Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([OH:45])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CN=C(N)C=1C.[CH3:62][C:63]1([CH3:71])[CH2:68][C:67](=[O:69])[O:66][C:65](=[O:70])[CH2:64]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:67](=[O:69])[CH2:68][C:63]([CH3:71])([CH3:62])[CH2:64][C:65]([OH:70])=[O:66])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: Cc1ccnc(N)c1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 32, 0.5 g, 0.80 mmol) in pyridine (5 ml), dimethyl amino pyridine (0.2 g, 1.6 mmol) was added, followed by 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (0.82 ml) was added. The contents were refluxed for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80-0.95 (m, 17H); 1.14-1.67 (m, 23H); 1.82-2.02 (m, 15H); 2.23-3.50 (m, 15H); 4.21-4.45 (m, 2H); 4.57 (s, 1H); 4.72 (s, 1H); 6.28-6.30 (m, 1H); 7.11-7.13 (m, 2H); 7.14-7.22 (m, 1H); 7.24-7.29 (m, 2H); ES Mass: 841 (100%), [M+1].
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH2:38][CH2:36][OH:37])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: NCCO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNCCO)CCC2)c1=O

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268 g) and ethanolamine using a similar method to that described for example 167f.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(C(C)CNS(C)(=O)=O)cc1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
To a degassed solution of 1.0 g (3.4 mmol) of material from Example 1, 0.8 g (5.1 mmol) of 2-methoxybenzeneboronic acid and 0.7 g (5.1 mmol) of potassium carbonate in 15 mL of dioxane and 5 mL of water was added 0.2 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with 10 mL of water and extracted three times with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded 1.0 g (90%) of the title compound as a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:25]([O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:32]2[CH:33]=[N:34][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:30][CH:31]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Reactant: CC(C)Oc1ccc(B(O)O)cn1
Product: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)nc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c) from 5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 8(b)) and 6-isopropoxypyridine-3-boronic acid (see step (b) above).
Reaction SMILES: C(#N)C.Cl[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[Cl:29])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:13])=[O:12])=[CH:7][N:6]=1.[F-:30].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>[Cl:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[CH:14]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([F:30])=[N:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: [F-]
Reactant: O=S(=O)(c1ccc(Cl)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 25 °C
Yield: 6.9 %

Procedure:
To an acetonitrile (2 ml) solution of 2-chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]pyridine (66 mg, 0.16 mmol) were added potassium fluoride (94 mg, 1.60 mmol) and tetraphenylphosphonium bromide (134 mg, 0.32 mmol). The resulting mixture was heated under reflux for 16 hours. After the reaction mixture was cooled to room temperature, dichloromethane was added thereto. The resulting mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=17:3 eluate is concentrated under reduced pressure to give the title compound (4.5 mg, 0.011 mmol, 7%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[OH:29])[CH2:22][CH2:21]4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.[N+](C1C=C(S(O[CH2:45][C@@H:46]2[CH2:48][O:47]2)(=O)=O)C=CC=1)([O-])=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:45][C@@H:46]5[CH2:48][O:47]5)[CH2:22][CH2:21]4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@@H]3CO3)CC2)c1=O

