Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[C:10]([OH:14])(=[O:13])[CH:11]=[O:12].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([CH:11]([OH:12])[C:10]([OH:14])=[O:13])=[C:4]([OH:5])[C:3]=1[OH:9]
Reactant: Oc1cccc(F)c1O
Reactant: O=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)c1ccc(F)c(O)c1O
Temperature: 0 °C
Yield: 59 %

Procedure:
51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolved at 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solution in 400 ml of water were added to this solution cooled to 0° C. The mixture was heated for 4 hours at 46° C., then cooled to 0° C. and the pH was brought to 4.6 by the addition of concentrated hydrochloric acid. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) and the aqueous phase was acidified with concentrated hydrochloric acid until a pH of 1.8 was obtained. Extraction was carried out with ethyl acetate and after evaporation of the solvent, 47.7 g of the desired product were obtained (mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro; 2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.Cl.[CH3:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][N:38]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])=[CH:34][CH:33]=1
Reactant: Cc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(C(=O)c1cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn1)CC2

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 62 mg (0.4 mmol) 6-methyl-2,3-dihydro-1H-indole-hydrochloride, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The precipitate formed was suction filtered and dried under HV.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH:18]([OH:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH3:27])[C:5]1=[O:28].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>CCOC(C)=O>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH3:27])[C:5]1=[O:28]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CN(C(=O)OC(C)(C)C)CCC3O)nc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CN(C(=O)OC(C)(C)C)CCC3=O)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a round bottom flask was added tert-butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxypiperidine-1-carboxylate (20-5) (25 mg, 0.060 mmol), DCM (1 mL), and Dess-MartinPeriodinane (27.9 mg, 0.066 mmol), and the resulting mixture was then stirred under an atmosphere of nitrogen at room temperature for 15 hours. The reaction mixture was then suspended in EtOAc, and washed with a saturated solution of Na2S2O3, followed by a saturated solution of sodium bicarbonate, then water, and finally brine. Organics dried over sodium sulfate, filtered & concentrated to give crude tert-butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-oxopiperidine-1-carboxylate (22-1). LRMS (M+H)+: observed=417.4, calculated=417.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC[C@@H](O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (dd, J=7.83, 1.01 Hz, 1 H), 7.79-7.69 (m, 2 H), 7.52 (td, J=7.52, 1.14 Hz, 1 H), 7.44 (d, J=8.59 Hz, 1 H), 7.33-7.27 (m, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.02 (s, 1 H), 5.04 (s, 2 H), 4.55-4.42 (m, 2 H), 3.89-3.76 (m, 2 H), 3.59-3.42 (m, 4 H), 3.37 (s, 2 H), 2.35 (s, 3 H), 2.16-1.97 (m, 2 H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:15]=1[CH2:16][N:17]1[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=[CH:22][C:21]=2[NH:20]C(=O)[C:18]1=[O:32]>CN(C)C=O>[Cl:4][C:1]1[C:18](=[O:32])[N:17]([CH2:16][C:15]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:14]=2[O:13][CH3:12])[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(Cn2c(=O)c(=O)[nH]c3ccc4ccccc4c32)c(OC)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)c(Cl)nc3ccc4ccccc4c32)c(OC)c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of 20% phosgene in toluene (10 ml, 19 mmol) was added to a solution of 1-(2,4-dimethoxybenzyl)benzo[f]quinoxaline-2,3(1H, 4H)-dione (950 mg; 2.6 mmol) in dry N,N-dimethylformamide (100 ml) with stirring at 0° C. The mixture was stirred at room temperature overnight, and evaporated to dryness. The residue was triturated with ice/water, filtered and dried in vacuo to give 900 mg (90%) of the title compound, m.p. 186° C. 1H-NMR (DMSO-d6): δ 3.80 (s, 3H), 3.82 (s, 3H), 5.65 (s, 2H), 6.45 (dd, 1H), 6.55 (d, 1H), 7.00 (d, 1H), 7.35 (m, 1H), 7.55 (m, 1H), 7.75 (m, 2H), 7.90 (m, 1H), 8.22 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(NC(C)C)(C)C.[NH2:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(C)(O)CN
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CC(C)(O)CNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (2 g, 11.98 mmol) in acetonitrile (10 mL) was cooled to −40° C., avoiding freezing. To this solution was added diisopropylamine (3.82 mL, 21.88 mmol) followed by 1-amino-2-methylpropan-2-ol (1.5 g, 16.83 mmol). The reaction mixture was removed from the cooling bath, warmed to room temperature and allowed to stir overnight (˜18 hours). Solvents were removed in vacuo and the residue was taken up in a minimum of dichloromethane (˜1.5-2 mL) and diluted with heptane until slightly cloudy. This mixture was loaded onto a 40 gram BioRad silica gel cartridge. Purification by flash chromatography (Analogix System, 20 min gradient, 0-25% methanol/dichloromethane, 40 mL/min.) provided 1-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropan-2-ol as a white solid. LCMS m/z 220.1, 221.8 (M+H)+, Rt 0.49 min.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43])(=[O:38])[CH:35]([CH3:37])[CH3:36]>O1CCCC1>[CH3:45][O:44][C:42]([C:41]1[CH:40]=[C:39]([C:34](=[O:38])[C:35]([Br:1])([CH3:37])[CH3:36])[CH:48]=[CH:47][CH:46]=1)=[O:43]
Reactant: [Br-]
Reactant: COC(=O)c1cccc(C(=O)C(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(=O)C(C)(C)Br)c1

