Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[N:5]([CH2:6][CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12>C(O)(=O)C.[Zn]>[C:4]1(=[O:17])[C:3]2[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:1][N:5]1[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1c2ccccc2CN1CCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 18.25 h

Procedure:
4-(2-Phthalimidoethoxy)benzaldehyde (6.8 g) was dissolved in glacial acetic acid (70 ml) at 60° C. Powdered zinc (9.1 g) was added, and the mixture heated at reflux and stirred vigorously for 18.25 hours before being filtered whilst hot, and allowed to cool to room temperature. The acetic acid was evaporated and the resulting gum dissolved in methanol (75 ml). Sodium hydroxide solution (10% w/v; 75 ml) was added, and the mixture stirred for 2 hours at room temperature, diluted with water (1 l), acidified to pH4 with hydrochloric acid, and then continuously extracted with dichloromethane for 3 hours. The dichloromethane layer was evaporated and the residue chromatographed on silica gel using 1.5% methanol in dichloromethane to afford the title compound, mp 106°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].[C:25]1([CH3:34])[C:26]([N:31]=[C:32]=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:34])=[O:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethyl-aniline (120 mg) was dissolved in chloroform (10 ml), and o-toluyl isocyanate (55 μl) was added to the solution. The mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution to precipitate a crystal which was then collected by filtration to give 130 mg (yield 70%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([Br:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH2:28])[C:23]=1[I:29].[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:24]1[N:25]=[CH:26][N:27]=[C:22]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([Br:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:23]=1[I:29]
Reactant: Nc1ncnc(Cl)c1I
Reactant: C[C@H](N)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1I)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Yield: 0 %

Procedure:
(S)-2-(1-Aminoethyl)-5-bromo-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.72 g, 2.16 mol) was treated with 6-chloro-5-iodopyrimidin-4-amine (1.55 g, 4.31 mol), cesium fluoride (0.66 g, 4.34 mol), N,N-diisopropylethylamine (1.88 mL, 10.79 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 70%, hexane-ethyl acetate) to give 0.39 g (32% yield) of the title compound as a solid. Purity 93%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:13][S:14]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:16])=[O:15]
Reactant: COC(=O)Cc1cccc(F)c1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)Cc1cc(F)ccc1S(=O)(=O)Cl
Reaction time: 16 h

Procedure:
Methyl (3-fluorophenyl)acetate (1.51 g) was added dropwise to chlorosulphonic acid (7 mL) with stirring and ice cooling. The cooling bath was removed and the mixture was allowed to stand at room temperature for 16 hours before being carefully added to a mixture of ice and ethyl acetate. The organic layer was separated, washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (1.42 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6](=[O:19])[N:7]([CH2:17][CH3:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15]C)[CH:9]=2>Br.CC(O)=O>[CH2:17]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)[CH:14]=[C:5]([CH2:4][C:3]([OH:20])=[O:2])[C:6]1=[O:19])[CH3:18]
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(OC)cc21
Agent: Br
Solvent: CC(=O)O
Product: CCn1c(=O)c(CC(=O)O)cc2ccc(O)cc21
Temperature: 250 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A suspension of (1-ethyl-7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester (4.0 g, 14.5 mmol) in 1:1 48% aqueous HBr—HOAc (30 mL) was heated at reflux for 48 h. The resulting solution was cooled to 250° C. and the resulting crystalline solid was stored at 0-50° C. for 2 h, then vacuum filtered, washed with water and air-dried to give the title compound (3.2 g, 89% yield) as tan needles.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[NH2:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:21])=[O:5]
Reactant: NC[C@H]1CCCO1
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NC[C@H]1CCCO1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available (R)-2-aminomethyltetrahydrofuran using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 1.50-1.58 (m, 2H), 1.66-0.191 (m, 3H), 3.13-3.29 (m, 2H), 3.39-3.46 (m, 1H), 3.60-3.67 (m, 1H), 3.85-3.94 (m, 1H), 7.69-7.82 (m, 3H), 8.03 (t, J=5.8 Hz, 1H), 11.42 (br s, 1H). MS (ESI+) m/z 515 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (500 mg, 1.16 mmol) (obtained as described in Reference Example 77(2)) in methylene chloride (25 ml) were added methanesulfonyl chloride (269 μl, 3.48 mmol) and triethylamine (488 μl, 3.48 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 3 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (96:4) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (546 mg, yield 92%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1.[CH3:30][Si](C=[N+]=[N-])(C)C>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH3:30])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
According to Scheme 7 Step 5: To a solution of 2-(3-acetamidophenyl)-4-(4-chlorobenzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 11(D) (80 mg, 0.19 mmol) in MeOH (3 mL) was added dropwise at 0° C. a solution of trimethylsilyldiazomethane 2M (1.3 mL, 2.70 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with 100 mL of a saturated solution of NaHCO3 and the aqueous layer was extracted twice with 100 mL of DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow solid. The crude solid was purified by flash chromatography with silica gel (AIT Flashmart prepacked column 7 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford a yellow solid. The solid was further triturated with diisopropylether and filtered to afford methyl 4-(4-chlorobenzyl)-2-(3-acetamidophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (35 mg, 42%) as a beige solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>O1CCCC1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][CH2:20][C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[C:24]#[N:25])[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Reactant: N#Cc1cccc(CBr)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(COCC2CC(c3ccc(CN4CCCC4)cc3)C2)c1
Temperature: 40 °C
Yield: 40.2 %

