Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](Cl)=[O:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:29]=2)=[O:40])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OC(=O)c2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A solution of 5.0 g (16.9 mmol) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate in 50 ml of methylene chloride was treated with 240 mg (1.96 mmol) of 4-dimethylamino-pyridine and 4.2 ml (29 mmol) of triethylamine and cooled to 0° C. Subsequently, 4.65 g (24.4 mmol) of 2-naphthoyl chloride were added portionwise and the reaction mixture was stirred at room temperature for 18 hours. Thereupon, the reaction mixture was treated with ice-water and extracted with methylene chloride. The combined methylene chloride phases were dried over magnesium sulphate, filtered and the solvent was distilled off in a water-jet vacuum. The crude product was chromatographed on silica gel with methylene chloride as the eluent. The thus-obtained product fractions were recrystallized from ether and n-hexane. There were obtained 7.4 g (97% of theory) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(naphthalen-2-ylcarbonyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 450 (M+H)+.
Reaction SMILES: [C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:20])[C:2]1[C:3](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5].[H][H]>>[CH:3]1([C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH:2]1[C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:20]
Reactant: [H][H]
Reactant: CC(C)CCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCC(C)C
Product: CC(C)CCCCCCOC(=O)C1CCCCC1C(=O)OCCCCCCC(C)C

Procedure:
2 g of catalyst A (3% Ru/SiO2) were placed in a 300 ml pressure reactor. The reactor was subsequently charged with 100 g of diisononyl phthalate (DINP). The hydrogenation was carried out at 120° C. and a pressure of 200 bar using pure hydrogen. The hydrogenation was continued until no more hydrogen was taken up and the reactor was subsequently vented. The conversion of the diisononyl phthalate was 100%. Diisononyl cyclohexane-1,2-dicarboxylate was obtained with a selectivity of over 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16](O)=[O:17])=[O:12].[CH3:31][O:32][NH2:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH:15]([OH:19])[C:16]([NH:33][O:32][CH3:31])=[O:17])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: CON
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl

Procedure:
The reaction can be carried out in analogy to reaction step 1.3 by reacting 3-((R)-1-(2-chlorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3N[CH:10]([C:16]4[S:20][C:19]([CH:21]([CH3:23])[CH3:22])=[N:18][CH:17]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].[CH2:26]1COCC1>O=[Mn]=O>[OH:15][C:12]1[C:13]2[O:14][C:6]3[CH:5]=[CH:4][C:3]([O:24][CH3:25])=[C:2]([Br:1])[C:7]=3[C:8]=2[CH:26]=[C:10]([C:16]2[S:20][C:19]([CH:21]([CH3:23])[CH3:22])=[N:18][CH:17]=2)[CH:11]=1
Reactant: C1CCOC1
Reactant: COc1ccc2oc3c(c2c1Br)NC(c1cnc(C(C)C)s1)CC3=O
Agent: O=[Mn]=O
Product: COc1ccc2oc3c(O)cc(-c4cnc(C(C)C)s4)cc3c2c1Br
Temperature: 110 °C
Yield: 73 %

Procedure:
A mixture of 14B (1.1 g, 2.6 mmol), MnO2 (6 g) in THF (20 mL) was heated to 110° C. and reacted overnight, then filtered. The filtrate was concentrated to give 14C (0.8 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[S:29]([C:25]1[CH:24]=[C:23]([NH:22][C:19]([C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][CH3:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:20])[CH:28]=[CH:27][CH:26]=1)(=[O:30])(=[O:31])[NH2:32]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-ethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.26) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISN) 454.3 [(M−H)−]; mp 252-253° C.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>O1CCCC1>[CH2:26]([O:25][P:24]([CH2:23][O:4][C:1](=[S:3])[CH3:2])([O:28][CH2:29][CH3:30])=[O:31])[CH3:27]
Reactant: CCOP(=O)(CCl)OCC
Reactant: CC([O-])=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(COC(C)=S)OCC
Yield: 70.4 %

