Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:18][C:5]1[CH:4]=[C:3]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CON(C)C(=O)c1ccc2cccnc2c1O
Solvent: CC(=O)O
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1O
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a stirred solution of 8-hydroxy-N-methoxy-N-methylquinoline-7-carboxamide (5.00 g, 21.5 mmol) in acetic acid (100 mL) was added N-chlorosuccinimide (3.16 g, 23.7 mmol) and the resulting mixture heated at 100° C. for 18 hours. After allowing the mixture to cool to ambient temperature, the reaction mixture was concentrated in vacuo, then neutralized with saturated sodium bicarbonate, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the desired product (4.68 g, 81%). LCMS calculated for C12H12ClN2O3(M+H)+: m/z=267.1; found: 267.0. 1H NMR (DMSO-d6, 400 MHz) δ 90.4 (1H, dd, J=4.0 and 1.2 Hz), 8.61 (1H, dd, J=8.8 and 1.6 Hz), 7.92 (1H, s), 7.80 (1H, dd, J=8.8 and 4.4 Hz), 3.45 (3H, s), 3.30 (4H, br s) ppm.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N:18]1[CH:17]=[CH:16][C:15]([C:14]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([S:8][C:9]([F:10])([F:11])[F:12])=[CH:4][C:3]=3[N:13]=2)=[CH:20][CH:19]=1
Reactant: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)Sc1ccc2oc(-c3ccncc3)nc2c1
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a mixture of 0.69 g of N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, 9 ml of tetrahydrofuran, and 0.63 g of triphenylphosphine, 1.05 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature and stirred for three hours. To the mixture, 0.21 g of triphenylphosphine and 0.35 g of 40% toluene solution of diethyl azodicarboxylate were added. The reaction mixture was stirred for further two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and the resultant crystals were washed with methanol to give 0.17 g of 2-(pyridin-4-yl)-5-(trifluoromethylthio)benzoxazole (hereinafter, referred to as “active compound 76”).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]2[O:15][CH2:16][O:17][C:12]2=[CH:11][C:10]=1[CH2:18][C:19]([O:21]C)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:16]1[O:15][C:13]2=[CH:14][C:9]3[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:25][NH:24][C:19](=[O:21])[CH2:18][C:10]=3[CH:11]=[C:12]2[O:17]1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccccc1)OCO2
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc3c(cc2C(c2ccccc2)=NN1)OCO3
Yield: 29.7 %

Procedure:
A solution of methyl 2-benzoyl-4,5-methylenedioxyphenylacetate (110 mg, 0.37 mmol) and hydrazine hydrate (30 μL, 0.53 mmol) in ethanol (15 mL) was refluxed for 5 days. The solvent was removed in vacuo and the resulting residue was separated by chromatography to yield the title compound (30 mg, 0.11 mmol, 29%), mp, 182°-184° C. 1H NMR (CDCl3) 8.59 (s, 1H), 7.60-7.41 (m, 5H), 6.83 (s, 1H), 6.63 (s, 1H), 6.03 (s, 2H), 3.46 (s, 2H). Anal. Calcd. for C16H12N2O3.0.25H2O: C, 67.48; H, 4.42; N, 9.84. Found C, 67.25; H, 4.21; N, 9.88.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:6]2[CH2:7][CH2:8][C@@:3]1([CH2:10][S:11]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:4](=O)[CH2:5]2.Cl.[NH2:30][OH:31].O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH:6]2[CH2:7][CH2:8][C@@:3]1([CH2:10][S:11]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:4](=[N:30][OH:31])[CH2:5]2
Reactant: NO
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(=O)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(=NO)C2
Reaction time: 2 h
Yield: 90.1 %