Procedure:
To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (50.0 mg, 0.20 mmol) prepared above (Step F) in 3 mL of tetrahydrofuran was added a solution of KotBu (0.42 mL, 0.41 mmol, 1M THF). After 30 minutes 3-(bromomethyl)-benzonitrile (42.0 mg, 0.21 mmol), in 1 mL of THF was added and then the reaction was heated to 40° C. (oil bath). After 3 hours the reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered through a fitted funnel and concentrated under reduced pressure. This material was purified by flash chromatography using a 4 g ISCO column, eluting with a gradient of 2%, 4%, 8% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound (29.0 mg, 39% yield) as a colorless oil and a mixture of cis:trans isomers.
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:14]([F:16])[F:15].[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:14]([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: COC(=O)CCCCCCCCCC=C(F)F
Reactant: C[Si](C)(C)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1ccc(NC(=O)CCCCCCCCCC=C(F)F)cc1
Reaction time: 2 h

Procedure:
2.5 g of 12,12-difluorododec-11-enoic acid methyl ester are added at room temperature to 1.53 g of 4-trimethylsilylaniline in 25 ml of toluene. The mixture is stirred for 2 hours at 80° and then concentrated by evaporation in vacuo. The residue is taken up in toluene, the toluene phase is washed with water, dried over sodium sulfate and concentrated to dryness by evaporation. The residue is taken up in hexane:ethyl acetate (9:1) and filtered over silica gel. Evaporation of the filtrate yields the title compound (nD24 =1.5038; compound no. 1-2).
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH2:9]([NH:11][NH:12][C:13]([NH2:15])=[S:14])[CH3:10]>CC(C)=O>[CH2:9]([N:11]([C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2])[NH:12][C:13]([NH2:15])=[S:14])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCNNC(N)=S
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)N(CC)NC(N)=S
Reaction time: 1 h

Procedure:
Ethoxalyl chloride (10.6 cc) is added dropwise, in the course of 10 minutes, to a solution, at 20° C., of 1-ethyl-thiosemicarbazide (11.9 g) in acetone (200 cc). The temperature rises to 43° C., the mixture is stirred for 1 hour without heating and is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), the residue is taken up in methanol (30 cc) and the crystallisation is started. After filtration and drying, 1-ethyl-1-ethoxalyl-thiosemicarbazide (13.2 g) is obtained in the form of a white solid melting at 170° C.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH2:8])[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:18]1([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[C:35](Cl)=[C:30]3[CH:29]=[CH:28]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[C:35]([NH:8][C@H:4]4[CH2:5][CH2:6][CH2:7][O:2][CH2:3]4)=[C:30]3[CH:29]=[CH:28]2)(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@H]1CCCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CCCOC1
Temperature: 75 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
(S)-(Tetrahydro-pyran-3-yl)amine hydrochloride (40.7 g, 296.09 mmol) and N,N-diisopropylethylamine (130 mL, 760 mmol) were added to a solution of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (100.0 g, 296.09 mmol) in ispropanol (1.0 L). The mixture was stirred at an internal temperature of 75° C. for 4 hours. The mixture was then allowed to cool down slowly and left still overnight. The resulting solid was collected by filtration and washed with cold isopropanol. The solid was then dried in a vacuum oven for 24 h to afford 114.0 g (95.7%) of (1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(S)-tetrahydro-pyran-3-yl-amine as a yellow solid. LCMS (Method D, ESI): RT=1.63 min, m+H=403.2; 1H NMR (400 MHz, DMSO) δ 9.21 (d, J=8.1 Hz, 1H), 8.92 (s, 1H), 8.13 (d, J=7.8 Hz, 2H), 7.77 (dt, J=25.1, 10.9 Hz, 2H), 7.66 (t, J=7.7 Hz, 2H), 7.02 (d, J=4.1 Hz, 1H), 4.28 (s, 1H), 3.88-3.65 (m, 3H), 3.56 (t, J=8.9 Hz, 1H), 2.00 (t, J=11.5 Hz, 1H), 1.93-1.63 (m, 2H), 1.53 (dd, J=9.4, 4.2 Hz, 1H), 1.28 (t, J=6.9 Hz, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.45 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a light yellow solid (0.2 g, 38%). MS (ISP) 531.0 [(M+H)+]; mp 250.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:23])[C:10](Br)([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH3:11].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>CN(C=O)C>[CH3:7][O:8][C:9](=[O:23])[C:10]([O:32][C:26]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=1[F:24])([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH3:11]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)C(C)(Br)c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Oc1ccc(F)cc1F)c1ccc(S(C)(=O)=O)cc1
Temperature: 65 °C

