Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][N:21]=3)[N:17]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)[N:17]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:15]=2)=[O:13])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)N[C@H]2CC[C@@H](C(C)(C)C)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@@H](NC(=O)c2cc(-c3ccc(Cl)c(Cl)c3)nn2Cc2ccc(C(=O)O)cn2)CC1

Procedure:
To a solution of the intermediate from step G (isomer B) (0.14 g, 0.24 mmol) in 10 ml of 1:1 THF/MeOH was added 5 N NaOH (1 mL). After stirring the reaction at room temperature for 2 hours, it was concentrated in vacuo. The residue was acidified with 1N HCl (10 ml) and the resulting mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4 filtered and concentrated in vacuo. This material was used in the next step without any further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:17]=1)=[N:7][C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[CH:9][N:10]=2.[NH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:22]=2[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[O:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:7]=[C:6]3[N:17]=[C:2]([C:25]4[CH:26]=[CH:27][C:21]5[O:20][C:19]([NH2:18])=[N:23][C:22]=5[CH:24]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Clc1ccc2ncc(N3CCOCC3)nc2n1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
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: C1COCCO1
Solvent: O
Product: Nc1nc2cc(-c3ccc4ncc(N5CCOCC5)nc4n3)ccc2o1
Yield: 71.8 %

Procedure:
A mixture of 6-chloro-3-morpholinopyrido[2,3-b]pyrazine (E-29) (100 mg, 0.4 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (108 mg, 0.6 mmol, 1.5 eq), Pd(PPh3)4 (50 mg, 0.04 mmol, 0.1 eq), and Na2CO3 (0.22 g, 2.0 mmol, 5.0 eq),) were dissolved in a mixture of 1,4-dioxane (15 mL) and water (5 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux temperature for 2 h. The reaction was complete based on TLC analysis. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (60:1:0.02 MeOH-DCM-NH3.H2O) to afford 5-(3-morpholinopyrido[2,3-b]pyrazin-6-yl)benzo[d]oxazol-2-amine (2) (100 mg, 72% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 8.86 (s, 1H), 8.26 (m, 1H), 8.06 (m, 2H), 7.92 (m, 1H), 7.55 (bs, 2H), 7.47 (m, 1H), 3.82 (m, 8H); ESI-MS m/z: 349.14 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH3:29])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:41][CH:40](CN)[CH2:39][O:38]1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH2:29][CH:40]([OH:41])[CH2:39][OH:38])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CC1(C)OCC(CN)O1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(NCC(O)CO)nc2n(C)c1=O
Yield: 63 %

Procedure:
Using a procedure analogous to Example 136, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.071 g, 0.14 mmol) and (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.055 g, 0.42 mmol) were combined in THF (1 mL) to provide 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(2-(2,3-dihydroxypropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea as a white solid (0.047 g, 63% yield; 2 steps).
Reaction SMILES: [C:1]1([PH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[P:16]([CH2:29][CH2:30][CH2:31]Cl)([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.[Li]>C1COCC1.O>[P:16]([CH2:29][CH2:30][CH2:31][PH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([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
Reactant: Pc1ccccc1
Reactant: ClCCCP(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(PCCCP(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
In a Schlenk flask were placed phenylphosphine (3.3806 g, 30.71 mmol) with THF (60 ml) and chilled to −30° C. in a freezer over 30 minutes. To this solution was added lithium diisopropylamide (16 ml, 32.16 mmol) and the resulting solution was allowed to warm to room temperature while stirring. In a 250 ml Schlenk flask was placed (C6H5)2P(CH2)3Cl (7.9089 g, 30.1 mmol) in 100 ml THF and the solution was cooled to −78° C. The lithium phenylphosphide solution was added to the (C6H5)2P(CH2)3Cl solution at such a rate that the temperature of the solution remained constant at −78° C. After addition, the solution was slowly warmed to room temperature. Degassed DI water (0.2 ml) was added to the dark orange solution. The color changed to yellow-orange. The solvents were removed in vacuo. The resulting gel was dissolved in toluene and filtered through Celite. Toluene was then removed in vacuo, leaving an orange-yellow oil. Yield: 10.0 g (99.1%). 31P{1H} NMR (CDCl3, 122 MHz, δppm: −16.30 and −52.86 (>99% pure). 1H NMR (CDCl3, 400 MHz, δ: 1.58–2.15 (3 complex peaks integrated to ˜7Hs), 4.12 (d of t, H—P) and 7.26–7.43 (complex pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1(B(O)O)C=CC=CC=1.B(O)(O)O.[NH2:25][CH2:26][CH:27]([OH:29])[CH3:28]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][CH:27]([OH:29])[CH3:28])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: OB(O)O
Agent: OB(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)CNC(=O)Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 92.9 %

