Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47]1([NH2:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Br[C:55]1[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCCCCC>[C:47]1([NH:53][C:55]2[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(O)c1ccc(Nc2ccccc2)cc1
Yield: 43.7 %

Procedure:
BINAP (0.1 g, 0.16 mmol) and Pd(OAc)2 (0.014 g, 0.06 mmol) were mixed in toluene (10 mL) and this first solution was purged with argon for 15 minutes. Phenylamine (0.3 gm, 3.22 mmol), 4-bromo-benzoic acid (0.776 g, 3.89 mmol) and Cs2CO3 (3.14 gm, 9.66 mmol) were mixed in toluene (20 mL) and this second solution was purged with argon for 15 minutes. The first solution was added to the second solution, and the resulting mixture was heated to reflux overnight. Additional BINAP (0.1 g, 0.16 mmol) and Pd(OAc)2 (0.014 g, 0.06 mmol) were then added and the mixture heated to reflux for a further 6 hours. The toluene was removed and the residue was acidified with 10% HCl. The product was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 950 mg crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 30:70 EtOAc:Hexane as the eluent) afforded 300 mg (43% yield) of 4-Phenylamino-benzoic acid.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[C:10]([CH3:9])[CH:15]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Temperature: 125 °C

Procedure:
A mixture of 4-iodo-aniline (25.0 g, 114.1 mmol), 2-methyl-4-chlorophenyl-boronic acid (29.17 g, 171.1 mmol), PdCl2(P(o-tolyl)3)2 (11.66 g, 14.8 mmol), and Na2CO3 (60.49 g, 570.7 mmol) in DME/EtOH/H2O (100/50/25 mL) was heated 125° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc (200 mL). The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate (500 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with 5-30% Hexane/EtOAc to afford 4′-Chloro-2′-methyl biphenyl-4-ylamine. 1H NMR (300 MHz, CDCl3): δ 7.24-7.08 (m, 5 H), 6.72 (d. J=7.2 Hz, 2 H), 3.70 (bs, 2 H), 2.27 (s, 3 H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCCl>[Cl:1][CH2:2][C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[C:8]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:9]=1)=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cn1cccc1C(=O)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CCl
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
solution of 30 g (0.19 mole) of 2-chloro-1-(1-methyl-1H-pyrrol-2-yl)-ethanone (10) in 180 mL 1,2-dichloroethane (DCE) under an argon atmosphere was cooled in an ice bath and 60 g AlCl3 (0.45 mole) was added in portions. After stirring for 10 minutes, a solution of 24 mL (0.19 mole) 4-chlorobenzoyl chloride in 110 mL DCE was added dropwise. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was poured into 1N HCl/ice and the aqueous layer was extracted three times with methylene chloride. The organics solutions were combined, washed with water, 1N NaOH, water, brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a solid which was recrystallized from ethyl acetate/methylcyclohexane to give 27.67 g of a solid: mp 130-132° C.; NMR 300 MHz (CDCl3) d 7.8 (m, 2H); 7.6-7.4 (m, 4H); 4.5 (s, 2H); 4.0 (s, 3H). Anal Calcd for C14H11Cl2NO2: C, 56.78; H, 3.74; N, 4.73. Found: C, 56.72; H, 3.76; N, 4.73.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2ccc(C#N)cc2)cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(-c3nnn[nH]3)cc2)cc1C
Temperature: 125 °C
Yield: 38.1 %

