Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[N:19]1([C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:22]3[CH2:21][CH2:20][N:19]([C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27])[CH2:24][CH2:23]3)=[N:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (250 mg, 0.88 mmol), 2-piperazin-1-yl-isobutyramide (173 mg, 1.01 mmol) and 4 Å molecular sieves (1.0 g) in 1,2-dichloroethane (15 mL) was stirred at RT under nitrogen atmosphere for 4 h. Sodium triacetoxyborohydride (280 mg, 1.32 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded on an Isolute® SCX-2 cartridge (25 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2 M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, MeOH:DCM: gradient 0:100 to 6:94). The solvents were reduced in vacuo to afford the title compound as a yellow solid (275 mg, 60%). LCMS (Method H): RT 2.41 min, [M+H]+ 440. 1H NMR (400 MHz, CDCl3): δ 7.04 (1 H, br s), 5.22 (1 H, br s), 3.97-3.95 (6 H, m), 3.85 (4 H, t, J=4.80 Hz), 2.67 (8 H, m), 1.25 (6 H, s)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(-c2ccncc2)c(C)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(-c2ccncc2)c(C)cc1N
Reaction time: 72 h
Yield: 106.1 %

Procedure:
4-[2-methyl-5-(methyloxy)-4-nitrophenyl]pyridine (Example 157, step A) (2.44 g, 9.99 mmol) was placed in a 250 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (1.17 g, 0.3 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (60 psi). The solution stirred for 72 h. The vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to give the title compound of step A (2.28 g, 10.6 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50-8.53 (m, 2H), 7.30-7.33 (m, 2H), 6.68 (s, 1H), 6.54 (s, 1H), 4.88 (bs, 2H), 3.75 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[O:13][CH:5]2[CH:6]=[CH:7]1.C1C[O:17][CH2:16]C1>CO>[F:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[F:1])[C@H:5]([OH:13])[C@@H:6]([O:17][CH3:16])[CH:7]=[CH:8]2
Reactant: Fc1cc2c(cc1F)C1C=CC2O1
Reactant: C1CCOC1
Solvent: CO
Product: CO[C@H]1C=Cc2cc(F)c(F)cc2[C@@H]1O
Yield: 88 %

Procedure:
To a flame dried round bottom flask, [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), (S)—(R)-PPF-PtBu2 (5.4 mg, 0.010 mmol) and 24 (72 mg, 0.40 mmol) were added followed by addition of THF (1.0 mL) and methanol (1.0 mL). The mixture was heated to reflux for 1 hour. The solvents were then removed in vacuo. The resulting solid was purified by flash chromatography (20% ethyl acetate in hexanes) to give 27 as a white crystalline solid (74.9 mg, 88%). The ee was determined to be 96.4% using HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 4% isopropanol in hexanes were 8.9 min and 10.1 min (major). Rf=0.27 on silica gel (30% ethyl acetate:hexanes); mp 129-131° (Et2O); [α]25D=+134.4° (c=9.3, CHCl3); IR (KBr, cm−1) 3269 (br), 2937 (w), 1597 (m), 1503 (s), 1306 (s), 1103 (s), 893 (s); 1H NMR (400MHz, CDCl3) δ 7.40 (1H, ddd, JH-F=10.8, 7.8 Hz, JH-H=0.6 Hz), 6.85 (1H, dd, JH-F=10.9, 7.8 Hz), 6.31 (1H, dd, J=10.0, 2.0 Hz), 6.05 (1H, dd. J=10.0, 2.0 Hz), 4.79 (1H, d, J=11.0 Hz), 4.05 (1H, ddd, J=11.0, 2.0, 2.0 Hz), 3.49 (3H, s), 2.94 (1H, d, J=2.2 Hz); 13C NMR (400 MHz, CDCl3) δ 151.0 (d, JH-F=12.5 Hz), 148.5 (dd, JH-F=12.5,2.9 Hz), 133.2 (dd, JH-F=5.2, 3.6 Hz), 128.9 (dd, JH-F=6.6, 4.4 Hz), 128.0 (d, JH-F=2.2 Hz), 126.5 (dd, JH-F=2.2, 1.5 Hz), 115.1 (d, JH-F=18.3 Hz), 114.8 (d, JH-F=19.8 Hz), 82.3, 72.0, 57.0. HRMS calcd for C11H10O2F2 (M+): 212.0649. Found: 212.0658.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: Clc1ccncn1
Reactant: CC(O)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccncn1)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 1-(4-bromophenyl)ethanol (1 g, 5 mmol) in 20 mL of anhydrous N,N-dimethylformamide was added sodium hydride (0.36 g, 15 mmol) at room temperature and then stirred for 1 hour, 4-chloropyrimidine hydrochloride (1 g, 6 mmol) was added, and then heated at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by chromatography with petroleum/ethyl acetate=1:1 to afford 4-(1-(4-bromophenyl)ethoxy)pyrimidine (1.2 g, 86% yield). LRMS (M+H+) m/z: calcd for 278.01. found 278. 1H NMR (300 MHz, CD3OD) δ 8.65 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (dd, J=6.0 and 1.2 Hz, 1H), 6.26 (q, J=6.6 Hz, 1H), 1.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:12][OH:13]>CCO>[NH2:10][C:9]1[O:13][N:12]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: NO
Reactant: N#CCC(=O)C1CCCCC1
Solvent: CCO
Product: Nc1cc(C2CCCCC2)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-cyclohexyl-3-oxopropanenitrile (1 g, 6.6 mmol, Step A) in EtOH (1 mL) at RT was added hydroxylamine (0.81 mL, 50% in H2O). The reaction was stirred 12 h at RT. The solid was filtered off, washed with 1N NaOH, then H2O and dried over P2O5 to give 5-amino-3-cyclohexylisoxazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:10]([F:15])[F:14])[CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: FC(F)Oc1cncc(Br)c1

