Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([C:21]1[C:20]2[N:25]=[CH:26][N:27]([CH3:28])[C:19]=2[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:12]([C:29]([F:32])([F:30])[F:31])[CH:13]=2)[N:22]=1)#[N:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCN)c(C(F)(F)F)c3)cc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCNS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (31 mg) was added to the solution of 6-[4-(3-Aminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg) in DCM (1 ml) containing DIPEA (44 uL). The mixture was stirred at rt for 1 hour, then solvent removed under vacuum and residue dissolved in NMP (1 ml) and purified by HPLC to give expected product, N-(3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl)methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3cccnc3)c2)n1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2nncc(-c3ccc(F)c(-c4cccnc4)c3)n2)cc1

Procedure:
5-[4-Fluoro-3-(pyridin-3-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine was coupled to 4-methoxyphenylboronic acid by the method of Example 2 to give 5-[4-fluoro-3-(pyridin-3-yl)phenyl]-3-(4-methoxyphenyl)-[1,2,4]triazine as an orange solid: δH (400 MHz, CDCl3) 7.18 (2H, dd, J 7.2, 7.2 Hz), 7.76 (1H, m), 8.27 (1H, m), 8.57 (2H, m), 8.71 (1H, m), 8.83 (1H, m), 8.98 (1H, m), 9.10 (1H, m), 9.48 (1H, m), 10.10 (1H, s); m/z (ES+) 359.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:18][CH:19]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(COC(=O)N2CCC(CNc3ncc(F)cn3)CC2)cc1

Procedure:
The solution of (4-methyl-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2a) (0.20 g, 0.76 mmol), 2-chloro-5-fluoro-pyrimidine (EXAMPLE 71, Step 1) (0.10 g, 0.76 mmol) and triethylamine (0.21 mL, 1.53 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (10 CH2Cl2: 1–10 IPA: 89–80 hexane) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-methyl-benzyl ester. M.S. (M+1): 359.33
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1CBr>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:23]2[CH:24]=[C:17]([F:16])[CH:18]=[CH:21][C:22]=2[F:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Product: N#Cc1ccc(N(c2cncnc2)c2cc(F)ccc2F)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2,5-difluorobenzyl bromide
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccc([N+](=O)[O-])cc1
Product: COc1ccc(C2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-nitrophenylhydrazine as described for compound 35. Crystallized from methanol. M.p. 179°-182° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][CH:9]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:26]=1[O:33][CH3:34])=[O:7]>CO.[C].[Pd]>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:26]=1[O:33][CH3:34])=[O:7]
Reactant: COc1cccc(CC2CN(C(=O)OCc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CC2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1OC
Yield: 101.3 %

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-(2,3-dimethoxybenzyl)piperazine (0.81 g) in methanol (20 ml) was hydrogenated over 10% palladium-carbon (50% wet, 0.30 g) at room temperature under atmospheric pressure for 90 minutes. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give colorless oil of 1-[3,5-bis (trifluoromethyl)benzoyl]-2-(2,3-dimethoxybenzyl)piperazine (0.64 g).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:26]4=[C:27]5[N:22]([CH:23]([CH3:28])[CH2:24][CH2:25]4)[CH:21]=[C:20]([C:29]([OH:31])=[O:30])[C:19](=[O:32])[C:18]5=[CH:17][C:16]=3[F:33])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:35]=[CH:34][C:7]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:26]4=[C:27]5[N:22]([CH:23]([CH3:28])[CH2:24][CH2:25]4)[CH:21]=[C:20]([C:29]([OH:31])=[O:30])[C:19](=[O:32])[C:18]5=[CH:17][C:16]=3[F:33])[CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: CC1CCc2c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CCc2c(N3CCN(Cc4ccc(N)cc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 37.1 %