Procedure:
A suspension of 10.0 g of 3',4'-dimethyl[1,1'-biphenyl]-4-carbonitrile, 3.45 g of sodium azide and 2.8 g of ammonium chloride in 300 mL of DMF was heated to a bath temperature of 125° C. for 20 hours. The reaction mixture was cooled, filtered, and evaporated and the residue was taken up in ethyl acetate and washed with water. The residue obtained after drying and evaporation was crystallized from ethyl acetate-dichloromethane to give 4.6 g of 5-(3',4'-Dimethyl[1,1'-biphenyl]-4-yl)-1H-tetrazole, mp 192°-194° C. The analytical sample melted 193°-194° C.
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.[CH2:34]([O:36][C:37](=[O:47])[CH2:38][CH2:39][C:40](=[O:46])[C:41]1[S:42][CH:43]=[CH:44][N:45]=1)[CH3:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:34]([O:36][C:37](=[O:47])[CH2:38][CH:39]([Br:1])[C:40](=[O:46])[C:41]1[S:42][CH:43]=[CH:44][N:45]=1)[CH3:35]
Reactant: CCOC(=O)CCC(=O)c1nccs1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(Br)C(=O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyltrimethylammonium tribromide (3.4 g, 8.91 mmol) in DCM (20 mL) is added dropwise to a solution of 4-oxo-4-thiazol-2-yl-butyric acid ethyl ester (1.9 g, 8.91 mmol) in DCM (30 mL. The mixture is stirred overnight at room temperature. 5% NaHCO3 (40 mL) is added to the mixture. The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed. The residue is purified by column (hexanes/ethyl acetate 3:1) to give 3-bromo-4-oxo-4-thiazol-2-yl-butyric acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[CH2:31]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:31][C:24]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=2[F:22])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(CO)c(F)c1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: COc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was reacted with (2-fluoro-4-methoxy-phenyl)-methanol analogous to Example 3a to afford 4-chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-(2-fluoro-4-methoxy-benzyl)-benzenesulfonamide:
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].C(N([CH2:19][CH3:20])CC)C>CO>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@H:10]3[C:19]4[C:20](=[CH:1][CH:3]=[CH:4][CH:13]=4)[CH2:6][C@@H:11]3[OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2]
Reactant: CCN(CC)CC
Reactant: Cc1nc2c(O)cccn2c1C=O
Solvent: CO
Product: Cc1nc2c(O[C@H]3c4ccccc4C[C@@H]3O)cccn2c1C=O
Yield: 52.3 %

Procedure:
3.30 g of 3-formyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine and 1.40 g (-)-1R,2S-indenoxide are reacted, analogously to the method described in Example 21, with 1.90 g of triethylamine in 425 ml of aqueous methanol (350 ml methanol+75 g water) at 50° C. After 8 hours the solution is evaporated and the residue dissolved in 150 ml water. 4 g of sodium carbonate is added and extracted with 4×100 ml ethyl acetate. The organic phases are washed with 2×200 ml sodium carbonate solution and 4×200 ml water, dried over magnesium sulfate and evaporated. The solid residue is mixed in 100 ml cyclohexane filtered and dried. 1.51 g of the title compound m.p. 187°- 192° C. is isolated [α]D22 =+112° (c=0.5, chloroform).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCCCCCCCCCCCCC(C)C
Temperature: 117 °C
Reaction time: 1.5 h

Procedure:
About 780 grams of isostearic acid (acid number=194.4), 1 gram of p-toluenesulfonic acid were charged to a flask equipped with a heating mantle, stirrer, sub-surface inlet tube with a nitrogen purge and a condenser. The contents of the flask were heated under nitrogen flow to 117° C. About 400 grams of methanol were then added via the sub-surface inlet tube over 3.5 hours (acid number=9.6), 200 grams of additional methanol were added and the reaction continued for another 1.5 hours to obtain a final acid number of 0.6.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:10][C:7]=2[S:8][CH:9]=1.FC(F)(F)C1C=CC(COC2C=CC=CC=2CO)=CC=1>C(OCC)(=O)C.C(O)C>[CH3:14][C:12]1[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[C:6]=2[CH:13]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccccc3OCc3ccc(C(F)(F)F)cc3)c(C)cc12
Agent: OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2c(CC(=O)O)csc2cc1OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Yield: 86 %

Procedure:
The title compound was prepared using compound 78D from the preceding step and compound 7A in a manner analogous to compound 77. Thus, chromatography on silica gel in ethyl acetate followed by trituration in ethanol afforded 0.16 g (86% yield) of the title compound as a white solid; mp 157-158° C. Calc for C26H21F3O4S: C, 64.19; H, 4.35; found: C, 63.43; H, 4.04.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:24]1[S:28][N:27]=[CH:26][N:25]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:28]1[C:24]([NH:6][S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])=[N:25][CH:26]=[N:27]1
Reactant: COC(=O)c1cccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500-mL two-neck flask was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D; 10 g, 19.22 mmol), palladium (ii) acetate (0.216 g, 0.961 mmol), and Xantphos (1.112 g, 1.922 mmol). Triethylamine (77 ml, 19.22 mmol), toluene (48.0 ml), and methanol (15.55 ml, 384 mmol) were added, and the reaction was fitted with a reflux condensor. The reaction was evacuated and back-filled with carbon monoxide three times, then the reaction was heated to 70° C. and stirred for four hours under an atmosphere of carbon monoxide. The reaction was filtered through a pad of diatomaceous earth, which was thoroughly washed with ethyl acetate. The filtrate was concentrated, triturated in ethyl acetate and filtered. The solids were collected and the filtrate was concentrated. The trituration procedure was repeated twice, and the solids resulting from each trituration were combined with the previously isolated material. After the third trituration, the mother liquor was purified via column chromatography (80 g silica gel column, gradient elution 0 to 50% EtOAc:Heptane). The clean product fractions were combined with the previously isolated material and the resulting slurry was concentrated to afford methyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate as a light yellow solid. m/z (ESI) 500.3 (M+H)+. 60 mg of methyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The material was concentrated, dissolved in acetonitrile and loaded onto a Biotage Isolute® PEAX ion exchange column (Biotage AB, Uppsala, Sweden) (pre-wetted with acetonitrile). The column was flushed several times with acetonitrile, then the product was liberated by flushing the column several times with about 1M HCl solution in MeOH/EtOAc. The second filtrate was concentrated to afford methyl 6-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.90 (d, J=9.2 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.53-8.44 (m, 2H), 8.29 (dd, J=1.3, 7.3 Hz, 1H), 7.96 (dd, J=2.1, 9.2 Hz, 1H), 7.76 (dd, J=7.3, 8.2 Hz, 1H), 3.95 (s, 3H). m/z (ESI) 350.1 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Product: CC(C)c1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 84 %

