Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCC(O)C.Cl[C:8]1[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10](Cl)[C:9]=1[Cl:17].[OH-].[NH4+]>O.C1(C)C=CC=CC=1.[Zn]>[Cl:14][C:12]1[C:11]([Cl:15])=[CH:10][C:9]([Cl:17])=[CH:8][N:13]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: COCC(C)O
Solvent: Cc1ccccc1
Product: Clc1cnc(Cl)c(Cl)c1
Yield: 164.4 %

Procedure:
To a 500 milliliter, 3-neck flask which was fitted with a reflux condenser, thermometer, stirrer and heater was added 100 milliliters of 1-methoxy-2-propanol, 25.1 grams (0.10 mole) of pentachloropyridine and 39.0 grams (0.60 gram atom) of zinc dust. The flask was heated, with stirring, to 90° C. until all the pentachloropyridine was dissolved. At this time, 100 milliliters of concentrated ammonium hydroxide was added over a 5 hour period. The pH of the mixture was ~12. The mixture was refluxed for 32 hours and the reaction mixture was diluted with two volumes of water and 100 milliliters of toluene. The mixture was filtered to remove insolubles. The toluene was removed by fractionation leaving 30.0 grams of crude 2,3,5-trichloropyridine as an amber-colored oil. Analysis by gas-liquid chromatography showed a yield of 2.1 grams of the desired product (12 percent of theoretical).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8][CH:7]([NH:16][CH:17]([C:26]([O:28]CC)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1=[O:31])([OH:3])=[O:2].[OH-].[Na+]>C(O)C>[C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8][CH:7]([NH:16][CH:17]([C:26]([OH:28])=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1=[O:31])([OH:3])=[O:2]
Reactant: CCCCCCCCC(NC1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCC(NC1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Yield: 92.7 %

Procedure:
690 mg of the 5-carboxymethyl-3-(1-ethoxycarbonylnonylamino)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one obtained in Example 18 was dissolved in 10 ml of ethanol and 4 ml of a 1N aqueous solution of sodium hydroxide and then reacted at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 5 ml of water. This solution was adjusted to pH 2 with hydrochloric acid. The precipitated white crystals were separated by filtration and washed thoroughly with water to obtain 600 mg of the desired compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([NH:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:12])[CH3:10])(OC(C)(C)C)=O.[ClH:19]>C(O)(=O)C.O1CCOCC1>[ClH:19].[CH3:1][NH:8][C@@H:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH3:10]
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CN[C@H](C)C(=O)NCC(=O)O

Procedure:
26.0 Grams of methyl Boc-D-alanylglycinate is dissolved in 340 ml of acetic acid, and 170 ml of a 6 N solution of hydrogen chloride in dioxane is added to the solution. The reaction mixture is allowed to stand for ten minutes and then the solvent is removed under vacuum. The residue is triturated with diethyl ether. The resulting white precipitate is filtered and washed with diethyl ether to afford methyl-D-alanylglycinate hydrochloride.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([NH:35][CH3:36])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([NH:35][CH3:36])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(NC)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CNc1ccc2cc(-c3cc(-c4nc5cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c6ccc(Cl)cc6)c5s4)ccn3)ccc2n1
Temperature: 170 °C

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(2-(methylamino)quinolin-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (4.1 mg, 0.006 mmol)) in pyridine (0.4 mL) was added LiI (50 mg, excess). The reaction mixture was heating in a microwave at 170° C. for 90 min. The mixture was concentrated in vacuo and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H32ClN4O3S: 623.2; found: 623.2. 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=5.2 Hz, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.34 (d, J=9.6 Hz, 1H), 8.22-7.20 (m, 3H), 7.70 (d, J=9.2 Hz, 1H), 7.61 (s, 3H), 7.07 (d, J=8.4 Hz, 1H), 5.28 (s, 1H), 3.24 (s, 3H), 2.64 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of 3-hydroxybenzoic acid (5 g), dimethyl formamide (50 ml), 3,4-dichloronitrobenzene (7 g) and anhydrous potassium carbonate (10 g) was stirred and heated at 100° C. for 14 hours. The solvent was removed under reduced pressure and the residue poured into water and acidified with 2 molar hydrochloric acid. The yellow solid which separated was recrystallised from toluene to give the required benzoic acid derivative (8.0 g) with a melting point of 172°-173° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:11][C:12]1[O:13][C:14]([CH3:28])([CH3:27])[CH:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[S:16](=[O:19])(=[O:18])[N:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:29]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:29][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]2[C:14]([CH3:28])([CH3:27])[O:13][C:12]([NH:11][C@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][OH:1])=[N:17][S:16]2(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1ccc(O)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)cc1
Yield: 24.4 %

