Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1I)[CH3:2].[CH3:15][O:16][CH2:17][C:18]#[CH:19].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:19]#[C:18][CH2:17][O:16][CH3:15])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1I
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccccc1C#CCOC
Reaction time: 4 h

Procedure:
A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the above prepared (2-iodo-phenoxy)-acetic acid ethyl ester, 128 ml of acetonitrile, 5.793 g (2 eq.) of 3-methoxy-1-propyne, 17.28 ml (3 eq.) of NEt3, 1.45 g (0.05 eq.) of (PPh3)2PdCl2, and 0.394 g (0.05 eq.) of CuI. After stirring for 4 h the bulk of the solvent was removed i. V. and the residue distributed between HCl and EtOAc. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/EtOAc=8/2), yielded 9.54 g of the title compound as light brown oil, MS: 248.2 (M)+.
Reaction SMILES: [CH3:1][CH:2]([C:16](N)=[O:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([F:15])[CH:4]=1.C(Cl)(=O)C(Cl)=[O:21]>C(Cl)Cl.ClCCCl>[CH3:1][CH:2]([C:16]([OH:17])=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([F:15])[CH:4]=1
Reactant: CC(C(N)=O)c1ccc(-c2ccccc2)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of flurbiprofen amide (3.0 g, 12.33 mmol) in DCM (70 mL) was added oxalyl chloride (1.87 g, 14.79 mmol) at 0° C. and refluxed for 16 h. Reaction mixture was cooled to RT and treated with LI-2b (2.45 g, 12.33 mmol) in DCE (10 mL) and stirred overnight. After usual aqueous work-up and chromatographic purification, 0.5 g of I-C1-NOPD14a were obtained. 1H NMR (CDCl3, 300 MHz): δ 1.55 (d, 3H, J=6.9 Hz), 2.94-2.97 (bs, 4H), 4.38-4.47 (bs, 3H), 4.68 (t, 2H, J=6.6 Hz), 7.13-7.55 (bs, 8H) MS: ES+ m/z 469.03 [M+H]+, 467.16 [M−H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[NH2:15][C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[NH:18][N:17]=1.[C:28](O)(=[O:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:28](=[O:38])[C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:15][C:16]4[CH:20]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)[NH:18][N:17]=4)=[O:34])=[CH:31][CH:30]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(=O)Nc4cc(-c5ccc(C)cc5)[nH]n4)cc3)n[nH]2)cc1

Procedure:
Compound 471 was prepared from 3-amino-5-(4-methoxyphenyl)pyrazole, 3-amino-5-(4-methylphenyl)pyrazole, and terephthalic acid. [M+H]+ calcd for C28H25N6O3: 493.20; found: 492.92.
Reaction SMILES: [CH3:1][C:2](=[CH2:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>FC1C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C=C(C)CCOc1cccc(NC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Fc1ccccc1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)OCCC2(C)C
Yield: 54 %