Procedure:
To fuming nitric acid (5 mL) cooled to 5° was added neat 4-bromoisopropylbenzene (1.0 g, 5.023 mmol) dropwise at such a rate that the reaction temperature remained below 10°. The reaction was stirred for 2 hours at 5-10°, quenched with ice (50 g), extracted with ethyl acetate (50 mL), and the organic extract was washed with water (2×25 mL) and brine (25 mL), then dried over magnesium sulfate.filtered and concentrated by rotary evaporation. The residue was purified by silica gel flash chromatography eluting with 5:95 ethyl acetate/hexanes to afford the title compound as a light yellow solid (1.03 g, 4.22 mmol, 84%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.27 (d, J=6.99 Hz, 6 H) 2.75-3.23 (m, 1 H) 7.29 (dd, J=8.82, 2.21 Hz, 1 H) 7.63 (d, J=8.09 Hz, 1 H) 7.69 (d, J=2.21 Hz, 1 H); MS (DCI) m/z 261/263 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].CCCCCC.C(OCC)(=O)C>C(#N)C>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCc1c(O)ccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1c(OCCNC(=O)OC(C)(C)C)ccc2ccccc12

Procedure:
To a solution of 1-ethylnaphthalen-2-ol (780 mg, 4.53 mmol) and K2CO3 (626 mg, 4.53 mmol) in 15 mL of acetonitrile was added tert-butyl (2-bromoethyl)carbamate (1.015 g, 4.53 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 7:3) showed the disappearance of 1-ethylnaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (5 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-ethylnaphthalen-2-yl)oxy]ethyl}carbamate which was dissolved in 10 mL of 4M HCl in dioxane and stirred for 1 h. The solvent was removed under vacuum and the residue was diluted with n-hexane (20 mL) and triturated at room temperature for 2 h. The solid was filtered and dried under vacuum at 50° C. to afford 2-[(1-ethylnaphthalen-2-yl)oxy]ethanaminium chloride as brown solid (821 mg, 72% yield). To a solution of 2-[(1-ethylnaphthalen-2-yl)oxy]ethanaminium chloride (100 mg, 0.397 mmol) in 10 mL of MeOH, K2CO3 (65 mg, 0.47 mmol) was added. After 10 min, 48 μL (0.58 mmol) of furan-2-carbaldehyde were added. The resulting solution was stirred for 1 h at room temperature, added with sodium borohydride (15 mg, 0.397 mmol) and allowed to stir for further 2 h at room temperature. The solvent was evaporated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 97:3) to afford 2-[(1-ethylnaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine as a brown solid (91 mg, 78% yield).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][CH:8]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:10].CCOC(C)=O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>O.CCOC(C)=O.C1COCC1>[OH:10][CH2:9][CH:8]([NH:7][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH2:11][CH:12]=[CH2:13]
Reactant: C=CCC(N)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CO)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
A solution of Na2CO3 (9.22 g, 86.92 mmol) in water (50 ml) was left under stirring at RT for 20 min prior addition of 2-aminopent-4-en-1-ol (D7) (8.3 g) and EtOAc (160 ml). After 30 minutes stirring, a solution of p-toluenesulfonyl chloride (12.9 g, 67.85 mmol) in EtOAc/THF (24/24 ml) was added over 15 minutes. The reaction mixture was stirred at RT for a weekend. Water (30 ml) and EtOAc (100 ml) were added to the reaction mixture, the phases were separated and the aqueous layer was extracted with EtOAc (2×80 ml). The combined organic phases were evaporated and the residue was purified by Biotage SNAP-Si (100 g) cartridge eluting with a mixture cHex/EtOAc from 80/20 to 50/50. Collected fractions after solvent evaporation afforded the title compound (D8) (5.5 g)
Reaction SMILES: [F-].[K+].[CH2:3]([O:5][C:6](=[O:34])[C:7]([F:33])([F:32])[C@@:8]([C:17]1[C:22]([F:23])=[C:21]([Si](CC)(CC)CC)[CH:20]=[C:19]([Br:31])[N:18]=1)([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH3:4].C(O)(=O)C.CN(C=O)C>C1COCC1.C(OCC)(=O)C>[CH2:3]([O:5][C:6](=[O:34])[C:7]([F:32])([F:33])[C@@:8]([C:17]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([Br:31])[N:18]=1)([NH:10][S@@:11]([C:13]([CH3:16])([CH3:14])[CH3:15])=[O:12])[CH3:9])[CH3:4]
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1nc(Br)cc([Si](CC)(CC)CC)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1nc(Br)ccc1F
Temperature: 25 °C
Yield: 88 %

