Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:32])[C:20]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:19]1[C:29](Cl)=[O:30].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][O:12][C:29]([CH:19]1[C:20]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[C:18]1([CH3:32])[CH3:17])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C12C=Cc1ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(C(=O)OCc2ccc(F)c(Oc3ccccc3)c2)C12C=Cc1ccccc12
Yield: 86.3 %

Procedure:
5.05 g (0.0232 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 5.4 g (0.0232 mol) of 3,3-dimethyl-spiro(cyclopropane-1,1'-indene)-2-carboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of toluene, were added dropwise at 20°-25° C., while stirring. The mixture was stirred at 25°-35° C. for a further 3 hours. The reaction mixture was poured into 150 ml of water, to which 5 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.3 g (86.4% of theory) of 3,3-dimethylspiro-(cyclopropane-1,1'-indene)-2-carboxylic acid 3-phenoxy-4-fluoro-benzyl ester were obtained as a viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([OH:55])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([O:55][CH2:2][CH3:3])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.04, 1.16, 2.38, 2.68, 3.34, 3.40, 3.54, 3.70, 3.82, 4.18, 4.62, 5.10, 5.95, 6.98, 7.10, 7.26, 7.38; IR (diffuse reflectance) 2971, 2934, 2350 (w), 2338 (w), 2063 (w), 1949 (w), 1710 (s), 1568, 1482 (s), 1419 (s), 1397 (s), 1348, 1287, 1228, 1096, cm−1 HRMS (FAB) calcd for C29H35ClN4O4+H 539.2425, found 539.2436.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[C:14]([CH3:19])[O:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:10][C:11]1[C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: Cc1noc(C)c1B(O)O
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: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1cc(C=O)c(C)o1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 3,5-dimethylisoxazole-4-boronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.4 g, 69%) as a yellow crystal.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)[CH3:3].[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([NH:1][C@H:2]([C:4]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)[CH3:3])=[O:25]
Reactant: C[C@H](N)C1(c2ccccn2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(Cl)cc1Cl)C1(c2ccccn2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 3-[(1S)-1-aminoethyl]-3-pyridin-2-ylazetidine-1-carboxylate (I-3, 1.35 g, 5.1 mmol) in CH2Cl2 (11 mL) was treated with 2,4-dichlorobenzoic acid (1.2 g, 6.1 mmol) EDCI (2.0 g, 10.2 mmol), and HOBt (690 mg, 5.1 mmol) and stirred at room temperature. After 18 h, the reaction was quenched with the addition of H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (120 g SiO2, 50-80% EtOAc/hexanes) to afford tert-butyl 3-{(1S)-1-[(2,4-dichlorobenzoyl)amino]ethyl}-3-pyridin-2-ylazetidine-1-carboxylate (I-4). Analytical LCMS: single peak (214 nm), 3.010 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: I[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].[I:20]C(CCCCCCCCCCCCCCC)CC(O)=O.FC(F)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(O)=O>>[I:20][CH:3]([CH2:2][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCC(I)CC(=O)O
Reactant: CCCCCCCCCCCCCC(I)CC(=O)O
Agent: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCCCCCCCC(I)C(=O)O

Procedure:
3-iodohexadecanoic acid, 3-iodooctadecanoic acid, and perfluorooctadecanoic acid.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(N(C)Cc4ccccc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(Benzyl-methyl-amino)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 30.1 from 150 mg (0.37 mmol) 4-(benzyl-methyl-amino)-1-[2-(4-bromomethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 14d) and 259 mg (1.82 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [C:1]([N:3]1[C@H:12]2[C@@H:7]([CH2:8][C:9](=[O:13])[CH2:10][CH2:11]2)[CH2:6][CH2:5][CH2:4]1)#[N:2].[CH3:14][N:15]([CH:17](N(C)C)N(C)C)[CH3:16]>C1(C)C=CC=CC=1>[C:1]([N:3]1[C@H:12]2[C@@H:7]([CH2:8][C:9](=[O:13])[C:10](=[CH:14][N:15]([CH3:17])[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CN1CCC[C@@H]2CC(=O)CC[C@H]21
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1C[C@@H]2[C@H](CCCN2C#N)CC1=O

