Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:26])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C.[Cl:39]C(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[ClH:39].[CH2:27]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:26])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1
Reactant: CC(Cl)Cl
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: O=C(Nc1cccc(NCc2ccccc2)c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a stirred solution of 0.53 g (1.5 mmol) of N-(3-aminophenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetamide (Example 16), 0.15 ml (1.5 mmol) of benzaldehyde, 0.18 ml (3 mmol) of acetic acid in 15 ml of dichloroethane 0.48 g (2.25 mmol) of sodium triacetoxyborohydride is added in small portions below 20° C., and the reaction mixture is stirred at room temperature for 2 hours. Then 30 ml of 8% sodium hydrogencarbonate solution is added to the mixture, the organic layer is separated and the water phase is extracted three times with 30 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is treated with 2.5 N hydrochloric acid in ethylacetate to yield 0.39 g (54%) of the title compound. Melting Point: 206-213° C. (dec.) (ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=O)[OH:9])=[C:4]([CH3:19])[C:3]=1[CH3:20].N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([Cl:29])([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:4]([CH3:19])[C:3]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(P(=O)(O)C(=O)c2ccccc2)c(C)c1C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(P(=O)(Cl)C(=O)c2ccccc2)c(C)c1C
Temperature: 0 °C

Procedure:
250 g of the acid from Example 2 were suspended in 670 ml of toluene and dissolved with 102.6 g of pyridine. 1546 g of thionyl chloride were added dropwise to the reaction mixture at 60° C. over the course of 1 hour. After a post-reaction time of 3 hours, the red-brown emulsion was cooled to 0° C., and the rust-brown crystals were filtered off. The solution which remained was evaporated under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[O:8].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](OC(F)(F)F)[CH:19]=2)[N:14]=[C:13]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[S:29](=[O:38])(=[O:37])[CH2:28][CH2:27]2)[CH:12]=1.[CH:39]1(N)CCCC(N)C1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[O:37]=[S:29]1(=[O:38])[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[CH2:32][N:26]([C:13]2[CH:12]=[C:11]([NH:9][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:8])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:39])[CH:19]=3)[N:14]=2)[CH2:27][CH2:28]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: NC(=O)c1ccccn1
Reactant: NC1CCCC(N)C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)c3ccccn3)c2c1
Temperature: 150 °C
Yield: 70.9 %

Procedure:
A mixture of pyridine-2-carboxylic acid amide (99 mg, 0.8 mmol), 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.8 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), cyclohexane-1,3-diamine (90 mg, 0.08 mmol), copper(I) iodide (1.5 mg, 0.008 mmol) and potassium phosphate (340 mg, 1.6 mmol) in 1,4-dioxane (3 mL) was heated in a 5 mL of microwave process vial for 3 hours at 150° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC and SPE to give 26 mg of the desired product (yield was 7.1%). MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.90-8.82 (d, J=8 Hz, 1 H), 8.77 (s, 1 H), 8.47-8.40 (d, J=7.6 Hz, 1 H), 8.20-8.13 (t, J=6.4 Hz, 1 H), 8.13-8.08 (d, J=7.6 Hz, 2 H), 7.92-7.85 (m, 2 H), 7.80-7.70 (q, J=8.4 Hz, 3 H), 7.62-7.56 (t, J=7.2 Hz, 1 H), 5.37 (s, 2 H), 4.80-4.50 (m, 2 H), 3.82-3.78 (t, J=2.8 Hz, 2 H), 2.60 (s, 3 H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[C:6]([N:8](C)[C:9](=[NH:12])SC)#[N:7].[OH-].[Na+].[CH2:16](O)C>O>[C:6]([NH:8][C:9]([NH:12][CH3:16])=[N:2][CH2:3][CH2:4][SH:5])#[N:7]
Reactant: CSC(=N)N(C)C#N
Reactant: NCCS
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC(=NCCS)NC#N