Procedure:
(1S)-1'-(((7,7-dimethyl-2-oxobicyclo(2.2.1) hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine) (30 g, 0.075 mole) in pyridine (500 mL) was heated in an oil bath to 70° C. (internal). Hydroxylamine hydrochloride (30 g) was added in three portions over ca. 20 minutes. After 2 hours, an additional 10 g of hydroxylamine hydrochloride was added (over 10 minutes). At 30, 40, and 50 minutes additional elapsed time, further 3 g lots of hydroxylamine hydrochloride were added. After another 30 minutes, the mixture was poured into water (2 L) and extracted 3 times with ethyl acetate (300 mL portions). The organic layers were combined, washed with 1N HCl (600 mL total), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. EtOH (abs; ca. 250 mL) was added to the resulting thick syrup and the solution allowed to stand at ambient temperature overnight. The mixture was filtered and the filtrate boiled down to ca. 80 mL. After standing, the mixture was again filtered and boiled down to ca. 20 mL. After a third filtration, the filtered solids were combined to give (1S)-1'-(((7,7-dimethyl-2-oximinobicyclo(2.2.1)hept-1-yl)-methyl) sulfonyl)spiro(1H-indene-1,4'-piperidine) (28 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(O)[CH:10]([OH:22])[CH2:9]1)=O)(C)(C)C.C(N(S(F)(F)[F:29])CC)C.CO>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([F:29])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[OH:22])=[CH:16][CH:17]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Solvent: ClCCl
Solvent: CO
Product: OC1CNCCC1(F)c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 24 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3,4-dihydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.213 g, 3.34 mmol) in methylene chloride (30 mL) at −78° C. was added diethylaminosulfur trifluoride (DAST, 3 mL). The resulting solution was stirred at −78° C. 4 h. Methanol (20 mL) was added to quench excess DAST and the mixture was allowed to remain at −78° C. 5 min before warming to rt. The mixture was concentrated and purified by silica gel chromatography (80% hexanes/20% ethyl acetate gradient) to afford 4-(4-chloro-phenyl)-4-fluoro-piperidin-3-ol (262 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23].O1CCCC1>[Pt]=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:23])[CH3:24]
Reactant: COc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Reaction time: 0.25 h

Procedure:
A 4.0 g. amount of N'-[2,6-dichloro-4-[(3-fluoro-4-methoxybenzylidene)amino]phenyl]-N,N-dimethylformamidine is dissolved in 100 ml. of warm tetrahydrofuran, then 500 mg. of platinum oxide that has been wetted with water is added and the mixture is hydrogenated in a Parr apparatus for 15 minutes. The reaction mixture is filtered and washed with tetrahydrofuran. The clear yellow solution is evaporated in vacuo to crystallize a solid. The solid is recrystallized from ethanol, filtered and washed with a small amount of ether to provide 2.0 g. of the desired product as granular yellow crystals, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[S:5][CH:6]=1.P(Cl)(Cl)([Cl:20])=O.[OH-].[Na+]>>[Cl:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[N:8][N:9]=1
Reactant: Cc1csc(-c2n[nH]c(=O)c3ccccc23)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(-c2nnc(Cl)c3ccccc23)n1

Procedure:
A dry 50 mL RBF set up with stirring bar and reflux condenser was charged with 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one (1.6 g, 6.6 mmol) and phosphorus oxychloride (7.4 ml, 78.9 mmol). The mixture was stirred under reflux for 18 hrs, then poured onto ice while stirring vigorously. To the iced mixture was added 6N NaOH until pH=9. Stirring was continued vigorously until solids formed. The solids were filtered, washed with water and dried in oven to afford 1-chloro-4-(4-methylthiazol-2-yl)phthalazine. MS m/z=262 [M+H]+. Calc'd for C12H8ClN3S: 261.7.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([N:11]([CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:36][CH2:35][CH2:34][CH2:33][CH2:32][O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([N:11]([CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10]
Reactant: CCCCCCCCCCCCCCCCCCN(C)C(=O)c1ccccc1CO
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)c1ccccc1COCCCCCl

Procedure:
[2-(Hydroxymethyl)phenyl]-N-methyl-N-octadecylformamide is reacted with 1-bromo-4-chlorobutane in acetone in the presence of potassium carbonate at the reflux temperature of the solvent to obtain [2-(4-chlorobutoxymethyl)phenyl]-N-methyl-N-octadecylformamide.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)=[CH:26][CH:25]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCc1ccc(Br)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CC(=O)OCc1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 20.2 %