Procedure:
A reaction mixture was prepared from 4.18 g. of trans-(±)-1-cyano-6-oxodecahydroquinoline, 5.0 g. of tris-dimethylaminomethane and 50 ml. of toluene. The reaction mixture was refluxed under nitrogen temperature for five hours and then was concentrated in vacuo. Five and seventy-six hundredths grams of a crude yellow solid comprising trans-(±)-1-cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline were obtained. This crude product was mixed with 2.25 g. of guanidine carbonate in 100 ml. of anhydrous methanol. This reaction mixture was heated to reflux under nitrogen overnight, and was then concentrated in vacuo. The resulting solid residue was triturated with hot methanol and filtered. The filter cake was washed twice with methanol and once with ether. A yield of 4.11 g. (78%) of trans-(±)-2-amino-6-cyano-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were obtained having the following physical characteristics. Mass spectrum, molecular ion at 229; infrared spectrum peaks at 3307.18, 3157.70, 2202.87, 1660.83, 1599.10, 1564.38, 1486.26.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:19][CH3:20].[Cl:21]Cl>Cl.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:19][CH3:20])[Cl:21]
Reactant: ClCl
Reactant: CCC1Cc2cc(OC(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OC(C)C(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following substantially the procedure described in Example 12, Step B, and using as the reactants 2-(1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)propionic acid (3.17 g., 0.01 mole), glacial acetic acid (50 ml.), chlorine (710 mg., 0.01 mole) and concentrated hydrochloric acid (1 drop) there is obtained 2-(1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)-propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]([C:13]#[N:14])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(=O)=O.CC(C)=O.[OH-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]([CH2:13][NH2:14])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(C#N)c1Oc1cc(Cl)cc(Br)c1
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccnc(CN)c1Oc1cc(Cl)cc(Br)c1
Reaction time: 0.67 h

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridine-2-carbonitrile (570 mg, 1.762 mmol) in tetrahydrofuran (7 mL) cooled over dry ice/acetone bath was added 2M LAH in THF (1.233 mL, 2.466 mmol) and the mixture stirred over dry ice-acetone bath for 40 minutes. After this time, the dry ice-acetone bath was replaced with a wet ice bath and mixture stirred for 5 minutes. The mixture was then treated with water (94 μL), 1.0N NaOH (94 μL) and more water (280 μL), and then stirred at room temperature for 30 minutes. After this time, the mixture was diluted with THF (7 mL) and filtered through celite. The solids were washed with additional THF (10 mL). The filtrates were combined, the solvent removed under vacuum, and the residue purified using Waters PrepPak and eluting with a gradient of 5-95% ACN/H2O with 0.1% TFA. The desired fractions were combined and the solvent removed in vacuo to give the title compound. LRMS (M+1)=328.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2I)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])(O)=O.[Na+]>COCCOC.Cl.[Cu]I.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]2[O:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1I)C1CN(C(=O)OCc2ccccc2)C1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(c2nc3ccccc3o2)C1
Temperature: 90 °C

Procedure:
To 195 mg (0.45 mmol) 3-(2-iodo-phenylcarbamoyl)-azetidine-1-carboxylic acid benzyl ester in 4.5 mL DME in a sealed tube under nitrogen were added 291 mg (0.89 mmol) Cs2CO3, 8.1 mg (44.6 μmol) 1,10-phenanthroline, 4.3 mg (22.3 μmol) CuI, and the mixture was heated at 90° C. for 16 hours. After cooling to room temperature, 5 mL H2O was added followed by 4 drops 1 M HCl, 5 mL NaHCO3 and the mixture was extracted with DCM (3×10 mL). The organic layers were combined and dried with Na2SO4. After filtration and evaporation of the solvent the product was purified by preparative HPLC.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]#[CH:50])[CH2:44][CH2:43]1)=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.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.C(N(CC)CC)C.CN(C=O)C>[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]#[C:50][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]3[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:3]=2)[CH2:44][CH2:43]1)=[O:41]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: C#CCC1CCC(C(=O)OC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 120 °C

