Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].[OH-].[Na+]>C(OCC)C.C(O)C>[NH2:12][C@@H:13]([CH2:14][S:15][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[C:16]([OH:18])=[O:17]
Reactant: N[C@@H](CS)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a mixed solution of diethyl ether (400 ml) and conc. hydrochloric acid (400 ml) was added in drops 4-methoxybenzyl chloride (280 g, 1780 mmol) dissolved in diethyl ether (400 ml) for 2 h, and the mixture was stirred for 1 h. The organic layer was separated and added to a solution which was prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was cooled to 0° C., and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid (250 g, 1035 mmol, Yield 64%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([I:11])=[CH:7][CH:8]=2)[C@@H:3]1[NH:12][C:13](=[O:19])OC(C)(C)C.Cl.[OH-].[Na+].[F:23][C:24]1[CH:32]=[CH:31][C:27](C(Cl)=O)=[CH:26][CH:25]=1>O1CCOCC1>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:13]([NH:12][C@H:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([I:11])[CH:5]=3)[CH2:10][C@@H:2]2[OH:1])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1c2cc(I)ccc2C[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(N[C@H]1c2cc(I)ccc2C[C@@H]1O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-hydroxy-6-iodo-indan-1-yl]carbamate (39.6 mmol, 14.9 g) in 1,4-dioxane (200 mL), add a solution of 4 M hydrogen chloride in dioxane (100 mL) at room temperature and stir for 2 hr. Concentrate the resulting suspension in vacuo and dry in a vacuum oven for 48 hr. Dissolve the residue in THF (25 mL) and cool in an ice bath for 30 min. Add 5 M aqueous sodium hydroxide (17.4 mL, 87.2 mmol) and 4-fluorobenzoyl chloride (3.78 mL, 40.4 mmol) dropwise. Warm the solution to room temperature and stir for one hour. Concentrate the black solution in vacuo and dilute with water (50 mL). Collect the solid by filtration and dry at 40° C. in a vacuum oven overnight to obtain the title compound (14.4 g, 91%). LC-ES/MS m/z 398 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][CH:33]1[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:32][CH:33]2[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Nc1cc(OCc2ccccc2)c(C(=O)O)cc1Cl
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1cc(OCc2ccccc2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
A solution of 4-amino-5-chloro-2-(phenylmethoxy)benzoic acid (2.78 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 11.5 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of 3-aminoquinuclidine (1.84 g, 14.6 mmol) in anhydrous tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (50 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo and rinsed with water in order to remove the remainins imidazole by-product. The residue was dried azeotropically with toluene, then taken up in tetrahydrofuran and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether/petroleum ethers (30°-60° C.), and recrystallized from ethyl acetate/hexane to afford 3.18 g (82%) of colorless solid; mp 170°-171° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH:43]([CH3:45])[CH3:44])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([O:42][CH:43]([CH3:44])[CH3:45])=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CC(C)Oc1ccc(N)c2c1CN(C)C2=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC(C)C)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2-methyl-4-(propan-2-yloxy)-2,3-dihydro-1H-isoindol-1-one (Compound 207A). MS (ES+): m/z 638.26 (100) [MH+]; HPLC: tR=1.21 min (UPLC, purity).
Reaction SMILES: [Li+].[OH-].F[C:4]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O.[SH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].Cl>CN(C=O)C.O>[OH:8][C:6]1[C:5]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:4]=2[S:18][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CS
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
LiOH (4.5 mmol, 0.11 g) was added to a solution of methyl 2-fluoro-4-trifluoromethylbenzoate 68a (2.25 mmol, 0.50 g) and methyl 2-mercaptoacetate 67d (2.25 mmol, 0.21 mL) in DMF (3 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for 1 h. Water was added and the resulting solution was acidified with 1N aqueous HCl. The precipitates were filtered, washed with water, and dried to give compound 68b.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.COCCOC.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:14]1[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1ccc(-c2cc3ccccc3s2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A two-necked 250 mL round-bottomed flask fitted with a reflux condenser (with gas inlet) and a rubber septum was flushed with argon before 2-bromopyridine (2.57 mL, 27 mmol) and ethyleneglycol dimethylether (80 mL, dry and degassed) were introduced. Tetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) was added and the solution stirred at room temperature for 10 minutes. Benzothiophene-2-boronic acid (5.0 g, 28.1 mmol) was then added, followed by anhydrous sodium bicarbonate (8.4 g. 100 mmol) and water (50 mL, degassed). The septum was replaced with a glass stopper and the reaction mixture was heated at 80° C. for 16 hours, cooled to room temperature and the volatiles removed in vacuo. Organics were extracted with ethyl acetate (3×100 mL), washed with brine and dried over magnesium sulfate. Removal of the organics yielded a pale yellow solid. Recrystallisation from ethanol yielded a colourless solid (3.9 g, 68%, two crops), m.p. 124-6° C.
