Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:53])[N:30]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39](B4OC(C)(C)C(C)(C)O4)[C:38]=3[CH3:52])[C:31](=[O:36])[N:32]2[CH3:35])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([N:30]2[C:29](=[O:53])[C:28]4[C:33](=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[N:32]([CH3:35])[C:31]2=[O:36])[C:38]=1[CH3:52])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: COc1ccc2c(=O)n(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3C)c(=O)n(C)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(-c3cccc(-c4c(Cl)cc(C(N)=O)c5[nH]c6cc(C(C)(C)O)ccc6c45)c3C)c(=O)n(C)c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (200 mg, 0.524 mmol), 7-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 14] (221 mg, 0.524 mmol), Cs2CO3 (512 mg, 1.57 mmol) and PdCl2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water (0.50 mL) was heated at 60° C. overnight, then at 90° C. for 4 h. The cooled mixture was concentrated, and the residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 50-100%), to give 3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) (164 mg, 92% yield). This material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO2-IPA (60:40) at 85 mL/min; sample preparation: 20.3 mg/mL in MeOH; injection: 0.75 mL.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:1][C:2]1[C:3]([C:10]([NH:16][CH2:15][CH2:14][NH2:17])=[O:12])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCN
Product: NCCNC(=O)c1nc(Cl)c(N)nc1N
Reaction time: 72 h
Yield: 59 %

Procedure:
A mixture of 2.0 g (10.0 mmol) of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate and 13.5 g (22.6 mmol) of ethylene diamine was allowed to stand for 3 days at ambient temperature. The excess amine was evaporated and the residue was crystallized from ethanol. There was obtained 1.38 g (5.9 mmol, 59%) of 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide: mp 173°-174° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[NH2:8].[C:13]1(=O)OC(=O)CCC1>>[N:5]1([C:6](=[O:9])[C:7]2[NH:8][CH:13]=[N:1][C:2]=2[N:3]([CH3:12])[C:4]1=[O:11])[CH3:10]
Reactant: O=C1CCCC(=O)O1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
Following the method of cook et al, Res. Comm. Chem. Path, Pharm. 13:497(1976), 4,5-diamino-1,3-dimethylpyrimidine-2,6-dione is heated with glutaric anhydride to yield the following: ##STR16##
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[O:20]1[CH2:25][CH2:24][CH2:23]OS1(=O)=O>C1COCC1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:23][CH2:24][CH2:25][OH:20])=[CH:11][CH:12]=1
Reactant: O=S1(=O)OCCCO1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCCOc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 4-phenylphenol (4.9 g, 29.0 mmol) and potassium tert-butoxide (3.64 g, 30.3 mmol) in THF (100 mL) was stirred at room temperature for 30 minutes. The solution was cooled at 0° C. and [1,3,2]dioxathiane 2,2-dioxide (Example 291, Step 5) (3.6 g, 26.34 mmol) in THF (25 mL) was added. The mixture was stirred at room temperature for 5 hours, and the solvent was removed under vacuum. The residue was dissolved in 6N HCl (15 mL) and heated at 100° C. for 16 hours. The mixture was cooled to room temperature, and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with H2O (3×25 mL) and brine (25 mL), dried (MgSO4), filtered, and concentrated to produce a white solid. 1H-NMR (200.15 MHz, CDCl3): d 7.57–7.49 (m, 4H), 7.45–7.37 (m, 3H), 6.98 (dd, 2H, J=6.72, 2.14), 4.17 (t, 2H, J=5.9), 3.88 (q, 2H, J=5.9), 2.07 (qn, 2H, J=5.9).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16])[CH3:14]>>[Cl:25][C:20]1[CH:19]=[C:18]([S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=1[O:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(F)cc(CC(=O)O)c2)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (iv) and the product of example 3 step (i).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[P:23]([O-:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][C:18]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[N:17][CH:16]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1ccc(Br)nc1
Reactant: CCOP([O-])OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)OC(C)(C)C)c2ccccc2)cn1
Yield: 86 %

Procedure:
To tert-butyl (6-bromopyridin-3-yl)(phenyl)methylcarbamate (4-e) (3.4 g, 9.4 mmol), diethyl phosphite (1.55 g, 11.27 mmol) and Et3N (1.14 g, 11.27 mmol) in THF was added PdCl2(dppf) (200 mg). The mixture was heated at reflux under nitrogen overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified over silica gel (DCM/MeOH=20/1) to provide the product, 4-f (3.4 g, 86%).
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12]CC3C=CC=CC=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1>C(O)C>[CH3:1][N:2]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CN(c1ccncc1)n1ccc2cc(OCc3ccccc3)ccc21
Solvent: CCO
Product: CN(c1ccncc1)n1ccc2cc(O)ccc21
Yield: 94.8 %

