Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([OH:23])[CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: O=C(O)c1cccc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 3-hydroxybenzoic acid as brown solid (41%). MS 424 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Product: COc1ccc(C=CC(=O)O)cc1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3 h) between 3-fluoro-4-methoxybenzaldehyde (6.080 g; 39.445 mmol) and malonic acid (7.798 g; 74.946 mmol) gave the product 3-(3-fluoro-4-methoxy-phenyl)-acrylic acid as a colorless solid (7.530 g; 97%). LC-MS: tR=0.86 min.; [M+H]+: no ionisation.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH:13]C=O)[CH3:12].C(O)C.[OH-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH2:13])[CH3:12]
Reactant: CC(NC=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(N)c1ccc2ccccc2c1
Yield: 98.7 %

Procedure:
A mixture of N-(1-naphthalen-2-yl-ethyl)-formamide (1.12 g), ethanol (10 mL) and 5 N sodium hydroxide (10 mL) is heated at reflux for 1 hour. The solution is cooled, poured into water and extracted with ether. The ether solution is dried with anhydrous potassium carbonate, filtered and concentrated to give the product (0.95 g) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:5][CH3:6].Cl.Cl[CH2:16][C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[CH3:3][CH:4]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:16][C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:12]=1)[CH2:5][CH3:6]
Reactant: CCC(C)c1ccc(O)cc1
Reactant: Nc1ncccc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(OCc2cccnc2N)cc1
Reaction time: 0.33 h
Yield: 35.2 %

Procedure:
The solution of (2-aminopyridin-3-yl)methanol (1.0 g) in THF (dry) (10 mL) was added dropwise to a solution of thionyl chloride (0.736 mL) in THF (dry) (30 mL) at 0° C. The mixture was stirred at room temperature for 30 min and concentrated in vacuo to give 3-(chloromethyl)pyridin-2-amine hydrochloride as a yellow gum. NaH (60%, 147 mg) was added to a mixture of 4-(1-methylpropyl)phenol (503 mg) in DMF (dry) (7 mL) at 0° C. The mixture was stirred at the same temperature for 20 min, then was added with the prepared 3-(chloromethyl)pyridin-2-amine hydrochloride (300 mg) at the same temperature. The mixture was stirred at 0° C. for 20 min, room temperature for 1 hr and 60° C. for 1 hr. Silica-gel was added to the mixture and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (151 mg) as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([OH:3])=O.S(Cl)(Cl)=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(OCC)(=O)C>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:4]([C:1]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(OCCn2ccnc2)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(OCCn2ccnc2)cc1)N1CCOCC1

Procedure:
Successive treatment of 1-[2-(4-carboxyphenoxy)ethyl]imidazole (1.4 g) with thionyl chloride (1.4 g) and morpholine (10 ml) as described in Example 25 gave N-[4-(2-imidazol-1-yl)ethoxybenzoyl]morpholine, m.p. 109°-111° C. (from ethyl acetate). Found: C, 63.80; H, 6.40; N, 13.87. C16H19N3O3 requires: C, 63.77; H, 6.36; N, 13.94%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Br)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH3:10]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
8.65 g of bromophenol and 8.75 g of 4-bromobutyric acid ethyl ester are dissolved in 120 ml of dimethylformamide, mixed with 32.6 g of cesium carbonate and stirred for 2 days at room temperature. The reaction mixture is filtered, the solvent is distilled off in a vacuum and the residue is distilled in a bulb tube at 180° C./0.4 mbar. 11 g of 4-(2-bromophenoxy)butyric acid ethyl ester is obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[C-:13]#[N:14].[Na+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]#[N:14]
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccccc1C(F)(F)F
Yield: 93 %

Procedure:
To a solution of 2-(trifluoromethyl)benzyl bromide (1.50 g) in ethanol (15 mL) was added a solution of sodium cyanide (461 mg) in water (15 mL) at ambient temperature, and the mixture was heated for 3 hours under reflux . After evaporation of the organic solvent, the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give [2-(trifluoromethyl)phenyl]acetonitrile (1.08 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[N:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: Clc1ncc2ccccc2n1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ncc2ccccc2n1
Yield: 55.2 %

Procedure:
The title compound (0.6 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.68 g) and 2-chloroquinazoline (0.53 g) according to the method of D30.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33](O)[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:50])[C@@H:47]([OH:49])[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:49][C@@H:47]([C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:50])[CH3:48])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)O)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.O>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[CH3:11])=[N:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: ClCCl
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ccc(C(F)(F)F)cn1
Yield: 74016.1 %