Procedure:
A solution of cysteamine hydrochloride (5.68 g) in water (20 ml) was added to a suspension of N-cyano-N,S-dimethylisothiourea (6.46 g) in ethanol (100 ml). A solution of sodium hydroxide (4.0 g) in water (20 ml) was added to the mixture and the suspension was heated under reflux for one hour. The resulting clear solution was concentrated to remove ethanol, a little more water was added and the alkaline aqueous solution was extracted with ethyl acetate. The aqueous solution was adjusted to pH4 with hydrochloric acid and extracted with ethyl acetate. This latter organic extract was dried and evaporated to give N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.12 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+].[Na+].[I-:23]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([I:23])[CH2:9][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:20])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[C:4]([F:10])[CH:3]=1
Reactant: C=Cc1ccc(Cl)cc1F
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)CC(I)c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mechanically stirred mixture of impure 4-chloro-2-fluoro-1-vinylbenzene (26.76 g, 154 mmol), sodium p-toluenesulfinate (28.8 g, 161 mmol) and NaI (34.6 g, 231 mmol) in MeCN (700 mL) was added (NH4)2Ce(NO3)6 (169 g, 308 mmol) portionwise. The mixture was stirred under a nitrogen atmosphere during 3 h at room temperature. The liquid was separated by decantation and the solids were washed with MeCN (3×100 mL). The solvent was evaporated in vacuo and re-dissolved in EtOAc (500 mL). The organic layer was washed with brine (400 mL), aqueous 10 wt % Na2S2O3 (2×200 mL) and brine (200 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated to arrive at 51.86 g of crude title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[N:23]1([CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N>ClCCl.C1CCCCC1.CO>[N:23]1([CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][NH:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[NH:11][C:10](=[O:18])[C:9]4=[CH:19][S:20][C:21]([CH3:22])=[C:8]34)=[O:6])[CH2:35][CH2:34]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1scc2c1N(C(=O)NCCBr)c1ccccc1NC2=O
Reactant: C1CCCN(CCCC2CCNCC2)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCN3CCCCCC3)CC1)c1ccccc1NC2=O
Yield: 29 %

Procedure:
Prepared analogously to Example 109 from 4-[[[2-bromo-ethyl]amino]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[3-(hexahydro-1H-azepin-l-yl)propyl]piperidine in a yield of 29% of theory. Colourless crystals m.p. 144°-145° C. RF =0.5 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2 v/v).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH3:23][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:24]=[C:25]([NH2:27])[S:26][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1-c1csc(N)n1
Yield: 62.8 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (2.20 g, 5.68 mmol) and thiourea (0.43 g, 5.68 mmol) in 95% EtOH (8.1 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)thiazol-2-amine (1.30 g) as yellow solids in 63% yield: 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H), 6.76 (s, 2H), 6.32 (s, 1H), 5.03 (s, 2H), 2.17 (s, 6H).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1.[CH2:29](I)[CH3:30]>>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:29][CH3:30])[CH:19]=2)[O:16][CH:17]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)cc1O
Reactant: CCI
Product: CCOc1cc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 270 and ethyl iodide, white powdery 1-(2-difluoromethoxyphenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7][C:8]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 0.865 g 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid methyl ester in 9.0 ml tetrahydrofurane was added 3.2 ml of a 1M of lithium hydroxide in water was added and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was acidified with 1 M hydrochloric acid. The solid was collected by filtration washed with water and dried under high vacuum to yield 0.805 g of the title compound as white solid, MS (EI): 331.1 (M−H).
Reaction SMILES: FC(F)(F)C1C=CC=C(C(F)(F)F)C=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[H][H]>O>[F:15][C:16]([F:26])([F:27])[C:17]1[CH:25]=[CH:24][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)cc1
Temperature: 105 °C
Yield: 54 %

Procedure:
1 g of 5% palladium on barium sulfate (recovered from Example 1) and 100 g of 4-trifluoromethylbenzoyl chloride were placed in a reaction vessel at room temperature with exclusion of water. A gentle stream of hydrogen gas was then introduced at atmospheric pressure. The mixture was subsequently heated to 100-110° C. and hydrogen gas was introduced continuously at atmospheric pressure. After liberation of acidic offgases had ceased (6.5 hours), the mixture was cooled to room temperature, the catalyst was removed by filtration, and the filtrate was distilled at 33 mbar. At a boiling point of 82-86° C., 4-trifluoromethylbenzaldehyde was obtained in a yield of 45.9 g. This corresponds to a yield of 54% of theory.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:8][N:9]([CH3:14])[S:10]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (50%, 8.46 g) was added to a solution of pyrazole (12 g) in tetrahydrofuran (200 mL) while stirring at 0° C. After 20 min, dimethylsulfamoyl chloride (17 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hr and allowed to warm to room temperature over 1 hr. The reaction system was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (25.3 g) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:6]3[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=3)[C:22]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC(=O)c1cccc(B(O)O)c1
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: CCO
Product: CC(=O)c1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C
Yield: 18.2 %