Procedure:
A solution of tetra-n-butylammonium thioacetate (12.8 g, 0.041 mol) and diethyl chloromethylphosphonate (5 g, 0.027 mol) is stirred in tetrahydrofuran (30 ml) overnight at room temperature. After evaporation of the solvent, the residue is purified by silica gel chromatography (2:1 heptane:acetone as eluant) to give diethoxyphosphinylmethylthioacetate (4.3 g). 1H-NMR: 4H, m, 4.20-4.11 ppm; 2H, d, 3.23; 3H, s, 2.40; 6H, m, 1.33.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2)[CH2:2][CH3:3].[F:15]C(F)(F)S([O-])(=O)=O.[Na+].Cl>ClCCl.O>[F:15][C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:14]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCCc1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc2c(F)c(O)ccc2c1
Reaction time: 8 h
Yield: 800.3 %

Procedure:
To a solution of 20 g of 6-propyl-2-naphthol and 1.8 g of sodium trifluoromethanesulfonate in 80 ml of dichloromethane was added 23.7 g of N,N′-difluoro-2,2′-dipyridinium bistetrafluoroborate. The reaction mixture was then stirred for 8 hours. The reaction solution was then poured in water. To the reaction mixture was then added diluted hydrochloric acid. The resulting organic phase was then separated. The resulting aqueous phase was extracted with toluene. The organic phase and the material thus extracted were together washed sequentially with water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an oily matter which was then purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 17.1 g of 1-fluoro-6-propyl-2-naphthol.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:9][CH:10]=1.CC(C)([O-])C.[K+].Cl.Cl[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35]>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])[CH:8]=[CH:9][CH:10]=1
Reactant: CN1CCCC1CCCl
Reactant: COCOc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(CCc2ccccc2OCCC2CCCN2C)c1
Yield: 55.2 %

Procedure:
Following a procedure similar to that described in Example 35(a), 2.37 g of 2-[2-(3-methoxymethoxyphenyl)ethyl]phenol (prepared as described in Preparation 21), 1.03 g of potassium t-butoxide and 1.69 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 50 ml of dimethylacetamide. The reaction mixture was then worked up as described in Example 35(a), and the crude product was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.87 g (yield 62%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2nccn2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2nccn2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 72 %

Procedure:
The title compound is prepared from imidazo[1,2-a]pyridine-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 72% of theory; LC (method 3): tR=1.82 min; Mass spectrum (ESI+): m/z=335 [M+H]+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([NH:10][C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][N:18]=4)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:22]4[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=4)[C:29]3=[O:30])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccnc1Nc1cccc2nsnc12
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1cccc2nsnc12
Yield: 7 %

Procedure:
The procedure of Example 1 was repeated using 2-(2,1,3-benzothiadiazol-4-ylamino)nicotinaldehyde (1.0 eq.; prepared in Synthetic Example 1c)), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.; prepared in Synthetic Example 2) and LDA (1.5 eq.) to obtain 1-(2,1,3-benzothiadiazol-4-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield 7%). The target product was purified through flash column chromatography and recrystallization, mp 191–192° C./DMF.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1([F:25])[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]1[NH2+:16][C@@H](C1C=CC=CC=1)C.[H][H]>[Pd].CO>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1([F:25])[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]1[NH3+:16]
Reactant: C[C@@H]([NH2+][C@@H]1[C@@H](O)CCCC1(F)F)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: [NH3+][C@@H]1[C@@H](O)CCCC1(F)F

Procedure:
(1R,6S)-2,2-difluoro-6-hydroxy-N-[(1R)-1-phenylethyl]cyclohexanaminium trifluoroacetate (74) in a solution of methanol (1.5 mL) was exposed to Pd/C (409 mg, 0.384 mmol) and hydrogen atmosphere (1 atm). The heterogeneous reaction mixture was filtered through a plug of celite and washed three times with 30 mL of methanol. The filtrate was concentrated under reduced pressure to yield (1R,6S)-2,2-difluoro-6-hydroxycyclohexanaminium trifluoroacetate (75) in quantitative yield. 1H NMR (500 MHz, CD3OD) δ 3.68 (s, 1H), 3.34 (t, J=16.6, 2H), 2.19 (s, 1H), 2.06 (s, 1H), 1.87 (d, J=56.3, 2H), 1.49 (s, 2H), 19F NMR (470 MHz, cd3od) δ −77.30 (s, 3F), −99.95 (d, J=242.9, 1F), −114.48-−116.71 (m, 1F).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)#[CH:23].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH2:20]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[CH:3]=[C:2]([C:23]#[C:22][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[CH3:12])[CH3:21]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 98.1 %