Procedure:
Following the basic procedure of Example 32, by reacting 2.42 g (10 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 2.52 g (11 mmol) of 4-bromobenzyl acetate, 790 mg (20%) of the expected compound were obtained in the form of a brown oil.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[O:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:11]([C:15]1[CH:20]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:18]=[CH:17][C:16]=1[O:25][C@H:26]([CH3:30])[C:27]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:28])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To 60% sodium hydride (74 mg, 2.2 mmol) in toluene (10 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (222 mg, 2.0 mmol) in toluene (5 mL) over a 5 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2R)-2-(2,4-di-t-butylphenyloxy)propanoyl chloride (16, 716 mg, 2.2 mmol) in toluene (5 mL) over a 5 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 4:1). Water (30 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with methylene chloride (1×25 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×50 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM silica gel 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×15 cm length) using hexane and ethyl acetate (19:1) afforded 360 mg (45%) of (5S)-N-((2R)-2-(2,4-di-t-butylphenyloxy)propanoyl)-5 -ethenylpyrrolidin-2-one (19a) as a thick oil: 1H NMR (CDCl3) δ1.28 (s, 9 H), 1.42 (s, 9 H), 1.77-1.80 (d, 3 H), 1.95-2.10 (m, 1 H), 2.23-2.33 (m, 1 H), 2.52-2.82 (m, 2 H), 4.91-4.97 (q, 1 H), 5.10-5.19 (m, 2 H), 5.80-5.90 (m, 1 H), 5.97-6.03 (m, 1 H), 6.49-6.53 (d, 1 H), 7.12-7.16 (d, 1 H), 7.35 (s, 1 H); 13C NMR (CDCl3) δ175.4, 172.9, 157.3, 153.4, 143.1, 137.2, 135.6, 124.3, 123.2, 115.8, 71.6, 57.9, 35.2, 34.2, 31.9, 31.4, 29.9, 24.3, 18.2; IR (neat) 2965 (vs), 1741 (vs), 1715 (vs), 1590 (s), 1230 (vs), 710 (w) cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][O:13][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:5][C:4]=1[C:17]([F:19])([F:18])[F:20])#[N:2]
Reactant: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 46 g (0.16 mol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2,3-dihydroxy-2-methyl-propionamide in 1 1 of dichloromethane and 46 ml (0.57 mol) of dry pyridine was cooled to 0° C. and 46 ml (0.59 mol) of methanesulfonyl chloride was added dropwise. The mixture was stirred at 0° C. for 5 h, then washed three times with 500 ml of saturated aqueous sodium hydrogen carbonate, 500 ml of 10% aqueous hydrochloric acid and 500 ml of brine. The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was crystallized with 200 ml of petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.I[CH2:34][CH3:35]>>[CH2:34]([N:21]([CH2:20][CH2:19][C:18]1[CH:29]=[CH:30][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCI
Product: CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in Example 102 using tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) and iodoethane and isolated as a yellow oil (0.175 g, 100%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.06 (m, 2H), 7.89-7.73 (m, 2H), 7.45-7.36 (m, 2H), 7.31 (s, 2H), 3.42 (s, 2H), 3.23 (t, J=35.4 Hz, 2H), 2.96-2.84 (m, 2H), 1.47 (s, 9H), 1.08 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 477 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C(O)C(O)Cc1ccc(O)cc1
Yield: 99.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid were dissolved in 50 ml of methanol, and 0.05 g of platinum oxide was added thereto. The mixture was stirred at 25° C. under atmospheric pressure for 6 hours in a hydrogen stream. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 10.1 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>CC(C)=O>[CH:12]1([C:10]([NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([O:1][S:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)(=[O:26])=[O:25])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[O:11])[CH2:13][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of cyclopropanecarboxylic acid (6-hydroxybenzothiazol-2-yl)amide (intermediate 6) (1.81 g, 7.72 mmol), 4-fluorobenzenesulfonyl chloride (1.5 g, 7.72 mmol) and triethylamine (2.14 ml, 15.45 mmol) in 43 ml of acetone, in a 100 ml round-bottomed flask equipped with a magnetic bar, is stirred for 1 hour at room temperature. The precipitate obtained is filtered off and the filtrate is evaporated. The residue is washed with acetone and ethyl ether, to give 1.92 g of 4-fluorobenzenesulfonic acid 2-(cyclopropanecarbonylamino)-benzothiazol-6-yl ester (off-white powder) in a yield of 66%.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:15][CH2:16][CH2:17][NH2:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCO>[NH2:18][CH2:17][CH2:16][CH2:15][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: NCCCN1CCN(c2ccccc2)CC1
Yield: 56.3 %

