Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4](=[O:9])[C:3]=1[OH:10].[CH3:11][O-:12].[Na+].[Na]>CO>[OH:10][C:3]1[C:4](=[O:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[O:12][CH3:11]
Reactant: C[O-]
Reactant: O=c1ccccc(Br)c1O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccccc(=O)c1O
Temperature: 80 °C

Procedure:
A solution of 3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1-one [27.5 g, described by T. Toda et al., Nippon Hagaku Zasshi, 88, 1234-5 (1967), (CA 68 101342)] and sodium methoxide (prepared from 12.6 g of sodium in methanol followed by evaporation of the methanol) in dimethyl sulfoxide (300 ml) is heated at 80° C for 1 hour. The solution is cooled poured on ice, acidified with 2N sulfuric acid and extracted with ethyl acetate. The organic extract is washed with brine, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate-hexane to give 2-hydroxy-3-methoxy-2,4,6-cycloheptatrien-1-one. Evaporation of the mother liquors gives 2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [OH:1][C@H:2]([CH3:20])[C@@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:4]([OH:6])=O.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH2:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH:28][C:4](=[O:6])[C@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C@H:2]([OH:1])[CH3:20]
Reactant: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O
Reactant: NOC1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.6 %

Procedure:
A mixture of (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoic acid (3.43 g, 0.012 mol), 2-tetrahydropyranyloxyamine (1.64 g, 0.014 mol), BOP (5.75 g, 0.013 mol), HOBt (1.76 g, 0.13 mol) and NMM (2.63 g, 0.026 mol) in DMF (30 mL) is stirred at 25° C. for 18 h. The mixture is concentrated in vacuo and the residue is taken up in EtOAc. The mixture is washed with ice-cold 0.1 M HCl, saturated aqueous sodium bicarbonate, and saturated aquesous sodium chloride. The organic phase is dried over sodium sulfate and concentrated in vacuo to give 6.02 g of a white solid. Chromatography on silica gel using EtOAc as eluent gives 4.05 g (90%) of (2R,3R)-3-hydroxy-2-(4-phenylcyclohe,(ylmethyl)butanoic acid 2-tetrahydropyranyloxyamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:10]([OH:12])=[O:11]
Reactant: ClCCCI
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCl)c1ccc(Cl)cc1Cl
Yield: 57.8 %

Procedure:
Step AD (1): 2-(2,4-Dichlorophenyl)acetic acid (10.25 g, 50.0 mmol) was deprotonated with NaHMDS (1.0 M in THF, 100 mL, 100 mmol) and reacted with 1-chloro-3-iodopropane (5.27 mL, 50.0 mmol) using a procedure analogous to Step AC (1) to afford, after purification by silica gel column chromatography, 5-chloro-2-(2,4-dichlorophenyl)pentanoic acid (8.15 g, 28.9 mmol, 58% yield) as a colorless oil. MS (M+H)+ 280.9. 1H NMR (500 MHz, chloroform-d) δ ppm 7.47 (d, J=2.14 Hz, 1 H) 7.34-7.40 (m, 1 H) 7.28-7.33 (m, 1 H) 4.22 (t, J=7.48 Hz, 1 H) 3.57 (t, J=6.41 Hz, 2 H) 2.27 (dddd, J=13.08, 10.64, 7.55, 5.34 Hz, 1 H) 1.95-2.05 (m, 1 H) 1.82-1.92 (m, 1 H) 1.68-1.81 (m, 1 H).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[OH:22])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[CH3:23][SH:24]>O1CCCC1>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:2]1([S:24][CH3:23])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: CS
Reactant: COc1ccc(O)c(C2(Cl)Sc3ccccc3N(C)C2=O)c1
Solvent: C1CCOC1
Product: COc1ccc(O)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
2-Chloro-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (12.3 g, compound No. 3) is added to a mixture of 30% aqueous methyl mercaptan solution (26 ml) and tetrahydrofuran (50 ml). The mixture is stirred for 1.5 hours at room temperature and concentrated in vacuo. The separated crystals are collected by filtration to give 10.0 g (78.3%) of the titled compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[CH2:36]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([CH:43]1[CH2:48][CH2:47][N:46]([C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: NCCSC(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and 4-benzylpiperidine (327 μl) were subjected to similar reactions to those described in References 2 and 4 to give 2-(4-benzylpiperidino)carbonylthioethylamine (crude formate: 210 mg). The product was dissolved in anhydrous methanol (3.5 ml). Triethylamine (432 μl) and mitocyin A (151 mg: 0.7 molar equivalent) were added to the solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 41 (300 mg) in the form of grayish blue powders with a yield of 81%.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:26]([O:29][CH2:30][C:31](=[O:32])[CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)(=[O:28])[CH3:27]
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Temperature: 0 °C
Yield: 32.1 %