Procedure:
0.8 g of phenyltrimethylammonium tribromide was added to a mixture comprising 1.5 g of the crude product of methyl m-isobutyrylbenzoate obtained in the above step (3) and 20 ml of tetrahydrofuran, and followed by a reaction at room temperature overnight. After completion of the reaction, the precipitated crystal was separated by filtration, then tetrahydrofuran was distilled off. The residue was dissolved in ethyl acetate, then washed with a saturated sodium chloride aqueous solution, followed by drying over anhydrous sodium sulfate. Then, concentration under reduced pressure was carried out, and then, rough purification was carried out by silica gel column chromatography to obtain 0.27 g of crude 3′-methoxycarbonyl-2-bromo-2-methylpropiophenone. The NMR spectrum data of this product were as follows.
Reaction SMILES: C[O-].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][C:10]#[N:11].[C:12]1([CH2:18][N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:12]1([CH2:18][N:19]2[CH2:24][CH2:23][C:22](=[C:9]([C:5]3[S:4][CH:8]=[CH:7][CH:6]=3)[C:10]#[N:11])[CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1cccs1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(=C1CCN(Cc2ccccc2)CC1)c1cccs1
Reaction time: 1 h

Procedure:
To a stirred mixture of 80 parts of sodium methoxide and 160 part of methanol are added successively 50 parts of 2-thiopheneacetonitrile and then dropwise 66 parts of 1-(phenylmethyl)-4-piperidinone. Upon completion, the whole is heated to reflux and stirring at reflux temperature is continued for one hour. The reaction mixture is cooled and evaporated. The residue is distilled in a molecular distillation-apparatus, yielding about 70 parts of α-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile as a residue.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:15][C:16]1([F:42])[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([S:30]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:22]=2)[CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:42][C:16]1([F:15])[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([C:37]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:38])=[CH:40][CH:41]=3)(=[O:32])=[O:31])[CH:22]=2)[CH2:17]1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Yield: 89 %

