Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]2)[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.CCOCC>[CH:1]1([CH2:4][NH:29][CH2:28][CH2:27][C:21]2([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc(C2(CCN)C=CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(C2(CCNCC3CC3)C=CCCC2)c1

Procedure:
3.45 g of cyclopropanecarboxylic acid chloride are placed in 50 ml of methylene chloride, whereafter 5.0 g of potassium carbonate are added, and then a solution of 7.0 g of 1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine in 10 ml of methylene chloride is added dropwise while stirring. The mixture is stirred at room temperature overnight and subsequently at reflux for 30 minutes and cooled. Then, the precipitate is removed by filtration under suction, the filtrate is evaporated, and the oil obtained is taken up in ether. The ethereal solution is washed with 1 N hydrochloric acid and subsequently with water, dried over magnesium sulfate and evaporated, and N-[2-[1-(m-methoxyphenyl)-2-cyclohexen-1-yl]ethyl]-cyclopropanecarboxamide remains as the residue. 6.5 g of this compound, dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise to a dispersion of 6 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. The mixture is boiled at reflux for 3 hours, cooled and worked-up in the usual manner, and there is obtained N-(cyclopropylmethyl)-1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine, the hydrochloride of which melts at 141°-142° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([NH:18][C:19]1([C:22]2[C:31]([F:32])=[C:30]3[C:25]([C:26](=[O:50])[C:27]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:28][N:29]3[C@@H:33]([CH3:44])[CH2:34][N:35](C(OC(C)(C)C)=O)[CH3:36])=[CH:24][C:23]=2[F:51])[CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O>[CH2:8]([O:15][C:16]([NH:18][C:19]1([C:22]2[C:31]([F:32])=[C:30]3[C:25]([C:26](=[O:50])[C:27]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:28][N:29]3[C@@H:33]([CH3:44])[CH2:34][NH:35][CH3:36])=[CH:24][C:23]=2[F:51])[CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cn([C@@H](C)CN(C)C(=O)OC(C)(C)C)c2c(F)c(C3(NC(=O)OCc4ccccc4)CC3)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1cn([C@@H](C)CNC)c2c(F)c(C3(NC(=O)OCc4ccccc4)CC3)c(F)cc2c1=O
Reaction time: 2.5 h
Yield: 95.6 %

Procedure:
To 2 ml of trifluoroacetic acid was added, with ice-cooling, 300 mg of ethyl (S)-7-(1-benzyloxycarbonylaminocyclopropyl)-6,8-difluoro-1-[2-(N-tert-butoxycarbonyl-N-methylamino)-1-methylethyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate. The resulting mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 10 ml of water in this order. The resulting mixture was adjusted to pH 8 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 240 mg (yield: 96.0%) of ethyl (S)-7-(1-benzyloxycarbonylaminocyclopropyl)-6,8-difluoro-1-[2-(N-methylamino)-1methylethyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: [F-:1].[K+].[C:3]([O:7][C@@H:8]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18](Cl)[N:17]=1)[CH3:9])([CH3:6])([CH3:5])[CH3:4]>CS(C)=O.C(OCC)(=O)C.O>[C:3]([O:7][C@@H:8]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([F:1])[N:17]=1)[CH3:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(Cl)n1
Reactant: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(F)n1
Temperature: 120 °C

Procedure:
Potassium fluoride (0.063 g, 1.08 mmol, 10 equiv) was added to a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.108 mmol) in DMSO (1.1 mL). The suspension was heated at 120° C. for 3 hours and then cooled to room temperature. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=3.8 Hz, 1H), 4.71 (m, 1H), 4.65 (m, 1H), 4.46 (m, 1H), 4.41 (m, 1H), 2.53 (s, 3H), 1.25 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 298.2 (M+H)+; Rt-0.96 min.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9]N(C)C)=O.Cl.[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[NH:27].C[O-].[Na+]>CO>[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]1[N:28]=[C:6]([C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[C:8]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:9][N:27]=1
Reactant: N=C(N)c1ccc(F)cc1F
Reactant: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Yield: 77.5 %