Procedure:
Freshly ground KF (195 mg, 3.36 mmol) was added to a solution of (R)-3-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (940 mg, 1.68 mmol) and acetic acid (0.192 ml, 3.36 mmol) in THF (7 ml). DMF (7 ml) was added and the suspension was stirred at rt. After 2 h the reaction mixture was diluted with ethyl acetate and washed with sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. The crude product (733 mg) was chromatographed over silica gel (cyclohexane/ethyl acetate 7:3) to give the title compound as a slightly yellow oil. 664 mg (88% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[CH3:11][NH2:12]>C(O)C>[CH3:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][OH:9])=[N:7][C:2]=1[NH:12][CH3:11]
Reactant: Cc1ccc(CO)nc1Cl
Reactant: CN
Solvent: CCO
Product: CNc1nc(CO)ccc1C
Yield: 37 %

Procedure:
0.96 g of (6-chloro-5-methylpyridin-2-yl)-methanol (6.09 mmol) and 7 ml of methylamine at 33% in ethanol are heated at 120° C in a bomb for 96 hours. 2 ml of methylamine at 33% in ethanol are added every 24 hours. The reaction mixture is concentrated under vacuum and the title compound isolated by chromatography on a silica column (eluent: cyclohexane/ethyl acetate; 40:60).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N+:8]([O-:10])=[O:9].C1([O:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)C=CC=CC=1.NC(N)=O.Cl>CS(C)=O.O>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:18](=[O:17])[CH2:7][N+:8]([O-:10])=[O:9])=[CH:20][CH:21]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1ccc(C(=O)Oc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: NC(N)=O
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)C[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a suspension of potassium tert-butoxide (24.3 g, 217.1 mmol) in DMSO (150 mL), was added CH3NO2 (11.7 mL, 217.1 mmol) added at 0° C. After stirring for 1 h, 4-methanesulfonyl-benzoic acid phenyl ester (20.0 g, 72.4 mmol) was added in one portion at 0° C. The reaction was warmed to room temperature and stirred for 5 hr. The reaction was poured into ice-water (200 mL) and followed by adding urea (2.17 g, 36.2 mmol). The reaction was acidified with 5.0M HCl to pH=5 at 0° C. The reaction was added to water (1L) and stirred for 1 h. The pale yellow solid was filtered and dried under vacuum to afford the desired compound (13.2 g, 75.2%). 1H NMR (400Mz, DMSO-d6) δ 8.19 (m, 4H), 6.63 (s, 2H), 3.35 (s, 3H). LCMS 244.5 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([CH2:34]C=C)([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:18]([CH3:33])[CH:17]=2)[CH2:11][CH:12]=[CH2:13])=[CH:8][CH:9]=1)=[O:4]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]2([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH3:33])[C:19]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[C:20]([CH3:22])[CH:21]=3)[CH2:34][CH:13]=[CH:12][CH2:11]2)=[CH:8][CH:9]=1)=[O:4]
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)OC)s1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(COc3cc(C)c(-c4ccc(C(F)(F)F)cc4)c(C)c3)CC=CC2)s1
Yield: 87 %

Procedure:
A solution of 5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carboxylic acid methyl ester (0.292 g, 0.567 mmol) in CH2Cl2 (270 mL) is treated with [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (0.0528 g, 0.0622 mmol) for 4 h and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% to afford 5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carboxylic acid methyl ester (0.240 g, 87%) as a colorless syrup. MS (ES): 487.4 [M+H]+.