Procedure:
To a solution of 40 mg of 4-[2-((S)-3-hydroxy-1-phenylpropylamino)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-5-yl]phenol in 1 ml of N,N-dimethylformamide were added, at room temperature, 11 mg of potassium tert-butoxide and 28 mg of methyl iodide, and the reaction mixture was stirred at constant temperature for 3 hours. The reaction solution was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (10 mg) with a molecular weight of 418.5 g/mol (C21H26N2O5S); MS (ESI): m/e=419 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH2:8]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenylethanol (24.4 g, 0.2 mole) in CH2Cl2 (200 mL) is added NEt3 (30.7 mL, 0.22 mole). The reaction mixture is cooled to 0° C. and methanesulfonyl chloride (16.3 mL, 0.21 mole) is added dropwise. The reaction mixture is allowed to reach room temperature and is stirred at room temperature overnight. Solvent is removed under reduced pressure. Water is added and the aqueous phase is extracted three times with Et2O. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure to give methanesulfonic acid phenethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)c(Br)c1
Yield: 96 %

Procedure:
A mixture of 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid (2.38 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (2.39 g, yield 96%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.60–2.71 (2H, m), 2.91–3.03 (2H, m), 3.69 (3H, s), 7.18–7.32 (1H, m), 7.60–7.70 (1H, m), 7.94 (1H, dd, J=2.2, 6.2 Hz), 8.23 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].N1C=CC=CC=1.O1CCCC1>ClCCl>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:13](=[O:14])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc2cnccc12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2cnccc12)Oc1ccccc1
Reaction time: 3 h

Procedure:
To 5-aminoisoquinoline (2.7 g) were added phenyl chloroformate (2.85 ml), pyridine (2.0 ml) and tetrahydrofuran (50 ml), and the mixture was stirred for 3 hrs. The reaction mixture was diluted with dichloromethane, and washed with water and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give the title compound (3 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([Cl:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][NH:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].ClCCl>CS(C)=O>[ClH:12].[Cl:12][C:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:21]([CH2:20]/[CH:19]=[CH:18]/[C:17]#[C:16][C:15]([CH3:24])([CH3:23])[CH3:14])[CH3:22])[C:8]=2[S:9][CH:10]=1
Reactant: CNC/C=C/C#CC(C)(C)C
Reactant: Clc1csc2c(CBr)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2c(Cl)csc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 77 %

Procedure:
To a solution of 0.34 g (1.3 mmol) of 7-bromomethyl-3-chiorobenzo[b]thiophene in 3 ml of dimethyl sulfoxide were added 0.246 g (1.31 mmol) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methyiamine hydrochloride, and 0.27 g (1.95 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 19 hours at room temperature, poured into 40 ml of dichioromethane, washed with 30 ml ×2 of water, and adjusted to pH 2 with 25 ml of water and 2N hydrochloric acid. The organic layer was separated washed with 20 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and cooled to crystallize. The crystals were suspended in isopropylalcohol, filtered, washed with isopropyl alcohol and dried to obtain 0.37 g (yield: 77%) of the above identified compound as white crystalline powder.
Reaction SMILES: C(OC(=O)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1)(C)(C)C.I[C:26]1[C:34]2[CH:33]=[N:32][CH:31]=[N:30][C:29]=2[N:28]([Si](C(C)C)(C(C)C)C(C)C)[CH:27]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[CH:10][N:9]=2)=[CH:22][CH:21]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)cn1
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)cn2)cc1

Procedure:
(4-Chloro-benzyl)-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine P-0001 was prepared in two steps from (4-chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 13 and 5-Iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 38 as shown in Scheme 8.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][C:28]=3[CH2:36][CH3:37])=[O:26])[CH:19]=2)[C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].O.Cl>CO>[Br:38][C:14]1[C:15]2[C:20](=[CH:19][C:18]([CH2:23][NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][C:28]=3[CH2:36][CH3:37])=[O:26])=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:39])=[O:2]
Reactant: CCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A mixture of 2-(1-bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (0.200 g, 0.341 mmol), prepared in the previous step, 1N NaOH (1.02 mL, 1.02 mmol), 10 mL of water and 100 mL of methanol was stirred under nitrogen at room temperature for 20 h (overnight). The reaction was acidified with 1N HCl until acidic by litmus paper. The methanol was removed under reduced pressure. The solid that precipitated and was collected by filtration and dried under reduced pressure to give the title compound (0.0576 g, 29%) as a white solid, mp 162-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.I[CH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc2n1C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
[3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid (0.062 g, 0.19 mmol) was dissolved in DMF (3 mL) and cooled to −10° C. and then sodium bis(trimethyl)amide solution (0.420 mL, 0.42 mmol, 1.0M solution) was added. The reaction was stirred for 1 hour then iodomethane (13 μL, 0.21 mmol) was added in one portion. Standard aqueous workup and purification by preparatory HPLC provided the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH3:19])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:4].[Cl:20][C:21]1[C:26](O)=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O.O1CCCC1>[Cl:20][C:21]1[C:26]([O:1][C@@H:2]([CH3:19])[C:3]([NH:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[O:4])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1
Reactant: Oc1cc(Cl)cnc1Cl
Reactant: C[C@@H](O)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Oc1cc(Cl)cnc1Cl)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a tetrahydrofuran solution (148 ml) of tert-butyl 4-{[(2R)-2-hydroxypropanoyl]amino}piperidine-1-carboxylate (5.13 g), 2,5-dichloropyridin-3-ol (3.40 g) and triphenylphosphine (6.41 g) was added dropwise at room temperature a tetrahydrofuran solution (40 ml) of di-tert-butyl azodicarboxylate (5.63 g) over 10 minutes. The reaction solution was stirred at room temperature for 1 hour, then poured into water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-({(2S)-2-[(2,5-dichloropyridin-3-yl)oxy]propanoyl}amino)piperidine-1-carboxylate (6.40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:32])[C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=3)=[O:17])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:32])[C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[O:17])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
53 mg (0.11 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 11.1E) were hydrolysed with TFA according to General Method 2. Yield: 36 mg (77% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].B.[K]>[Ni].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11]
Reactant: N#CCc1c(F)cccc1F
Agent: [Ni]
Agent: B
Agent: [K]
Solvent: CCO
Product: NCCc1c(F)cccc1F
Reaction time: 5 h