Procedure:
6 g of 1-(3-trifluoromethylbenzoyl)-l-methanesulfonyl-2-(N,N-dimethylamino)ethene and 4.6 g of 2,4-difluorobenzamidine hydrochloride were dissolved in 30 ml of methanol at room temperature and 1.2 g of sodium methoxide was added thereto. The resulting mixture was heated under reflux for an hour. The solvent was distilled away under reduced pressure. The residue was washed with water and then dried to obtain 6 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine (Compound 147).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].[C:21]1([N:27]([CH2:34][C:35](O)=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:35](=[O:36])[CH2:34][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:3]1=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CN(c1ccccc1)c1ccccc1)NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol) in dry CH2Cl2 (20 ml)was added diphenylamino ethanoic acid (0.19 g, 0.82 mmol) under nitrogen. To the reaction was added EDC (0.18 g, 0.9 mmol) and DMAP (cat) and the reaction mixture was stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate:water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (2:1) to give the desired product in 69% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH3:20])=[CH:16][CH2:17]3)=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])=[C:4]([O:25][CH3:26])[CH:3]=1>CCO.[Pd]>[F:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([CH:15]([CH3:20])[CH2:16][CH2:17]3)=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CC=C2C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CCC2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-methyl-1H-indene-5-carboxylate (21.5 mg, 0.061 mmol) in EtOH (2 mL), was added a catalytic amount of 10% Pd/C. The flask was stirred at room temperature under H2 overnight. The mixture was filtered through Celite. The solvent was evaporated in vacuo to give methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-methylindane-5-carboxylate. LCMS calc.=379.2; found=378.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 7.72 (s, 1H); 7.18 (s, 1H); 7.11 (d, J=8.6 Hz, 1H); 6.62 (d, J=12.0 Hz, 1H); 3.73 (s, 3H); 3.69 (s, 3H); 3.29-3.23 (m, 2H); 3.02-2.90 (m, 2H); 2.45-2.34 (m, 1H); 1.73-1.66 (m, 1H); 1.38 (d, J=6.2 Hz, 3H); 1.30 (d, J=6.6 Hz, 6H).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:27]=[N:26][C:25]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:7][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][CH2:10]3)[CH2:16][CH2:15]2)=[N:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ncc(C(F)(F)F)cn3)CC2)C1
Temperature: 120 °C
Yield: 41 %

Procedure:
Sodium t-butoxide (625 mg, 6.51 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (600 mg, 2.17 mmol, 1.0 eq.) and 2-chloro-5-(trifluoromethyl)pyrimidine (391 mg, 2.17 mmol, 1.0 eq.) in toluene (15 ml) and the reaction mixture was degassed with nitrogen. BINAP (80 mg, 0.13 mmol, 0.06 eq.) and Pd(OAc)2 (10 mg, 0.04 mmol, 0.02 eq.) were added and the resulting mixture was heated at 120° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to afford the crude product which was purified by column chromatography (silica gel; 0-1% MeOH/MC) to yield the pure desired product as a white solid. Yield: 41% (350 mg, 1.2 mmol).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[C:8]([C:18]([NH2:20])=[O:19])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[C:10]2[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[C:8]([C:18]([NH2:20]=[O:29])=[O:19])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(N)=O)c2c1oc1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(C(=O)[NH2+][O-])c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of N-pyrid-4-yl)-4-isopropyloxy dibenzo[b,d]furan-1-carboxamide (50 mg, 0.144 mmol) (example 34) and m-chloroperbenzoic acid (50-55%) (125 mg, 0.722 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 40% acetone-chloroform as the eluent to give 27 mg of N-pyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid, mp: 247-248° C. (dec)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][C:3]=1[O:39][CH2:40][CH2:41][OH:42]>CO.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]=2)=[CH:4][C:3]=1[O:39][CH2:40][CH2:41][OH:42]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(OCCO)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ccc2c(c1)c(-c1ccc(F)c(OCCO)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A suspension of 3-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 14AX (1.5 g) and catalytic amount of Pd on carbon (5 wt %, 300 mg) in 40 mL of methanol/toluene (1:1) was stirred under a hydrogen atmosphere for 1 d and filtered through Celite. The filtrate was concentrated to provide 3-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-1-trityl-1H-indazol-5-ylamine 15AX (1.4 g) as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=O)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=O)(OC(C)(C)C)=O>>[CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:33]3[CH2:32][CH2:31][NH:30][CH2:35][CH2:34]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([NH:3][C:4](=[O:5])[CH3:6])[CH:12]=3)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(NC(C)=O)cc1C2=C1CCNCC1

Procedure:
Compound 10f was synthesized by an adaptation of Procedure 7, substituting compound 7f for compound 6a, and substituting N-Boc-piperidone for N-carbethoxynortropinone. MS m/z=420.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.[Cl-].[Na+].O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.107 g. 0.0005 mol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassium hydroxide (0.224 g, 0.004 mol) and allowed to stir for 10 min at RT. 2-trifluoromethyl-5-vinyl pyridine (0.095 g, 0.00055 mol) was added and stirred for further 1 h. at 60 deg C., After completion of TLC, Reaction mixture was diluted with brine (5 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as brown oil (0.11 g, 57% yield). 8-Ethyl-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.000258 mol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.032 g, 0.000258 mol) in THF (2 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.080 g, 65% yield).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([S:19]([NH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: NN1CCOCC1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.7 %

