Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1.C=O.[C:14](O)(=O)C>O.CO>[CH3:11][N:2]([CH3:1])[C:3]1[S:4][C:5]2[CH2:14][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN(C)c1nc(CCN)cs1
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Solvent: CO
Product: CN(C)c1nc2c(s1)CNCC2
Reaction time: 2.5 h
Yield: 219.2 %

Procedure:
2-Dimethylamino-4-(2-aminoethyl)thiazole (1.7 g, see preceding preparation), formaldehyde (0.78 ml of a 37% solution in water, 9.6 mmol) and acetic acid (0.15 ml, 2.6 mmol) were combined in methanol (100 ml). After 2.5 hours at room temperature, the reaction mixture was treated with additional formaldehyde (0.15 ml, 1.8 mmol) and allowed to stir for an additional 16 hours. The reaction was then filtered, and the filtrate was concentrated in vacuo and purified by column chromatography (eluant: 89:10:1 of chloroform:methanol:concentrated ammonium hydroxide), providing the title product as a white solid (1.04 g, 5.7 mmol).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[O:13].O>O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][C:2]([O:4][CH3:5])=[O:3])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:16]=1)=[O:13]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
Methyl chloroformate(42 μL, 0.54 mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt(200 mg, 0.49 mmol) in tetrahydrofuran(5 mL) under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension to give the title compound(171.2 mg, 78.6%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].[CH2:29](N)[CH2:30][NH2:31]>P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[NH:2]1[CH2:29][CH2:30][N:31]=[C:1]1[C:3]1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#N)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=NCCN3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Yield: 86.7 %

Procedure:
To a 10-mL microwave tube were added 6-cyano-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (33 mg, 0.088 mmol), ethylenediamine (1 mL, 14.81 mmol), and phosphorus pentasulfide (0.585 mg, 2.63 μmol), and the mixture was degassed for 5 min. The tube was sealed and the mixture was heated at 120° C. in a microwave. The mixture was concentrated and the residue was purified using reverse-phase HPLC under acidic conditions to give 32 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.46 (m, 6H), 2.11 (s, 3H), 2.17 (s, 3H), 2.24 (s, 3H), 4.35 (d, J=5.05 Hz, 2H), 4.75 (quin, J=6.69 Hz, 1H), 5.87 (s, 1H), 7.49-7.60 (m, 2H), 8.16-8.26 (m, 2H), 8.39 (s, 1H). MS: (M+H)+=419.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=O.[C:6]([O:10][C:11]([N:13]1[CH:22]([CH2:23][NH:24][CH:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C>C(#N)C>[C:6]([O:10][C:11]([N:13]1[CH:22]([CH2:23][N:24]([CH:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:4][CH2:3][O:2][CH3:1])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: COCC=O
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)NCC1Cc2ccccc2CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CC#N
Product: COCCN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of methoxyacetaldehyde (0.15 gm, 2.03 mmol), 3-{[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylamino]-methyl}-3,4dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester from preparation 3BC Step C (0.31 gm, 0.68 mmol) in acetonitrile was added sodium triacetoxyborohydride (0.72 gm, 3.38 mmol). After stirring overnight under a nitrogen atmosphere at r.t., additional acetaldehyde (0.25 gm) dissolved in acetonitrile and sodium triacetoxyborohydride (0.21 gm) was added, and the mixture was stirred for about 8.5 hours. The mixture was quenched at r.t. with 5N NaOH (5 mL). The aqueous phase was separated from the organic and extracted with ethyl acetate (4×). The combined organics were washed with a brine solution, and then dried, filtered and concentrated. Chromatography (gradient of ethyl acetate in hexane, 0 to 12%) gives about 0.23 g of 3-{[[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethyl]-(2-methoxy-ethyl)-amino]-methyl}-3,4dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a yellow oil (70%). MS (m/z, ES+): 517.2.
Reaction SMILES: [O:1]=[C:2](N(OC)C)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:8].[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(NC(=O)CCCCC(=O)N(C)OC)cc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CCCCC(=O)Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
6-Oxo-6-(N,O-dimethylhydroxylamino)-N-(4-methoxyphenyl) hexanamide (454 mg) was dissolved in tetrahydrofuran (13 mL) and cooled to -78° C. Benzylmagnesium chloride in tetrahydrofuran (2.0M, 1.6 mL) was added and reaction was warmed to 20° C. After 24 hours, additional benzylmagnesium chloride in tetrahydrofuran (2.0M, 0.4 mL) was added. After 24 hours, 1.0M aqueous hydrochloric acid (10 mL) was added and reaction extracted using dichloromethane (2×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting solid was chromatographed eluting with 30:70 ethyl acetate:hexanes to afford the title compound (Rf of 0.68 in 70:30 ethyl acetate:hexanes) as white crystals (200 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([OH:13])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([N:27]([O:28][CH3:29])[CH3:26])=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1coc2c(Br)cccc12
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1coc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-bromo-1-benzofuran-3-carboxylic acid (8.9 g, 37 mmol), CDI (9.1 g, 56 mmol) and DCM (200 mL) was stirred for 4 hours at room temperature, and then MeNHOMe (5.5 g, 56 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (300 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4. The solvent was concentrated in vacua. The residue was purified with silica gel chromatography to give 7-bromo-N-methoxy-N-methyl-1-benzofuran-3-carboxamide. 1H-NMR (400 MHz, CDCL3) δ ppm 8.33 (s, 1H), 8.21 (d, J=8.0, 1 H), 7.51 (d, J=7.6 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 3.72 (s, 3H), 3.39 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])[C:13](=[O:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11]3[CH2:32][CH2:33][C:34](=[O:35])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].O>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])[C:13](=[O:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[C:11]3[CH2:32][CH2:33][C:34](=[O:35])[C:10]2=3)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)propanoate (intermediate 27, 125 mg, 0.26 mmol) in 1,4-dioxane (3 mL) is treated with aqueous lithium hydroxide (2.0 M, 390 μL, 0.78 mmol), and the mixture is stirred at room temperature over night. Water is added, and the mixture is extracted with dichloromethane. The aqueous phase is acidified with 1M aqueous hydrogen chloride and extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. Yield: 91 mg; ESI mass spectrum: [M+H]+=470; Retention time HPLC: 0.85 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)[CH3:2].C=O.[C:31]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:25])([CH3:26])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:23])[CH3:24])=[CH:14][C:13]=2[CH3:27])[CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Yield: 30.6 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 30 mg, 0.0788 mmol), formaldehyde (23.66 mg, 0.788 mmol), sodium cyanoborohydride (3.9 mg, 0.788 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (5% ethyl acetate in hexane, Rf=0.27) to give the title compound(9.5 mg, 31%) as a white solid:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:47])([CH3:46])[CH2:27][CH2:28][N:29]1[C:34]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:33]=2[C:32]([CH2:43][CH3:44])([CH2:41][CH3:42])[O:31][C:30]1=[O:45]>>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:25][C:26]([CH3:47])([CH3:46])[CH2:27][CH2:28][N:29]2[C:34]3[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([CH2:43][CH3:44])([CH2:41][CH3:42])[O:31][C:30]2=[O:45])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)N)c2c(OC)cccc21
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OCC(=O)N3)c2c(OC)cccc21