Procedure:
To a solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 53 mg, 0.14 mmol) in CH2Cl2 at 0° C. was added 2-acetoxyacetyl chloride (19 mg, 0.14 mmol) and diisopropylethylamine (0.072 mL, 0.42 mmol) and the resulting mixture stirred at 0° C. Upon completion of the reaction completion, the solvent was evaporated and the resulting residue triturated with methanol-diethyl ether to yield 2-oxo-2-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethyl acetate (20 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]([C@@H:17]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:14][C:15]=3[Cl:16])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:33]([C:35]1[CH:43]=[CH:42][C:38](C(O)=O)=[CH:37][C:36]=1[F:44])#[N:34]>>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]([C@@H:17]([NH:25][C:26](=[O:32])[C:38]4[CH:42]=[CH:43][C:35]([C:33]#[N:34])=[C:36]([F:44])[CH:37]=4)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:14][C:15]=3[Cl:16])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc3c(N)n[nH]c3c2)c(Cl)[nH]1
Reactant: N#Cc1ccc(C(=O)O)cc1F
Product: N#Cc1ccc(C(=O)N[C@@H](Cc2ccccc2)c2nc(-c3ccc4c(N)n[nH]c4c3)c(Cl)[nH]2)cc1F

Procedure:
The product from Example 122 Part B was coupled with 4-cyano-3-fluorobenzoic acid using the methods described in Part F of Example 120. MS: 500.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.[O-:27]P([O-])([O-])=O.[K+].[K+].[K+]>O.[Pd]>[OH:27][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(Br)cnc23)C1
Agent: [Pd]
Agent: [K+]
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(O)cnc23)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 186 (24 mmol, 1 eq, 10 g) in 100 ml of water are added successively palladium on activated carbon (10%, 1.2 mmol, 0.05 eq, 1.2 g) and K3PO4 (48 mmol, 2 eq, 10.25 g). The mixture is degassed and stirred vigorously at 130° C. for 8 hours. After cooling to room temperature, the reaction mixture is filtered on celite and a 5 N hydrochloric acid solution (10 ml) is added (until pH 7). The water is removed under reduce pressure and the crude is triturated with hot THF. After filtration and evaporation of THF, 1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one x149 is obtained (1.9 g).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:7]=1)=[O:4].[C:21](OC(=O)CC)(=O)CC>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH:9]([CH3:11])[CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:21])=[N:7]2)=[CH:13][CH:14]=1
Reactant: CC1CC(NC(=O)C(F)(F)F)=NN1c1ccc(F)cc1
Reactant: CCC(=O)OC(=O)CC
Solvent: O
Product: CCC(=O)NC1=NN(c2ccc(F)cc2)C(C)C1
Reaction time: 2 h

