Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Cl:20][CH2:21][C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[O:23]>CCOC(C)=O>[Cl-:20].[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][O:11][C:9]([C:4]12[CH2:5][CH2:6][N+:1]([CH2:21][C:22](=[O:23])[C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2)=[O:10]
Reactant: O=C(OCc1cccc(F)c1)C12CCN(CC1)CC2
Reactant: O=C(CCl)c1cccs1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(C(=O)OCc3cccc(F)c3)(CC1)CC2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a solution of 3-fluorobenzyl quinuclidine-4-carboxylate (41 mg, 0.16 mmol) dissolved in EtOAc (2 ml), 2-chloro-1-(thiophen-2-yl)ethanone (20.0 mg, 0.12 mmol) was added. The reaction was stirred at room temperature for three days, and then the precipitate was collected by suction filtration to obtain 4-((3-fluorobenzyloxy)carbonyl)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (30 mg, 45.4% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@@H:14]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26]([NH2:28])=[O:27])[C:15]1([CH3:33])[CH3:32]>ClCCl>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26](=[O:27])[NH2:28])[C:15]1([CH3:33])[CH3:32])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)[C@H](O)CC[C@@H]1Nc1c(C(N)=O)cnn2cccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@@H](OS(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cccc12
Reaction time: 15 h

Procedure:
Triethylamine (0.131 mL, 0.936 mmol) and methanesulfonyl chloride (0.029 mL, 0.375 mmol) were added to a solution of 4-((cis-3-hydroxy-2,2-dimethylcyclopentyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (90 mg, 0.312 mmol, from Intermediate 16) in dichloromethane (5 mL). After 15 h at room temperature, the mixture was diluted with dichloromethane (60 mL), washed with saturated sodium bicarbonate (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give crude cis-3-(3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylcyclopentyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:11]1[CH:10]=[C:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1)=[C:16]=[S:17]
Reactant: COc1ncccc1-c1ccnc(N)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1ncccc1-c1ccnc(N=C=S)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.62 g, 2.7 mmol) and the reaction mixture was stirred at 40° C. for 4 hours. The reaction was cooled to room temperature and chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield 2′-isothiocyanato-2-methoxy-3,4′-bipyridine (0.46 g, 1.9 mmol, 71.8% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.67 (d, J=2.44 Hz, 1 H), 8.26 (dd, J=4.88, 1.53 Hz, 1 H), 8.15 (dd, J=8.24, 2.44 Hz, 1 H), 7.89 (dd, J=7.32, 1.53 Hz, 1 H), 7.48 (d, J=8.24 Hz, 1 H), 7.15 (dd, J=7.32, 4.88 Hz, 1 H), 3.91 (s, 3 H). MS (LC/MS) R.T.=2.87; [M+H]+=244.9.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([N:6](C)[C:7]2[N:12]=[C:11]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:32](Cl)Cl>>[C:23]1([NH:29][C:30]([N:1]2[CH2:2][CH2:32][CH:4]([CH2:3][NH:6][C:7]3[N:12]=[C:11]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[N:15]=[CH:14]4)[CH:10]=[CH:9][N:8]=3)[CH2:5]2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCCl
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCNC1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N1CCC(CNc2nccc(-n3cnc4ccccc43)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 21 mg of 2-[(pyrrolidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine in 1 mL of CH2Cl2 was added 11 mg of phenyl isocyanate. The mixture was stirred at room temperature for 4 h, then concentrated. The residue was purified by flash chromatography, eluting with a gradient system of 1:1 hexanes-acetone to 1:2 hexanes-acetone, to yield 24 mg of the title compound as an off-white foam. 1H NMR (500 MH, CDCl3): δ 8.63 (s, 1H), 8.41 (d, J=4.8, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.87 (dd, J=1.2, 6.9 Hz, 1H), 7.36-7.46 (m, 3H), 7.25-7.32 (m, 2H), 7.03 (dt, J=1.2, 7.3 Hz, 1H), 6.85 (d, J=5.5 Hz, 1H), 6.18 (s, 1H), 5.70 (br s, 1H), 3.46-3.76 (m, 5H), 3.36 (dd, J=6.6, 9.8 Hz, 1H), 2.70-2.81 (m, 1H), 2.17-2.26 (m, 1H), 1.70-1.92 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH2:6])=[S:5].[CH2:7]([O:9][C:10](=[O:16])[CH:11](Cl)[C:12]([CH3:14])=O)[CH3:8].O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:7]([O:9][C:10]([C:11]1[S:5][C:4]([CH2:3][O:2][CH3:1])=[N:6][C:12]=1[CH3:14])=[O:16])[CH3:8]
Reactant: COCC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(COC)nc1C
Temperature: 25 °C