Procedure:
Add a 2 ml CH2Cl2 solution of Tetrahydro-pyran-4-ylamine (62 mg, 0.0610 mmol, 1.1 eq) and triethylamine (365 mg, 3.6 mmol, 6.5 eq) to a 2 ml CH2Cl2 solution of 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid. Add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (245 mg, 0.555 mmol, 1.0 eq) and stir reaction at room temperature for 18 hours. Remove volatiles on rotovap and purify by silica gel chromatography, followed by SCX ionic chromatography to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamide (240 mg, 89% yield). Mass Spectrum (m/e): 489.71 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[CH:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[CH:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)c(=O)cc(-c1ccccc1)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(-c2ccccc2)cc(=O)c2cc(C(=O)O)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To 0.9 gram of methyl 1-methyl-2-phenyl-4-quinolone-6-carboxylate obtained in Example 7 are added 0.5 gram of sodium hydroxide and 40 ml of water and the mixture is stirred at 60° C. for two hours. The mixture is acidified with acetic acid, and crystals which separate out therefrom are collected by filtration, and dried to give 0.5 gram of 1-methyl-2-phenyl-4-quinolone-6-carboxylic acid, colorless powder, melting at above 30° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[C:11]([N:16]([CH3:18])[CH3:17])=[CH:10][C:9]=1[NH:19][C:20](=O)[CH2:21][C:22]([C:24]1C=C[CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.[C:34](O)([C:36](F)(F)F)=[O:35]>C(Cl)Cl>[C:30]([C:26]1[CH:27]=[C:21]([C:20]2[CH2:36][C:34](=[O:35])[NH:7][C:8]3[CH:13]=[C:12]([C:14]#[N:15])[C:11]([N:16]([CH3:17])[CH3:18])=[CH:10][C:9]=3[N:19]=2)[CH:22]=[CH:24][CH:25]=1)#[N:31]
Reactant: CN(C)c1cc(NC(=O)CC(=O)c2cccc(C#N)c2)c(NC(=O)OC(C)(C)C)cc1C#N
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from {5-cyano-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-dimethylamino-phenyl}-carbamic acid tert-butyl ester (Example M78) (0.28 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (36 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](Cl)=[N:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([O:8][C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[NH2:1])=[N:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 1.25 h
Yield: 74 %

Procedure:
To a stirred solution of 3-aminophenol (1.41 g, 12.93 mmol) in dry tetrahydrofuran (70 mL) at room temperature, was added cesium carbonate (6.32 g, 19.39 mmol). After stirring for a further 75 mins, added 7-(benzyloxy)-4-chloro-6-methoxyquinazoline from the previous step (3.89 g, 12.93 mmol) in one portion and the reaction mixture was heated at 75° C. for 24 h. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was partitioned between water (200 mL) and a mixture of dichloromethane (160 mL) and 2-propanol (60 mL). The mixture was filtered through a celite plug and the organic layer was separated and dried over MgSO4 and concentrated under reduced pressure. Trituration with diethyl ether, followed by filtration and drying under reduced pressure, afforded 3-(7-(benzyloxy)-6-methoxyquinazolin-4-yloxy)aniline as a cream solid (3.57 g, 74%) which was taken into the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 7.21-7.55 (m, 8H), 6.57-6.63 (m, 3H), 5.33 (s, 2H), 4.03 (s, 3H), 3.73 (brs, 2H); LC-MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([S-:11])[CH3:10].[Na+]>CN(C=O)C.O>[CH2:9]([S:11][CH:3]([CH3:4])[CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: CC[S-]
Reactant: C/C=C/C(=O)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)SCC
Temperature: 25 °C
Yield: 14 %

Procedure:
Ethyl crotonate (commercially available, for example, from Aldrich) (2.37 g, 20.8 mmol) was dissolved in DMF (60 ml) and stirred at room temperature. Sodium ethanethiolate (commercially available, for example, from Aldrich) (1.66 g, 19.7 mmol) was added portionwise. On completion of the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic solutions were dried (MgSO4), and concentrated in vacuo, for an extensive period of time to remove excess DMF. The residue was applied to a silica cartridge (50 g), eluting with a gradient of EtOAc-cyclohexane (2%-6%) to give the title compound as a colourless oil (527 mg, 14%): 1H NMR δ (CDCl3) 4.16 (2H, q, J=9 Hz), 3.28-3.18 (1H, m), 2.66-2.55 (3H, m), 2.44 (1H, dd, J=15, 8 Hz), 1.33 (3H, d, J=7 Hz), 1.31-1.23 (6H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8].[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:6]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:23]([CH3:22])[CH2:28]2)=[CH:16][CH:17]=1
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(c1cccnc1)N(CCCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCCN(C(=O)c2cccnc2)c2ccc(F)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 48 h
Yield: 57.2 %