Procedure:
A mixture of 3.0 g. of 3-amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline (prepared in Example 44) and 5.0 ml. of propionic anhydride is allowed to remain at room temperature for 2 hours. The reaction mixture is poured into water and the water is decanted. This step is repeated. The precipitate is treated with saturated sodium bicarbonate solution then is filtered. The solid is dissolved in dichloromethane. The solution is columnized and the desired product is recrystallized as described in Example 26 (A) to give 2.77 g. as colorless plates, m.p. 125°-126.5° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C@@H:27]12[N:34]([CH3:35])[C@@H:31]([CH2:32][CH2:33]1)[CH2:30][C:29](=[O:36])[CH2:28]2>O1CCCC1>[OH:36][C:29]1([C:19]2[N:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])[C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:28][CH:27]2[N:34]([CH3:35])[CH:31]([CH2:32][CH2:33]2)[CH2:30]1
Reactant: CN1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C2CCC1CC(O)(c1cc3ccccc3n1S(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1 equivalent of lithium diisopropylamide (15.5 mMol in tetrahydrofuran) is added via cannula to a solution of 1 equivalent of 1-phenylsulfonyl-1H-indole in tetrahydrofuran at -78° C. The reaction mixture is stirred at this temperature for 1.5 hours, warmed to room temperature for 1 hour and then cooled again to -78° C. To this solution is then added a solution of 1.02 equivalents of 3-tropanone in tetrahydrofuran and the resulting mixture is allowed to warm to room temperature over 18 hours. The reaction mixture is then partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The phases are separated and the organic phase washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography. Fractions shown to contain product are combined and concentrated under reduced pressure to provide 3-hydroxy-3-(1-phenylsulfonylindol-2-yl)-8-methyl-8-azabicyclo-[3.2.1]octane.
Reaction SMILES: [NH2:1]CC(O)=O.[CH3:6][O:7][C:8](=[O:19])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][F:18])[CH:12]=1.N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[F:18][CH2:17][C:13]1[CH:12]=[C:11]([N:10]([CH2:9][C:8]([O:7][CH3:6])=[O:19])[NH2:1])[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)O
Reactant: COC(=O)CNc1cccc(CF)c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1cccc(CF)c1
Reaction time: 1 h

Procedure:
The glycine (Intermediate 54, 1 g, 5.1 mmol) was dissolved in acetic acid (10 ml) and water (1 ml) and cooled to ~5° C. Sodium nitrite (0.37 g, 5.4 mmol) in water (1.3 ml) was added to the glycine solution dropwise, maintaining the temperature at or below 5° C. The reaction was stirred at this temperature for 1 h. Zinc (1.33 g, 20.3 mmol) was then added slowly to the reaction keeping the temperature below 4° C., and the reaction was stirred for 1 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×100 ml) followed by saturated aqueous sodium bicarbonate (1×100 ml) then water (100 ml), dried (Na2SO4) and concentrated in vacuo to give an orange oil (1.06 g). The crude material was purified by chromatography on silica (Merck 9385, 28 g) eluted with ether-hexane 1:4 to give the title compound (Intermediate 55, 453 mg, 40%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[S:6][CH:7]=1.[C:13]1([CH:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([O:20][CH:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:22][CH2:23]2)[N:4]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: CCC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 0 °C
Yield: 26.9 %

Procedure:
A stirred mixture of 4-chloromethyl-2-propionylaminothiazole (0.64 g), 4-(diphenylmethoxy)piperidine (0.8 g) and sodium bicarbonate (0.3 g) in N,N-dimethylformamide (8 ml) was heated at 80° to 90° C. for 2 hours. The reaction mixture was poured into ice water. The resulting precipitate was collected, washed with water and dried in vacuo. The precipitate was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give white crystals. The crystals were recrystallized from a mixture of toluene and diisopropyl ether and dried under reduced pressure to give 2-propionylamino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.35 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=4)[CH2:17][CH2:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CCCCCC.CN(C)C=O>[C:31]([O:30][C:29](=[O:35])[NH:28][CH2:27][CH2:26][O:24][C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][N:15]=[C:14]2[C:10]2([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:19][CH:20]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2

Procedure:
Sodium hydride (0.626 g, 15.64 mmol, 60% suspension in mineral oil) was washed under dry conditions under nitrogen atmosphere with n-hexane. Dimethylformamide (20 mL) was added followed by 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (2.1 g, 7.11 mmol) under stirring. After the exothermic reaction had ceased stirring was continued at room temperature for 1 h before tert-butyl (2-bromoethyl)carbamate (4.78 g, 21.33 mmol) was added dropwise as a solution in dimethylformamide (10 mL). The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. Ice water was added (60 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane:methanol=100:1). Yield: 2.5 g (5.7 mmol, 36%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCCCCC.CCOC(C)=O>[N:17]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCCCC1