Procedure:
The Compound [II] (0.71 g), mixed with 10% palladium on charcoal (0.2 g) and acetic acid (25 ml), was hydrogenated with the calculated volume of hydrogen under normal pressure at room temperature. After the calculated volume of hydrogen was taken up, palladium on charcoal was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in a small amount of water, and neutralized with 10% sodium hydroxide solution. The resulting precipitate was collected, dried, and purified by column chromatography on silicagel using a mixture of chloroform and ethanol (10:1) as the developing solvent. The purified product was recrystallized from ethanol to give 0.25 g (yield: 37.1%) of 8-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [I]) as pale yellow needles, m.p. 215.5°-217.5° C. (decompd.).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]Br>>[Br:10][C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:9])[CH3:8])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CC(C)c1ccccc1
Product: CC(C)c1ccc(Br)cc1

Procedure:
This example describes the reaction of cumene with liquid bromine to give 4-bromocumene. 10 g of cumene, 5 g of catalyst composite material, zeolite K-L and 2.14 ml bromine were mixed in a batch reactor. The reaction mixture was stirred and heated up to 70° C. After completion of the reaction, the mixture was let to cool to room temperature and analysed by gas-chromatography. The conversion of cumene and the selectivity for 4-bromocumene were found to be 10.7 wt. % and 78.8%, respectiveley.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:7][CH2:6]1.[CH2:21]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]([CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:7][CH2:6]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CNc2ccccn2)cc1
Reactant: Cc1ccccc1C(=O)NC1CCN(CCCCl)CC1
Product: Cc1ccccc1C(=O)NC1CCN(CCCN(Cc2ccccc2)c2ccccn2)CC1

Procedure:
The title compound is prepared in a similar manner to Example 11 from 1-(3-chloropropyl)-4-(2-methylbenzamido)piperidine and 2-(benzylamino)pyridine.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[O:16]=[C:12]1[C:11](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 6-phenyl-1,3-dihydro-indol-2-one (41.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9]N1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:9][CH2:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1ccncc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: ClCSc1ccncc1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A solution of 4-methylthiopyridine (2.28 g, 18.2 mmol), N-chlorosuccinimide (3.0 g, 23 mmol) and pyridine (2.9 mL, 3.0 mmol) in benzene (40 mL) was heated at 50°-60° C. for 3 h. The mixture was allowed to cool to room temperature. The solvent was decanted and the residue was rinsed with benzene (2×10 mL). The organic phases were combined and evaporated. The residue was passed through a pad of silica gel (40 g) to give the title material (1.35 g) contaminated with the starting material. The impure product was repurified on silica gel preparative plates (eluted with CH2Cl2 /CH3CN: 1/1) to give the pure title material (926 mg, 32%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:19](=O)[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[NH:12]1.[Cl:21]C(OC(Cl)(Cl)Cl)=O>C1(C)C=CC=CC=1.ClCCCl>[Cl:21][C:19]1[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[F:1])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=c1c2c([nH]n1-c1cc([N+](=O)[O-])ccc1F)CCCC2
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one (66.87 g) in toluene (125 ml) and 1,2-dichloroethane (175 ml), there was added trichloromethyl chloroformate (71.57 g), and the resultant mixture was allowed to react in an autoclave at a temperature of 120° to 130° C. under a pressure of 25 kg/cm2 for 3 hours. After cooling, the solvent was removed by distillation. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1:6) as an eluent to give 3-chloro-2-(2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole. m.p., 109.1° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:10]([CH3:11])[O:9][C@@H:6]([O:7]C)[CH2:5][C@H:4]1[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15].O>C(O)(=O)C>[CH3:1][O:2][C@H:3]1[C@H:10]([CH3:11])[O:9][C@@H:6]([OH:7])[CH2:5][C@H:4]1[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15]
Reactant: CO[C@H]1C[C@@H](NC(=O)C(F)(F)F)[C@@H](OC)[C@H](C)O1
Solvent: CC(=O)O
Solvent: O
Product: CO[C@H]1[C@H](C)O[C@@H](O)C[C@H]1NC(=O)C(F)(F)F
Temperature: 100 °C
Yield: 98.1 %