Procedure:
3.04 g (0.02 mmol) of 2-amino-4-nitrotoluene and 7.26 g (0.04 mol) of 2-chloro-5-trifluoromethylpyridine are stirred in the molten state for 5 hours at 160° C. After cooling, 200 ml of water are added thereto and the product is taken up in methylene chloride. The solvent is evaporated off and the residue is purified by column chromatography (silica gel, methylene chloride:hexane=2:1), affording 4.4 g of N-(5-trifluoromethyl-2-pyridyl)-2-methyl-5-nitroaniline (m.p. 103°-105° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[S:15][CH:14]=[C:13]([C:16]3[S:20][C:19]([NH:21]C(=O)C)=[N:18][C:17]=3[CH3:25])[CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[ClH:26].CCO>>[ClH:26].[NH2:21][C:19]1[S:20][C:16]([C:13]2[CH:12]=[C:11]([S:8]([N:5]3[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]3)(=[O:10])=[O:9])[S:15][CH:14]=2)=[C:17]([CH3:25])[N:18]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCC(O)CC3)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(S(=O)(=O)N2CCC(O)CC2)c1
Temperature: 90 °C

Procedure:
To N-(5-{5-[(4-hydroxypiperidin-1-yl)sulfonyl]-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide (39) (400 mg; 1 mmol; 1 eq) is added hydrochloric acid 1.25 M in EtOH (16 ml; 1.25 M; 19.9 mmol; 20 eq) and the mixture is heated at 90° C. for 8 h 30. The reaction mixture is cooled down to RT and a precipitate is formed. It is filtered and washed with cold EtOH, affording the hydrochloride salt of Compound (45) as light yellow powder (328.3 mg; 83%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[O:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:16](=[O:17])[CH2:15][CH2:14][C:13]([OH:18])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccccc1NC(=O)CCC(=O)O

Procedure:
To a solution of 2-tert-butylaniline (1.0 g, 6.7 mmol) in toluene (15 mL) was added tetrahydrofuran-2,5-dione (0.81 g, 8.1 mmol) and the reaction mixture was refluxed for 1 h. The reaction mixture was cooled and filtered to obtain 4-(2-tert-butylphenylamino)-4-oxobutanoic acid, which was dissolved in acetic acid (20 mL) and sodium acetate (3.02 g, 36.86 mmol) and was stirred at 80° C. overnight. The reaction was quenched with water, the layers separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The resulting solid was recrystallized from ethanol, to obtain pure 1-(2-tert-butylphenyl)pyrrolidine-2,5-dione (930 mg, 60%). LC/MS: m/z 232.3 (M+H)+ at 1.264 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[NH:28][CH2:27][CH2:26][CH2:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[NH:28][CH2:27][CH2:26][CH2:25]4)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc2c1NCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2c1NCCC2
Yield: 50.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 340 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 212 mg of 8-amino-1,2,3,4-tetrahydroquinoline and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 210 μl of pyridine and 5.0 ml of N,N-dimethylformamide. 243 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(1,2,3,4-tetrahydroquinolin-8-yl)acetamide are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [O:1]=[C:2]([C@H:20]([CH3:36])[C@@H:21]([O:27][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[C@@H:22]([CH3:26])[CH2:23][CH:24]=[CH2:25])[C:3]([CH3:19])([CH3:18])[C@@H:4]([O:10][Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[C@H:5]([CH3:9])[C:6]([OH:8])=[O:7].[C:37](O)([CH3:40])([CH3:39])[CH3:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]=[C:2]([C@H:20]([CH3:36])[C@@H:21]([O:27][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:33])[Cl:34])=[O:29])[C@@H:22]([CH3:26])[CH2:23][CH:24]=[CH2:25])[C:3]([CH3:19])([CH3:18])[C@@H:4]([O:10][Si:11]([CH2:12][CH3:13])([CH2:16][CH3:17])[CH2:14][CH3:15])[C@H:5]([CH3:9])[C:6]([O:8][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:7]
Reactant: CC(C)(C)O
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (2S,3S,6R,7S,8S)-5-oxo-3-(triethylsilyloxy)-2,4,4,6,8-pentamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoic acid (11.8 g), tert-butanol (4.5 g), and 4-dimethylaminopyridine (0.2 g) in 20 mL of CH2Cl2 is cooled on ice and treated with dicyclohexylcarbodiimide (4.6 g) over a 5-minute period. The mixture is allowed to warm to ambient temperature and is stirred for 3 hours. The slurry is diluted with CH2Cl2 and filtered, and the filtrate is washed sequentially with sat. aq. citric acid, 5% NaHCO3, and brine. The solution is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:37][C:38](=[NH:55])[C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[CH:42][N:43]2[CH2:48][CH2:49][C:50]([O:52]CC)=[O:51]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:55]=[C:38]([C:39]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:40]=3[CH:41]=[CH:42][N:43]4[CH2:48][CH2:49][C:50]([OH:52])=[O:51])[N:37]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CCC(=O)O)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.8 %