Procedure:
A mixture of 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland, 1.394 mmol), sodium chlorodifluoroacetate (Aldrich, Buchs, Switzerland, 1.672 mmol) and potassium carbonate (2.79 mmol) in acetonitrile (10 ml) was refluxed for 4 h 45 min. The reaction was cooled and diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated to give the title compound as a brown oil. (HPLC: tR 2.91 min (Method A); M+H=224, 226 MS-ES).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]=[O:27])=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:28][Mg]Br>C1COCC1.[Cl-].[NH4+]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]([OH:27])[CH3:28])=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(C(C)O)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (42 mg) in THF (1 ml) was added 0.93M methylmagnesium bromide in THF (0.18 ml) at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. Another 0.93M methylmagnesium bromide in THF (0.18 ml) was added at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (3:1) to give ethyl 3-[1-ethyl-6-(1-hydroxyethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (34 mg) as a colorless oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: NCCc1ccc(N)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCc1ccc(N)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Isopropyl N-cyano-3 pyridinecarboximidate (1.0 g, 5.3 mmol) was dissolved in methanol (15 ml), and 2-(4-aminophenyl)ethylamine (0.80 g, 5.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give N-cyano-N'-[2-(4-aminophenyl)ethyl]-3-pyridinecarboximidamide (0.88 g, 3.3 mmol, yield: 63%) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S(=O)(=O)(O)O.[CH:14]([C:16]([CH3:18])=O)=[CH2:15].[OH-].[Na+]>C(O)(=O)C.O>[CH3:18][C:16]1[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:15][CH:14]=1
Reactant: C=CC(C)=O
Reactant: Nc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccnc2c(Br)cccc12
Temperature: 90 °C

Procedure:
2-Bromoaniline (5.16 g, 30 mmol) dissolved in acetic acid and conc. sulfuric acid was treated with a solution of methyl vinyl ketone in acetic acid. The reaction mixture heated to 90° C. for 14 h. The cooled mixture was poured into water and basified with sodium hydroxide and extracted into EtOAc. The organics were dried over Na2SO4, and concentrated the purified by SGC (Combiflash 0-100% EtOAc: hexanes over 30 minutes) followed by recrystallization from hot hexanes furnished 4-methyl-8-bromoquinoline (2.3 g). 1H NMR (CDCl3) δ 8.92 (d, 1H), 8.08 (d,1H), 8.01 (d,1H), 7.45 (t,1H), 7.32 (d,1H), 2.71 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](O)[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3ncccc3c(O)n2)cc1
Product: COc1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Yield: 98.5 %

