Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9]>O.C1COCC1>[CH:1]([N:4]([CH3:5])[S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9])(=[O:18])=[O:19])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CNC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer. The flask was charged with isopropylmethylamine (0.85 g, 11.6 mmol) followed by THF (50 mL). The mixture was cooled to 0° C. by placing the flask in an ice bath. Potassium hydroxide (23.2 mmol) was dissolved in water (20 mL) and added to the flask. An addition funnel was installed and charged with 2-nitrobenzenesulfonyl chloride (11.6 mmol) in THF (40 mL). The solution was added dropwise over 20 minutes, then the ice bath was removed. TLC (dichloromethane) indicated that the reaction was complete after addition of the 2-nitro-benzenesulfonyl chloride. The reaction was concentrated under diminished pressure, water (100 mL) was added, the mixture extracted with ethyl acetate (150 mL), dried (Na2SO4), and filtered. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a plug of silica gel (400 g in a 600 mL sintered glass funnel), and eluted with dichloromethane. Fractions were taken (100 mL) until the product eluted, as determined by TLC. Fractions containing the product were collected, and the solvent was removed in vacuo to yield N-(isopropyl)-N-(methyl)-2-nitrobenzenesulfonamide as a pale yellow oil. 3.08 g, (88%). 1H-NMR (CDCl3): δ 1.12-1.14 (d, 6H, J=6.7 Hz); 2.81 (s, 3H); 4.18-4.24 (m, 1H, J=6.7 Hz); 7.61-7.69 (m, 3H); 8.03-8.06 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30](C)C)#[N:2].N[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[C:37]#[N:38]>ClCCl.CO>[C:37]([C:36]1[CH:35]=[C:34]([NH:2][C:1]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][C:13]4[CH:14]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:28]=[CH:29][N:30]=2)[CH:41]=[CH:40][CH:39]=1)#[N:38]
Reactant: N#Cc1cccc(N)c1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4cccc(C#N)c4)c3cc2OC)c1
Yield: 71 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 3-aminobenzonitrile (31 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 71% yield (82 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:28])=[O:29])=[C:23]([F:31])[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14](=O)[CH2:15][C:16](O)([CH3:18])[CH3:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C:3]2[N:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH3:17])[S:31][C:2]=2[NH2:1])[CH:9]=1
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nc(C=C(C)C)sc1N
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A mixture of N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-hydroxy-3-methylbutanamide (240 mg, 0.762 mmol), Lawesson's reagent (308 mg, 0.76 mmol) and pyridine (2.5 mL) was heated to 100° C. for 18 hours. After cooling, DCM was added and the mixture washed with water, sodium hydrogen carbamate (sat. aq.) and brine, and concentrated to dryness. 4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-amine (51.0 mg) was isolated as a pale yellow solid. LCMS (ESI) m+H=295.3; NMR (400 MHz, DMSO-d6): δ 7.38 (d, 1H); 7.31 (dd, 1H); 7.09 (d, 1H); 6.24 (t, 1H); 5.50 (s, br, 2H); 3.83 (s, 3H); 2.02 (d, 3H); 1.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13]([NH2:15])=[O:14])=[C:4]([F:16])[CH:3]=1.[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:26](=O)[CH2:25][CH2:24][CH2:23]1)=[O:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:14])[NH:15][C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[C:4]([F:16])[CH:3]=1
Reactant: CC(C)Oc1cc(NC(N)=O)c(F)cc1Cl
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(OC(C)C)c(Cl)cc2F)CCC1

Procedure:
7.00 g of 4-chloro-2-fluoro-5-isopropoxyphenylurea and 4.44 g of ethyl cyclopentanone-2-carboxylate are heated at reflux temperature for 1.5 hours with 0.3 g of toluene-4-sulphonic acid monohydrate in 150 ml of benzene. The water which forms is removed with a water separator. The reaction mixture is subsequently evaporated to dryness and the residue is purified by chromatography on a silica gel column using methylene chloride as the eluent and recrystallized from diethyl ether/n-hexane. There is obtained ethyl 2-[3-(4-chloro-2-fluoro-5 -isopropoxyphenyl)-ureido]-1-cyclopentenecarboxylate, m.p. 166°-169° C.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([N:22]=[C:23]=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:24]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1cccc2ccccc12

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(1-naphthyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 1-naphthyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product precipitated from methylene chloride and filtered. The resulting solid was titruated with 1:3 triethyl amino:methylene chloride. The filterate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with 1 N HCl in water. The desired product precipitated from solution and was collected by filtration (0.11 g, 10%). EI-MS m/z 324 (M+H)+
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=1.O>C1COCC1.[S].[P]>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][C:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: CCOP(=O)(OCC)c1ccc(F)cc1
Agent: [K+]
Agent: [P]
Agent: [S]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 19 h
Yield: 81.7 %

