Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=1)[CH2:8][CH2:7]2)=[O:4]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:23]([Cl:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[Cl:28])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
Mg (1.02 g, 41.8 mmol) was added to a sol. of compound C2 (4.70 g, 8.36 mmol) in MeOH (230 mL). The reaction mixture was stirred at rt for 2 h. Mg (1.02 g, 41.8 mmol) was added again, and the mixture was stirred for 2 h again. The reaction mixture was heated to 70° C. and stirred at this temperature for 16 h. The mixture was allowed to cool down to rt, and was quenched with aq. sat. NH4Cl (5 mL). EtOAc was added, and the mixture was washed with water (2×) and brine (1×). The org. phase was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the crude by FC (EtOAc/heptane 5:45→6:44→7:43→8:42) yielded the title compound (595 mg, 13%). LC-MS: tR=1.18 min; ES+: 564.18.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([NH:42][C@@H:43]([CH3:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:40]=[CH2:41]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[N:42]([CH2:39][CH:40]=[CH2:41])[C@H:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:50])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CCN[C@@H](C)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: C=CCN(C(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)[C@@H](C)c1ccccc1
Yield: 36 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (S)-N-allyl-α-methylbenzylamine: yield 36%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][N:42]1[CH:46]=[CH:45][CH:44]=[CH:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][CH:44]=[CH:43]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: BrCCCn1cccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3cccc3)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (75 mg, 0.17 mmol) was dissolved in DMF (1 mL) at room temperature. K2CO3 (47 mg, 0.34 mmol) was added followed by 1-(3-bromopropyl)-pyrrole and the reaction was allowed to stir at 70° C. for 3 hrs. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate. Organic layers were washed with brine, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (1/1 ethyl acetate/hexanes) to afford the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]([CH3:25])[C:17](N1CCOCC1)=[O:18].[Mg].[Cl-].[NH4+]>O1CCCC1.O>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C@@H:16]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[CH3:25]
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Temperature: 35 °C
Yield: 103.6 %

Procedure:
1-Bromo-2-fluorobenzene (15 g) and 40 g of 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine was dissolved in 200 ml of tetrahydrofuran, to which 44 g of magnesium turnings was added, and the mixture was vigorously stirred. The reaction vessel was cooled when a temperature of the reaction solution was raised to 35° C., and 16.7 g of 1-bromo-2-fluorobenzene was added dropwise to the reaction solution at 35° to 37° C. over the period of 10 minutes. After stirring at 30° to 35° C. for 2 hours, the reaction solution was ice-cooled, to which 100 ml of a saturated aqueous solution of ammonium chloride and 100 ml of water were added. The mixture was extracted with ethyl acetate (200 ml×2, 100 ml). Then, the extract was washed with water and an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=10:1 to 5:1) to give 22.4 g of (2S)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:26]=1>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:30])=[C:27]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:26]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)N3CCCCC3)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
Piperidine (56 mg, 0.6576 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (169 mg, 0.8815 mmol) were added to a methylene chloride solution (20 ml) of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (173 mg, 0.3827 mmol) and the resulting solution was stirred at room temperature for 8 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by flash column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (129 mg, 0.2485 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61](=[O:68])[NH:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1)([CH3:59])([CH3:58])[CH3:57].CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:56]([O:60][C:61](=[O:68])[NH:62][C@@H:63]1[CH2:67][CH2:66][N:65]([C:24](=[O:26])[CH2:23][N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([O:30][CH3:31])=[CH:4][C:5]=3[O:28][CH3:29])[C:13]2=[O:27])[CH2:64]1)([CH3:59])([CH3:57])[CH3:58]
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with {1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50.9 mg, 0.11 mmol), HATU (49.4 mg, 0.12 mmol), and (R)-Pyrrolidin-3-yl-carbamic acid tert butyl ester (25.7 mg, 0.12 mmol), DMF (3 ml) is added. The stirring mixture is treated with DIPEA (33 μL, 0.275 mmol) and stirred at RT for 1 hour. Water is added to the mixture with stirring giving rise to a solid. This is filtered off and washed with water to afford the title compound, [M+H]+ 616
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]([O:25]C(=O)C2C=CC=CC=2)[CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][C:10]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:8])([CH3:7])[CH3:6]>>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]([OH:25])[CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:11][C:10]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=2[O:44][C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1ccc(CC[C@@H](CC2CCCCC2)OC(=O)c2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
13.3 ml of a 0.58M ethanolic solution of sodium ethoxide were added to 1.62 g (2.57 mmol) of (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-benzoyloxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 101), and the resulting mixture was stirred at room temperature for 8 hours, after which it was heated under reflux for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with water and then extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 150 g of silica gel, using a 2:8 by volume mixture of acetonitrile and benzene as the eluent. The concentrated eluate was recrystallized from diisopropyl ether, to give 1.14 g (yield 85%) of the title compound, melting at 141° -142° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[NH:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([OH:32])=O)(=[O:26])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:21]([CH3:22])[C:30](=[O:32])[C:29]1[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:25])=[O:26])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1OCc1ccccc1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(2-(benzyloxy)phenyl)-N-methylpyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow foam (83%). MS (ESI): m/z=541.140 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH:3]=O.[NH2:14][C:15]([NH2:17])=[O:16].COC1C=CC=CC=1N>C(O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][C:2]1[O:16][C:15]([NH2:17])=[N:14][CH:3]=1
Reactant: COc1ccccc1CC(Cl)C=O
Reactant: NC(N)=O
Solvent: COc1ccccc1N
Solvent: CCO
Product: COc1ccccc1Cc1cnc(N)o1