Procedure:
A mixture of N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (2.5 g, 11.4 mmol) and AlCl3 (4.52 g, 34.3 mmol) in fluoro-benzene (50 mL) was heated at reflux overnight. After cooling, the reaction mixture was poured into water. The organic layer was separated and the aqueous phase was extracted with EtOAc (40×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 54%).
Reaction SMILES: [CH2:1]([C:5]1[CH:16]=[C:15]([SH:17])[CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH3:4].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.P(Br)(Br)Br.FC(F)(F)C1C=CC(C2C=CC(CO)=CC=2)=CC=1>>[CH2:1]([C:5]1[CH:16]=[C:15]([S:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: FC(F)(F)c1ccc(-c2ccc(CBr)cc2)cc1
Reactant: CCCCc1cc(S)ccc1OCC(=O)OC
Agent: BrP(Br)Br
Agent: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: CCCCc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 100F and 1-(bromomethyl)-4-[4-(trifluoromethyl)phenyl]benzene prepared from and phosphorous tribromide and (4′-trifluoromethyl-biphenyl-4-yl)-methanol in a manner analagous to Example 3B. 400 MHz 1H NMR (CDCl3) δ 7.68 (m, 4H), 7.51 (d, 2H), 7.29 (d, 2H), 7.15 (m, 2H), 6.60 (d, 1H), 4.62 (s, 2H), 4.04 (s, 2H), 3.79 (s, 3H), 2.60 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.88 (t, 3H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:41][CH2:42][O:43][Si:44]([O:52][CH2:53][CH3:54])([O:49][CH2:50][CH3:51])[CH2:45][CH2:46][CH2:47][NH2:48]>CCOCC>[CH2:50]([O:49][Si:44]([O:52][CH2:53][CH3:54])([O:43][CH2:42][CH3:41])[CH2:45][CH2:46][CH2:47][NH:48][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([N:14]=[N:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=2)=[CH:29][CH:28]=1)[CH3:51]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CCCCCCc1ccc(N=Nc2ccc(OCCCCCC(=O)O)cc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCCCc1ccc(N=Nc2ccc(OCCCCCC(=O)NCCC[Si](OCC)(OCC)OCC)cc2)cc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
One g. (3.73×10-3 mol) of 4'-hexyl-4-hydroxyazobenzene (1) converted into a sodium salt with sodium methylate and 1.03 g (3.69×10-3 mol) of 2-tetrahydropyranyl 6-bromohexanoate and 5 ml of dimethylacetamide added thereto were heated for reaction at 100° C. for 73 hours. After the reaction was completed, the reaction mixture was diluted with water and left to cool to room temperature. The yellow crystals which were consequently precipitated were separated by filtration. The crystals were extracted with ethyl acetate, dried with magnesium sulfate, and subjected to vacuum distillation for expulsion of the solvent. The residue of the vacuum distillation was recrystallized with a mixture of hexane with benzene. Consequently, 1 g of 6-[4-(4-hexylphenylazo)-phenoxy]-hexanoic acid was obtained. A mixture of 200 mg (5.05×10-4 mol) of this carboxylic acid with 5 ml of thionyl chloride was refluxed for 2 hours to expel excess thionyl chloride and then mixed with 3 ml of dry ether and 0.15 g (1.485×10-3 mol) of triethylamine. This mixture kept cooled with ice and a solution of 0.11 g (4.98×10-4 mol) of triethoxyaminopropylsilane in 3 ml of dry ether added dropwise thereto were stirred for two hours, then filtered to expel the formed salt in an atmosphere of nitrogen gas, and subjected to vacuum distillation at room temperature to expel the solvent. Consequently, 213 mg of yellow waxy N-(3-triethoxysilylpropyl)-6-[4-(4-hexylphenylazo)phenoxy]hexanoic acid amide was obtained.
Reaction SMILES: [I-].[K+].C[Si](Cl)(C)C.[CH2:8]([O:15][CH2:16][C:17]1[N:18]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41]C)=[N:39][CH:40]=2)[C:19]([S:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>C(#N)C>[CH2:8]([O:15][CH2:16][C:17]1[N:18]([CH2:34][C:35]2[CH:40]=[N:39][C:38](=[O:41])[CH2:37][CH:36]=2)[C:19]([S:25][C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(Cn2c(COCc3ccccc3)nc(C(C)C)c2Sc2cc(Cl)cc(Cl)c2)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CC(C)c1nc(COCc2ccccc2)n(CC2=CCC(=O)N=C2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a solution of 83 mg of potassium iodide in acetonitrile was added 64 μl of trimethylsilyl chloride under ice-cooling and stirring. The mixture was allowed to warm up, and after 10 minutes, 150 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-(2-methoxypyridin-5-ylmethyl)-4-isopropyl-1H-imidazole was added, and the mixture was stirred with heating at 60° C. After 1 hour, the solution was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1)to give 50 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-(5,6-dihydro-6-oxopyridin-3-ylmethyl)-4-isopropyl-1H-imidazole (115a)(yield 34%).
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].O>C(O)(C)C>[C:1]([S:14]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCCN(CC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 56 °C

Procedure:
A one-liter flask fitted with a thermocouple, addition funnel, heating-mantle, reflux condenser and overhead stirrer was charged with C4F9SO2NH(C4H9) (133.0 g; 0.375 mole), and sodium carbonate (33.0 g). The mixture was heated to 93° C. and ethyl bromoacetate (69.0 g; 0.411 mole) was slowly added over a period of 8 hours, and then the ensuing mixture was allowed to stir overnight at 93° C. To this mixture was added water (120.0 mL) and the temperature was 56° C., at which point sulfuric acid (39.0 g; concentrated) at a rate to keep the temperature below 100° C. Two phases formed and the bottom layer was recovered and washed with water (150 mL). This crude material was distilled (110-125° C.; 3.3 mm Hg) to yield C4F9SO2N(C4H9)CH2CO2C2H5(107.0 g). A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2N(C4H9)CH2CO2C2H5(103.0 g; 0.241 mole) KOH (18.0 g; 0.273 mole) water (50 mL) and isopropanol (50.0g). The mixture was heated at reflux for 2 hours, and a Dean-Stark trap was added. As isopropanol was removed from the trap, an equivalent amount of water was added to the reaction mixture. When the reaction mixture reached 101° C. water (25 mL) was added and the mixture was cooled to 56° C.; upon addition of sulfuric acid (26.7 g; concentrated) the temperature rose o 78° C. and two phases appeared. The bottom phase was distilled (139-147° C.; 3.6 mm Hg) to yield a creme colored solid, C4F9SO2N(C4H9)CH2CO2H.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH3:20][C:21]1[C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccn1)N(C)C(=O)N2