Reaction SMILES: [Na:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C([O-])(=O)C.[Na+]>>[Na:1].[C:32]([O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(c1ccc(O)cc1)(c1ccc(OS(=O)(=O)O)cc1)c1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Product: CCOC(=O)C(c1ccc(OC(C)=O)cc1)(c1ccc(OS(=O)(=O)O)cc1)c1ccccn1
Reaction time: 1 h

Procedure:
15 g. of the above-described ethyl α-(4-hydroxyphenyl)-α-(4-sulphoxyphenyl)-2-pyridine-acetate sodium salt were treated with 75 ml. acetic anhydride and 15 g. anhydrous sodium acetate for 18 hours at ambient temperature and then heated and stirred for 1 hour. The reaction mixture was filtered and the solution treated with excess diethyl ether to give an abundant precipitate. The product was filtered off and purified with ethanol-ether to give the desired ethyl α-(4-acetoxyphenyl)α-(4-sulphoxyphenyl)-2-pyridine-acetate sodium salt in the form of colourless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH2:22][CH:21]4[N:23]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:30]([Cu])#[N:31].O>CN(C=O)C>[F:27][C:25]([F:26])([F:28])[C:24]([N:23]1[CH:21]2[CH2:20][CH2:19][CH:18]1[CH2:17][C:16](=[C:6]1[C:5]3[CH:4]=[CH:3][C:2]([C:30]#[N:31])=[CH:15][C:14]=3[O:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22]2)=[O:29]
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(Br)ccc31)C2)C(F)(F)F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of Compound 5d (3 g, 6.46 mmol) in DMF (100 mL) was added CuCN (0.69 g, 7.70 mmol). The reaction mixture was refluxed for 2 d and then cooled to room temperature. The mixture was poured into water (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed sequentially with H2O (100 mL), brine (100 mL), then dried (MgSO4) and concentrated. The crude product was purified by normal phase chromatography, using a gradient of ethyl acetate (0% to 10%) in heptane to give compound 5e. MS m/z (M+H+) 410.9; 1H NMR (CDCl3) δ 1.41 (m, 2H), 1.85 (m, 2H), 2.96 (m, 4H), 4.44 (m, 1H), 4.73 (m, 1H), 7.23 (m, 3H), 7.33 (m, 2H), 7.43 (dt, 1H), 7.51 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=1)=[O:3].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=[O:3]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cc(O)c(Cl)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(NC(C)=O)c(Cl)cc1Cl
Yield: 99.9 %

Procedure:
A stirred mixture of 35.0 g (0.16 mole) of 2,4-dichloro-5-hydroxyacetanilide, 33.1 g (0.24 mole) of potassium carbonate, and 34.1 g (0.24 mole) of methyl iodide in 300 mL of acetone was heated at reflux for approximately 18 hours. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure to leave 37.4 g of 2,4-dichloro-5-methoxyacetanilide as a solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[C:20]([CH2:21][C:22]([OH:24])=O)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].[CH3:27][N:28]([CH3:31])[CH:29]=O>>[CH3:27][N:28]([CH:31]=[C:21]([C:20]1[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:13][N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=12)[CH:22]=[O:24])[CH3:29]
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2ccccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1c(-c2ccccc2)nn2ccccc12
Reaction time: 20 h

Procedure:
Phosphorus oxychloride (27.6 g) was added dropwise to N,N-dimethylformamide (16.6 ml) for 20 minutes under ice-cooling, 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetic acid (9.08 g) was added to the solution thus obtained and the reaction mixture was stirred at 90°-100° C. for 20 hours. After cooling, the reaction mixture was poured onto ice (20 g). The mixture was made alkaline with 24% aqueous solution of sodium hydroxide (pH≈9) and stirred at 90° C. for 1 hour and 20 minutes. After cooling, the resulting mixture was extracted with ethyl acetate three times. The combined extract was washed with water and dried over magnesium sulfate. The solvent was removed and recrystallized from a mixture of ethyl acetate and isopropanol to give 3-(N,N-dimethylamino)-2-(2-phenylpyrazolo[1,5-a]pyridine-3-yl)acrylaldehyde (cis and trans mixture) (5.00 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Br:20]
