)c1cc(C)nn1CC1CC1
Yield: 47.7 %

Procedure:
A mixture comprising 3.8 g of ethyl 3-methyl-1H-pyrazole-5-carboxylate, 3.8 g of cyclopropylmethyl methanesulfonate and 4.6 g of tri-n-butylamine was allowed to react at 110 ° C. for three hours without using any solvent. Then the reaction mixture was allowed to cool and diethyl ether was added thereto. The obtained mixture was successively washed with 1 N hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (eluent: hexane:ethyl acetate=14 : 1). Thus 0.62 g of the aimed ethyl 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylate (compound No. 1001) (yield: 12.1 %) and 2.45 g of ethyl 1-cyclopropylmethyl-3-methyl-1H-pyrazole-5-carboxylate (yield: 54.3 %) were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH3:16])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]#[N:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]=[C:27]([S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35])[CH:26]=[CH:25]2>C(Cl)(Cl)Cl>[N:18]#[N:19].[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH3:16])[N:8]([C:46](=[O:47])[C@H:38]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])[NH:37][S:34]([C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=2)[CH:28]=1)(=[O:36])=[O:35])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Reactant: C[C@H](NCc1ccccc1)C(=O)OC(C)(C)C
Agent: N#N
Solvent: ClC(Cl)Cl
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(Cc3ccccc3)[C@@H](C)C(=O)OC(C)(C)C)cc2cc1OC
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred solution of 4.42 g of N-benzylalanine tert-butyl ester in 20 ml of chloroform was carefully added N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness to give 2.50 g (83 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine tert-butyl ester in the form of a powder. The flavianate; M.P. 168°-172° C (dec.)