Procedure:
A solution of 1-(methyl-4-pyridinylamino)-5-phenylmethoxy-1H-indole (9 g) in 250 mL ethanol containing 0.6 g 10% palladium on activated charcoal was hydrogenated at 50 psi at 50° C. for three hours via Parr hydrogenation apparatus. After cooling, the mixture was filtered through Celite and concentrated. The residue was eluted through silica with 5% methanol in dichloromethane via flash column chromatography to yield 6.2 g solid. A three gram portion was recrystallized from acetonitrile to yield 2.6 g solid, m.p. 191°-193° C. This was again recrystallized from acetonitrile to yield 2.2 g crystals, m.p. 192°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]([CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]2)[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(C(c2cc(F)cc(F)c2)C(C)(C)C)C1

Procedure:
A mixture of 720 mg (2.14 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine-1-carboxylate and 600 mg of palladium on activated carbon (10%) in 6 mL of ethyl acetate and 5 mL of MeOH was pressurized to 50 psi with hydrogen gas at room temperature for 72 h. The solution was filtered through CELITE and the filtrate was concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 0.88 (s, 9H), 1.43 (s, 9H), 2.69 (d, J=11 Hz, 1H), 3.09-3.18 (m, 21), 3.71 (t, J=8.2 Hz, 1H), 3.81 (m, 1H), 4.12 (t, J=8.5 Hz, 1H), 6.49 (br, 1H), 6.69 (m, 2H);
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([S:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])([CH3:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:26][C:27]([F:41])([F:40])[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[CH:38]=O)=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([CH3:18])([S:19][C@@H:20]1[CH2:23][O:24][C@@H:38](/[CH:37]=[CH:36]/[CH:35]=[CH:34]/[C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:40])[F:41])=[CH:33][CH:32]=2)[O:22][CH2:21]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(C)(SC(CO)CO)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(C)(S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction was carried out in the same manner as in Example 4 using (RS)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol and (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as described in Reference example 25 to obtain the title compound, a major product as a colorless foam.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][CH2:41][S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:48][C:47]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[O:18][C:44](=[O:45])[C:43]=1[S:42][CH2:41][CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(OCCc2ccccc2)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(OCCc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-(2-phenylethoxy)acetophenone (0.336 g, 1.40 mmol), lithium bis(trimethylsilyl)amide (0.257 g, 1.54 mmol), chlorotrimethylsilane (0.195 mL, 1.54 mmol), THF (15 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (0.417 g, 1.40 mmol). m.p. 104-106° C.; 1H NMR (400 MHz, DMSO-d6) δ2.75 (t, 2 H), 2.97 (t, 2 H), 3.04 (t, 2 H), 4.25 (t, 2 H), 6.79 (s, 1 H), 7.25 (m, 14H), 11.95 (bs, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[IH:14]>>[I:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: I
Reactant: Clc1ccc(-c2ccccc2)cn1
Product: Ic1ccc(-c2ccccc2)cn1

Procedure:
15.98 g of 2-chloro-5-phenylpyridine were dissolved in 150 ml of 55% aqueous hydroiodic acid and the solution was heated at reflux for 2 hours. Upon cooling a solid precipitated and this was filtered off and washed with water The solid was partitioned between diethyl ether and 2M sodium hydroxide solution, and the organic phase was dried over sodium sulphate and evaporated to give 15.87 g of 2-iodo-5-phenylpyridine which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][CH:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:6]=1[CH3:16].[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:28][N:29]([C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][CH:4]([C:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:7][C:6]=2[CH3:16])[CH2:3][CH:2]([CH3:1])[CH3:27])=[CH:26][CH:25]=1)=[O:24])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)cc1

Procedure:
A solution of 4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}benzoic acid (182 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate. Ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (186 mg, 83%).
Reaction SMILES: CON(C)[C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1COCC1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.[BH4-].[Na+]>CCOCC.CO>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:4]([OH:20])[CH2:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of 1.30 g (4.5 mmol) of N-methoxy-N-methyl-3-(1-(t-butoxycarbonyl)piperidin-4-yl)propionamide (from EXAMPLE 188, Step A) in 25 (of THF at 0° C. was treated with 3.0 mL of 2.0 M (4-fluoro)phenylmagnesium bromide in ether and stirred cold for 1 h. The reaction was quenched with 100 mL of 0.5 N HCl and extracted with 150 mL of ether. The extract was washed with 50 mL of sat'd NaCl, dried and concentrated. The crude ketone in 10 mL of MeOH at 0° C. was treated with 110 mg (2.2 mmol) of NaBH4 and the resulting mixture was stirred cold for 30 min. The reaction was quenched with 5 mL of 1.0 N NAOH. The quenched mixture was partitioned between 100 mL of ether and 25 m of H2O and the layers were separated. The organic layer was dried; the aqueous layer was extracted with 100 mL of ether, the extract dried and the organic layers combined and concentrated. Flash chromatography on 40 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 566 mg (37%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>ClC(Cl)C>[C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:2]([CH3:1])[C:3]3[C:8]([C:9]=2[CH:10]=1)=[CH:7][C:6]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:5][CH:4]=3)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c2ccccc2c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1c2ccc(C(=O)c3ccccc3)cc2c2cc(C(=O)c3ccccc3)ccc21
Reaction time: 3 h