Reactant: COC(=O)c1cc(OC)c(OCCCBr)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCBr)cc1N
Temperature: 40 °C
Yield: 100 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 2.02 g (5.75 mmol) of methyl 5-methoxy-4-(3-bromopropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-6 and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.2 g of 5 wt. % palladium/carbon (containing 49% water). The resulting mixture was heated to the same temperature for 2 hours, while hydrogen was introduced to the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, precipitating a crystalline product. The crystalline product was dried under reduce pressure, to give 1.83 g (isolated yield: 98.1%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(3-bromopropoxy)anthranilate.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[N:16]([C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH3:18])[C:15](=[O:26])[CH:14]([Se]C3C=CC=CC=3)[CH:13]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:12][C:11]2=[O:40])=[CH:6][CH:5]=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[N:16]([C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH3:18])[C:15](=[O:26])[CH:14]=[C:13]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:12][C:11]2=[O:40])=[CH:8][CH:9]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)C([Se]c2ccccc2)C(c2ccccc2)NC(=O)[C@@H]1c1ccc(Cl)cc1
Agent: OO
Solvent: C1CCOC1
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)C=C(c2ccccc2)NC(=O)[C@@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
Hydrogen peroxide (500 μL, 30% in water) was slowly added to a solution of (3S)-1,3,6,7-tetrahydro-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-phenyl-6-(phenylseleno)-1,4-diazepine-2,5-dione (300 mg, 0.49 mmol) in tetrahydrofuran (6 mL). After 20 min., the solvent was evaporated under reduced pressure and the residue was partitioned between 1N sodium hydrogenocarbonate (20 mL) and ethyl acetate (50 mL), dried (Na2SO4) and evaporated. Purification by column chromatography (AcOEt/hexanes/CH2Cl2, 1:2:2) afforded the title compound (200 mg, 85%) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.70 (d, J=7.2 Hz, 3H, CH3), 5.28 (s, 1H, CH), 5.70 (d, J=1.6 Hz, 1H, CH), 6.35 (q, J=7.2 Hz, 1H, CH), 6.83 (d, J=8.8 Hz, 2H, ArH), 7.09 (d, J=8.8 Hz, 2H, ArH), 7.18–7.42 (m, 7H, ArH), 7.53 (d, J=8.8 Hz, 2H, ArH). Mass spectrum (LCMS, ESI pos.): Calcd for C25H20Cl2N2O2: 450.0; found: 451.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:22](OC(=O)C)(=[O:24])[CH3:23].CO>N1C=CC=CC=1>[C:22]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(C)=O
Reaction time: 8 h

Procedure:
To a solution of t-butyl (3RS)-3-hydroxytetradecanoate (20.0 g) in dry pyridine (100 ml) was added acetic anhydride (7.8 ml) at ambient temperature. The mixture was stirred at the same temperature overnight. Acetic anhydride (3 ml) was added to the mixture. The mixture was stirred for additional 2 hours at the same temperature. To the mixture was added methanol (50 ml) under ice-cooling. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The organic solution was washed with 1N hydrochloric acid and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (400 g) (chloroform:methanol 100:1 V/V) to give t-butyl (3RS)-3-acetoxytetradecanoate (14.04 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH2:21][CH3:22])=[C:6]([NH:8][C:9]([NH:11]C(=O)C2C=CC=CC=2)=[S:10])[CH:7]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH2:21][CH3:22])=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:7]=1
Reactant: CCCc1ccc(C)cc1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1ccc(C)cc1NC(N)=S
Temperature: 50 °C
Yield: 83.9 %

Procedure:
