Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.ClC1C=C([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)C=CC=1Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][C:52]=1[C:60]([F:63])([F:62])[F:61].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:37])=[N:34][CH:35]=2)=[CH:53][C:52]=1[C:60]([F:63])([F:62])[F:61]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(F)c(C(F)(F)F)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 4-fluoro-3-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as brown amorphous solid. MS: 436.4 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH:12]2[CH:5]([CH2:6][O:7][Si:8]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:9][Si:10]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:11]2)[O:4][CH:3]1[N:25]1[CH:30]=[CH:29][C:28](=[O:31])[NH:27][C:26]1=[O:32].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C.CO>N1C=CC=CC=1>[O:32]=[C:26]1[NH:27][C:28](=[O:31])[CH:29]=[CH:30][N:25]1[CH:3]1[O:4][CH:5]2[CH2:6][O:7][Si:8]([CH:22]([CH3:23])[CH3:24])([CH:19]([CH3:21])[CH3:20])[O:9][Si:10]([CH:16]([CH3:17])[CH3:18])([CH:13]([CH3:14])[CH3:15])[O:11][CH:12]2[CH:2]1[O:1][C:33](=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[Si]1(C(C)C)OCC2OC(n3ccc(=O)[nH]c3=O)C(O)C2O[Si](C(C)C)(C(C)C)O1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)OC1C2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OCC2OC1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 4 is O-Acetylated using well known literature procedures (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 150-160 and references cited therein and in Greene, T. W. and Wuts, P. G. M., eds, Wiley-Interscience, New York.) Acetic anhydride (2 to 2.5 eq.) and triethylamine (4 eq.) is added to a solution of 4 (1 eq.) and N,N-dimethylaminopyridine (0.1 eq.) in anhydrous pyridine. After stirring at room temperature for 1 hour the mixture is treated with methanol to quench excess acetic anhydride and evaporated. The residue is redissolved in ethyl acetate, washed extensively with aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, and evaporated. The compound is used without further purification.
Reaction SMILES: C1CC1.[CH2:4]([O:6][C:7]([CH:9]1[CH2:11][C:10]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:5].[N:24]([O-])=[O:25].[Na+].O>C(C(O)=O)(F)(F)F>[CH2:4]([O:6][C:7]([C:9]1[CH2:11][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:25][N:24]=1)=[O:8])[CH3:5]
Reactant: O=N[O-]
Reactant: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Agent: C1CC1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C1=NOC(c2ccccc2)(c2ccccc2)C1
Temperature: 18 °C
Yield: 87.7 %