Procedure:
67.0 g (0.37 mol) of 9-methylcarbazole were dissolved in 400 ml of dry dichloroethane, to which 105.0 g (0.79 mol) of AlCl3 were added. 104.0 g (0.74 mol) of benzoyl chloride were added dropwise with stirring and cooling with ice. Stirring was continued for another 3 hours at room temperature, and the reaction mixture was then decomposed with ice and hydrochloric acid and the organic phase was washed to neutrality with water and NaHCO3 solution. The remaining water was removed by azeotropic distillation. The dichloroethane solution was concentrated, whereupon the diketone crystallized out. It was recrystallized once more from dichloroethane; m.p. 222° C.; (Lit. 16): m.p. 2190° C.), colorless crystals. Yield: 114.2 g (79.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:15][CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:26])[CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[CH2:1]([O:8][C:9]([N:11]([CH2:15][CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:26])[CH2:12][CH2:13][O:14][S:35]([CH3:34])(=[O:37])=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C1CCN(CCO)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCN(CCC1C(=O)Nc2ccccc21)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
3-[2-[N-(Benzyloxycarbonyl)-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one (256 mg) was dissolved in dichloromethane (5 ml), added with triethylamine (0.20 ml) and methanesulfonyl chloride (0.11 ml) with ice cooling and stirred at room temperature for 1.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:2) to obtain 158 mg of the title compound. Yield: 51%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[OH:35])[CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:34]=3[N:25]=[CH:26][CH:27]=[CH:28]4)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc2cccnc12
Product: CC(NC(=O)c1coc(Oc2cccc3cccnc23)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 58.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with quinolin-8-ol (38 mg, 0.26 mmol) to give the title compound (37 mg, 58%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([S:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:17]=[C:16]([NH2:32])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CO>[CH2:6]([S:13][C:14]1[N:15]=[C:16]([NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[C:18]([NH:20][C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[N:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(N)nc(SCc2ccccc2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(NS(C)(=O)=O)nc(SCc2ccccc2)n1

Procedure:
Methanesulfonyl chloride (85 μl) was added to a solution of the subtitle product of step ii) (0.20 g) and N,N-diiosopropylethylamine (0.26 ml) in DCM (10 ml) at 0° C. The ice-bath was removed and stirring maintained for 2 h. The reaction solution was extracted with H2O (2×20 ml) and the organics dried (MgSO4) and concentrated to yield a brown oil. The residue was diluted in methanol (110 ml) and treated with potassium carbonate (0.15 g) for 2 h at room temperature. The volatiles were removed in vacuo and the residue partitioned between EtOAc (20 ml) and H2O (20 ml). The aqueous was further extracted with EtOAc (2×20 ml), the organics combined, dried (MgSO4) and concentrated to yield the subtitle compound as a crude white solid. This material was used directly in the next step. Yield: 0.23 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:20]([CH:24]([CH3:26])C)[CH:21]([CH3:23])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH3:17])([C:14]([N:20]2[CH2:21][CH2:23][CH2:26][CH2:24]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 4-methylpiperidine-1,4-dicarboxylic acid mono-tert-butyl ester (229 mg, 0.94 mmol) in DMF (10 mL) were added DIPEA (0.493 mL, 2.83 mmol), pyrrolidine (0.118 mL, 1.41 mmol) and HATU (537 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with a 0.1N aqueous HCl solution and brine, dried over Na2SO4, filtered and concentrated to give 4-Methyl-4-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester as a white solid (279 mg, 100%). LCMS (Method H): RT 4.00 min; [M+Na]+ 319
Reaction SMILES: [NH2:1][CH:2]([C@H:4]1[C@@H:7]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[NH:6][C:5]1=[O:14])[CH3:3].N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[O:23]>C(Cl)Cl>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:22]([NH:1][CH:2]([C@H:4]1[C@H:7]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[NH:6][C:5]1=[O:14])[CH3:3])=[O:23])([O-:34])=[O:33]
Reactant: CC(=O)OCC[C@H]1NC(=O)[C@H]1C(C)N
Reactant: O=C(Cl)OCc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)NC(=O)OCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Trans and cis-3-(1-aminoethyl)-4-(2'-acetoxyethyl)-2-azetidinone (0.6575 g, 0.00328 mole) is dissolved in 10 ml CH2Cl2, cooled to 0° C., and treated with 1.1 mole each of pyridine and o-nitrobenzyl chloroformate. The reaction mixture is stirred at 0° for 20 min, the ice bath is removed and stirring continued for another 30 min. The solution is diluted with CH2Cl2, washed with H2O, dried and evaporated in vacuo. Column chromatography ##STR207## of the residue gives 0.7790 g (0.00206 mole, 63% yield) of the product.