To N-((5-methyl-2-propylphenyl)carbamothioyl)benzamide (C72) (3.21 g, 10.3 mmol) in methanol (80 mL) was added sodium hydroxide (2 N, 10.3 mL, 20.5 mmol) and heated at 50° C. for 2 hours and then stirred at room temperature over the weekend. The reaction was concentrated, diluted with water, extracted with dichloromethane, filtered through a phase separator, concentrated, and dried in a vacuum oven to provide the title compound as a tan solid (1.80 g, 83%): mp 143-145° C.; 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.12 (dd, J=7.8, 1.2 Hz, 1H), 7.04 (s, 1H), 5.99 (d, J=254.5 Hz, 2H), 2.57 (d, J=7.5 Hz, 2H), 2.33 (s, 3H), 1.59 (dq, J=14.8, 7.4 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 181.96, 137.53, 136.74, 134.00, 130.69, 129.72, 127.85, 32.90, 23.66, 20.80, 13.93; ESIMS m/z 209 ([M+H]+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[F:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[F:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCN=[N+]=[N-])c2cccc(F)c2F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(F)c2F)C1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of (3R)-tert-butyl 3-((2-azidoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (3.4 g, 8.58 mmol) in ethyl acetate (50 mL) was added wet Pd/C (0.1 g). Under a hydrogen filled balloon the reaction was allowed to stir overnight. The reaction mixture was filtered through a pad of Celite and the solvent was removed. The residue was isolated by the preparative HPLC to give (R)-tert-butyl 3-((R)-(2-aminoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (3 g, 94%). 1H NMR (CDCl3, 400 MHz) δ 7.22 (m, 3H), 4.48 (d, 1H), 4.01 (d, 1H), 3.65 (m, 1H), 3.42 (m, 2H), 3.08 (m, 4H), 1.88 (m, 1H), 1.55 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[C:10]([Cl:24])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:24][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:25])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(COc2cc(Cl)c3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
To a mixture of methyl(4-chloro-6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (140 mg) and THF (1 mL) was added 1N NaOH (1 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual solid was crystallized from EtOAc to give the title compound (95 mg).
Reaction SMILES: O=[C:2]([CH:8]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH3:9])[C:3](OCC)=[O:4].C(=O)(O)O.[NH2:27][NH:28][C:29]([NH2:31])=[NH:30]>CCO>[NH2:30][C:29]1[NH:31][C:3](=[O:4])[C:2]([CH:8]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH3:9])=[N:27][N:28]=1
Reactant: CCOC(=O)C(=O)C(C)NC(=O)c1cccc(C(F)(F)F)c1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: CCO
Product: CC(NC(=O)c1cccc(C(F)(F)F)c1)c1nnc(N)[nH]c1=O
Yield: 92.3 %

Procedure:
A solution of ethyl 2-oxo-3-{[3-(trifluoromethyl)benzoyl]amino}butanoate (8.75 g, 27.6 mmol) and aminoguanidine bicarbonate (3.75 g, 27.6 mmol) in EtOH(aq) (80%, 200 mL) was heated at reflux for 3h. Concentration gave crude N-[1-(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)ethyl]-3-(trifluoromethyl)benzamide (8.34 g) as a colourless solid which was used without further purification. 1H NMR (DMSO-d6): δ8.87 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 8.20-8.15 (m, 2H), 7.93-7.89 (m, 1H), 7.75-7.69 (m, 1H), 7.00 (bs, 1H), 5.16 (p, J=7.1 Hz, 1H), 1.40 (d, J=7.1 Hz, 3H). MS m/z 326 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 340 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([C:15](OCC)=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li+].[BH4-].C1COCC1.Cl>CCOC(C)=O>[CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:15][OH:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCc2ccc(S(C)(=O)=O)cc2O1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)OC(CO)CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 7-(methylsulfonyl)chromane-2-carboxylate (0.6 g, 2.1 mmol), LiBH4 (0.18 g, 8.5 mmol) and THF (8 ml) was stirred at 0° C. for 15 min and 2 h at room temperature. HCl (10%) and EtOAc was added, the organic phase was dried (Na2SO4), filtered and concentrated to give the title compound. Yield 0.66 g. MS m/z (rel. intensity, 70 eV) 507 (20), 485 (25), 265 (23), 244 (13), 243 (M+1, bp).