Procedure:
To a solution of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (1.80 g, 5.05 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (1.80 g, 8.59 mmol) in DMF (40 ml) was added triethylamine (2.82 ml, 20.2 mmol) and Copper(I) iodide (0.096 g, 0.505 mmol). The reaction mixture was degassed by bubbling nitrogen for 15 min. Then tetrakis(triphenylphosphine)palladium(0) (0.292 g, 0.253 mmol) was introduced and degassed for additional 10 min by bubbling nitrogen. The reaction mixture was heated at 80° C. for 6 h. The reaction was quenched with sat. NaHCO3, extracted with TBME (3×40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (0% to 40% AcOEt/Heptane) to give the titled compound (2.40 g, 98% yield). 1H-NMR (500 MHz) 3 ppm; 7.65 (s, 1H), 7.28 (s, 1H), 3.97 (brd, J=11.3 Hz, 2H), 3.90 (s, 3H), 3.76 (m, 2H), 3.34 (dt, J=2.0, 11.7 Hz, 2H), 3.24 (ddd, J=3.4, 8.8, 12.2 Hz, 2H), 3.08 (brs, 2H), 2.98 (brs, 1H), 2.80 (dddd, J=3.9, 3.9, 3.9, 3.9 Hz, 1H), 2.52 (s, 3H), 1.87 (m, 2H), 1.60-1.74 (m, 6H), 1.48 (s, 9H), 0.89 (t, J=6.8 Hz, 3H)); MS (ESI) [M+H]+485.4.
Reaction SMILES: C1N2CCN(CC2)C1.I[C:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]=1.C[Si](Cl)(C)C.[CH3:21][PH:22](=[O:27])[O:23][CH:24]([CH3:26])[CH3:25]>C1(C)C=CC=CC=1.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>[OH:15][CH:12]1[CH2:13][CH2:14][C:10]([CH2:21][PH:22](=[O:27])[O:23][CH:24]([CH3:26])[CH3:25])=[CH:11]1
Reactant: CC(C)O[PH](C)=O
Reactant: OC1C=C(I)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Product: CC(C)O[PH](=O)CC1=CC(O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of DABCO (11.8 g, 105 mmol) and 3-iodo-cyclopent-2-enol (5.5 g, 26.3 mmol) in anhydrous toluene (300 cm3) was added trimethylsilyl chloride (3 g, 27.6 mmol). The reaction mixture was stirred at room temperature for 15 min, after which time isopropyl methylphosphinate (4.8 g, 39.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (760 mg, 2.5 mol %) were added. The reaction mixture was heated at 70° C. for 24 h after which time a second portion of tetrakis(triphenylphosphine)palladium(0) (760 mg, 2.5 mol %) was added and heating continued for a further 24 h. The reaction mixture was filtered while still hot and aqueous ethanol (50 cm3) added to the filtrate, which was then concentrated in vacuo. The product was isolated by short column vacuum chromatography on silica gel (15% ethanol/ethyl acetate) to yield the title compound (3) as a slightly coloured oil (3.5 g, 65%): 1H NMR (300 MHz, CDCl3) δ 1.25 (3H, t, J=6.4, OCHCH3), 1.327 and 1.333 (3H, 2×d, J=6.2 and 6.2 Hz, OCHCH3), 1.49 and 1.51 (3H, 2×d, J=14.4 and 14.4 Hz, PCH3), 1.76-1.92 (1H, m, C(5)—H), 2.33-2.52 (2H, m, C(5)—H′ and C(4)—H), 2.60-2.78 (1H, m, C(4)—H′), 4.55 (1H, m, OCHCH3), 4.95 (1H, m, C(3)—H), 6.57 (1H, m, C(2)—H); 13C NMR (75.46 MHz, CDCl3) δ 13.8 and 14.0 (PCH3, d, JPC=101 and 101 Hz), 23.88 and 23.91 (POCCH3, d, 3JPOCC=4.9 and 4.6 Hz), 24.31 (POCCH3, overlapping d, 3JPOCC=3.4 Hz) 26.89 and 26.91 (C(4), d, 3JPC=12.8 and 12.5 Hz), 29.27 and 29.35 (C(5), d, 2JPC=8.8 and 8.6 Hz), 76.94 and 73.65 (POCHCH3, d, 2JPOC=6.0 and 6.3 Hz), 76.94 and 77.18 (C(3), d, 3JPC=5.0 and 7.5 Hz), 138.11 and 138.22 (C(1), d, JPC=126 and 126 Hz), 147.54 (C(2), d, J=10.6 Hz), −P NMR (121 MHz, CDCl3) δ 38.9, 39.0, (ESI) 207.1154 (MH+-C9H20O3 requires 207.1150).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]([CH3:16])=[CH:4][CH:3]=1.[F:17]C1C=CC(C(O)=O)=C(I)C=1C>>[F:17][C:4]1[CH:3]=[CH:2][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]=1[CH3:16]
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Reactant: Cc1c(F)ccc(C(=O)O)c1I
Product: Cc1c(F)ccc(C(=O)O)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 4-fluoro-2-iodo-3-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH:6]([NH:8][CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH3:7].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH:6]([N:8]([CH2:9][CH:10]([O:11][CH3:12])[O:13][CH3:14])[S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:7]
Reactant: COc1cccc(C(C)NCC(OC)OC)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cccc(C(C)N(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 23.9 g. (0.1 mole) of 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)benzylamine in 100 ml. of dry pyridine is stirred, cooled and treated with a solution of 20.2 g. (0.107 mole) of tosyl chloride in 100 ml. of dry pyridine. The mixture is stirred at 25° C. for three days, poured into 800 ml. of water and extracted with ether. The combined ether extracts are washed with dilute hydrochloric acid and then with water, dried, filtered and evaporated to yield 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)-N-tosyl-benzylamine.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]([OH:23])=O)=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:24][S:25]([NH:28][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][C:10]=2[CH:11]=1)=[O:23])(=[O:27])=[O:26]
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reaction time: 5 h
Yield: 80.6 %