Procedure:
The product is prepared analogously to Example 14a starting from 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 1-(3-amino-3-methyl-butyl)-4,4-diethyl-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one. The crude product is purified by column chromatography (silica gel, dichloromethane/MeOH 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.[CH:54]([N:57]([CH:60]([CH3:62])[CH3:61])CC)([CH3:56])[CH3:55].CC1C=CC(C)N1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:57]1[CH:60]([CH3:61])[CH:62]=[CH:56][CH:54]1[CH3:55])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: CC1C=CC(C)N1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3C(C)C=CC3C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2,5-dimethyl-2,5-dihydro-1H-pyrrole in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]=[P:11](Cl)([Cl:13])[Cl:12]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][P:11]([Cl:13])([Cl:12])=[O:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NP(=O)(Cl)Cl)cc1

Procedure:
A mixture of 39 g (0.33 m) of 4-aminobenzonitrile and 250 ml of POCl3 was heated under reflux for 3 hours. The excess POCl3 was removed by vacuum distillation to yield 72.7 g, m.p. softens 128°, melts 131°-133.5°.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrBr.C[O-:27].[Na+].Cl>ClC(F)(F)C(Cl)(Cl)F.C(O)C>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:27])=[O:16])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C[O-]
Reactant: CCCCCCCCc1ccc(C(=O)Cc2ccccc2)cc1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: CCCCCCCCc1ccc(C(=O)C(O)c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
120 g (0.35 mole) of 4-n-octyldeoxybenzoin are dissolved in 500 ml of 1,2,2-trichloro-1,1,2-trifluoroethane. 16 ml (56 g, 0.35 mole) of bromine are added dropwise in the course of one hour, while irradiating with UV light, so that the solution is continuously decolorized. Thereafter, the reaction solution is heated at the boil for one hour, and thin layer chromatography is used to check for complete conversion. The solvent is completely stripped off, 140 g of crude product being obtained as the residue. This is dissolved in 100 ml of ethanol, and a solution of 56.7 g (1.05 moles) of sodium methylate in 200 ml of ethanol is added dropwise at room temperature to the stirred solution, the internal temperature increasing to 35° C. The reaction mixture is stirred for a further 15 hours at room temperature, after which it is discharged onto 1 l of semiconcentrated hydrochloric acid and stirring is continued for about a further 30 minutes. The precipitate is filtered off, washed with water and recrystallized from petroleum ether (60°-80° C.) to give 103.2 g (91% yield) of 4-n-octylbenzoin of melting point 65°-70° C.). According to thin layer chromatography, this product is only slightly contaminated. Column chromatography over silica gel 60 using methylene chloride as the mobile phase gives 70 g (62%) of analytically pure 4-n-octylbenzoin (thin layer chromatography over silica gel/CH2Cl2 : R=0.78; toluene: R=0.18).
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].[H-].[Na+].ClC(C)[C:11]([C:13]1[CH:14]=C(CC(O)=O)C(OC)=C[CH:18]=1)=O>C1COCC1.O>[C:3]([S:6][C:13]([CH3:14])([CH3:18])[CH3:11])([CH3:5])([CH3:4])[CH3:2]
Reactant: COc1ccc(C(=O)C(C)Cl)cc1CC(=O)O
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)SC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a 50 mL round bottom flask containing 0.9 grams (8.82 mmole) of the sodium salt of 2-methyl-2-propanethiol was added 0.25 grams of sodium hydride (11.3 mmole) and the resulting mixture placed under vacuum and then under a nitrogen atmosphere. To the mixture was then added 15 mL of anhydrous tetrahydrofuran and the mixture cooled to 0° C. To the cooled mixture was added 1.5 grams (5.84 mmole) of 9 dissolved in 15 mL of anhydrous THF over a period of 10 minutes. After addition, the reaction mixture was allowed to stir, at room temperature and under a nitrogen atmosphere for 18 hours. After 18 hours the volatile components of the reaction mixture were removed under reduced pressure to give a brown solid. The brown solid was dissolved in 80 mL of H2O and aqueous washed with 100 mL of diethyl ether. The aqueous layer was then acidified with 1 mL of concentrated HCl (pH=1) and then extracted (2×100 mL) with diethyl ether and organic layers combined, dried over MgSO4, filtered and volatile components removed under reduced pressure to give 1.75 grams of the t-butyl thioether product which was used without any further purification.