Procedure:
Prepared from 3-nitro-5-trifluormethyl-benzoic acid and piperidine (TPTU, CH2Cl2/CH3CN, Et3N): MS: [M+1]+=303; TLC Rf=0.27 (hexane/AcOEt 7:3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:16])=[C:5]([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[S:3][C:4]([CH3:16])=[C:5]([C:12]([F:15])([F:14])[F:13])[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(Br)sc(C)c1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)sc(C)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-bromo-5-methyl-4-(trifluoromethyl)thiophene-3-carboxylate (250 mg, 0.79 mmol, 1.00 equiv), (4-chlorophenyl)boronic acid (185 mg, 1.18 mmol, 1.50 equiv), K3PO4 (620 mg, 2.92 mmol, 3.71 equiv), Pd(PPh3)4 (73 mg, 0.06 mmol, 0.08 equiv), dioxane (20 mL). The resulting solution was stirred overnight at 90° C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). The collected fractions were combined and concentrated under vacuum. This resulted in 200 mg (69%) of ethyl 2-(4-chlorophenyl)-5-methyl-4-(trifluoromethyl)thiophene-3-carboxylate as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:37]1[CH2:42][CH2:41][C:40]([C:48]([O:50][CH2:51][CH3:52])=[O:49])([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH:38]=1)(=O)=O>O1CCOCC1.O.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>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:37]3[CH2:42][CH2:41][C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:39][CH:38]=3)=[CH:14][CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(=O)OCC)CC=C(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
A flask was charged with 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (3.9 g, 10.73 mmol) and potassium carbonate (6.77 g, 48.3 mmol) in dioxane (60 ml) and Water (25 ml), and stirred at room temperature for 10 minutes under nitrogen. Then Pd(PPh3)4 (1.240 g, 1.073 mmol) and diethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1,1-dicarboxylate (4.22 g, 11.27 mmol) were added to the reaction mixture. The flask was sealed, flushed with nitrogen for three times and heated at 100° C. for 1 hour. The organic solvent was evaporated under vacuum and EtOAc (3×100 ml) was used to extract and the combined organic solvent was washed by saturated aqueous sodium bicarbonate solution, brine, and dried over Na2SO4, then concentrated. The residue was purified by flash chromatography (heptanes/acetone 1/2) to afford diethyl 4′-(5-nitropyridin-2-yl)-5,6-dihydro-[1,1′-biphenyl]-4,4(3H)-dicarboxylate (2.8 g, 61%) as yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.25 (t, J=7.20 Hz, 6H) 2.30 (dt, J=6.28, 3.24 Hz, 2H) 2.53 (dd, J=4.67, 1.77 Hz, 2H) 2.76 (dd, J=3.98, 2.08 Hz, 2H) 4.20 (q, J=7.20 Hz, 4H) 6.19 (s, 1H) 7.06-8.88 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6]([Si](C)(C)C)=[CH:5]2.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[CH:5]2
Reactant: Cc1cc2[nH]c([Si](C)(C)C)cc2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc2[nH]ccc2cc1F

Procedure:
A mixture of 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)aniline (plus ca. 10% of the undesired isomer) (10.3 g, 46.6 mmol) and copper(I) iodide (17.75 g, 93.2 mmol) in DMF (200 mL) was stirred at 100° C. for 4 hours. The mixture was then treated with ethyl ether (300 mL) and filtered. The filtrate was washed with water (200 mL) and extracted with ether. The organics were combined and washed with water, brine, and dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 5-35% ethyl acetate in hexane to give 1.9 g 5-fluoro-6-methyl-2-(trimethylsilyl)-1H-indole containing ˜10% of the undesired isomer, 5-fluoro-4-methyl-2-(trimethylsilyl)-1H-indole plus desilylated product, 5-fluoro-6-methyl-1H-indole (2.8 g) with ˜10% of the undesired isomer, 5-fluoro-4-methyl-1H-indole. Silylated material, 5-fluoro-6-methyl-2-(trimethylsilyl)-1H-indole containing ˜10% of the undesired isomer, was re-dissolved in methanol (20 mL) and stirred with potassium carbonate overnight, filtered and concentrated. All desilylated material was combined (3.7 g) and recrystallized from CH2Cl2 and hexane to provide 5-fluoro-6-methyl-1H-indole (1.9 g).