Procedure:
To a solution of 1.76 g; 6.5 mmol of compound VI in 35 ml of acetic acid there were added 140 ml of water. The solution was then heated at 100° C. for 1 hour. The solvent was then evaporated off and the residue was recrystallized from carbon tetrachloride to give 1.64 g (yield 98%) of 4-O-methyl-2,3,6-trideoxy-3-trifluoroacetamido-α-L-ribohexopyranose (VII); m.p. 113°-115° C.; [α]D23° =-61.5° (c=0.5 in CHCl3); mass spectrum; m/e 257 (M+). The p.m.r. spectrum showed absoption at: 1.27 (d, CH3 --C--5), 2.96 (dd, J=9.5 and 4.0 Hz, C--4--H), 3.44 (s, CH3O), 4.00 (dq, J=6.5 and 9.5 Hz, C--5--H), 4,69 (m, C--3--H) and 5.32 (broad s, WH =6.0 Hz, C--1--H).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([C:5]1=[CH:6][N:7]([C:25]([CH3:26])([CH3:28])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 104A (143 mg, 0.350 mmol), anhydrous dichloromethane (5 mL), and trifluoroacetic acid (200 mg, 1.75 mmol). The pale yellow solution was stirred at room temperature for 4 hours. The pH of the reaction mixture was adjusted to ˜9 by addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated by rotary evaporator to afford the title compound. The crude product was used without purification for the next step. MS (ESI+) m/z 310 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A resealable tube was charged with 1-benzyloxy-4-iodobenzene 100 (5.00 g, 16.1 mmol), acetonitrile (80 mL), and triethylamine (10 mL). Dichlorobis(triphenylphosphine)palladium (II) (0.733 g, 1.05 mmol), copper (I) iodide (0.200 g, 1.05 mmol), and (trimethylsilyl)acetylene (2.06 g, 2.96 mL, 20.9 mmol) were added. The system was purged with argon, the tube was sealed, and the mixture stirred at 60° C. for 17 h. The reaction mixture was filtered twice through a pad of Celite along with ethyl acetate. The filtrate was concentrated to afford (4-benzyloxy-phenylethynyl)trimethylsilane (101) as an orange brown solid which was used without purification.
Reaction SMILES: I.[C:2]1([N:8]2[C:12]([NH:13][C:14](=[NH:17])SC)=[CH:11][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](N)[CH2:25][NH2:26]>>[C:2]1([N:8]2[C:12]([NH:13][C:14]3[NH:26][CH2:25][CH2:24][N:17]=3)=[CH:11][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CSC(=N)Nc1cc(-c2ccccc2)nn1-c1ccccc1
Agent: I
Product: c1ccc(-c2cc(NC3=NCCN3)n(-c3ccccc3)n2)cc1

Procedure:
N(1,3-Diphenyl-5-pyrazolyl)-S-methyl isothiourea hydroiodide (43.6 g.) and ethylene diamine (12.0 g.) were reacted as described in Example VI to give 26.0 g. of the product, mp 228°-230° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11](O)[CH3:12])[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].Cl>CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([CH:11]=[CH2:12])[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CCCCCC
Product: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 94.8 %

Procedure:
A solution of 50 grams of 2,6-di tert.butyl-4-(α-hydroxyethyl)phenol in 100 milliliters of hexane was stirred vigorously with 100 milliliters of concentrated HCl for 1 hour. The hexane layer was separated and the hexane removed by distillation under aspirator vacuum. The residual 2,6-di tert.butyl-4-(α-chloroethyl)phenol was dissolved in 100 milliliters of pyridine and the solution was heated under reflux for 30 minutes. Pyridine was removed by distillation under aspirator vacuum and the residue, after washing with water, was crystallized from acetone at -78° C. There was obtained 44 grams of product with a melting point of 36°-39° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][C:13]([OH:15])=O.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:12]/[C:13]([N:22]2[CH2:23][CH2:24][NH:19][C:20](=[O:25])[CH2:21]2)=[O:15])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: O=C1CNCCN1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Reaction time: 16 h
Yield: 71.6 %

