Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:20]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH2:21][OH:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C@@H:20]([O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:29])[CH3:30])[CH:31]([CH3:32])[CH3:33])[CH:21]=[O:22])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)[Si](O[C@@H](C=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Freshly distilled dimethyl sulfoxide (0.85 g, 10.8 mmol) was added by syringe to a -78° C. solution of oxalyl chloride (0.69 g, 5.41 mmol) in anhydrous THF (22.6 mL). After 10 minutes, the alcohol of Step 3 (2 g, 4.51 mmol) in anhydrous THF (2.3 mL) was added over a period of 1.2 minutes to the -78° C. solution. The solution was stirred for 20 min. and then triethylamine (2.28 g, 22.6 mmol) was added dropwise. The 78° C. bath was removed and the reaction solution was allowed to warm to room temperature. After 1 hour at room temperature, the white, opaque mixture was poured into H2O (25 mL). The solution was extracted with ether (2×5 mL). The combined organic layers were washed with 1N HCl (25 mL), 5% NaHCO3 (25 mL) and brine (25 mL), and then dried with MgSO4. The filtrate was concentrated at 30° C. in vacuo to give the title compound as a clear, pale yellow liquid (2.08 g, 104% crude yield, TLC, 10% ethyl acetate in hexane, Rf 0.32). 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: C(N(CC)CC)C.NCCCN1C=CN=C1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([NH:31][CH2:32][CH3:33])=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[O:34]1CCCC1>>[CH2:32]([NH:31][C:24]1[CH:23]=[C:22]2[C:27]([C:18](=[O:34])[NH:19][CH:20]=[N:21]2)=[CH:26][C:25]=1[N+:28]([O-:30])=[O:29])[CH3:33]
Reactant: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: NCCCn1ccnc1
Solvent: CCN(CC)CC
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]

Procedure:
Triethylamine (10 ml, 71.7 mmol) and 1-(3-aminopropyl)imidazole (5 ml, 41.9 mmol) were added to a tetrahydrofuran solution (10 ml) of 4-chloro-7--ethylamino-6-nitroquinazoline obtained from 7-ethylamino-6-nitro-4(3H)-quinazolone (610.3 mg, 2.61 mmol) in Reference Example 13 under ice-cooling. The mixture was stirred at room temperature for 19 hours and at 50° C. for 12 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (elution with chloroform:methanol=30:1) to give Solid A (800 mg, 89.9%).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 20 g (156 mmol) of isonipecotamide, 32.4 g (234 mmol) of potassium carbonate, 2 g (12 mmol) of potassium iodide and 18.6 ml (156 mmol) of benzyl bromide in 400 ml of acetonitrile is heated at reflux for 5 hours. The solvent is evaporated off and the residue is taken up in a dichloromethane/water mixture. After decanting, extracting with dichloromethane, washing the organic phases with brine and drying, removal of the solvent by evaporation yields the expected product.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][O:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][OH:22]>[Cl-].[Zn+2].[Cl-]>[OH:22][CH2:21][CH2:20][N:19]1[CH2:10][CH2:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:9]
Reactant: NCCO
Reactant: O=C1OCCC1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3,3-diphenyldihydrofuran-2(3H)-one (0.5 g, 2.098 mmol), 2-aminoethanol (1282 mg, 20.98 mmol) and zinc chloride (0.23 g, 1.679 mmol) was heated neat at 100° C. for 16 hours. The reaction mixture was cooled and partitioned in H2O/ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated to yield the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 8H), 7.23 (m, 2H), 3.81 (q, J=5.42 Hz, 2H), 3.52 (t, J=5.42 Hz, 2H), 3.45 (t, J=6.44 Hz, 2H), 2.85 (t, J=5.52 Hz, 1H), 2.79 (t, J=6.44 Hz, 2H); MS (ESI+) m/z 282 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([CH2:16][OH:15])=[CH:18][CH:19]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(CO)cc3)cc12
Temperature: 110 °C