Procedure:
To a solution of crude 6-Bromo-3-methyl-4-pyridin-2-yl-3,4-dihydro-1H-quinazolin-2-one (600 mg, 0.002 mol) in DME/H2O (12 mL/4 mL) is added 3,5-dimethylisoxazole-4-boronic acid (265 mg, 0.002 mol), Pd(PPh3)4 (77 mg, 0.08 mmol) and Na2CO3 (332 mg, 3.14 mmol). After addition, the mixture is refluxed for 3 h. The mixture is concentrated in vacuum and the residue is purified by preparative HPLC to give the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:56][CH:57]([F:59])[F:58])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:56][CH:57]([F:59])[F:58])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:34][CH2:35]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To the stirred solution of 2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 11) (0.100 g, 0.180 mmol) in DMF (2.0 mL) and N,N-diisopropylethylamine, (63 μL, 0.361 mmol) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.046 g, 0.216 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. On completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated and aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum to give off-white solid, which was purified by flash chromatography on silica gel using an automated ISCO system (12 g Redisep column, eluting with 0-5% methanol/chloroform) to get 2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (100 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1cccnc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccnc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with 2-amino-3-pyridin-3-yl-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([NH:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH3:15])=[O:12].O[Li:31].O>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([NH:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=1)[CH3:15])=[O:12].[Li+:31]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(F)c(F)c2)cc1
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCCN1Cc1ccc(F)c(F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E17) (36 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3,4-difluorobenzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D34) (38 mg). (LiOH H2O: 1.5 eq; reaction time: 24 hrs)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.N1C2C=CC=C(N)C=2C=N1.[F:28]C1C=C(F)C=CC=1I>>[F:1][C:2]1[CH:7]=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1
Reactant: Fc1ccc(I)c(F)c1
Reactant: Nc1cccc2c1cnn2-c1ccccc1F
Agent: Nc1cccc2[nH]ncc12
Product: Nc1cccc2c1cnn2-c1ccc(F)cc1F

Procedure:
Similarly prepared to Intermediate 1 from 1H-indazol-4-amine and 2,4-difluoro-1-iodobenzene.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:14])([F:13])[C:10]1=[O:15].C[Si]([Br:20])(C)C>>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:14])([F:13])[C:10]1=[O:15]
Reactant: O=C1N(c2ccccc2CO)CC1(F)F
Reactant: C[Si](C)(C)Br
Product: O=C1N(c2ccccc2CBr)CC1(F)F
Yield: 25 %

Procedure:
60 mg (0.28 mmole) of compound 4a are treated with 4 equivalents (0.15 ml) of trimethylsilylbromide at ambient temperature for 35 min. The compound obtained is purified by silica gel plate chromatography using an ether:pentane mixture (1:6). This gives 16 mg of compound 5d corresponding to a 25% yield.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>CN(C=O)C>[N:10]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][N:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[S:12][C:11]=12
Reactant: Nc1nc2ccccc2s1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(n1)sc1ccccc12
Temperature: 25 °C

Procedure:
Ethyl bromopyruvate (9.8 g, 50 mmol) was added dropwise to a stirred solution of 2-aminobenzothiazole (7.5 g, 50 mmol) in DMF (100 ml) at room temperature. After the addition, the reaction mixture was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and quenched with ice cold water. The aqueous layer was neutralized with NH4OH and the separated solid was filtered. It was washed well with water and dried. The crude product obtained was taken to next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:17][C:14]([F:15])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 51 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 51%; MS: m/z=463 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]1([CH2:41]CO)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:17]=1
Reactant: OCCc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCc4ccccc4)cc3)c2cc1OC
Yield: 56 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-phenyl-1-ethanol (32 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (42 mg, yield 51%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][CH:11]1[NH:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:39]([C:41]1[C:57]([F:58])=[CH:56][C:44]([O:45][C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=2[F:55])=[C:43]([O:59]C)[CH:42]=1)[CH3:40]>ClCCl.O>[CH2:39]([C:41]1[C:57]([F:58])=[CH:56][C:44]([O:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([N:16]3[CH2:15][CH2:14][NH:13][C:12](=[O:17])[CH:11]3[CH3:10])=[O:51])=[CH:48][C:47]=2[F:55])=[C:43]([OH:59])[CH:42]=1)[CH3:40]
Reactant: CC1NCCNC1=O
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCNC(=O)C3C)cc2F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (74 μL, 0.42 mmol), 3-methylpiperazin-2-one (23.3 mg, 0.20 mmol), EDCI (39.1 mg, 0.20 mmol) and HOBt (27.6 g, 0.20 mmol) were successively added to a suspension of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 50 mg, 0.17 mmol) in dichloromethane (0.55 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (10 mL) and water (10 mL). After separation, the organic layer was washed with water (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2 to 95:5) as eluent. The title product was obtained as a white solid (24 mg, 36%).