Procedure:
Potassium carbonate (0.15 g, 1.08 mmol) was added to a mixture of 2-Bromo-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester and 2,4-difluorophenol in DMF (5 ml) and heated at 60-70° C. for 2-3 Hrs then cool the reaction mixture to RT and poured onto water (25 ml) which was then extracted with ethyl acetate (2×25 ml), organic layer was washed with water (2×25 ml), dried over sodium sulfate and solvent was removed under reduced pressure to get 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester as oil which was taken in a mixture of methanol (5 ml) and sodium hydroxide in water (0.04 g in 5 ml). This mixture was stirred at room temperature for overnight. Methanol was removed from the reaction mixture, acidified with 1N HCl, extracted with ethyl acetate (2×25 ml), washed with brine (20 ml), solvent was removed to get the desired product 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 3.45 (s, 3H), 6.71-6.75 (m, 1H), 6.81-6.93 (m, 2H), 7.86 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([N+:33]([O-])=O)[CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.C(O)(=O)C.[Fe]>[CH2:1]([C:5]1[O:6][C:7]2[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([NH2:33])[CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(N)c2)cc1
Temperature: 120 °C
Yield: 28.2 %

Procedure:
A solution of 2-butyl-3-[3′-nitro-4′-(3-phenyl-propoxy)-biphenyl-4-ylmethyl]-benzofuran (53 mg, 0.105 mmol) in ethanol (1 mL) and acetic acid (1 mL) was treated with Fe (26.4 mg, 4.5 equiv., 0.472 mmol) and heated to 120° C. for 3 h. After cooling to room temperature, the solution was poured into a 20% aq NaOH/ice water solution (Ph>8) and extracted with ether (3×20 mL). The combined organic layers were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by prep thin layer chromatography (25% ethyl acetate in heptane) afforded 4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-ylamine (14.5 mg, 29%).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH3:9])=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C1COCC1>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][C:2]1([C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:4][CH2:5][N:1]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CC=C(C)C)CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-tert-Butyl 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (2.29 g, 0.00999 mol) was dissolved in anhydrous THF (30 mL) and the solution was cooled to −78° C. prior to the drop-wise addition of 1.0 M of lithium hexamethyldisilazide in THF (16 mL) over 15 min. After stirring for 1 h, 1-bromo-3-methylbut-2-ene (1.6 mL, 0.014 mol) was added and the resultant solution was stirred for 5 hours at −78° C. The reaction was quenched by the drop-wise addition of saturated NH4Cl (15 mL). After gradually warming to room temperature (RT), the reaction mixture was diluted with EtOAc (100 mL) and water (10 mL). The organic layer was washed with water (15 mL) and the combined aqueous phases were extracted with EtOAc several times. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to afford the desired product, which was used in the subsequent step without further purification. LC-MS: 198.2 (M−Boc+2H)+ and 320.2 (M+Na)+.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[Cl:12][C:13]1([Cl:19])[CH2:15][CH:14]1[C:16]([NH2:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:12][C:13]1([Cl:19])[CH2:15][CH:14]1[C:16]([NH:18]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])/[C:3]([OH:5])=[O:4])=[O:17]
Reactant: CCCCCCC(=O)C(=O)O
Reactant: NC(=O)C1CC1(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCC/C=C(\NC(=O)C1CC1(Cl)Cl)C(=O)O
Yield: 6 %

Procedure:
A mixture of 1.19 g (7.5 mmoles) of 2-ketooctanoic acid, 0.77 g (5.0 mmoles) of 2,2-dichlorocyclopropanecarboxamide, and 5 ml toluene were reacted using the same procedure as in the previous example. The crude product (537 mg) was purified by conversion to the methyl ester (BF3 /CH3OH), preparative TLC (silica gel G, 4:1 hexane-EtOAc) and saponification of the pure Z-methyl ester (0.3M LiOH/CH3OH) to give 88 mg of Z-2-(2,2-dichlorocyclopropanecarboxamido)-2-octenoic acid as a partially crystalline gum. NMR spectrum (DMSO-d6): 9.68 δ(s, 1H, NH), ##STR8## 0.87δ(t, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=3)[S:10][C:3]=12.[OH-].[Na+].Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)[S:10][C:3]=12
Reactant: COC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of methyl 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylate (0.200 g, 0.62 mmole), prepared by the method described in PC10795A, section A, example 26, in EtOAc (5 ml) was added 1N aqueous NaOH solution (1.85 ml, 1.85 mmole). The reaction mixture was stirred at 50° C. for 1 h, cooled to room temperature, diluted with H2O (10 ml) and acidified with 1N HCl to pH˜2. The resulting solution was extracted with 10% MeOH in CH2Cl2 (5×10 ml), dried over MgSO4 and concentrated and dried under vacuum to give yellow solid (0.181 g, 98%). 1H NMR (300 MHz, DMSO-d6) □7.67 (1H, d, J=5.09 Hz) 8.41 (1H, s) 8.65 (1H, s) 8.71 (1H, bs); ESIMS (MH+): 309.95.