Procedure:
2-(4-Chlorophenyl)acetic acid (1.9 kg, 11.1 mol, 1.00 eq), toluene (1 L), phenylboronic acid (67 g, 549 mmo, 0.049 eq.), and boric acid (68 g, 1.10 mol. 0.099 eq) where charged to a 20 L jacketed reactor in the specified order. After the resulting mixture had been heated with stirring to 40° C., 1-amino-2-propanol (908 g, 12.09 mol, 1.085 eq) and toluene (1 L) were added. The reaction mixture was then heated to reflux while the water coproduct was removed in a Dean-Stark trap. Refluxing and water removal were continued until conversion of 2-(4-chlorophenyl)acetic acid exceeded 98%. Such conversion is usually achieved with 8-12 hours of refluxing. Water coproduct removed in the Dean-Stark trap totaled 265 mL (14.72 mol). After the reaction mixture had been cooled to 60-70° C., 5 wt % aqueous sodium bicarbonate (2 L) was added slowly while the reaction mixture was maintained at 60-70° C. Water (10 mL) was then added slowly while the stirred reaction mixture was maintained at ≧50° C. The diluted reaction mixture was cooled to 30° C. and stirred at that temperature for 30 minutes. The resulting solid precipitate was filtered and vacuum dried for 48 hours at 50° C. to provide 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide (2.356 kg, 92.9% yield not corrected for purity, 90.12% purity by HPLC peak area).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2ccc(OC(C)C)c(C#N)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)O)ccc1-c1noc(-c2ccc(OC(C)C)c(C#N)c2)n1
Yield: 86.9 %

Procedure:
A solution of 23 mg (0.05 mmol) of tert-butyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from Step A) in 4:1 v/v CH2Cl2/TFA was stirred at rt for 30 min. The mixture was concentrated. Purification by HPLC B gave 17 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.47 (d, J=6.2, 6H), 2.66 (s, 3H), 2.74 (t, J=7.8, 2H), 3.01 (t, J=7.8, 2H), 4.76-4.82 (m, 1H), 7.11 (d, J=9.0, 1H), 7.19-7.21 (m, 2H), 8.01 (d, J=8.3, 1H), 8.33 (dd, J=2.3, 8.9, 11H), 8.42 (d, J=2.1, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:9].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][O:9][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][O:17]1
Reactant: CC(CO)(CCCCCBr)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(CCCCCBr)(COC1CCCCO1)c1ccccc1
Yield: 73.7 %

Procedure:
According to the method described for the synthesis of 207d, 206h (51.0 g, 179 mmol) was reacted with 3,4-dihydro-2H-pyran (18.80 g, 223 mmol) and p-toluenesulfonic acid hydrate (1.21 g, 6.36 mmol). Filtration through aluminum oxide (370 g) and concentration in vacuo afforded 207h (48.75 g, 76%) as a yellowish oil. 1H NMR (CDCl3): δ 7.35-7.17 (m, 10H), 4.53 (m, 1H), 4.49 (m, 1H), 3.82 (m, 2H), 3.79 (m, 1H), 3.68-3.60 (m, 2H), 3.45-3.35 (m, 2H), 3.32 (t, 4H, J=6.9), 1.82-1.18 (m, 28H), 1.35 (s, 6H). 13C NMR (CDCl3): δ 146.12, 128.11, 126.66, 125.89, 99.18, 99.04, 76.46, 62.02, 61.83, 42.17, 42.07, 38.91, 38.73, 34.12, 32.80, 30.70, 29.04, 25.66, 23.33, 22.97, 22.89, 19.49, 19.39. HRMS (LSIMS, nba): Calcd for C19H30BrO2 (MH+): 369.1429, found: 369.1430.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28]Cl.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([Cl:24])[CH:26]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.067 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 3 mg (0.08 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 16 mg (0.08 mmol) of 3,4-dichlorobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:28]([CH3:30])[CH3:29].CN(C=O)C>O>[CH:28]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(OC(C)C)ccc3c2=O)cc1
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A mixture of Formononetin (1, 1.34 g, 5 mmol) (G. Y. Gao, et. al. Bioorg. Med. Chem. 2003, 11, 4069), K2CO3 (0.69 g, 5 mol), 2-bromopropane (1.23 g, 10 mmol) and DMF (10 mL) was refluxed with stirring for 3 hrs (TLC monitoring). The mixture was then cooled and evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus obtained was collected, purified by column chromatography (MeOH/CH2Cl2=1:100), and crystallization from EtOH to give 2 (1.46 g, 94% yield). M.p.: 245-246° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1([CH2:19]O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:19][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1CCCCC1
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1