Procedure:
A mixture of 2-chloro-3-(2-methoxylphenyl)-propionaldehyde (10 g, crude from above) and urea (9.6 g, 0.16 mol) was dissolved in ethanol (250 mL) and then heated to reflux overnight. The solvent was evaporated to dryness. The residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were adjusted to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by silica gel column chromatography to yield the yellow-red solid product. (0.72 g, 0.35% from 2-methoxyaniline). ESI-MS m/z calc. 204.1. found 205.1 (M+1)+ 1H NMR (CDCl3) δ 7.26-7.20 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.91-6.86 (m, 2H), 6.35 (s, 1H), 4.49 (bs, 2H), 3.85 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:30]4[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=4)(=[O:35])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[ClH:11]>CO.O=[Pt]=O>[ClH:11].[NH2:1][C:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][N:3]=1
Reactant: Nc1cc(C(=O)O)ccn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: NC1=NCCC(C(=O)O)C1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
2-Aminopyridine-4-carboxylic acid (Farmaco. Ed. Sci. 1958, 13, 485; 1.38 g, 10 mmol) was dissolved in 90% methanol (210 ml) and conc. HCl(4.9 ml, 60 mmol) was added. The solution was hydrogenated over PtO2 (200 mg) in a Parr shaker apparatus at room temperature and 29 psig for 2 hours. Filtration and evaporation gave 1.57 g (88%) crude white crystals identified as the product by 300 MHz nmr and ir 1728 cm-1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][C@H:34]([CH3:38])[CH2:33]2)=[CH:28][CH:27]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[CH2:33][C@H:34]2[CH3:38])=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)C[C@H]1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chlorophenyl)-3-(R)-methylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a white solid: 1H NMR (CDCl3, 300 MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28 (m, 1H), 3.80–3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m, 3H) ppm; MS (ES) expect M+H=435.1, found 435.0.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C@H:20]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C@H:20]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CCn2c1cc1cc(OCc3ccccc3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1CCn2c1cc1cc(O)ccc12
Yield: 98.5 %

Procedure:
A mixture of (R)-tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.320 g, 0.848 mmol), Pd(OAc)2 (0.019 g, 0.085 mmol) and ammonium formate (0.214 g, 3.39 mmol) in methanol (20 mL) was heated under reflux overnight. After cooling the mixture was filtered through celite and then the solvent was removed under reduced pressure. Water (10 mL) and DCM (10 mL) were added and the 2 layers separated. The aqueous layer was extracted with DCM then the combined organics dried by passing through a phase separator cartridge. The solvent was removed under reduced pressure to give (R)-tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.240 g, 0.835 mmol, 99% yield, >70% ee) as a colorless oil. Exact mass calculated for C17H21NO3: 287.2, found: LCMS m/z=288.2, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.56 (s, 9 H), 3.40 (m, 2 H), 4.13 (t, J=6.6 Hz, 2 H), 5.11 (s, 2 H), 5.80 (s, 1 H), 7.00 (dd, J1=9.0, J2=2.2 Hz, 1 H), 7.18 (m, 2 H), 7.33 (m, 1 H), 7.39 (m, 2 H), 7.48 (m, 2 H), 7.55 (s, 1 H) 1H NMR (400 MHz, d6-DMSO) δ ppm 1.44 (s, 9 H), 2.18 (m, 1 H), 2.52 (dd, J1=15.9, J2=7.7 Hz, 1 H), 2.62 (dd, J1=15.9, J2=7.1 Hz, 1 H), 2.74 (m, 1 H), 3.54 (m, 1 H), 3.91 (m, 1 H), 4.05 (ddd, J1=9.8, J2=8.5 Hz, J3=4.3 Hz 1 H), 5.88 (s, 1 H), 6.54 (m, 1 H), 6.76 (d, J=2.3 Hz, 1 H), 7.06 (d, J=8.6 Hz, 1 H), 8.54 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CC=C(c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CC=C(c2ccc(F)cc2)CC1
Yield: 96 %