Procedure:
A solution of 3-Acetylphenylboronic acid (23 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA55 (7 mg, 18% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C@@:13]3([CH3:22])[CH2:14][CH2:15][CH2:16][C@:17]([C:19]([OH:21])=[O:20])([CH3:18])[C@@H:12]3[CH2:11][CH2:10][C:8]=2[CH:9]=1)[CH3:3].[N+](=[CH2:25])=[N-]>CO>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13]3([CH3:22])[CH:12]([CH2:11][CH2:10][C:8]=2[CH:9]=1)[C:17]([C:19]([O:21][CH3:25])=[O:20])([CH3:18])[CH2:16][CH2:15][CH2:14]3)[CH3:1]
Reactant: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(C(=O)O)CCC[C@]21C
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1(C)CCCC2(C)c3ccc(C(C)C)cc3CCC12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82242.3 %

Procedure:
Dehydroabietic acid (50 mg, 0.116 μmol, Helix Biotech) was dissolved in 2 ml of methanol (HPLC grade, Fisher Scientific) and cooled to 0° C. on ice in a round bottom flask. An excess (30 μmol) of ethereal diazomethane (obtained by distillation) was added and the reaction was stirred for 5 minutes. The non-reacted diazomethane was evaporated and solvent was then removed by rotary evaporation. This reaction is shown schematically in FIG. 4. The product was purified by preparative TLC (1000 μm PK6F 60 Å, Whatman) silica gel plates developed in hexane:ethyl acetate 95:5 (v:v, Rf: 0.25). This step provided 30 mg of a clear oil as the methyl ester that was pure by NMR (see FIG. 5). 1H NMR (CDCl3, 300 MHz) δ1.35-1.42 (m, 12H), 1.50-2.05 (m, 7H), 2.43 (t, J=8.80 Hz, 2H), 2.90-3.05 (m, 3H), 3.80 (s, 3H), 7.02 (s, 1H), 7.14 (d, J=8.19 Hz, 1H), 7.31 (d, J=8.19 Hz, 1H). The product also gave the following electron impact mass spectra: (%) 315 (2.9, M+1), 314 (13, M), 299 (16.4), 240 (20.1), 239 (100), 197 (6.1), 173 (5.0), 141 (5.7).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:34]=[CH:35][C:36]([S:42](=[O:47])(=[O:46])[N:43]([CH3:45])[CH3:44])=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:33]5[CH:34]=[CH:35][C:36]([S:42](=[O:46])(=[O:47])[N:43]([CH3:45])[CH3:44])=[C:37]([C:38]([OH:40])=[O:39])[CH:41]=5)[CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)N(C)C)c(C(=O)O)c1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42 mg, 0.10 mmol), 5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid (31 mg, 0.10 mmol), 1 M K2CO3 (0.30 mL, 0.30 mmol), and Pd-FibreCat 1007 (8 mg, 0.004 mmol) were dissolved in DMF (1 mL) and heated at 80° C. for 3 hr in an oil bath. The mixture was filtered and purified by reverse phase HPLC to yield 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4-(N,N-dimethylsulfamoyl)-2′-methylbiphenyl-3-carboxylic acid. ESI-MS m/z calc. 522.6, found 523.5 (M+1)+; retention time 1.79 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CC1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1CC1c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
In a round bottom flask, mixed the tert-butyl 2-(4-bromophenyl)cyclopropanecarboxylate 2 (3.7 g, 12.0 mmol) in methanol/tetrahydrofuran (1:1, 30 mL) and heated to 50° C. Separately dissolved lithium hydroxide (1.4 g, 60 mmol) in water (15 mL) and then added to the solution of 2. Increased the heat to 65° C., and monitored by HPLC for reaction completion (<1% pA of 2, ˜3 h). The reaction mixture was then cooled to room temperature and distilled to ½ volume. Cooled the suspension to <20° C. and acidified (exothermic addition) the product mixture to pH<2 with 2N HCl (˜30 mL) to precipitate the product. Stirred the resulting suspension at 20° C. for NLT 0.5 h. Filtered the suspension and washed the wetcake with water (˜20 mL). Dried the wetcake at 45° C. under vacuum. Isolated 2.96 g of an off-white solid (98% pA, 97 wt %=99% wt-adjusted yield). 1H NMR (400 MHz, CDCl3) δ 1.35-1.40 (m, 1H), 1.65-1.69 (m, 1H), 1.85-1.89 (m, 1H), 2.53-2.58 (m, 1H), 6.97 (d, 2H, J=8.37), 7.40 (d, 2H, J=8.37). 13C NMR (100 MHz, CDCl3) δ 17.7, 24.2, 26.7, 120.2, 127.7, 131.3, 138.1 & 178.9 with 2 peaks overlapping.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)[CH2:6][C:7](=[O:18])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[CH3:2].C([O-])(=O)C.[NH4+:25]>CCO>[CH2:1]([O:3][C:4](=[O:20])/[C:5](/[NH2:25])=[CH:6]/[C:7](=[O:18])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)cc1F
Yield: 59.1 %