Yield: 15.1 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (200.0 mg, 0.73 mmol), 4-(hydroxymethyl)phenylboronic acid (90.0 mg, 0.59 mmol), 2 N aqueous potassium carbonate (1.1 mL, 2.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I I) (60.0 mg, 0.073 mmol) in toluene (1.5 mL) and EtOH (2.3 mL) was degassed with N2 for 3 minutes and heated to 110° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was acidified to pH 5 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 μm; 28% MeCN in water (0.225% TFA) to 28% MeCN in water (0.225% TFA) for 12 min; Flow Rate: 30 mL/min) to afford the title compound (27 mg, 11% yield) as a white solid. MS (ES+) 302.9 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.76 (s, 1H), 7.45 (m, 4H), 4.69 (s, 2H).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@@H:7]([O:20]CCOCCOCCOCC(O)=O)[C@@H:6]1[NH:34][C:35](=[O:37])[CH3:36])(=O)C.Cl.C(OC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CCCCN)C1C=CC=CC=1.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[OH:20][CH:7]1[O:8][C@H:9]([CH2:15][OH:16])[C@H:10]([OH:11])[C@H:5]([OH:4])[C@H:6]1[NH:34][C:35]([CH3:36])=[O:37]
Reactant: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 142.2 %

Procedure:
The above prepared (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid (2.820 g, 5.246 mmol) and (S)-6-amino-2-((S)-2,6-diamino-hexanoylamino)-hexanoic acid benzyl ester hydrochloride (preparation see below, 0.829 g, 1.749 mmol) were dissolved in a mixture of 32 ml, of CH2Cl2 and 3.2 mL of DMF, treated successively with Hünig's base (2.096 ml, 12.25 mmol), 1-hydroxy-7-azabenzotriazole (0.714 g, 5.248 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.006 g, 5.248 mmol), and stirred over night at ambient temperature. All volatiles were removed i.V., and the crude reaction mixture purified by preparative HPLC (38 runs, Gemini, 5μ, C18) to give after lyophilization 1.650 g of the title product as white powder. MS (ISP): 1945.8 [M+Na]+. NMR (600 MHz, DMSO).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1>C1COCC1.[Zn+2].[Br-].[Br-].[Pd]>[CH2:2]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C=CCCCBr
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(=O)OC)cc1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
A mixture of dry Mg (900 mg, 37 mmol) and ZnBr2 (5.63 g, 25 mmol) in THF (25 mL) was treated with 5-bromopent-1-ene (4.45 mL, 37.6 mmol) and the subsequent suspension was heated at 56° C. for 18 h. The mixture was cooled to room temperature and methyl 4-bromobenzoate (7.1 g, 33 mmol) and tetrakis-triphenylphosphine) palladium(0) (1.0 g, 0.865 mmol) were added, and the mixture was stirred at room temperature for 24 h. The mixture was quenched with 3N HCl (aqueous) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous MgSO4 and evaporated at reduced pressure. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate/hexane) to give the crude title compound which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9])#[N:2]>O.[OH-].[Na+].[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:11]=[CH:12][CH:13]=1)#[N:2]
Reactant: N#Cc1cccc(C=CC(=O)O)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cccc(CCC(=O)O)c1

Procedure:
A solution of 3-cyano-cinnamic acid (11.5 g) in water (200 ml) and 2M sodium hydroxide solution (35 ml) was hydrogenated at 60 psi over 10% palladium on charcoal for 1.5 hours. The catalyst was filtered off and the filtrate was acidified with 2M hydrochloric acid to precipitate the product as a white solid, m.p. 103° C.
Reaction SMILES: [N:1]1([CH2:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.C1(=O)N(OC(N(C)C)=[N+](C)C)C(=O)CC1.C(N(CC)C(C)C)(C)C.[NH2:45][CH:46]([CH2:48][CH2:49][CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH3:47]>CN(C=O)C>[CH2:54]([N:51]([CH2:52][CH3:53])[CH2:50][CH2:49][CH2:48][CH:46]([NH:45][C:13](=[O:15])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:47])[CH3:55]
Reactant: O=C(O)CCN1CCCc2ccccc21
Reactant: CCN(CC)CCCC(C)N
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2ccccc21

Procedure:
The procedure was carried out as described previously in step (b) of Example 8 with Compound 7 (1.9 g, 9.3 mmol), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (3.4 g, 11.2 mmol), N,N-diisopropyl ethylamine (3.4 mL, 19.5 mmol), 2-amino-5-diethylaminopentane (2.2 g, 13.9 mmol) and DMF (40 mL). Compound 10 was obtained (2.64 g) as a viscous liquid and used without any further purification. The structure of Compound 10 is given below:
Reaction SMILES: [F:1][C:2]1[C:7]([B:8](C2C(F)=C(F)C(F)=C(F)C=2F)[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].[OH2:35]>CCCCCCC.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([B:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])[OH:35])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34]
Reactant: O
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: OB(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