Procedure:
7-(4-Methoxyphenyl)-[1,6]naphthyridin-5-ol (13 g) and POCl3 (275 mL) was heated to 135° C. for 26 hours in a sealed tube. The mixture was cooled and the POCl3 was evaporated. The residue was poured onto ice and neutralized with 2M Na2CO3 and the precipitate was filtered and washed with H2O to yield 13.8 g of the title compound (98.5%), mp 126-127° C.
Reaction SMILES: [BH4-].[Li+].CO.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20](OCC)=[O:21])[CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1>O1CCCC1>[F:26][C:6]([F:5])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccnc(-c2ccc(OC(F)(F)F)cc2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccnc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
After lithium borohydride (3.0 M solution in tetrahydrofuran) (0.05 mL) and methanol (0.006 mL) was added dropwise to an ice-cold solution of ethyl 2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylate (29 mg) in tetrahydrofuran (3.0 mL), the mixture was stirred for 1 hr, then returned to room temperature and stirred for 30 min. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate. After washing with 2N hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, the organic phase was separated out. The solvent was distilled off under reduced pressure to afford the title compound (13 mg) as the residue.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH2:28][CH3:29])=[CH:19][C:4]=2[N:3]=1
Reactant: CCI
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
To a suspension of 6-chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) (30 mg) and potassium carbonate (60 mg) in N,N-dimethylformamide (0.5 ml) was added iodoethane (25 mg) and the mixture was stirred at 90° C. for 1.5 hrs. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol (100:1) to give 6-chloro-3-ethoxy-5,9-diaza-benzo[c]-fluoren-7-one (18 mg) as a yellow powder. ESI−MS: m/z 311 (MH+); 1H-NMR (CDCl3): δ1.54 (3H, t, J=7 Hz), 4.25 (2H, q, J=7 Hz), 7.39 (1H, dd, J=9 Hz, 2.5 Hz), 7.43 (1H, d, J=2.5 Hz), 8.10 (1H, d, J=5.5 Hz), 8.35 (1H, d, J=9 Hz), 8.95 (1H, d, J,=5.5 Hz), 9.04 (1H, s).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:16][CH3:17])=[C:7]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:8]=1.[O:18]1CCC[CH2:19]1>C1(C)C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:16][CH3:17])=[C:7]([CH:9]2[O:15][C:19](=[O:18])[NH:11][C:10]2=[O:14])[CH:8]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1cc(F)ccc1OC
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 9, ethyl 1-(5-fluoro-2-methoxyphenyl) -1-hydroxymethanecarboximidate hydrochloride (9.9 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(5-fluoro-2-methoxyphenyl)oxazolidine-2,4-dione (5.12 g., 60%; m.p. 186°-188° C.; m/e 225).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH:5]([OH:41])[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH:5]([OH:41])[C:4]([OH:42])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)C(O)CNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)NCC(O)C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-benzoylamino}-2-hydroxypropionic acid ethyl ester (0.99 g, 1.61 mmol) in ethanol (15 mL) and THF (15 mL) was stirred and 1 M sodium hydroxide (6 mL) was added. The mixture was stirred at 40° C. for 4 hours and acidified with 1 N hydrochloric acid. After evaporation in vacuo the residue was purified on semipreperative HPLC (Gilson system). The pure fractions were combined and evaporated in vacuo to afford 0.749 (79%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Fc1ccc(Sc2ccc(Br)cc2)c(F)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(F)cc3F)cc2)c1C
Yield: 16.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,4-difluorobenzene (0.176 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,4-difluoro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.04 g, 16%) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]>C(OCC)(=O)C.CCCCCC>[CH3:34][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]
Reactant: CCOC(=O)/C=C(\C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 76 %

Procedure:
Using ethyl (2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)but-2-enoate obtained in Example 179, the title compound was synthesized in the same manner as in Example 180. Yield: 76%. Melting point: 100-101° C. (ethyl acetate-hexane).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:24]2[N:28]=[CH:27][NH:26][N:25]=2)=[C:6]([NH:9][C:10](=[O:23])[CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]2=[O:22])[S:7][CH:8]=1.I[CH3:30]>CN(C=O)C.O>[Br:3][C:4]1[C:5]([C:24]2[N:28]=[CH:27][N:26]([CH3:30])[N:25]=2)=[C:6]([NH:9][C:10](=[O:23])[CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]2=[O:22])[S:7][CH:8]=1
Reactant: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1nc[nH]n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc(-c2c(Br)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (4.2 mg of a 60% dispersion in mineral oil, 0.107 mmol) was added to a solution of N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (31 mg, 0.0715 mmol) in DMF (0.1 mL) at 0° C. The suspension was stirred for 5 minutes after which iodomethane (12 mg, 0.058 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes then diluted with water, extracted with ethyl acetate, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give N-(4-bromo-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide. Retention time (min)=1.740, method [7], MS (ESI) 447.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 8.33 (d, J=5.2 Hz, 1H), 7.85 (bs, 1H), 7.61 (bs, 1H), 7.11 (s, 1H), 4.94 (s, 2H), 4.02 (s, 3H), 3.41-3.36 (m, 2H), 3.01-2.97 (m, 2H).
Reaction SMILES: [CH:1]1([O:7][N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]1([O:7][NH:8][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione (11.8 mmol, 2.89 g) was combined with hydrazine (13.0 mmol, 0.41 mL) in anhydrous THF (20 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 18 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (10.6 mmol, 2.20 g) and diisopropylethylamine (14.2 mmol, 2.47 mL) was added. After stirring at room temperature for 24 hours, the reaction was concentrated to a yellow solid and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The product was concentrated to a yellow solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) providing 2.53 g (83%) of a white solid. Rf: 0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.86 (2H,d), 7.00 (2H,d), 6.67 (1H,s), 3.98-3.95 (1H,m), 3.88 (3H,s), 2.00-1.94 (2H,m), 1.75-1.55 (2H,m), 1.35-1.17 (6H,m).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5](F)[CH:4]=1)#[N:2].[CH3:12][NH:13][NH2:14]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:6]([CH:7]=[N:14][N:13]2[CH3:12])=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: CNN
Product: Cn1ncc2ccc(C#N)cc21

Procedure:
The title compound was prepared according to the method described in Example 8, Step A, 4-cyano-2-fluorobenzaldehyde and methyl hydrazine as starting materials: 1H NMR (CDCl3) δ 8.07 (s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.37 (d, J=8.3 Hz, 1H), 4.14 (s, 3H).