Procedure:
A solution of 0.065 mole of 4-(p-fluorophenyl)-3-cyclohexen-1-one (obtained as in Example 7) and 6 g. of sodium borohydride in 130 ml. of ethanol is stirred at room temperature for about 5 hours. The bulk of the solvent is removed on a rotary evaporator and the residue diluted with water. The precipitated solid is collected on a filter and recrystallized from Skellysolve B to give a 96% yield of 4-(p-fluorophenyl)-3-cyclohexen-1-ol having a melting point of 73° to 74.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[CH:20]([O:22]CCCC)=[CH2:21]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13])(=[O:22])[CH3:21]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccc(C(C)=O)c(OC)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
Methyl 4-bromo-3-methoxybenzoate (0.53 g, 2.2 mmol), 1,3-bis(diphenylphosphino)propane (0.050 g, 0.12 mmol), sodium carbonate (0.510 g, 4.81 mmol) and palladium (II) acetate (0.024 g, 0.11 mmol) were combined in a 5 mL microwave vial. The vial was sealed and purged with argon. Methanol (2.50 mL, 61.7 mmol) and n-butyl vinyl ether (1.12 mL, 8.74 mmol) were added by syringe, and the mixture was sonicated under argon flow for several minutes, then heated to 90° C. over night. Upon cooling to room temperature, celite (1 g) was added. The mixture was diluted with methanol (5 mL) and the slurry was then filtered. The filter cake was washed with methanol and to the pale red/brown methanolic filtrate was added 6M aqueous HCl (2.5 mL). The solution turned yellow and then turbid white over stirring at room temperature (0.5 h). The solvent was removed under reduced pressure and the residue obtained was partitioned between ethyl acetate (50 mL) and half-saturated aqueous sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (30 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (15-85% EtOAc/hexanes gradient) to afford the title compound (0.396 g, 87%). LC-MS: (FA) ES+ 209; 1H NMR (300 MHz, DMSO) δ 7.69-7.53 (m, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]#[N:13])=[C:9]([CH3:14])[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:15](Br)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]#[N:13])=[C:9]([CH3:14])[N:8]=[C:5]2[N:6]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1[nH]c2ncc(Cl)cc2c1CC#N
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(Cl)cc-2c1CC#N

Procedure:
A mixture of 5-chloro-3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine (147 mg, 0.7 mmol) and phenacylbromide (142 g, 7 mmol) in 12 ml CH3CN was refluxed for 22h. The reaction mixture was cooled and precipitated title compound was collected and washed with small portions of ice cold diethyl ether. Treatment of the filtrate with diethyl ether afforded a second and third lot of pure title compound. Total yield 257 mg (91%) calculated as the hydrobromide.
Reaction SMILES: [H-].[Na+].Br[C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH:10]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([CH2:16][O:17][C:4]2[N:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Brc1ncccn1
Reactant: OCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cnc(OCC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
NaH (1.1 equivalent) is added to an equimolar mixture of 2-bromopyrimidine and cyclohexylmethanol in THF. The reaction mixture is stirred at +60° C. for 18 hours, cooled to room temperature, partitioned between H2O and ethyl acetate. Organic portion is separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(cyclohexylmethoxy)pyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)=[CH:3][CH:2]=1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)CN(Cc2ccncc2)c2ccc(O)cc21
Reactant: O=C=NCC1CCCCC1
Product: CC1(C)CN(Cc2ccncc2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(4-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (5.8 mg, 19%) having the following characteristics.