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:15]=[C:16]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:23][NH:22][CH2:21]1>C(Cl)(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:23][N:22]([C:9]([O:11][CH3:12])=[O:10])[CH2:21]1
Reactant: COC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CNC3)c(F)c2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)N1CC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)C1
Reaction time: 8 h

Procedure:
Triethylamine (150 μL, 1.08 mmol) and methyl chloroformate (65 μL, 0.84 mmol) were added to a chloroform (5 mL) suspension of (S)-N-[[3-[3-fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 82, 153 mg, 0.50 mmol) and stirred overnight. Additional chloroform (25 mL) was added and the solution washed with water (15 mL) and brine (15 mL). Drying over magnesium sulfate, filtration, and evaporation gave a foam. Chromatography over silica gel (50 g, 40-60 μm) eluting with 1-3% methanol-chloroform gave the title compound as a white solid. FAB-HRMS: theory 366.1465 (M+1); meas. 366.1468.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.[CH3:18][CH:19]([CH2:34][C:35](=O)[CH3:36])[C:20](=O)[CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O>C1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]2[N:1]3[C:35]([CH3:36])=[CH:34][C:19]([CH3:18])=[C:20]3[CH2:21][N:22]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])[C:3]=2[CH:13]=1
Reactant: CC(=O)CC(C)C(=O)CN1C(=O)c2ccccc2C1=O
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Yield: 54.3 %

Procedure:
2-Amino-2',5-dichlorobenzophenone (200 mg, 0.752 millimole) and 3-methyl-1-phthalimidohexane-2,5-dione (225 mg, 0.823 millimole) were dissolved in 10 ml of benzene, and 20 mg of p-toluenesulfonic acid was added. The mixture was heated under reflux for 4 hours, and 2 ml of N,N-dimethylformamide was added. The benzene was evaporated under reduced pressure, and 8 ml of ethanol and 0.3 ml of hydrazine hydrate were added. The mixture was heated under reflux for 30 minutes. The ethanol was evaporated under reduced pressure, and 25 ml of benzene was added. The mixture was heated under reflux for 5 minutes. After cooling, the solid was separated by filtration. The filtrate was washed with water and an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the concentrate was chromatographed on silica gel. The column was first eluted with benzene to recover unchanged 2-amino-2',5-dichlorobenzophenone, and then with benzene-ethyl acetate (49:1) to afford 145 mg of 8-chloro-6-(2-chlorophenyl)-1,3-dimethyl-4H-pyrrolo[1,2-a][1,4]benzodiazepine as yellow crystals in a yield of 54%. The product showed the same spectral data as those of the compound obtained in Example 32.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:11].Cl.O.N([O-])=O.[N-:26]=[N+:27]=[N-].[Na+]>>[OH:1][C:2]1[CH:7]=[C:6]([N:8]=[N+:26]=[N-:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:11]
Reactant: COc1ccccc1NC(=O)Nc1ccc(N)cc1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1NC(=O)Nc1ccc(N=[N+]=[N-])cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
The N-(2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea (300 mg. 1.17 mmol) was added to HCl/H2O (1.17 mL/2.34 mL), cooled to 0° C. Solution nitrite (80.7 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. The sodium azide (76 mg, 1.17 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. The it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(F)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg), 4-fluorophenyl boronic acid (0.451 moles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.