20 g (39 mmol) of tris(pentafluorophenyl)borane are suspended in 150 ml of heptane and, under reflux, a solution of 1.8 ml (97.5 mmol) of water in 40 ml of toluene is then added over a period of 30 minutes. The mixture is subsequently stirred for another five hours under reflux. The solution is subsequently cooled to 0° C. Over a period of 30 minutes, the product precipitates as a white solid. The product is isolated and washed three times with 50 ml each time of pentane and subsequently dried in an oil pump vacuum. This gives 11.5 g (80%) of colorless bis(pentafluorophenyl)hydroxyborane. The boroxin content is 10%. 1H-NMR(C6D6, 400 MHz): −133.1 (m, 4 F, o-B(C6F5)2), −147.9 (m, 2 F, p-B(C6F5)2), −161.1 (m, 4 F, m-B(C6F5)2) ppm.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].O.S(=O)(=O)(O)[OH:20]>C(O)(=O)C>[C:16]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:14][C:13]2=[O:15])(=[O:20])[CH3:17]
Reactant: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1.20 g of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90 ml of acetic acid is added 0.45 g of mercuric sulfate, 0.9 ml of water and 0.3 ml of sulfuric acid. The reaction mixture is heated at reflux for 5 hours, cooled to room temperature and quenched with 150 ml of water. The resulting mixture is concentrated in vacuo, diluted with 150 ml of water and extracted with 6:1 chloroform-methanol. The combined organics are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.67 g of the desired product as a white solid.
Reaction SMILES: [CH:1]1([C:6]([OH:23])([C:17]#[C:18][Si](C)(C)C)[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+]>CO>[CH:1]1([C:6]([OH:23])([C:17]#[CH:18])[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#C[Si](C)(C)C)C2CCCC2)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Temperature: 40 °C
Yield: 55 %

Procedure:
A solution of 6-(2-cyclopentyl-2-hydroxy-4-trimethylsilanyl-but-3-ynyl)-2,2-dimethyl-[1,3]dioxom-4-one (−27.5 mmol, crude material from step 1 above), CsF (7.6 g, 50.0 mmol), and MeOH (75 mL) was stirred at room temperature overnight. HPLC at this time still showed starting material, so the reaction was heated at 40° C. for an additional 4 hours, at which time all starting material had been consumed. The reaction was concentrated and purified by flash chromatography through silica, eluted with 30% ethylacetate/hexanes, yielding 4.0 g of product (61% yield for two steps). 1H NMR (CDCl3): δ 1.63 (m, 4H), 1.72 (s, 3H), 1.74 (s, 3H), 2.16 (m, 1H), 2.49 (s, 1H), 2.53 (s, 1H), 2.58 (s, 1H), 5.43 (s, 1H), ESIMS (M+Na+): 287.1.
Reaction SMILES: C12(C=CC3C=C(C(O)=O)C=CC=3O1)CC2.C[O:17][C:18](=[O:46])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]2[CH:29]=[C:30]([CH:42]3C[CH2:43]3)[C:31]3[O:38][C:35]4([CH2:37][CH2:36]4)[CH2:34][C:33]([CH3:40])([CH3:39])[C:32]=3[CH:41]=2)=[CH:22][C:21]=1F.C(OC(=O)CC1C=CC=C(O)C=1)(C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:42]([C:30]1[CH:29]=[C:28]([C:27]#[C:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:18]([OH:46])=[O:17])=[CH:21][CH:22]=2)[CH:41]=[C:32]2[C:31]=1[O:38][C:35]([CH3:36])([CH3:37])[CH2:34][C:33]2([CH3:40])[CH3:39])[CH3:43]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F
Agent: CC(C)(C)OC(=O)Cc1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-(Intermediate 49, 0.05 g, 0.18 mmol) in anhydrous dichloromethane (5 mL) was treated with tert-butyl-3-hydroxy phenyl acetate (Reagent F, 0.04 g, 0.18 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.029 g, 0.1 mmol) and 4-dimethylaminopyridine (0.022 g, 0.18 mmol). The resulting solution was stirred at ambient temperature overnight. The reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 7% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil that solidified on standing (0.020 g, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([S:15]Cl)=[O:14]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][C:13](=[O:14])[S:15][N:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)SCl