Procedure:
25.8 ml (12.9 mmol) of potassium diphenylphosphide solution in THF (manufacturer: Aldrich) are added dropwise at -5° C. to a solution of 3.09 g (13.2 mmol) of diethyl 4-fluorophenylphosphonate, prepared as described in Phosphorus Sulfur 1980, 9(2), 197.202, in 20.0 ml of THF. After stirring for 19 hours at 23° C., the mixture is hydrolyzed by adding 20 ml of degassed water and stirring for 15 min. After extraction with ethyl acetate, and drying the organic phase over Na2SO4, the mixture is concentrated on a rotary evaporator. 4.20 g of diethyl 4-diphenylphosphinophenylphosphonate (82% of theory) are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:35]([N:19]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[C:40]([NH:42][S:2]([CH3:1])(=[O:4])=[O:3])[CH:39]=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Add methanesulfonyl chloride (13 μl, 0.170 mmol) dropwise to a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.082 g, 0.154 mmol) and pyridine (15 μl, 0.185 mmol) in dichloromethane (2 mL) at 0° C. under nitrogen. Stir the orange suspension for 0.5 h, then remove the cooling bath and warm the mixture to room temperature and stir overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N HCl, water and brine (10 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with ethyl acetate/hexanes (70:30), to provide the title compound as a white solid (0.055 g, 58%): ESI MS 610 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[CH3:11]C(C)([O-])C.[K+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:11])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-bromo-2-fluoro-benzaldehyde (Aldrich, 2.30 g, 11.3 mmol) and methyltriphenylphosphonium bromide(Aldrich, 4.93 g, 13.6 mmol) in ether (50 mL), potassium tert-butoxide(1.52 g, 13.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solid was filtered off and the filtrate was concentrated. The residue was treated with 30% ethyl acetate/hexanes (3 mL) and the solid was removed by filtration. The filtrate was filtered through a silica gel pad eluting with 30% ethyl acetate/hexanes to give a yellow oil. 1.54 g, 68%.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.[N:28]1([S:32]([NH:35][C:36](=[O:55])[C:37]2[CH:42]=[C:41](Cl)[C:40]([O:44][CH2:45][CH:46]3[CH2:53][CH2:52][C:49]4([CH2:51][CH2:50]4)[CH2:48][CH2:47]3)=[CH:39][C:38]=2[F:54])(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([S:32]([NH:35][C:36](=[O:55])[C:37]2[CH:42]=[C:41]([CH:10]3[CH2:1][CH2:2]3)[C:40]([O:44][CH2:45][CH:46]3[CH2:53][CH2:52][C:49]4([CH2:51][CH2:50]4)[CH2:48][CH2:47]3)=[CH:39][C:38]=2[F:54])(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro- N-(methylsulfonyl)benzamide with N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide, the title compound was obtained as a colorless solid (0.39 g, 66%): 1H NMR (300 MHz, CDCl3) δ 8.74-8.59 (m, 1H), 7.64-7.54 (m, 1H), 6.64-6.52 (m, 1H), 4.31-4.18 (m, 4H), 3.93-3.81 (m, 2H), 2.35-2.20 (m, 2H), 2.13-2.00 (m, 1H), 1.99-1.72 (m, 5H), 1.40-1.20 (m, 2H), 1.02-0.85 (m, 4H), 0.73-0.61 (m, 2H), 0.37-0.14 (m, 4H); MS (ES+1) m/z 437.2 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.[C:14]([C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](O)=O)[CH:19]=[CH:20][CH:21]=1)#[N:15].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:24]([CH2:23][CH2:22][C:18]4[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=4)[C:14]#[N:15])=[N:13][N:12]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NNC(=O)c1ccc2[nH]nnc2c1
Reactant: N#Cc1cccc(CCC(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(CCc2nnc(-c3ccc4[nH]nnc4c3)o2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
A mixture of 1H-benzotriazole-5-carbohydrazide (354 mg, 2.00 mmol), 3-(3-cyanophenyl)propionic acid (350 mg, 2.00 mmol) and phosphorus oxychloride (5 mL) was stirred at 100° C. for 4 hr. After cooling, the reaction mixture was poured into water and neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from methanol/water to give the title compound (104 mg, yield 16%) as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triethylamine (1.52 ml) and ethyl chlorooxoacetate (1.11 ml) were successively added to a solution of 4-chloroaniline (1.16 g) in methylene chloride (26 ml), and the mixture was stirred at room temperature for 14 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct liquid separation, the resultant organic layer was successively washed with a 10% aqueous solution of citric acid and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, hexane was added to the residue to deposit crystals, and the crystals were collected by filtration and dried to obtain the title compound (1.89 g).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17](=[NH:19])[NH2:18])=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:22](CC)CC)C.O.NN>C(O)C>[CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17](=[NH:18])[NH:19][NH2:22])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Agent: NN
Solvent: O
Solvent: CCO
Product: N=C(NN)c1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.400 g (5.358 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide were initially charged in 26 ml of ethanol, and the mixture was cooled to 0° C. 2.169 g (21.431 mmol) of triethylamine and 335 mg (5.358 mmol) of 80% strength hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and dried under high vacuum. This gave 1.070 g (purity 77%, 56% of theory) of the target compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.N1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:27]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)[C:28](=[O:30])[CH3:29])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CC(=O)Cc1ccncc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1