Procedure:
The subtitle compound was prepared using a similar method to that described for Example 299a from N-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 167d) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH2:30](Cl)Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([CH3:30])[C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)c(F)c4)CC3)cc2o1
Reactant: ClCCl
Agent: Cl
Product: CN(CCCc1ccc(F)c(F)c1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Condensation of 6-(trans-4-[3-(3,4-difluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (400 mg, 1.0 mmol) with p-formaldehyde (740 mg, 24.7 mmol) following the procedure described in Example 17, except CH2Cl2 (15 mL) was also added, followed by formation of the HCl salt, gave 6-(trans-4-{[3-(3,4-difluorophenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (226 mg, 52%), as a white solid: mp 224-227° C.; IR (KBr): 2945, 1764 cm−1; 1H NMR (500 MHz, DMSO-d6):, δ 11.50 (s, 1H), 9.94 (s, 1H), 7.40-7.34 (m, 2H), 7.16 (s, 1H), 7.12-7.09 (m, 1H), 7.00 (s, 2H), 3.33-3.29 (m, 1H), 3.18-3.11 (m, 1H), 3.03-2.97 (m, 1H), 2.71 (d, J=5 Hz, 3H), 2.68-2.63 (m, 2H), 2.59-2.50 (m, 1H), 2.14-1.98 (m, 4H), 1.94-1.88 (m, 2H), 1.66-1.51 (m, 4H); ESI-MS (m/z): 401 [M+H]+; HPLC: method A, 5.97 minutes (97.1%); Anal. Calcd for C23H26F2N2O2.HCl: C, 63.23; H, 6.23; N, 6.41. Found: C, 62.94; H, 6.56; N, 6.32.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[C@H:13]([C:23]([O:25]C)=[O:24])[O:12][C:11]1([CH3:28])[CH3:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[C@H:13]([C:23]([OH:25])=[O:24])[O:12][C:11]1([CH3:28])[CH3:27])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(F)cc2F)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
Under ice cooling, a solution of 31 mg of lithium hydroxide dissolved in 5 ml of water was added dropwise to a solution of 402 mg of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(2,4-difluorophenyl)-5-oxazolidinecarboxylate dissolved in 10 ml of methanol. After the mixture was stirred at room temperature for 45 minutes, the reaction mixture was concentrated under reduced pressure. Water and diethyl ether were added to the residue, and the aqueous layer was collected by separation. The aqueous layer was adjusted to about pH 2 by adding 10% aqueous hydrochloric acid thereto under ice cooling and then extracted with chloroform. After the chloroform layer was washed with water and dried, the solvent was removed to obtain 385 mg of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(2,4-difluorophenyl)-5-oxazolidinecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:18]1C=CN=C1)=O.N.C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCS(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Br)c(C(N)=O)c1
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To 2-bromo-5-(ethylsulfonyl)benzoic acid (Preparation 73, 8.10 g, 27.6 mmol) dissolved in THF (200 mL) was added carbonyldiimidazole (8.72 g, 41.4 mmol). The reaction was left to stir for 5 minutes under nitrogen before ammonia was bubbled through the solution. A temperature rise from 22° C. to 41° C. was observed over 10 minutes. The temperature then started to fall, reaching 35° C. after 5 minutes, after which the flow of ammonia was stopped. The reaction mixture was left to stand as a saturated ammonia solution for 30 minutes before removal of the solvent under reduced pressure. The residue was partitioned between EtOAc (500 mL) and water (500 mL) and the layers separated. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to give the crude product. Trituration with CH2Cl2 gave the title compound as a solid in 28% yield, 2.23 g. A further portion of the title compound was isolated by drying of the filtrate and further trituration, to give a further 8%, 650 mg.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:18](C=O)C>C1COCC1>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: Cc1c(F)ccc(C(=O)O)c1Cl
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1c(F)ccc(C(N)=O)c1Cl

Procedure:
To a solution (60 ml) of 2-chloro-4-fluoro-3-methylbenzoic acid (5.66 g) synthesized by a known method in THF were added thionyl chloride (10.7 g) and DMF (0.2 ml) with stirring under ice-cooling, and the mixture was stirred at 70° C. for 3 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in dry THF (50 ml) and added dropwise to a mixture of concentrated aqueous ammonia (130 ml) and THF (86 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were collected by filtration, washed with diethyl ether and dried to give 2-chloro-4-fluoro-3-methylbenzamide (4.82 g) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23].[H-].[Na+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH3:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To 82 mg (0.28 mmol) of 1-benzyloxycarbonyl-4-(methoxycarbonylamino)piperidine from Step A and 0.045 mL (0.56 mmol) of ethyl iodide in 4 mL of DMF under nitrogen was added 22 mg (0.56 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 1 h and was then poured into water containing 1 mL of 2N hydrochloric acid and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 50% ethyl acetate/hexanes to afford 87 mg of title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 22 h

Procedure:
30.8 g of 4-fluoro-3-methoxybenzonitrile, 39.1 g of 2,4-dichlorophenol and 78.2 g of caesium carbonate are dissolved in 180 ml of dimethylformamide and stirred at 120° for 22 h. After cooling, the solution is diluted with diethylether, washed with water, an 1N aqueous solution of sodium hydroxide, an 1N aqueous solution of hydrogen chloride and finally with brine. The organic phase is dried over magnesium sulfate and evaporated to yield 4-(2,4-dichlorophenoxy)-3-methoxybenzonitrile.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[C:14]1([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][C:22]([C:30]([OH:32])=[O:31])([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CO>[C:14]1([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][C:22]([C:30]([O:32][CH3:8])=[O:31])([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCC
Reactant: O=C(O)C12CC3CC(C1)CC(c1ccccc1)(C3)C2
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CC3CC(C1)CC(c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Trimethylsilyldiazomethane 2M solution in hexane (8.15 mL, 16.31 mmol) was added dropwise to a stirred solution of 3-phenyl-1-adamantanecarboxylic acid (2.09 g, 8.15 mmol, CAS 37589-22-3) in toluene (20 mL) and methanol (10 mL) over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 60 minutes. The reaction mixture was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (2.140 g, 97%) as a colourless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccnc(Cl)n1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: NC(=O)c1ccnc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)n1