Procedure:
2-(2,6-Difluorophenyl)acetonitrile (2.34 g, 15.28 mmol) was added to potassium boron hydride (3.29 g, 61.12 mmol) and Raney nickel (0.897 g, 15.28 mmol) in 50 mL of absolute ethanol while stirring. Then, vigorously stirring was continued at room temperature for 5 hrs.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: O
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. Melting Point: 115-118° C. (water)
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH:19]([F:21])[F:20])[C:15](OC)=[O:16])[CH:8]=[CH:7]2.C[O-].[Na+].Cl.[NH2:27][OH:28]>CO>[F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH:19]([F:21])[F:20])[C:15]([NH:27][OH:28])=[O:16])[CH:8]=[CH:7]2
Reactant: COC(=O)C(c1ccc2cc(OC(F)F)ccc2c1)C(F)F
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)C(c1ccc2cc(OC(F)F)ccc2c1)C(F)F
Reaction time: 16 h

Procedure:
A mixture of 32 g. of methyl 6-difluoromethoxy-2-naphthyl-α-difluoromethylacetate, 10 g. of sodium methoxide, 14 g. of hydroxylamine hydrochloride, and 500 ml. of methanol are allowed to stand for 16 hours. The mixture is then filtered and evaporated. The residue is neutralized by the addition of aqueous 1N hydrochloric acid and extracted by ether. The ether solution is then washed with water, dried, and evaporated to afford 6-difluoromethoxy-2-naphthyl-α-difluoromethyl acethydroxamic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[CH3:11].[NH:12]1[CH:16]=[N:15][C:14]([C:17]([O:19]C)=[O:18])=[N:13]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:12]2[CH:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[N:13]2)=[CH:4][C:3]=1[CH3:11]
Reactant: COC(=O)c1nc[nH]n1
Reactant: Cc1cc(B(O)O)ccc1F
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: Cc1cc(-n2cnc(C(=O)O)n2)ccc1F

Procedure:
This intermediate was prepared from 4-fluoro-3-methylphenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]([C:8]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCOCC
Product: O=C(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 3,4-difluorobenzoyl chloride (2.206 g, 12.5 mmol) in ethyl ether (20 mL) was cooled to 0° C. and treated with the crude mixture from Example 31 (25 mmol). The reaction was stirred at 0° C. (3 h) and quenched with aqueous ammonium chloride solution. The resulting mixture was stirred at room temperature overnight. The aqueous layer was extracted with two additional portions of ethyl ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (5% EtOAc/hexane) afforded the title compound (28).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:27]=[CH:26][C:25]([O:29][CH3:30])=[O:28])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Product: COC(=O)C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1

Procedure:
4-(5-Bromo-3-tri fluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (a) above (3.7 g, 9.0 mmol) rected with methyl acrylate under the conditions of Example 183d to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 316 (M-Bu+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[NH:15][C:14](=[O:19])[CH:13]([CH3:20])[CH2:12][C:11]=3[CH2:10]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C([SiH](CC)CC)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][CH:16]3[CH:11]([CH2:12][CH:13]([CH3:20])[C:14](=[O:19])[NH:15]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC1CC2=C(CCC(Cc3ccc(O)cc3)C2)NC1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1CC2CC(Cc3ccc(O)cc3)CCC2NC1=O
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
3,4,5,6,7,8-Hexahydro-6-((4-hydroxyphenyl)methyl)-3-methylquinolin-2[1H]-one (1.5 g) was suspended in triethylsilane (3 ml) and TFA (3 ml) was added. The mixture was left to stir for 30 minutes then was evaporated under reduced pressure. The residue was dissolved in chloroform and washed with sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was recrystallised from isopropanol to give the title compound (0.6 g,) mp. 217°-223° C.