Procedure:
20 g of methoxythioacetamide are added, with vigorous stirring, to 31.3 g of 2-chloroacetoacetic acid ethyl ester in 400 ml of benzene at room temperature and then, using a water separator, heated under reflux for 41/2 hours. After cooling to room temperature, the benzenic reaction solution is diluted with 500 ml of ethyl acetate, washed twice using 80 ml of 10% sodium carbonate solution each time and twice using 50 ml of water each time, dried over sodium sulfate and filtered. The solvent mixture is evaporated off. The yellow oil that remains is crystallised by trituration with diisopropyl ether. The beige-coloured crystals melt at 36°-37° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.[CH:15](OCC)=[O:16]>>[OH2:16].[CH:15]([N:14]1[CH2:13][CH2:12][NH:11][C:10]1=[N:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:16]
Reactant: Clc1ccc(N=C2NCCN2)c(Cl)c1
Reactant: CCOC=O
Product: O
Product: O=CN1CCNC1=Nc1ccc(Cl)cc1Cl

Procedure:
A solution of 6.9 g 2-(2,4-dichlorophenylimino)imidazolidine and 150 ml ethyl formate was refluxed gently on the steam bath for twenty minutes. The mixture was cooled and filtered to give a white solid. Recrystallisation from propan-2-ol gave the novel compound 1-formyl-2-(2,4-dichlorophenylimino)imidazolidine hydrate, melting point 168°-170° C.
Reaction SMILES: C[CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][C:6]([CH3:10])=[C:7]([F:9])[F:8].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>O1CCCC1>[CH3:12][S:13]([O:11][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])=[C:7]([F:9])[F:8])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CCCC(C)O)=C(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CCCCOS(C)(=O)=O)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To 100 ml of tetrahydrofuran, 5.00 g (33 mmol) of methyl 6,6-difluoro-5-methyl-5-hexenol and 4.20 g (37 mmol) of methanesulfonyl chloride were dissolved, followed by drop-wisely adding 4.40 g (44 mmol) of triethylamine under ice-cooling. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 7.50 g (yield: 99%) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH3:20].Cl>O.CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][O:19][CH3:20])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: COCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(Br)cc1C=O
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To 600 ml of acetone solution containing 30.0 g (0.15 mol) of 5-bromo-2-hydroxybenzaldehyde was added 20.6 g (0.15 mol) of potassium carbonate, and then, 12.5 ml (0.17 mol) of chloromethylmethyl ether was added dropwise to the mixture over 30 minutes under ice-cooling. After stirring the mixture at the same temperature for 30 minutes, the mixture was further stirred at room temperature for 5 hours. After completion of the reaction, 600 ml of water was added to the reaction mixture. A pH of the mixture was adjusted to 7.6 with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 28.4 g of the title compound as a pale yellowish oil. (Yield: 77%)
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:24][CH:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:29]5[CH2:28][CH2:27][NH:26][CH:25]([CH3:24])[CH2:30]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1.[OH2:15].[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:29]5[CH2:28][CH2:27][NH:26][CH:25]([CH3:24])[CH2:30]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1.[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:29]5[CH2:28][CH2:27][NH:26][CH:25]([CH3:24])[CH2:30]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CCN1
Product: O