Procedure:
EXAMPLE 83 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-pyrimidine-4-carboxylic acid amide (2-chloro-pyrimidine-4-carboxylic acid amide was prepared according to G. D. Davies, D. E. O'Brien, L. R. Lewis, C. C. Cheng, J. Heterocyclic Chem., 1:130–131(1964):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of trans-1-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester (83.7 g) in dry dimethylformamide (80 ml), imidazole (36.76 g) and t-butyldimethylsilyl chloride (54.26 g) were added, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid and water and dried over magnesium sulfate. Removal of the solvent gave trans-1-benzyloxycarbonyl-4-t-butyldimethylsilyloxy-L-proline methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[C:8](=[N:10]O)[CH3:9].[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9]
Reactant: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N)c(Cl)cc32)cc1
Yield: 78.1 %

Procedure:
A mixture of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime (514 mg, 1.41 mmol), Zn power (4.6 g, 70.64 mmol), NH4Cl (1.5 g, 28.26 mmol) in MeOH (20 mL) and HOAc (4 mL) was heated at reflux overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was diluted with CH2Cl2 (200 mL) and aqueous ammonia (20 mL). The organic layer was separated, washed with H2O, dried (NaSO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with MeOH—CH2Cl2 (1:15) to afford 385 mg (78%) of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine as yellow oil. MS (ESI): m/z=350.0 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.C=O.[C:14](O)(=[O:16])C.C([BH3-])#N.[Na+]>C(OCC)(=O)C.O>[CH3:11][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:14][OH:16]
Reactant: CC(=O)O
Reactant: CN(C)c1cccc(CO)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)c1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round-bottomed flask, (3-(dimethylamino)phenyl)methanol (1 g) and paraformaldehyde (2.5 g) were added to acetic acid (150 mL) to give a suspension. Sodium cyanoborohydride (2.6 g) was added slowly. The mixture was stirred at room temperature overnight. After concentration of the solvent, water and ethyl acetate (1:1, 100 mL) were added. After separation, the aqueous layer was extracted by ethyl acetate (2×20 mL). The combined organic layers were washed with water (3×50 mL), saturated aqueous NaHCO3 (2×30 mL), and dried over Na2SO4. After filtration and concentration, the residue was taken up into CH2Cl2 and the product was purified by flash chromatography (Varian, Superflash SF40-80 g column), eluting with 0-20% methanol/dichloromethane, to provide the title compound.
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[N:16]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[C:17]=[O:18]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([N:16]2[C:3](=[O:15])[CH2:4][N:5]([C:6]3[CH:7]=[CH:8][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:10][CH:11]=3)[C:17]2=[O:18])[CH:20]=1
Reactant: COC(=O)CNc1ccc(C(C)C)cc1
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2C(=O)CN(c3ccc(C(C)C)cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of methyl-2-(4-isopropylanilino)acetate (1.10 g, 5.31 mmol) in toluene (30 mL) was treated with methyl 3-isocyanatobenzoate (1.03 g), and the resulting solution was stirred at ambient temperature for 20 h. The reaction mixture was evaporated, and a portion (0.6 g) of the resulting solid material used directly in the next step. The compound was dissolved in methanol, and treated with sodium methoxide (0.84 mL of 0.5 M in methanol). The resulting solution was stirred for 1 h, then evaporated and partitioned between water and ethyl acetate (50 mL each). The organic extract was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residual material was separated by preparative thin-layer chromatography (silica gel, 30:70 ethyl acetate-hexane) to afford pure product, methyl-3-[3-(4-isopropylphenyl)-2,5-DIOXO-imidazolidin-1-yl]-benzoate, as a waxy solid. 1H NMR (CDCl3, 300 MHz): δ 8.16 (1H, t, J=1.8 Hz), 8.07 (1H, dt, J=7.6, 1.5 Hz), 7.67 (1H, ddd, J=8.0, 2.0, 1.1 Hz), 7.56 (1H, t, J=7.9 Hz), 7.51 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 4.47 (2H, s), 3.92 (3H, s), 2.91 (1H, m, J=7.0 Hz), 1.25 (6H, d, J=7.0 Hz). Mass spectrum (ES+): m/z 353 (36), 321 (100).