Procedure:
A solution of oxalyl chloride (4.19 g, 33.0 mmol) in dichloromethane (12.5 ml) was added dropwise at room temperature to a solution of 3-chlorocinnamic acid (5.48 g, 30.0 mmol) and N,N-dimethylformamide (2 drops) in dichloromethane (240 ml). After 2 h the solution was evaporated and the residue redissolved in dichloromethane (160 ml), then a solution of piperazin-2-one (2.70 g, 27 mmol) and triethylamine (6.07 g, 60.0 mmol) in dichloromethane (80 ml) was added dropwise at 0° C. The reaction mixture was allowed to reach room temperature over 16 h, then poured onto 10% aq. potassium hydrogensulfate solution. The organic layer was washed with sat. aq. sodium hydrogencarbonate solution and 10% aq. sodium chloride solution, dried, and evaporated to produce the title compound (5.12 g, 72%). Yellow solid, MS (EI)=264.1 (M)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:18]=2[CH:19]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:18]=2[CH:19]=1)=[O:11]
Reactant: COC(=O)c1ccc2oc(CCCO)cc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(CCC=O)cc2c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Oxalyl chloride (2 M solution in CH2Cl2, 40 mL, 80 mmol) was placed under Ar into a reaction flask, equipped with addition funnel, inlet thermometer and drying tube charged with Drierite, and cooled to −70° C. A mixture of DMSO (12.2 mL, 171.2 mmol) and dry CH2Cl2 (30 mL) was added dropwise. After 30 min a solution of 95 (14.3 g, 61 mmol) in CH2Cl2 was slowly added and the mixture was stirred at −70° C. for 60 min. After that time triethylamine (45.2 mL, 405 mmol) was added dropwise at −60° C. The mixture was allowed to warm to room temperature, water (100 mL) was added carefully and the stirring continued for 10 min. Organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×75 mL). Combined organic were washed with 2 M HCl (30 mL), dried over Na2SO4 and concentrated. Column chromatography (SiO2, EtOAc/hexanes, 5/1) followed by recrystalliztion (EtOAc/hexanes, 1/3) afforded 97 as light yellow crystals (12.93 g, 91%): mp. 48-49° C. 1H NMR (DMSO-d6) δ9.70 (s, 1H), 8.20 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 6.75 (s, 1H), 3.87 (s, 3H), 3.07 (m, 2H), 2.96 (m, 2H). Anal. (C13H12O4.0.1H2O) C, H.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33][C:34](=[O:46])[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39](Br)[CH:38]=1)[CH3:36])C.C(=O)([O-])[O-].[Na+].[Na+].O.[OH-].[Li+]>C1(C)C=CC=CC=1.CO.O.C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:41]3[CH:42]=[C:37]([CH:35]([C:34]([OH:46])=[O:33])[CH3:36])[CH:38]=[CH:39][C:40]=3[O:43][CH3:44])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)c1ccc(OC)c(Br)c1
Reactant: CC1(C)OB(c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)C(=O)O)cc1-c1ccc(F)c2c1CN(C(=O)OCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a mixture under N2 of 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (82 mg, 0.20 mmol, 1.00 eq.), (±)-2-(3-bromo-4-methoxy-phenyl)-propionic acid ethyl ester (63 mg, 0.20 mmol, 1.00 eq.) and sodium carbonate (85 mg, 0.80 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (4 mL), tetrakis(triphenylphosphine) palladium (0) (12 mg, 0.01 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×5 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated in vacuo. To a solution of the previous residue in DMF (0.9 mL), 1M aq. NaOH soln. (1.3 mL) was added. The mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was redissolved in THF (2 mL) and water (2 mL). Lithiumhydroxide monohydrate (23 mg, 0.54 mmol, 2.71 eq.) was added and the mixture was stirred at 50° C. for 18 hours. Formic acid was added (0.2 mL). The solution was diluted with DCM. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. layers were dried over MgSO4, filtered and concentrated in vacuo.