Procedure:
The cyclopropane derivative, 2,2-diphenylcyclopropanyl carboxylate ethyl ester (0.97 g, 3.7 mmol) was dissolved in 3.7 mL CF3CO2H. Into the solution was added NaNO2 (0.28 g, 4.0 mmol, 1.1 eq.) in several ports so that the reaction temperature did not excess 40° C. After addition, the reactants were stirred at room temperature (about 18° C.) for half an hour. And the reactants were poured into an iced water and extracted with diethyl ether (2×20 mL); the ethereal solutions were combined and subsequently washed with sat. NaHCO3 (2*20 mL), then water (20 mL) and brine (20 mL). The washed ethereal solution was then dried over anhydrous Na2SO4. After removing the desiccant, the ethereal solution was concentrated to obtain a light brown oil. The crude product 1H NMR of the crude product showed that the reaction was clean and a virtual 100% yield. The crude product was further purified over silica chromatography (Rf: 0.45, eluent: 20% ethyl acetate in petrol) to obtain 5,5-diphenylisoxazoline carboxylate ethyl ester 0.958 g (89% yield) as a white solid. 1H NMR (400 MHz, CDCl3): 7.41-7.26 (10H, m), 4.34 (2H, q, J=7.1 Hz), 3.86 (2H, s), 1.36 (3H, t, J=7.1 Hz). 13C NMR (400 MHz, CDCl3): 160.54, 151.09, 142.99, 128.54, 128.02, 125.95, 94.79, 62.15, 46.78, 14.12.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)[CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([N:8]([CH3:26])[CH:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:14]3)[CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 150 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a suspension of tert-butyl 2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-7-azaspiro[4.5]decane-7-carboxylate (470 mg, 1.13 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (235.7 mg, 1.76 mmol) in n-BuOH (5 mL) was added DIPEA (482.6 g, 3.74 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the title compound as a white solid (280 mg, 52.0%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]([CH3:23])[CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:10][C:11]1[CH:6]=[N:5][C:4]([N:20]2[CH2:21][CH2:22][CH:18]([N:17]([CH3:23])[CH3:16])[CH2:19]2)=[CH:3][CH:2]=1
Reactant: CN(C)C1CCNC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC(N(C)C)C2)nc1
Yield: 185 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with N,N-dimethylpyrrolidin-3-amine (260 mg, 1.2 mmol) to afford the desired product (380 mg, 89%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 11.35 (s, 1H), 9.00 (s, 1H), 8.10 (d, J=8.7 Hz, 1H), 8.02 (dd, J=2.7, 0.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.30 (dd, J=8.9, 2.7 Hz, 1H), 6.35 (d, J=8.9 Hz, 1H), 3.88-3.77 (m, 1H), 3.62-3.72 (m, 1H), 3.49-3.37 (m, 1H), 3.33-3.22 (m, 1H), 2.94-2.76 (m, 1H), 2.68 (s, 3H), 2.34 (s, 6H), 2.34-2.18 (m, 1H), 2.06-1.89 (m, 1H); ESI MS m/z 411 [M+H]+
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:30]([NH:33][C:34]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH2:20]1)=[O:35])([CH3:32])[CH3:31]
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: CC(C)N=C=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
A 10 mL CH2Cl2 solution of 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (254 mg, 0.73 mmol), NEt3 (0.20 mL, 1.4 mmol), isopropyl isocyanate (192 mg, 2.2 mmol), and 4-dimethylaminopyridine (12 mg, 0.1 mmol) is stirred under N2, at room temperature for 18 hours. The reaction mixture is concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give pure product (110 mg, 42% yld). MS(ES+) 360.2(M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[OH:20][CH2:21][C:22]([NH2:24])=[NH:23]>>[OH:20][CH2:21][C:22]1[N:24]=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:23]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Reactant: N=C(N)CO
Agent: Cl
Product: O=C(O)c1cnc(CO)nc1-c1ccccc1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and 2-hydroxy-acetamidine hydrochloride followed by saponification as described in Example 3c), there was obtained 2-hydroxymethyl-4-phenyl-pyrimidine-5-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)cc1
Product: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)cc1
Yield: 78.7 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methoxyphenyl)benzamide (556.9 mg, 1.17 mmol) and acetic anhydride (0.13 ml, 1.41 mmol), the procedure of Inventive Example 94 was repeated to obtain 476.8 mg (78.7%) of the title compound in the form of colorless powder.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43])=[O:4]
Reactant: CNC(=O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 46 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Vb, 60 mg, 0.139 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.092 mL, 0.835 mmol), 2-amino-N-methylacetamide-HCl (31.2 mg, 0.250 mmol), and HATU (95 mg, 0.250 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention=33.0 min) to give single enantiomer 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (33 mg, 0.064 mmol, 46.4% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.23 (2 H, m), 7.66-7.79 (4 H, m), 7.52-7.66 (3 H, m), 5.20 (1 H, s), 3.88-4.00 (2 H, m), 3.78-3.88 (2 H, m), 2.75 (3 H, s); HPLC Peak RT=9.1 min (Analytical Method B).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4F)cc23)CC1
Yield: 79.4 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 5.4 μL (0.0458 mMol) 2-fluorobenzoyl chloride, 12.2 mg (80%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[C:21]1([CH2:27][C:28]([O:20][C:9]2[CH:8]=[CH:7][C:6]3[C@@H:5]4[C@H:14]([C@H:15]5[C@@:2]([CH2:3][CH2:4]4)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]5)[CH2:13][CH2:12][C:11]=3[CH:10]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)Cc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
Oestrone (2 g.) in pyridine (10 ml.) was treated for three days at room temperature with phenylacetyl chloride (3 ml.). The mixture was diluted with water (50 ml.) and the product extracted with ether (50 ml.) containing a little chloroform. The extract was washed with water (50 ml.) then 2N-sulphuric acid (25 ml.) then water again (50 ml.) and the solvent was evaporated in vacuo. Filtration of the residue in methylene chloride through a short Florisil column and crystallisation from light petroleum (b.p. 40°/60°)-ether gave the title compound in two crops (total 1.54 g., 54%), m.p. 114°-116°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+:36]>CO>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:26][CH:27]=2)=[CH:15][CH:16]=1)[C:5]([O-:7])=[O:6])[CH3:2].[Na+:36]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-ethoxy-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (135 mg), which is the product of Example 1, in methanol (2 ml) an aqueous solution of sodium hydroxide (1N, 0.55 ml) was added. The mixture was stirred at room temperature for 2 hours. At the end of this time the methanol was evaporated under reduced pressure and an aqueous solution of hydrogen chloride (1N, 0.55 ml) and ethyl acetate were added to the residue. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to afford the desired compound (121 mg) as a gum.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:31]([C:30]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=3)=[O:32])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Temperature: 25 °C

Procedure:
35 ml of nitrobenzene are cooled in an ice-bath and then treated in succession with 5.2 g of aluminum chloride and 5.0 g of 4-methylbiphenyl. The mixture is brought to room temperature and then treated with 7.7 g of 3,4-dichlorobenzoyl chloride. The mixture is stirred at room temperature, poured into water and extracted with methylene chloride. The extracts are washed with 2N hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel with toluene/ethyl acetate 9:1. 3,4-Dichlorophenyl 4'-methyl-4-biphenylyl ketone is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[C:22](=N)(OCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(-c3ccccc3)n1-2