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carboxylic acid (6 mg) was reacted with methyl sulfonamide (120 mg), EDCI (80 mg) and DMAP (20 mg) in anhydrous DMF (0.5 ml). After 5 hours, water was added and the solution subjected to preparative HPLC. Genevac evaporation provided N-(methylsulfonyl)-4-(phenylamino)thieno[3,2-c]quinoline-7-carboxamide as a solid (6 mg, 81% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].O>CN(C=O)C>[N+:7]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9.67 g (70 mmol) of potassium carbonate is added to a solution of 6.96 g (50 mmol) of 3-nitrophenol in 500 ml DMF, and then it is stirred for 10 minutes at room temperature. It is mixed with 14.1 g (50 mmol) of 2-(4-bromo-butyl)-isoindole-1,3-dione and stirred for 4 hours at 60° C. After cooling, it is mixed with water and extracted with ethyl acetate. The combined organic phases are dried (MgSO4), filtered and concentrated by evaporation. 17.2 g (50 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: Br[CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[O:3]1.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[O:3]1)[CH3:22]
Reactant: CN(C)C1=C(c2cccc(C(F)(F)F)c2)C(=O)C(Br)O1
Reactant: CCO
Product: CCOC1OC(N(C)C)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this example, 0.16 g of sodium was added to 10 ml of anhydrous ethanol at room temperature resulting in the formation sodium ethoxide. A solution containing 2.5 g of 2-bromo-3-oxo-4-(3-trifluoromethylphenyl)-5-dimethylamino-2,3-dihydrofuran in 10 ml of ethanol was slowly added and the resulting mixture stirred at room temperature for one hour. The mixture was then evaporated to remove solvent. The residue was dissolved in methylene chloride, washed with water, dried over magnesium sulfate evaporated yielding in oil residue. The residue was chromatographed eluting with tetrahydrofuran:chloroform mixtures. The produced fractions afforded 1 g of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)[CH:32]=1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: OB(O)c1cccnc1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4cccnc4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 3-pyridylboronic acid by the method described for Example 36 Step 3. MS (ES+) 521 ([MH]+).