Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: 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.Br[C:48]1[CH:49]=[C:50]([C:58]([NH:60][C:61]2[CH:62]=[C:63](/[CH:68]=[CH:69]/[C:70]([O:72]CC)=[O:71])[CH:64]=[CH:65][C:66]=2[F:67])=[O:59])[C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2.[NH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1.CC(C)([O-])C.[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[F:67][C:66]1[CH:65]=[CH:64][C:63](/[CH:68]=[CH:69]/[C:70]([OH:72])=[O:71])=[CH:62][C:61]=1[NH:60][C:58]([C:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:57]=[C:48]([N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)[CH:49]=1)=[O:59]
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(Br)cc3ccccc23)c1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)c(NC(=O)c2cc(N3CCCCC3)cc3ccccc23)c1

Procedure:
A Biotage Process Vial (5-20 mL) was charged with BINAP (0.36 mmol), Pd2(dba)3 (0.18 mmol), ethyl(E)-3-[3-[(3-bromonaphthalene-1-carbonyl)amino]-4-fluoro-phenyl]prop-2-enoate (15) (1.81 mmol), piperidine (5.44 mmol), and potassium tertbutoxide (3.62 mmol). The vial was charged with DMF (5 mL) and irradiated at 100-130° C. for 1 h, using the microwave reactor Smith Synthesizer. After irradiation, the sample was cooled and diluted with water and extracted with ethyl acetate (3×50 mL). The organic layer was washed with water, brine and dried over Na2SO4 and the solvent evaporated to dryness to afford crude 29, which was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]([CH2:15][OH:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C@@H:9]1[CH2:10][CH2:11][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[CH:13]([CH2:15][OH:16])[NH:14][C:25]1=[O:27])[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(N)CO)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution (5S)-N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-(hydroxymethyl)-D-lysine (180 mg, 0.37 mmol) in DCM (5 mL) were added EDC (106 mg, 0.55 mmol) and HOAT (50 mg, 0.37 mmol). After 30 min, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (0%→10% MeOH/DCM) to give the title compound (100 mg). MS 471.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21]CC)=[O:20].[OH-].[Na+]>CN(C=O)C.C1COCC1.O>[CH3:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[N:6]([CH2:18][C:19]([OH:21])=[O:20])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1C)OCC(=O)N2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C)OCC(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 7-methyl-6-(methyloxy)-2H-1,4-benzoxazin-3(4H)-one (2.13 g, 11 mmol) in DMF (20 mL) was added NaH (528 mg, 13.2 mmol) in two portions. The reaction mixture was stirred for 30 minutes at room temperature, and ethyl bromoacetate (1.22 mL, 11 mmol) was added. The reaction mixture was stirred for 3 hour until all starting material was consumed, then poured into cold water (200 mL). The precipitate was collected by filtration, washed with water, and dried in the air to afford a pale solid. This solid was dissolved in THF (22 mL) and NaOH (2.0 M, 5.5 mL) was added, and the reaction mixture was stirred at room temperature for 2 h, poured into cold water (100 mL), and extracted with EtOAc (2×100 mL). The aqueous layer was acidified with HCl (6 N) to pH˜1, extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with brine, and dried (Na2SO4). The solvent was removed via rotovap to give the title compound (2.35 g, 85%) as a pale solid. MS (ES) m/e 252 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:18]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To solution of (2,4-dichloro-phenoxyacetic acid (0.200 g, 0.9 mmol), 2-amino isonicotinic acid methyl ester (207 mg, 1.36 mmol) and DMAP (0.222 g, 1.81 mmol) in DMF 13 mL was added PyBOP (946 mg, 1.81 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9-4:6) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.229 g, 71% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[CH2:26][OH:27])[CH2:13][CH2:12]2)[CH:5]=1.Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[CH2:26][O:27][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:13][CH2:12]2)[CH:5]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3CO)CC2)c1
Reactant: ClCCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3COCCCN3CCOCC3)CC2)c1
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
Aqueous sodium hydroxide (50% w/w, 10 g, 125 mmol) and tetrabutylammonium hydrogen sulfate (0.20 g) were added successively to a solution of {2-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-5-nitro-phenyl}-methanol (0.50 g, 1.46 mmol) in toluene (5 mL). The mixture was heated to reflux with vigorous stirring for 45 min then 4-(3-chloro-propyl)-morpholine (0.50 g, 3.00 mmol) was added and reflux continued for 28 h. The reaction mixture was cooled and the organic phase separated. The aqueous phase was extracted with ethyl acetate (3×5 mL). The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue which was purified by preparative TLC eluting with 2% methanol in chloroform to afford 4-(3-{2-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-5-nitro-benzyloxy}-propyl)-morpholine (550 mg, 80%) as a solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:10]([Cl:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14]2)[CH3:5].[BH3-]C#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.CO.O>[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:10]([Cl:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH2:19][N:2]([CH3:3])[CH3:1])[CH:15]=[CH:14]2)[CH3:5]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)nc12
Reactant: CNC
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
Dimethylamine (5.6 M solution in EtOH, 0.27 ml, 1.54 mmol, 1.5 equiv) was added to a solution of (7-chloro-2-formyl-quinolin-8-yl)-acetic acid ethyl ester (285 mg, 1.03 mmol) in anhydrous THF (5 ml). The reaction mixture was stirred at room temperature for 18 hours. A solution of NaCNBH3 (77 mg, 1.23 mmol, 1.2 equiv) in methanol (2 ml) was added, immediately followed by the addition of acetic acid (308 mg, 5.13 mmol, 5.0 equiv). After 5 minutes at room temperature, TLC analysis indicated complete conversion. The reaction mixture was diluted with water, adjusted to pH=8 with concentrated aqueous NaHCO3 solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of CH2Cl2/MeOH 99:1 to 90:10) to afford the title compound (245 mg, 78%) as a colorless solid. 1H NMR (400 MHz, d6-DMSO): δ=8.45 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 4.47 (s, 2H), 4.08 (q, J=7.3 Hz, 2H), 2.50 (s, 6H), 1.16 (t, J=7.3 Hz, 3H). MS (ES+): 307.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.O/[N:30]=[C:31](\[NH2:50])/[C:32]1[CH:37]=[CH:36][C:35]([C@H:38]2[CH2:49][CH2:48][C:40]3([NH:44][C:43](=[O:45])[N:42]([CH3:46])[C:41]3=[O:47])[CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:30]=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([C@H:38]4[CH2:49][CH2:48][C:40]5([NH:44][C:43](=[O:45])[N:42]([CH3:46])[C:41]5=[O:47])[CH2:39]4)=[CH:36][CH:37]=3)[N:50]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: CN1C(=O)NC2(CC[C@H](c3ccc(/C(N)=N/O)cc3)C2)C1=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Cc1ccc(-c2nc(-c3ccc([C@H]4CCC5(C4)NC(=O)N(C)C5=O)cc3)no2)cc1
Temperature: 140 °C
Yield: 21 %