Procedure:
A solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 1.8 parts of ethyl benzimidate hydrochloride in 30 parts by volume of chloroform is stirred at room temperature for 24 hours and then washed with water.The chloroform layer is dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with diethyl ether yields 8-chloro-1,6-diphenyl-4H-s-triazolo-[4,3-a] [1,4] benzodiazepine as crystals. Recrystallisation from a mixture of ethyl acetate and n-hexane yields colorless needles melting at 192° C to 193.5° C.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:18][CH:17]=2)[CH2:12][C:11]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCN([S+](F)F)CC.[FH:65].[FH:66].F.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:18][CH:17]=2)[CH2:12][C:11]1([F:66])[F:65])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@H]3CC[C@H](OC(=O)c4ccccc4)C(=O)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Reactant: F
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(OC(=O)c4ccccc4)C(F)(F)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Yield: 87.2 %

Procedure:
To a solution of tert-butyl 4-(6-((1S,45)-4-(benzoyloxy)-3-oxocyclohexyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)-2-fluorobenzoate (730 mg, 1.034 mmol) in DCM (7 mL) at RT was added XtalFlour-E (939 mg, 4.14 mmol) followed by triethylamine trihydrofluoride (0.674 mL, 4.14 mmol). The resultant mixture was stirred at RT for 5 hours. The mixture was filtered and the filtered solution was directly applied for ISCO separation: 24 g silica gel, 0 to 70% EtOAc in Heptane, 30 min. A light yellow solid (670 mg, 0.902 mmol, 87% yield) was obtained. LC-MS (m/z): (MH+) 728.0 at 0.95 min (non-polar MS method). 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (s, 2H) 1.19-1.39 (m, 21H) 1.48-1.68 (m, 11H) 1.86-2.08 (m, 2H) 2.08-2.21 (m, 1H) 2.26-2.47 (m, 2H) 2.47-2.63 (m, 1H) 3.21-3.44 (m, 1H) 5.22-5.51 (m, 1H) 7.41-7.55 (m, 4H) 7.60 (s, 1H) 7.96 (d, J=7.82 Hz, 1H) 8.06-8.19 (m, 2H) 8.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)nc(NC2CCCCC2)c1C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
To a stirred solution of 2,4-dichloro-5,6-dimethylpyrimidine (9.3 g, 0.05 mol, Step C) in dimethylformamide (100 mL) was added cesium carbonate (37.6 g, 0.12 mol). Cyclohexylamine (5.7 g, 0.058 mol) was then added, keeping the temperature of the reaction mixture at 70° C. After 48 hours, the reaction mixture was concentrated, and the residue was quenched with water (200 mL). The resulting mixture was extracted with dichloromethane (3×120 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The solvent was removed by distillation, and the crude product was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (10:1-10:2) to yield 4.9 g (38.9%) of the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05-1.14 (m, 1H), 1.28-1.33 (m, 4H), 1.61 (d, J=12.36 Hz, 1H), 1.72 (s, 2H), 1.80 (s, 2H), 1.93 (s, 3H), 2.19 (s, 3H), 3.85 (d, J=7.52 Hz, 1H), 6.66 (d, J=7.79 Hz, 1H); MS (ESI) m/z 240.3 (M+1)+.
Reaction SMILES: [C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][Cl:33]>CN(C=O)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][CH2:32][Cl:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Temperature: 85 °C
Yield: 54.1 %

Procedure:
To a mixture of (1R)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (3.67 g, 12.19 mmol) in DMF (90 mL) is added potassium carbonate (8.4 g, 60.9 mmol) and 1-bromo-2-chloroethane (5.0 mL, 60.9 mmol). The mixture is heated to 85° C. for 24 h. The temperature is then increased to 95° C. and heated for 4 h. Mechanical stirring is employed and the reaction heated an additional 1.5 h. The mixture is then partitioned between water and Et2O. The layers are separated and the organic layer washed with water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography with silica gel using hexane/CH2Cl2 (60/40) gave 2.4 g (54%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])=O)[CH3:2].B([O-])=O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])[CH3:2]
Reactant: CCOC(=O)C(=O)c1sccc1Nc1c(C)cccc1Cl
Agent: O=B[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1sccc1Nc1c(C)cccc1Cl

Procedure:
0.32 g (1 mmole) of 3-(2-chloro-6-methylanilino)-2-thiophenglyoxylic acid ethyl ester and 1 g of sodium boranate are warmed to 80° in 10 ml of dimethylformamide for 2 hours. The mixture is then poured onto water and washed with diethyl ether, and the aqueous phase is acidified and extracted with ethyl acetate. Concentration of the organic phase and column chromatography (silica gel/methylene chloride) give, in the first fraction, 3-(2-chloro-6-methylanilino)-2-thiophenacetic acid ethyl ester.