Procedure:
A mixture of 5 parts of N-(4-chlorobutyl)-N-(4-fluorophenyl)-3-pyridinecarboxamide, 2.77 parts of (1,1-dimethylethyl) 2-methyl-1-piperazinecarboxylate, 1.58 parts of sodium carbonate and 94 parts of N,N-dimethylformamide was stirred for 48 hours at 90° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 3.5 parts (57.2%) of (1,1-dimethylethyl) 4-[4-[(4-fluorophenyl)(3-pyridinylcarbonyl)amino]butyl]-2-methyl-1-piperazinecarboxylate as a residue (int. 43).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-].[Li+].[Cl-]>C1COCC1.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:21])=[O:3])[CH2:7][CH2:8]2)=[O:20])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 24 h
Yield: 155.1 %

Procedure:
To a stirred solution of [4-(4-chloro-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (1.0 g, 3.03 mmol) in 12 mL of THF and 4 mL of MeOH, was added LiOH (0.39 g, 16.14 mmol in 3 mL of water). After 3 h at ambient temperature the solvent was removed in vacuo, then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1 N HCl (pH 4), frozen at −78° C. then lyophilized for 24 hours to yield the title product (1.33 g, 4.70 mmol, >99% yield) with LiCl salt. MS (ESI) m/z 282.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.26 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24]OS(C)(=O)=O)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCn1ccnc1

Procedure:
To a solution of 0.218 g methyl 8-(p-chlorophenylsulfonamido)-4-(2-methylsulfonyloxyethyl)-octanoate in 2 ml dimethylformamide is added 0.101 g imidazole and then the solution is heated at 100° for 8 h. The mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water (2×20 ml), dried, filtered and evaporated to give an amber oil which is purified by preparative thin layer chromatography using ethyl acetate as eluent to give methyl 8-(p-chlorophenylsulfonamido)-4-[2-(1-imidazolyl)ethyl]-octanoate as a yellow oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][C:13]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][CH2:21][C:22](NCOC)=[O:23])([CH3:15])[CH3:14]>O1CCCC1.CCCCCC>[CH3:15][C:13]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][CH2:21][C:22](=[O:23])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([CH3:12])[CH3:14]
Reactant: Brc1nccs1
Reactant: COCNC(=O)CCCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1nccs1
Temperature: -70 °C
Yield: 33.3 %

Procedure:
A solution of 2-bromothiazole (3.6 g) in dry tetrahydrofuran (100 ml) was cooled to −78° C. under an atmosphere of nitrogen. A 2.5M solution of n-butyllithium in hexane (8.8 ml) was added dropwise over 15 minutes maintaining the temperature below −60° C. The product from step (a) (2.46 g) in tetrahydrofuran (20 ml) was then added over 15 minutes again keeping the temperature below −60° C. The reaction mixture was then maintained at −70° C. for 1 h, then allowed to warm to −10° C. over 1.5 h. The reaction mixture was then partitioned between 10% ammonium chloride solution and ethyl acetate and the resulting colloid was filtered through celite. The organic extracts were dried over magnesium sulfate, filtered and the filtrate evaporated. The resulting dark brown oil was purified by flash chromatography, eluting with hexane:ethyl acetate (2:1) to give the subtitle compound as a pale yellow oil (0.9 g, 15%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C)C=O.S(Cl)(Cl)=O>O1CCCC1>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 100 g (0.55 mol) of acid 5 in 600 ml of tetrahydrofuran (THF) and 1 ml of N,N-dimethylformamide (DMF) 131 g (1.1 mol) of thionyl chloride were added. The mixture was stirred under reflux for 4 h and at room temperature for 12 h. The mixture was concentrated to 300 ml and added to a mixture of 1500 g of ice and 1500 ml of ammonia. The mixture was stirred for 3 h at 5° C. The resulting crystals were isolated at 10° C., washed with water, 100 ml of iso-propanol, and 100 ml of MTBE and dried in a vacuum oven at 50° C. Recrystallisation from toluene/MTBE (3/1). Yield: 68%.