Procedure:
4-Phenylpiperazine (5.00 g, 30.8 mmol, 1.00 equiv, Aldrich), 3-bromopropylamine hydrobromide (8.09 g, 37.0 mmol, 1.20 equiv) and potassium carbonate (8.51 g, 61.6 mmol, 2.00 equiv) were stirred in refluxing acetone (200 mL) and EtOH (40 mL) for 14 hours. After removal of the solvents, water (250 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2Cl2 (4×250 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3-MeOH-NH (2 M in MeOH) 100:10:5 to 100:20:10) to give 3.80 g (56%) of yellow oil, which was characterized spectroscopically.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:28])([CH3:27])[C:9]([C:11]2[S:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:14][C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(#N)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:27])([CH3:28])[C:9]([C:11]2[S:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[CH:14][C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH3:29])[CH3:42]
Reactant: Cc1cc(C(C)(C)C(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(C)(C)C(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(4-hydroxy-3-methylphenyl)-2-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}propan-1-one (intermediate 105, 62.0 mg) in anhydrous acetonitrile (2 ml) was added caesium carbonate (106 mg) and ethyl bromoacetate (18 μl) and the reaction stirred at room temperature under nitrogen for 20 hours. The solid residue was filtered, and the filtrate was concentrated in vacuo and the residue purified by flash column chromatography, eluting with 1% EtOAc/cyclohexane yielded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](OCC)=[O:15])=[N:6]1.[NH3:23]>CO>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:23])=[O:15])=[N:6]1
Reactant: N
Reactant: CCOC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: CO
Product: NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10.18 g (34 mmol) of the ester from Example 21A are initially charged in 150 ml methanol which has been saturated with ammonia at 0-10° C. The mixture is stirred at room temperature for two days and subsequently concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31]
Reactant: Cn1c(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccc(Cl)cc2)n1C
Yield: 66.01 %

Procedure:
3-Benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-07) (340.0 mg, 66.01%) was synthesized as a light yellow solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-07) (500.0 mg, 1.08 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]1[CH:29]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[O:30][CH:31]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:31]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[O:30][CH:29]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:24]2[CH2:25][CH:26]([OH:28])[CH2:27][N:23]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:1](=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:33][CH:34]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above procedure Dodecanoic acid (2.00 g, 10 mmol) was coupled with the amine 100 (6.10 g, 11.45 mmol) using HBTU (4.54 g, 1.2 eq.) and DIEA (5 mL, 3.00 eq). After work-up and column purification the pure amide 102b was isolated as a pale yellow solid (Yield, 5.2 g, 71%). 1H NMR (DMSO-d6, 400 MHz) δ=7.73-7.68 (m, 1H), 7.42-7.31 (m, 4H), 7.27-7.09 (m, 5H), 6.91-6.80 (m, 4H), 4.97 (d, J=3.90 Hz, 1H), 4.94 (d, J=3.90 Hz, 1H), 4.41-4.05 (m, 2H), 3.71 (s, 6H), 3.59-3.41 (m, 1H), 3.35-3.11 (m, 2H), 3.05-2.91 (m, 3H), 2.22-1.78 (m, 6H), 1.51-1.0 (m, 24H), 0.82 (t, J=6.34 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.85, 170.93, 170.83, 158.10, 157.97, 145.09, 144.75, 135.87, 135.73, 135.47, 135.42, 129.60, 129.55, 127.85, 127.78, 127.57, 126.63, 126.53, 113.18, 113.09, 85.78, 85.11, 68.58, 67.45, 63.33, 55.60, 54.99, 54.96, 53.43, 38.21, 38.02, 36.30, 35.43, 34.17, 32.54, 31.31, 29.09, 29.03, 29.01, 28.97, 28.79, 28.74, 28.67, 26.19, 25.33, 24.55, 24.15, 22.10, 21.21, 13.94.