Procedure:
3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D4) (117 mg) was added to EDCI (114 mg) and HOBT (81 mg) dissolved in DMF (2.5 ml). This was stirred at RT for 10 minutes and then ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg) in DMF (2.5 ml) was added and stirring continued at RT for 2 hours then at 80° C. overnight. The reaction mixture was evaporated to dryness and extracted from H2O (25 ml) with EtOAc (2×25 ml). The combined organics were evaporated and treated with 2 M aq. NaOH (10 ml) and EtOH (10 ml), stirred at 50° C. for 2 hours then evaporated to remove the EtOH. The remaining solution was acidified, filtered and the precipitate washed with EtO/H2O then recrystallised from hot EtOH/H2O then from DMSO. Washing with Et2O and MeOH gave the title compound (46 mg) as a white solid. δH (d6-DMSO, 400 MHz): 1.37 (6H, d), 2.81 (2H, t), 4.50 (2H, t), 4.89 (1H, septet), 7.08 (1H, d), 7.35 (1H, apparent t), 7.46 (1H, d), 7.60 (1H, d), 7.81 (1H, d), 7.94 (1H, d), 8.15 (1H, dd), 8.23 (1H, d). MS (ES−): C22H2035ClN3O4 requires 425; found 424 (M−H+).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Br:15])[CH:8]=1)C.[OH-].[K+].CO>O>[Br:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:16])=[O:3])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCOC(=O)CCc1ccc(OC)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CCC(=O)O)cc1Br

Procedure:
154 g (0.535 mol) of ethyl3-(3-bromo-4-methoxyphenyl)propanoate are mixed with 45 g (0.8 mol) of potassium hydroxide, 600 ml of methanol and 300 ml of water. The mixture is heated at reflux for 3 hours, and the methanol is then evaporated off. The solution obtained is washed with ether; the aqueous phase is acidified and extracted with ether. The organic phase is dried (Na2SO4), and the solvents are evaporated off: white solid (132.7 g; 96%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][C:15]=1[NH:29][NH:30]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:20][C:18]1[CH:19]=[C:14]([Cl:13])[C:15]([N:29]2[C:9](=[O:10])[NH:8][C:6]([C:5]3[CH:11]=[CH:12][C:2]([I:1])=[CH:3][CH:4]=3)=[N:30]2)=[CH:16][C:17]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)c(Cl)cc1Cl
Reactant: O=C=NC(=O)c1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1Cl
Yield: 34.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 0.300 g, 0.800 mmol), tert-butyl 2-(2,4-dichloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazine carboxylate (Intermediate-83, 0.397 g, 1.6 mmol), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.150 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.09 (s, 9H), 4.31 (d, J=4.2 Hz, 2H), 7.40-7.58 (m, 2H), 7.61-7.78 (m, 2H), 7.93-8.02 (br d, 2H), 8.17 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH2:37][CH3:38])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH2:37][CH3:38])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC/C=C/[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of 18.3 (0.040 g, 0.077 mmol) in THF/MeOH (2/1) (1.5 mL) was added LiOH (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford 18 (0.0130 g, 34% yield). MS ESI (neg.) m/e: 489.2 (M−H)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1.I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][N:14]([CH:18]([CH3:20])[CH3:19])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Cl)ncnc21
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Cs2CO3 (382 g, 1.2 mol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (120 g, 0.78 mol) in DMF (1.0 L) at room temperature. The resulting mixture was stirred for 30 min. 2-Iodopropane (267 g, 1.6 mol) was added and the reaction and stirred for 5 h at room temperature. The reaction mixture was filtered and the solid was washed with EtOAc (3×500 mL). The combined filtrates were washed with water (3×500 mL) and brine (3×250 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound as a yellow solid (151 g, 94%). MS: 19.6 (MH+); HPLC Rf: 4.89 min. (HPLC method 4).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]=12.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1ccn2ccnc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccn2ccnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 18 %

Procedure:
The title compound is prepared from imidazo[1,2-a]pyridine-7-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 18% of theory; LC (method 4): tR=1.56 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[O:6])[CH:2]=[CH2:3].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([S:31][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:9]1)(=[O:32])[CH3:30]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (12.4 g: 30.46 mmole) and 90% potassium thioacetate (5.22 g: 45.69 mmole) in dimethylformamide (130 ml) is heated with stirring at 60° C. for 4 hours. The reaction mixture is diluted with ethyl acetate (200 ml) and ice water (200 ml). The organic layer is taken, successively washed with water (3 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give crude (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-phthalimidomethylpyrrolidine (9.33 g). Yield: 81%.