Procedure:
A solution of 4-isobutylbenzoic acid (0.130 g, 0.728 mmol), EDC (0.139 g, 0.728 mmol) and HOBt hydrate (0.111 g, 0.728 mmol) in DMF (1.0 ml) was stirred at ambient temperature for 1-1.5 hours. To the mixture was added (Z)-N′-hydroxy-4-{(7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl}benzimidamide (0.200 g, 0.662 mmol) as solution in 1.0 ml DMF at ambient temperature. The resulting mixture was heated to about 140° C. for additional 2 hours. Solvent was removed in vacuo. The crude product was purified on a Prep HPLC system using 20-99% 50 mM NH4OAc buffer in acetonitrile at 81 mL/min to afford (7S)-7-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (0.062 g, 0.139 mmol) as light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[S:26])[CH:19]=1.O>CN(C=O)C>[CH3:27][C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[CH2:10][NH:11][C:12]4=[O:17])=[CH:6][CH:7]=2)=[S:26])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=S)Nc2ccc(-c3cccc4c3CNC4=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A solution of Example 1D (0.1 g, 0.44 mmol) in DMF (3 mL) was treated with m-tolylisothiocyanate (0.06 mL, 0.45 mmol), stirred at room temperature overnight, then cooled to 0° C., treated with water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 3% methanol/dichloromethane to give 72 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H); 4.53 (s, 2H); 6.96 (d, J=7.12 Hz, 1H); 7.23 (t, J=7.80 Hz, 1H); 7.29 (d, J=7.80 Hz, 2H); 7.57–7.69 (m, 7H); 8.68 (s, 1H); 9.84 (s, 1H); 9.88 (s, 1H); MS (ESI(−)) m/e 372 (M−H)−.
Reaction SMILES: [C:1]([Si:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[C:31]([C:36]([O:38][CH3:39])=[O:37])[C:32]([O:34][CH3:35])=[O:33])=[N-]>C(Cl)(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH3:35][O:34][C:32]([C:31]1([C:36]([O:38][CH3:39])=[O:37])[CH2:10][C:9]1([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:33]
Reactant: C=C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccccc1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccccc1
Temperature: 100 °C
Yield: 69.1 %

Procedure:
To a mixture of t-butyldiphenyl-(3-phenyl-3-butenyloxy)-silane (3.0 g, 7.0 mmol) and dimethyl diazomalonate (1.1 g, 7.0 mmol), which was synthesized by the method described in Synth. Commun. (1987, 17, 1709-1716), was added rhodium (II) acetate dimmer (62 mg, 0.14 mmol) under argon atmosphere, and the mixture was heated at 100° C. for 10 min. After cooling to room temperature, the mixture was diluted with chloroform (4 mL), separated and purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 4:1) to give the title compound (2.5 g, yield 70%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[NH:5][CH2:4][C:3]#[N:2])[CH:18]=[CH2:19]
Reactant: C=CCOC(=O)Cl
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)NCC#N
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a suspension of 110 g of aminoacetonitrile hydrochloride in 1.2 l of acetonitrile were added at 20° C. 121.5 g of triethylamine. The mixture was cooled in an acetone-ice bath and 144.7 g of allyl chloroformate were added slowly, the temperature being maintained below 20° C. Subsequently, 121.5 g of triethylamine were added at such a rate that the temperature did not rise above 20° C. The mixture was stirred at 20° C. for 2 h and then, the solids were removed by filtration. The mother liquor was concentrated in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated potassium hydrogen sulfate solution, saturated potassium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residual oil was distilled in vacuo to yield 132.6 g of cyanomethyl-carbamic acid allyl ester as a colorless oil, b.p. 100° C./0.07 mbar.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14]1([CH2:20][C:21](O)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:20]([C:21]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(C(=O)O)C(O)c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Product: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures Y, Z with phenyl-acetic acid, Z1 and Z2. LC-MS-conditions 02: tR=0.95 min; [M+H]+=220.18.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]2[OH:32])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15].O>CS(C)=O.ClCCl>[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C:20]2=[O:32])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 120.7 %