Reactant: COc1ccc(C(N)=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nsc(=O)o2)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-methoxybenzamide (0.30 g, 1.10 mmol) in toluene (10 ml) was added chlorocarbonylsulfenyl chloride (0.80 ml, 9.92 mmol). The resulting reaction mixture was refluxed at 80° C. for 3 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed with twice with water, twice with 5% NaHCO3, again with water, and was dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.475 g) that was carried forward to the next step without further purification.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22](N)=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N([O-])=[O:34].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[CH2:1]([C@@:4]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:34])[NH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=N[O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)[nH]c3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.5 g, 3.47 mmoL) in 3.5 M H2SO4 (25 mL) was added 2 M NaNO2 (15 mL) at 0° C. The reaction mixture was stirred at rt overnight. The reaction was treated with aqueous NaOH solution (8%), and the mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (891 mg, 59%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.15-2.38 (m, 3H), 2.51-2.60 (m, 2H), 2.94 (m, 1H), 4.99-5.11 (m, 2H), 5.65-5.74 (m, 2H), 6.67 (m, 1H), 6.89 (d, 2H), 7.00 (t, 2H), 7.13-7.20 (m, 2H), 7.20-7.27 (d, 2H), 7.33 (m, 1H), 7.46 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([N:17]=C=O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][C:5]([N:8]=C=O)=[CH:4][CH:3]=1.C=O.NC1C=CC=CC=1>>[NH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1.[CH2:1]([C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: C=O
Solvent: Nc1ccccc1
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
A novel process for making 4,4'-methylene diphenyl diisocyanate and corresponding oligomer in improved selectivity and yield comprises condensing formaldehyde and aniline under neutral or basic conditions to yield an anil condensate, followed by reacting the anil condensate with additional aniline and a protonic salt of aniline to yield 4,4'-methylene dianiline and corresponding oligomer, then followed by conventional phosgenation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCN(c2ccc(N)cc2F)CC1
Yield: 92.6 %

Procedure:
A solution of 1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine (5.00 g, 20.9 mmol) (from Step A above) and 10% palladium-on-carbon (0.20 g, 0.2 mmol) in ethyl acetate (100 mL) and ethanol (50 mL) was hydrogenated at 50 psi in a Parr shaker for 4 h. The mixture was filtered through Celite™. The Celite™ was washed with ethyl acetate (50 mL) and the solvent was evaporated to give 3-fluoro-4-(4-methyl-1-piperazinyl)benzenamine as a white solid (4.05 g, 93%, mp 89-91° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(Cl)CCl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (300 g, 1.4 mol) in DCM (8.4 L) at rt was added cyclopropanamine (79.64 g, 1.4 mol) and EDC (320.9 g, 1.67 mol) in one portion. After stirring overnight, the solution was washed with water and the aqueous phase was reextracted with DCM. The combined organic phases were dried over Na2SO4, filtered and evaporated. The remaining solid was triturated with diisopropyl ether, filtered, washed and dried in vaccuo to yield 260 g (73.4%) 4-bromo-N-cyclopropyl-2-methylbenzamide: 1H-NMR (300 MHz, CDCl3): δ=7.34 (s, 1H), 7.27 (d, 1H), 7.14 (d, 1H), 5.96 (bs, 1H), 2.85 (m, 1H), 2.38 (s, 3H), 0.85 (m, 2H), 0.59 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.[C@@H]1(NC(=O)C(F)(F)F)CCC=CC1>>[CH:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(N[C@H]1CC=CCC1)C(F)(F)F
Product: O=C(O)c1cccc(Cl)c1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
106.5 g of m-Chloroperbenzoic acid (70%) was charged portionwise to the vessel containing the cooled (10-15° C.) solution of 69.5 g of the N-(cyclohex-3-en-1(R)-yl)-2,2,2-trifluoro-acetamide of step A maintaining temperature <30° C., and rinsed through with 69.5 ml of chlorobenzene. The mixture obtained was stirred at 20 to 25° C. for 1 h and the reaction was followed by TLC until completion. Upon completion of the reaction, the mixture obtained was cooled to 0 to −5° C., stirred for 30 min and the solid precipitate (mCBA) obtained was filtered off and washed with 2×34.8 ml of chlorobenzene. The resultant filtrate was washed with 347.6 ml of 10% sodium thiosulfate solution to remove peroxides, and the resultant aqueous layer was back extracted with 208.6 ml of chlorobenzene. The combined organic layers obtained were washed with 347.6 ml of 5% sodium bicarbonate solution to ensure a pH>7 of the aqueous phase and the resultant aqueous layer was back extracted with 208.6 ml of chlorobenzene. The combined organic layers were washed with 347.6 ml of water.