Procedure:
1-Cyclopropyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3 -carboxylic acid is prepared under the conditions of Example 1 but starting from 1 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 3 g of 2-methylpiperazine in 10 cm3 of pyridine. The pure product is obtained after a supplementary purification by recrystallization from 200 cm3 of dimethylformamide. 0.5 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid hemihydrate is obtained in the form of a yellow solid melting at 343° C.
Reaction SMILES: [CH:1](/[P:4](=[O:7])([OH:6])[OH:5])=[CH:2]/[CH3:3].[OH-:8].[Na+:9].[Br:10]NC(=O)C>O>[OH:8][CH:2]([CH3:3])[CH:1]([P:4](=[O:6])([O-:5])[O-:7])[Br:10].[Na+:9].[Na+:9]
Reactant: CC(=O)NBr
Reactant: C/C=C\P(=O)(O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(O)C(Br)P(=O)([O-])[O-]
Temperature: 25 °C

Procedure:
10.8 g. of cis-propenylphosphonic acid is dissolved in 50 ml. of water and the pH of the solution is adjusted to 4.2 by the addition of 2.5 N sodium hydroxide. 13.8 g. of N-bromoacetamide is added and the suspension is stirred at room temperature. The reaction is complete when the N-bromoacetamide is in solution and the mixture is negative to starch-iodide paper. The solution is lyophilized and the residue is triturated several times with chloroform to give sodium (2-hydroxy-1-bromopropyl)-phosphonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:33]([NH2:34])=[CH:32][N:31]=[CH:30][N:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)([Cl:44])=[S:43]>ClCCl>[ClH:44].[ClH:44].[ClH:44].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:42](=[S:43])[NH:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Nc1cncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: Fc1ccc(Cn2c(NC3CCN(CCn4c(=S)[nH]c5cncnc54)CC3)nc3ccccc32)cc1
Reaction time: 3 h
Yield: 15.4 %

Procedure:
To a stirred mixture of 4.6 parts of N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine, 2.25 parts of N,N-diethylethanamine and 195 parts of dichloromethane were added dropwise 1.75 parts of carbonothioic dichloride. Upon completion, stirring was continued for 3 hours at reflux temperature. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in ethanol and 2-propanol. The salt was filtered off and dried, yielding 1 part (15.4%) of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-7,9-dihydro-8H-purine-8-thione trihydrochloride.dihydrate; mp. 244.7° C. (compound 143).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.IC.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cccc(CC#N)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc(C(C)C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3-methoxyphenyl)acetonitrile (1.0 g, 6.79 mmol) and iodomethane (0.42 mL, 6.79 mmol) in THF (10 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1M in THF; 6.8 mL, 6.8 mmol). The reaction was warmed to room temperature and stirred for 1 hour. The mixture was partitioned between H2O and EtOAc and acidified with 1N aqueous HCl, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[CH:15]([OH:19])([CH2:17][CH3:18])[CH3:16].C(N(CC)CC)C>C(OCC)C>[CH:15]([O:19][C:3](=[O:4])[C:2](=[CH2:1])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)O
Reactant: C=C(CCCc1ccccc1)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(CCCc1ccccc1)C(=O)OC(C)CC
Temperature: 25 °C

Procedure:
27 g of 2-methylene-5-phenylvaleric acid chloride are added dropwise to a solution of 100 ml of sec.-butanol and 20 ml of triethylamine in 300 ml of diethyl ether at 25° to 30°. When the addition is complete, the obtained mixture is stirred at room temperature for another hour; 500 ml of ice water are then added and the mixture is shaken thoroughly. The organic phase is collected, dried over sodium sulfate and concentrated. 19.5 g of 2-methylene-5-phenylvaleric acid sec.-butyl ester (b.p. 115° to 126° under 0.01 mm Hg) are obtained.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].CCN(CC)CC>CC#N>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Yield: 77.6 %