Procedure:
Triethylamine (374 μL, 2.68 mmol) and sulfur trioxide-pyridine complex (256 mg, 1.61 mmol) were added to a mixed solution of tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-hydroxypiperidine-1-carboxylate synthesized in Example (201b) (100 mg, 0.268 mmol) in dimethyl sulfoxide (1 mL) and dichloromethane (1 mL) at room temperature, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 120 mg of the title compound as an orange foamy substance, which was used for the next reaction without purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][C:15](N)=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH3:20])=[N:13]3)[CH2:4][CH2:3]1.[ClH:21].N([O-])=O.[Na+].[OH-].[Na+]>O.C(O)CCCCCCC.[Cu]>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][C:15]([Cl:21])=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH3:20])=[N:13]3)[CH2:4][CH2:3]1
Reactant: Cl
Reactant: Cc1ccc2c(N3CCC(O)CC3)c(F)cc(N)c2n1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCCCO
Product: Cc1ccc2c(N3CCC(O)CC3)c(F)cc(Cl)c2n1
Reaction time: 0.08 h

Procedure:
5-(4-Hydroxy-1-piperidyl)-6-fluoro-8-aminoquinaldine (2.0 g) was dissolved in 7 ml of water and 20 ml of concentrated hydrochloric acid and 0.53 g of sodium nitrite in 3 ml of an aqueous solution was added dropwise to the solution at 0° C. After 5 minutes, one drop of n-octanol (defoaming agent) and then 0.46 g of copper powder were added to the mixture at a time. Foaming was observed immediately. After foaming stopped the reaction mixture was stirred for additional 3 minutes at 0°-5° C. The reaction mixture was diluted with water and rendered alkaline with an aqueous sodium hydroxide solution to precipitate solids which were then collected by filtration and dissolved in mixed solvent of methanol-chloroform to remove insoluble substances. After concentration, the residue was purified through silica gel column chromatography (chloroform:methanol=5:1) to give 1.62 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-8-chloroquinaldine.
Reaction SMILES: N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+].Br[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]1[CH2:40][CH2:39][NH:38][C:37]1=[O:41]>CCCCCC.[Cu](I)I.C(OCC)(=O)C.O1CCOCC1>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]1[CH2:40][CH2:39][N:38]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[C:37]1=[O:41]
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: O=C1NCCN1c1ccc2ccccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1N(c2cncc(C(F)(F)F)c2)CCN1c1ccc2ccccc2c1
Temperature: 110 °C
Yield: 50.9 %

Procedure:
Copper iodide (12.6 mg, 0.066 mmol), trans-1,2-diamino cyclohexane (22.79 mg, 0.199 mmol) and potassium carbonate (183.5 mg, 1.32 mmol) were added to 1,4-dioxane (5 mL) and 3-bromo-5-trifluoromethyl-pyridine (150 mg, 0.66 mmol) previously degassed with argon (10 minutes). The reaction was purged with argon for a further 10 minutes, followed by the addition of 1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 140 mg, 0.66 mmol) and the resulting mixture was heated to reflux at 110° C. for 15 hours. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was filtered through celite and the bed was washed with chloroform. The organic layer was dried over Na2O4 and concentrated. Purification by column chromatography (using silica gel of mesh size of 60-120, 30% EtOAc in hexane as eluant) afforded 120 mg (52% yield) of 1-naphthalen-2-yl-3-(5-trifluoromethyl-pyridin-3-yl)-imidazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>O.[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([N:60]4[CH2:65][CH2:64][O:63][CH2:62][CH2:61]4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(N3CCOCC3)cc12
Temperature: 70 °C

Procedure:
A vial was charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.647 g, 1.858 mmol), DavePhos (0.088 g, 0.223 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.085 g, 0.093 mmol). The vessel was flushed with Ar(g), then lithium bis(trimethylsilyl)amide (1.0 M in THF) (9.29 mL, 9.29 mmol) and morpholine (0.486 mL, 5.58 mmol) were added in sequence. The vial was sealed and heated at 70° C. for one hour at which point the mixture was diluted with water and saturated ammonium chloride. The mixture was extracted with DCM (3×30 mL). The aq. layer was extracted with ethyl acetate and 10% iPrOH/EtOAc, and the solid was taken with the organic layer. The different organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-10% MeOH:DCM w/1% NH4OH) to afford (S)-2′-amino-3-morpholino-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an orange solid.