Procedure:
A mixture of 4-((quinolin-2-yl)methoxy)benzaldehyde (2.5 g, 9.5 mmol), 1-(pyridin-4-yl)propan-2-one (1.3 g, 9.5 mmol) and piperidine (162 mg, 1.9 mmol) in toluene (50 mL) was heated at reflux for 18 h, concentrated, and the residue chromatographed on silica eluting with a gradient of ethyl acetate in hexanes giving impure title substance (2.4 g) as a yellow solid which was chromatographed again on silica eluted with 1% and 2% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide giving a 3:1 mixture of the title substance contaminated with the pyridyl starting material. Yield 2.0 g, 55%. The title substance appeared to be a 10:1 mixture of two isomers by NMR. 1H NMR (CDCl3, 400 mHz, partial) δ 2.35 (s, 3H, major isomer), 2.23 (s, 3H, minor isomer). HPLC-MS 6.09 min, m/e 381 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31]([CH2:30][O:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:32])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide in THF (58.7 mL, 58.75 mmol) was added dropwise to a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.41 mmol) in DMF (100 mL) over a period of 10 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes. Ethyl bromoacetate (8.92 g, 53.41 mmol) was added dropwise over 10 minutes (exotherm. Temperature kept below 30° C. using a cold water bath) and the reaction was stirred at ambient temperature for 20 hours.
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]2[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1.C1(C=CC(O)=CC=1)O.Br[CH2:31][C:32](=[CH2:38])[C:33](OCC)=[O:34]>O1CCCC1.[Zn]>[CH2:31]=[C:32]1[C:33](=[O:34])[O:1][C:2]([CH2:3][O:4][C:5]2[CH:15]=[CH:14][C:8]3[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=3[CH:6]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:38]1
Reactant: O=C(COc1ccc2ccc(=O)oc2c1)c1ccccc1
Reactant: C=C(CBr)C(=O)OCC
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(COc2ccc3ccc(=O)oc3c2)(c2ccccc2)OC1=O
Temperature: 0 °C
Yield: 77.8 %

Procedure:
To a solution of 4a (0.84 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was refluxed under nitrogen atmosphere for 18 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound; Yield: 77.8%; mp: 105°-106° C.; IR(KBr) νmax : 1758, 1719, 1616; UV(CHCl3) λmax (log ε): 321 (4.22), 243 (3.62); 1H-NMR (CDCl3): δ3.24 (dt, 1H, 4'-H), 3.66(dt, 1H, 4'-H), 4.17, 4.24 (two d, 2H, OCH2), 5.71 (t, 1H, vinylic H), 6.24 (d, 1H, 3-H), 6.31 (t, 1H, vinylic H), 6.72 (d, 1H, 8-H), 6.78 (dd, 1H, 6-H), 7.35 (d, 1H, 5-H), 7.40-7.52 (m, 5H, aromatic H), 7.62 (d, 1H, 4-H). Anal Calcd for C21H16O5:C, 72.41; H, 4.63. Found: C, 72.30; H, 4.67.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:31][C:32]1[C:37]([F:38])=[C:36]([F:39])[CH:35]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([CH:46]3[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[C:33]=1C=O.C1CCCCC1.[CH2:63]([O:65][CH2:66][CH3:67])C>C(OCC)C>[F:31][C:32]1[C:33]([CH:67]=[CH:66][O:65][CH3:63])=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([CH:46]3[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[CH:35]=[C:36]([F:39])[C:37]=1[F:38]
Reactant: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3C=O)cc2)CC1
Reactant: CCOCC
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Product: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3C=COC)cc2)CC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
27 ml (48 mmol) of a 1.8 M solution of phenyllithium in cyclohexane/diethyl ether (7:3) are added dropwise at −65° C. to a solution/suspension of 45 mmol of methoxymethyltriphenylphosphonium chloride in 280 ml of dry diethyl ether. The mixture is stirred at the same temperature for 30 minutes, then kept at −10° C. for 30 minutes and subsequently re-cooled to −50° C. 16 mmol of 3,4,5-trifluoro-4′-(4-propylcyclohexyl)biphenyl -2-carbaldehyde are added at this temperature. The reaction mixture is allowed to thaw slowly, and stirring is continued at room temperature. Ice-water is added to the reaction mixture, and the organic phase is separated off and washed with cold water. After drying using sodium sulfate, the mixture is evaporated under reduced pressure, and the residue is stirred with n-heptane and filtered. The filtrate is chromatographed on silica gel (n-heptane/ethyl acetate 98:2), giving 3,4,5-trifluoro-2-(2-methoxyvinyl)-4′-(4-propylcyclohexyl)biphenyl (mixture of Z and E isomers).