Procedure:
The desired product was prepared using the method described in Example 1176A starting with N-hydoxyphthalimide and cyclohexylmethanol.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])(=[O:3])[CH3:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>CN(C)C=O>[CH3:29][N:30]([CH3:32])/[CH:31]=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])=[O:3]
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Temperature: 110 °C
Yield: 98 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.00 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) was added N,N-dimethylformamide dimethyl acetal (0.45 mL, 3.17 mmol). The reaction mixture was heated at 110° C. for 18 hours. The solvent was removed in vacuo, and the residue was washed with water to afford the title compound in 98% yield (1.12 g): 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.58 (d, J=12.0 Hz, 1H), 5.28 (d, J=12.0 Hz, 1H), 4.50 (s, 2H), 4.01-3.95 (m, 2H), 3.48-3.43 (m, 2H), 3.08 (s, 3H), 2.81 (s, 3H), 2.48 (s, 3H); MS (ES+) m/z 439.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1COc2c(Br)cccc2N1
Agent: [H-]
Agent: [Na+]
Product: O=C1COc2c(Br)cccc2N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
To a solution of 8-bromo-4H-benzo[1,4]oxazin-3-one (343 mg, 1.5 mmol) in 10 ml anhydrous dimethylformanide was added sodium hydride (120 mg of a 60% suspension in mineral oil, 3.0 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial gas evolution ended. Benzyl bromide (0.22 ml, 1.8 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for 30 minutes. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml) and the combined organic fractions were washed with water (2×25 ml) and brine (2×25 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography (5%–15% Ethyl acetate/Hexane in 30 minutes) to give 402 mg of 4-benzyl-8-bromo-4H-benzo[1,4]oxazin-3-one as a yellow solid (84%). MS: 318 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O.[H][H]>[OH-].[Na+].[Ni]>[NH2:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]([OH:12])=[O:11]
Reactant: COCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
4-(2-Methoxyethylamino)-3-nitro-5-sulphamyl-benzoic acid (3.2 g) was dissolved in 1N sodium hydroxide (10 ml) and hydrogenated after addition of moist Raney-Nickel (1 g). When the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the resulting 3-amino-4-(2-methoxyethylamino)-5-sulphamyl-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until pH 3. After recrystallization from water, the melting point was 209°-211° C.
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][C:13]2[C:14]([O:22][CH3:23])=[N:15][C:16]([CH3:21])=[C:17]([CH2:19][CH3:20])[CH:18]=2)C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH2:19]([C:17]1[CH:18]=[C:13]([CH2:12][CH2:11][CH2:10][NH:9][C:8]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH2:38][CH2:37]2)=[O:24])[C:14]([O:22][CH3:23])=[N:15][C:16]=1[CH3:21])[CH3:20]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(CCCNC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(CCCNC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-[3-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)propyl]carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].O=C(Cl)[O:12][C:13](Cl)(Cl)[Cl:14].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:14][C:13]([O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)Oc1ccc(Cl)c(Cl)c1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
3,4-Dichlorophenol (2.35 g) was dissolved in anhydrous dichloromethane (50 ml) at room temperature under an atmosphere of argon. The mixture was cooled to −30° C. and diphosgene (3.92 g) and N,N-Diisopropylethylamine (2.51 ml) were added slowly in the order specified. The resulting solution was then stirred at 0° C. for 3 hours, then at room temperature for 18 hours and finally at reflux for 2 hours. The solution volume was measured and used accordingly.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[C:9]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]1)=[O:6].[CH2:26]([C:30]1[CH:35]=[CH:34][C:33]([CH:36](Br)[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)[CH:27]([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:43]([C:40]1[CH:41]=[CH:42][C:37]([CH:36]([NH:1][C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]2)=[O:6])[C:33]2[CH:34]=[CH:35][C:30]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3cc(Cl)ccc32)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)n3cc(CCCC(=O)O)c4cc(Cl)ccc43)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A mixture of 4-[1-(3-aminobenzoyl)-5-chloroindol-3-yl]butyric acid (700 mg), bis(4-isobutylphenyl)methyl bromide (705 mg) and diisopropylethylamine (620 mg) in dichloromethane (20 ml) was stirred at 20° C. for 1 hour, and then bis(4-isobutylphenyl)methyl bromide (150 mg) and diisopropylethylamine (70 mg) were added. After stirred at 20° C. for 3 hours, the reaction mixture was poured into iced 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (10:1 to 1:1) to give 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-5-chloroindol-3-yl]butyric acid (803 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])/[CH:23]=[N:16]/[S:15]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:18])=[O:17]
Reactant: CC(C)(C)C(=O)Nc1cccc(O)c1S(N)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=N/S(=O)(=O)c1c(O)cccc1NC(=O)C(C)(C)C

Procedure:
A solution of N-(3-hydroxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide (15.2 g, 55.9 mmol) and N,N-dimethylformamide dimethylacetal (9.7 ml, 72.6 mmol) in DMF (65 ml) is stirred at 60° C. for 1 h. Volatiles are evaporated at reduced pressure. Chromatography of the residue (21.8 g) dissolved in dichloromethane (silica gel, hexanes/EtOAc=1:1) gives N-(2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-3-hydroxy-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][NH:34][CH2:31][CH2:32][CH3:33])=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CCCN
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CCCNCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and propylamine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.25-3.8 (m, 12H), 3.05 (t, J=7.5 Hz, 2H), 1.74 (m, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 394 (+H)+;