Procedure:
3.8 g of N-aminomorpholine (36.9 mmol) and 5.1 ml of triethylamine (3.7 g, 36.9 mmol) were dissolved at room temperature in 40 ml of methylene chloride. Again at room temperature 4.8 ml of n-butanesulfonyl chloride (5.8 g, 36.9 mmol) were added dropwise to this solution over the course of one hour. After 20 h of stirring at room temperature the reaction mixture was extracted by shaking twice with 50 ml of water and the organic phase was dried over magnesium sulphate and concentrated. The 6.7 g of crude product obtained were recrystallized from 30 ml of tert-butyl methyl ether. The constitution of the target compound was verified by NMR spectroscopy.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[NH:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1)(C)(C)C.CO.[ClH:27]>>[ClH:27].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:19][CH2:20][CH2:21][OH:22])=[O:23])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(=O)NCCO)cc1
Agent: Cl
Solvent: CO
Product: NCCCCc1ccc(C(=O)NCCO)cc1
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of 27 (0.4 g, 1.19 mmol) was stirred at room temperature in a mixture of methanol/HCl (1:1, 40 mL). The reaction was finished in 2 h according to HPLC analysis. The solvent was removed under reduced pressure to provide 0.33 g (98%) 28 as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.60 (m, 4H), 2.63 (m, 2H), 2.78 (m, 2H), 3.31 (m, 2H), 3.50 (m, 2H), 7.28 (d, 2H), 7.80 (d, 2H), 7.97 (br s, 2H), 8.46 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-methoxy-3-nitrobenzoic acid (10.0 g, 0.051 mol), and thionyl chloride (25 g, 0.212 mol), were refluxed together for 24 h. The reaction mixture was cooled to RT and concentrated to dryness. The off-white solid was carried onto the next step.
Reaction SMILES: I[Si](C)(C)C.[C:6]([C:8]1[C:9]([O:18]C)=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)#[N:7]>C(Cl)(Cl)Cl>[C:6]([C:8]1[C:9]([OH:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1)#[N:7]
Reactant: COc1ncc(C(F)(F)F)cc1C#N
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodotrimethylsilane (6.2 ml, 0.044 mol) was added with stirring to a solution of 3.15 g (0.016 mol) of 3-cyano-2-methoxy-5-(trifluoromethyl)pyridine in 80 ml of chloroform under nitrogen and the mixture was allowed to stir at ambient temperature overnight. It was then concentrated by evaporation under reduced pressure and the residue partitioned between ether and 1N aqueous sodium hydroxide. The ethereal phase was extracted with more aqueous sodium hydroxide and the combined alkaline solutions were cooled and acidified with concentrated aqueous hydrochloric acid. The resulting mixture was extracted with ether several times and the combined ether extracts dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was triturated with hot hexane, filtered, and dried to obtain 1.8 g (62 percent of theory) of the title compound as off-white crystals melting at 177-178.5° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CN(C)C=O.O1CCCC1.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([OH:34])=[O:33])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([OH:34])=[O:33])=[CH:36][CH:37]=1)(=[O:4])=[O:3]
Reactant: CC(C(=O)O)c1ccccc1OCCOc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccccc1OCCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
38 mg (0.332 mM) of methanesulfonyl chloride are added to a mixture of 0.25 ml of dimethylformamide and 1.5 ml of tetrahydrofuran in a 15 ml reactor. 100 mg (0.332 mM) of 2-{2-(4-aminophenoxy)ethoxy}phenylpropanoic acid are then added, followed by addition of 0.060 ml (0.74 mM) of pyridine. The reaction medium is then stirred for 48 hours at room temperature. After extraction with ethyl acetate, 20 mg of 2-{2-[4-(methylsulfonylamino)phenoxy]ethoxy}phenyl-propanoic acid are obtained (yield: 16%).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][CH2:22][CH:23]([C:25]([O:27][CH3:28])=[O:26])[N:24]=4)=[CH:16][C:15]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>ClCCl>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[N:24]=4)=[CH:16][C:15]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:11])=[O:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1COC(c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)=N1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
Into 40 mL of dichloromethane was dissolved 1.10 g of Compound 22, followed by addition of 498 mg of bromotrichloromethane at −20° C. Further, 700 mg of DBU was added dropwise at the same temperature and the whole was stirred at the same temperature for 5 minutes and then warmed to 0° C., followed by 3.5 hours of stirring. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous sodium hydrogen carbonate solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=20/1) to obtain 597 mg of the title compound as colorless powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][CH2:43]O.[Cl:45][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]2[C:55]=1[C:54](=[O:56])[NH:53][N:52]=[CH:51]2.Cl>C1COCC1>[Cl:45][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]2[C:55]=1[C:54](=[O:56])[N:53]([CH2:43][CH2:42][C:33]1[CH:34]=[CH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:32]=1)[N:52]=[CH:51]2
Reactant: O=c1[nH]ncc2cccc(Cl)c12
Reactant: OCCc1ccc2ccccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2c(Cl)cccc2cnn1CCc1ccc2ccccc2n1
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (9.00 g, 34.3 mmol) in THF (100 mL), DEAD (5.44 mL, 34.3 mmol) was added at 0° C. After stirring for 15 min, 2-(quinolin-2-yl)ethanol from Example a1 (2.97 g, 17.17 mmol) was added. After another 15 min, 8-chlorophthalazin-1(2H)-one (3.1 g, 17.17 mmol) was added. The mixture was stirred overnight at room temperature; LC-MS indicated complete conversion to the product. 1 N HCl was added (pH=4). The mixture was extracted with EtOAc (3×50 mL), the EtOAc layers were discarded. The aqueous layer was neutralized by aq.NaHCO3 and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was suspended in EtOAc. The solid was filtered through a Büchner funnel. The purity of the title product was 95%.