Procedure:
The title compound is prepared by combining N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (intermediate J), 4-prop-2-ynyl-cyclohexanecarboxylic acid methyl ester (prepared as described by Rieger J. M., Brown M. L., Sullivan G. W., Linden J. and Macdonald T. L.′; J. Med. Chem.(2001), 44, 531-539), copper (I) iodide, triphenylphosphine and dichlorobis(triphenylphosphine)palladium(II) in a 2:1 mixture of triethylamine/DMF, and heating by microwave irradiation for 3600 seconds at 120° C. Purification by column chromatography affords the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].O>C1(C)C=CC=CC=1>[CH:1](=[N:13]/[C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[O:10][CH3:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccccc1N
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1/N=C/c1ccccc1
Yield: 99.8 %

Procedure:
To benzaldehyde (26.1 g, 25.0 mL, 0.246 mol, 1.21 equiv) in toluene (100 mL) was added 2-methoxyaniline (25.1 g, 23.0 mL, 0.204 mol, 1.00 equiv). The reaction mixture was heated to reflux with azeotropic removal of water with a Dean-Stark trap for 12 h. The reaction mixture was concentrated and dried under high vacuum to afford (E)-N-benzylidene-2-methoxyaniline as a yellow oil (43.0 g, >99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of 2-chloro-5-trifluoromethyl-benzoic acid (2.8 g, 12.5 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 7 ml, 14 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 2 hours, methanol (10 ml) was added. After stirring for 20 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide methyl 2-chloro-5-trifluoromethyl-benzoate (2.6 g, 87% yield).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[CH2:30]([O:29][C:27]([NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)Cl
Reactant: NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Solvent: CC#N
Product: CCOC(=O)NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21

Procedure:
[7-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid ethyl ester (482) was synthesized following the general scheme above, from amine (273-I) and ethyl chloroformate. Overall yield (18%). HPLC ret. time 2.84 min, 10-99% CH3CN, 5 min run; ESI-MS 406.5 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][C:3]=1[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=1.[H-].[Na+].Br[CH2:30][O:31][C:32](=[O:34])[CH3:33].CO>CN(C=O)C>[CH3:30][O:31][C:32](=[O:34])[CH2:33][N:8]([C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=2)[CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: CC(=O)OCBr
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide (40 mg, 0.1 mmol) in DMF (0.6 mL) at 0-5° C., NaH (8 mg, 0.2 mmol, 60% in mineral oil) was added and the mixture was stirred for 25 min at rt. Upon addition of bromomethylacetate (21 μL, 0.2 mmol), the mixture was stirred at room temperature for 12 hrs. Addition of MeOH (0.3 mL) was followed by filtration and purification on preparative HPLC to afford [[4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl]-(2-methoxy-phenyl)-amino]-acetic acid methyl ester 17-1.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:17].C(Cl)(Cl)Cl>ClCCl>[CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:17])([CH3:3])[CH3:2]
Reactant: CC(C)OCc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)OCc1cccc[n+]1[O-]
Reaction time: 3 h

Procedure:
A stirred solution of 2-isopropoxymethylpyridine (18.4 g, 0.121 mol) in dichloromethane (200 mL) at room temperature was treated portionwise with meta-chloroperoxybenzoic acid (42.1 g, 0.121 mol), stirred for 3 h, poured into CHCl3 (450 mL) and washed with 2.5-M aqueous NaOH solution (2×250 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as a pale yellow oil; NMR δH (400 MHz, CDCl3), 1.19-1.21 (6H, d, J=6 Hz), 3.71-3.80 (1H, sept, J 6.5 Hz), 4.58 (2H, s), 7.37 (2H, m), 7.47-7.49 (1H, d, J 7 Hz) and 8.25-8.27 (1H, d, J 7.5 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]3[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:45][O:44][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][O:38]4)=[CH:13][N:14]=3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:21]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
To a stirred solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (142 mg) in DMF (3 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (67 mg), HOBT (77 mg), and EDCI hydrochloride (109 mg), and the resulting mixture was stirred at ambient temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated NaHCO3 solution, and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=5:1) to give tert-butyl [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (100 mg) as a pale yellow oil.