Procedure:
1-(3,3-Diphenylpropyl)homopiperazine (2.0 g, 6.79 mmol) was dissolved in CH3CN (60 mL) and treated with methyl bromoacetate (1.56 g, 10.18 mmol) and Et3N (1.42 mL, 10.18 mmol). The mixture was refluxed for 18 h and subsequently concentrated in vacuo. The residue was subjected to flash silica gel column chromatography (eluent: CH2Cl2/MeOH, 96/4, v/v) to give Methyl [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (1.93 g) in 78% yield, TLC Rf=0.53 (10% CH3OH—CH2Cl2); RPLC tR=4.71 min (>85%), 220 nm (Method A); ESI/MS m/e 367.1 (M++H, C23H30N2O2).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][O:4]1)[CH3:2].CN(C=O)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.[Cl-].[NH4+]>O1CCCC1.O.[Fe]>[CH2:13]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=2)[CH2:5][O:4]1)[CH3:14]
Reactant: CCC1(CC)OCc2cccc(O)c21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC)OCc2cccc(Oc3ccc(N)cn3)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of 3,3-diethyl-1H-isobenzofuran-4-ol (Intermediate 179, 0.03 g, 0.15 mmol) in dry DMF (3 ml) potassium carbonate (0.08 g, 0.6 mmol) and then 2-Chloro-5-Nitropyridine (0.026 g, 0.17 mmoli) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in tetrahydrofuran (5 ml)/water (2.5 ml), iron (0.04 g, 0.75 mmol) and then ammonium chloride (0.4 g, 0.75 mmol) were added and the reaction mixture was stirred overnight at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (0.025 g) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:16](=[O:18])[CH3:17])=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1ccc(O)cc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)c1cc(C)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
3-Chloro-4-methylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (747 mg) and acetyl chloride (656 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was dried under the reduced pressure. Scandium trifluoromethanesulfonate (414 mg) was added to the compound thus obtained, and the mixture was suspended in toluene (5 ml) to prepare a suspension which was then heated under reflux overnight. The reaction solution was cooled to room temperature, and the reaction solution was then filtered. The solvent was removed from the filtrate by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give 1-(4-chloro-2-hydroxy-5-methyl-phenyl)-ethanone (193 mg, yield 15%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=O)=O.[NH2:31][CH2:32][CH:33]([C:35]1[CH:36]=[CH:37][C:38]([OH:44])=[C:39]([NH:41][CH:42]=[O:43])[CH:40]=1)[OH:34].O.C(OCC)(=O)C>CN(C)C=O>[CH:42]([NH:41][C:39]1[CH:40]=[C:35]([CH:33]([OH:34])[CH2:32][NH:31][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH:36]=[CH:37][C:38]=1[OH:44])=[O:43]
Reactant: CS(=O)(=O)OCCOc1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reactant: NCC(O)c1ccc(O)c(NC=O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=CNc1cc(C(O)CNCCOc2ccc(-c3ccc(C(=O)OCc4ccccc4)cc3)cc2)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
A mixture of benzyl 4′-(2-methanesulfonyloxyethoxy)-biphenyl-4-carboxylate (0.117 g) and N-[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl]formamide (0.054 g) in N,N-dimethylformamide (2 mL) was stirred at 80° C. overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=20/1-10/1) to afford benzyl 4′-{2-[2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]ethoxy}biphenyl-4-carboxylate (0.016 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)c2)c(-c2cccnc2F)c1F
Reaction time: 4 h
Yield: 76 %

Procedure:
Tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (551 mg) was dissolved in ethyl acetate (5 mL) and 2-propanol (3 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added at room temperature. The reaction mixture was stirred for 4 hr and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 327 mg, 76%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1cc(F)c(F)cc1C(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C=O)c1cc(F)c(F)cc1C(=O)COC(=O)c1ccccc1

Procedure:
A solution of benzoic acid (40.3 g) and triethylamine (61 ml) in dichloromethane (200 ml) was added dropwise over 20 minutes to the solution of 2'-(2-chloroacetyl)-4',5'-difluoro-N-methylformanilide at 0° under nitrogen and the resultant solution stirred overnight at ambient temperature. The mixture was washed with water (3×250 ml) and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel eluted with dichloromethane:methanol (50:1) to give the novel compound 2-[4,5-difluoro-2-(N-methylformamido)phenyl-2-oxoethyl benzoate in the form of an oil.