Procedure:
A mixture of (E)-6-(4-chloro-2-fluorophenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (3; 15.0 g, 0.05 mol) and ammonium acetate (7.7 g, 0.1 mol) in EtOH (100 mL) was stirred and heated to reflux for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (200 mL) and washed with saturated aqueous sodium carbonate (Na2CO3, 100 mL). After drying over MgSO4, silica gel (50 g) was added and the solvent was removed. The residue was washed with 20% ethyl acetate (EtOAc)/hexanes (300 mL) to give after solvent removal (2Z,5E)-2-amino-6-(4-chloro-2-fluorophenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (7; 6.1 g, 41%) as a light orange solid: mp 102-103° C.; 1H NMR (400 MHz, CDCl3) δ 9.4 (br s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.52 (t, J=8.5 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.19-7.08 (m, 2H), 6.87 (d, J=15.9 Hz, 1H), 6.14 (s, 1H), 6.05 (br s, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H13ClFNO3, 297.056. found, 297.056. Further washing of the silica gel with 40% EtOAc/hexanes (400 mL) gave more (2Z,5E)-2-amino-6-(4-chloro-2-fluorophenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (7; 8.8 g of 70% pure by 1H NMR spectroscopy) for a total of 12.2 g (82%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:5][CH:6]=[CH:7][CH:8]=1.Cl.[C:18](Cl)(Cl)=[S:19]>>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:3]2[NH:2][C:18]1=[S:19]
Reactant: Nc1cccnc1Nc1ccccc1F
Reactant: S=C(Cl)Cl
Agent: Cl
Product: Fc1ccccc1-n1c(=S)[nH]c2cccnc21
Reaction time: 3 h

Procedure:
3-Amino-2-(2-fluoroanilino)pyridine hydrochloride (3 g.) is dissolved in 25 ml. of 2.5 N hydrochloric acid and treated with 2 ml. of thiophosgene. After stirring 3 hours the mixture is clarified by filtration, and the filtrate is neutralized with ammonium hydroxide. The product separates and is recrystallized from methanol to give 1,3-dihydro-3-(2-fluorophenyl)imidazo[4,5-b]pyridin-2-thione.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21].CC1NC=CN=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NCc1ccc(Cl)cc1)C(=O)O
Reactant: CCCCC(=O)Cl
Agent: Cc1ncc[nH]1
Product: CCCCC(=O)N(Cc1ccc(Cl)cc1)[C@H](C(=O)O)C(C)C
Yield: 77.7 %

Procedure:
In a manner similar to Example 5 and starting from 15 g (62 mmol) of N-(4-chlorobenzyl)-L-Valine, 12 mL (99 mmol) of valeryl chloride and 7.7 g (93 mmol) of 2-methylimidazole, 15.7 g (77%) of N-(4-chlorobenzyl)-N-valeryl-L-Valine is obtained. The solid is recrystallised from a mixture of EtOH:H2O 1:1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[O:15]1[C@H:17]2[CH2:18][C@H:19]([C:22]([CH3:24])=[CH2:23])[CH2:20][CH2:21][C@@:16]12[CH3:25]>C1(C)C=CC=CC=1.CN(C)C=O>[C:7]1([S:13][C@H:17]2[CH2:18][C@H:19]([C:22]([CH3:24])=[CH2:23])[CH2:20][CH2:21][C@@:16]2([OH:15])[CH3:25])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ccccc1
Reactant: C=C(C)[C@@H]1CC[C@@]2(C)O[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@](C)(O)[C@@H](Sc2ccccc2)C1
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of 164 g (1 M) of the above diastereomeric mixture, 83 g of potassium carbonate and 60.5 g (0.556 M) of thiophenol in a mixture of 380 ml of toluene and 20 ml of dimethylformamide was heated under reflux for 10 hours. After cooling to room temperature and addition of water, the separated organic layer was successively washed with water and with brine, dried over sodium sulfate and evaporated. After distillation in a bulb apparatus, the desired thioether (131 g; ca. 100% yield) was separated from unreacted (+)-(1R,2S,4R)-1,2-epoxy-8-p-menthene. The title compound thus prepared was characterized as follows: