Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>[O-2].[Mn+4].[O-2].C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(CO)c2[C@@H]2CCCN12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 15.2 g (50 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-1-(hydroxymethyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, 60 g of manganese (IV) oxide and 300 ml of methylene chloride is stirred at room temperature for 1.5 hours. The mixture is suction filtered over Dicalit, the residue is rinsed with methylene chloride and the filtrate is evaporated. After recrystallization from methylene chloride/ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde of melting point 224°-225°.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21]C)=[O:20])=[CH:16][CH:17]=3)[C:12]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH:31]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>O.C(O)C>[C:33]1([C:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=4)[NH:10][CH:11]=3)[CH2:28][CH:29]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc2c(c1)c(CCCCN1CC=C(c3ccccc3)CC1)cn2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
4.68 g of methyl 1-benzenesulfonyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylate [obtainable from methyl 1-benzenesulfonyl-3-(4-chlorobutyl)-indole-5-carboxylate and 4-phenyl-1,2,3,6-tetrahydropyridine] are boiled with 1 g of KOH in 7 ml of water and 14 ml of ethanol for 16 hours, and the mixture is concentrated and worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid, m.p. 284°-285°.
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=CN(C)C)[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.CO[CH:25](OC)[N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)Cl.CO.CO>O>[C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=[CH:25][N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: CCCCN(CCCC)C(OC)OC
Reactant: CN(C)C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCCN(C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)CCCC

Procedure:
As described for 9a but using N,N-di-n-butylformamide dimethylacetal. Colorless needles (75%). M.p. 107–109° C. TLC (silica gel, CH2Cl2—MeOH, 9:1): Rf 0.42. UV: (10% MeOH in water): λmax 235 (10200), 325 nm (25700). 1H NMR ([D6]DMSO): δ 0.93 (t, 6H, CH3), 1.33, 1.64, 3.70 (3m, 12H, —CH2—); 2.45, 2.80 (2m, 2H, H2—C(2′)); 3.60 (m, 2H, H2—C(5′)); 3.92 (m, 1H, H—C(4′)); 4.48 (m, 1H, H C(3′)); 5.04 (t, 1H, 3J(H,H)=5.8 Hz, 5′-OH); 5.39 (d, 1H, 3J(H,H)=4.0 Hz, 3′-OH); 6.55 (pt, 1H, 3J(H,H)=6.3 Hz, H—C(1′)); 8.78 (s, 1H, N═CH); 9.08 (s, 1H, H—C(8)). Anal. calcd. for C18H29N7O3 (391.5): C 55.23; H 7.47; N 25.05; found: C 55.36, H 7.66, N 24.97.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:29]=3)[CH:23]=2)[CH2:18][CH2:17]1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:29]=3)[CH:23]=2)[CH2:18][CH2:17]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(-c2cccc(N3CCN(C(=O)C4COCCN4C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(N3CCN(CC4COCCN4C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a solution of 3-{4-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carbonyl}-morpholine-4-carboxylic acid tert-butyl ester (0.21 g, 0.42 mmol) in dry THF (3 mL) at room temperature under a nitrogen atmosphere was added lithium aluminium hydride (LiAlH4) (0.05 g, 1.27 mmol). The reaction was heated at reflux for 2 h. The solution was then cooled to room temperature, quenched with 15% NaOH and then extracted with dichloromethane (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was then purified by Preparative HPLC to obtain 0.09 g (43%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:6]2>CO.[Ni]>[NH2:13][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)OC(C)(C)C)CC2
Agent: [Ni]
Solvent: CO
Product: COc1cc2c(cc1N)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Example 53E (550 mg, 1.78 mmol) in methanol (10 mL) was added Raney Ni (55 mg) and the mixture was stirred at ambient temperature under hydrogen for 16 hours. The mixture was filtered, concentrated and dried under vacuum to give the crude title compound. MS: 279 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:18]([O:22][C:23]1[C:24]([CH:29]=O)=[N:25][CH:26]=[CH:27][N:28]=1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:18]([O:22][C:23]1[C:24]([CH2:29][N:15]2[CH2:14][CH2:13][CH:12]([C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[CH2:17][CH2:16]2)=[N:25][CH:26]=[CH:27][N:28]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: O=C(Cc1ccccc1Cl)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 78 %

Procedure:
After dissolving 252 mg of 1-(1-benzylpiperidin-4-yl)-2-(2-chlorophenyl)ethanone in 3 ml of 1,2-dichloroethane, 0.1 ml of 1-chloroethyl chloroformate was added while stirring on ice, and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, 3 ml of methanol was added to the residue, and heating to reflux was continued for 30 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue and the precipitate was filtered out to obtain 171 mg of 4-(2-chlorophenylacetyl)piperidine hydrochloride. After then suspending 98 mg of the 4-(2-chlorophenylacetyl)piperidine hydrochloride in 3 ml of dichloromethane, 77 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 114 mg of sodium triacetoxyborohydride were added while stirring on ice, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture to render it alkaline, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (112 mg, 78% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].CCN(CC)CC.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.O>[Cl:16][C:11]1[CH:10]=[C:9]([C:8](=[C:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:23])([CH3:24])[CH2:22]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:29]=[CH:28]/[C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: C=CC(=O)OCC
Reactant: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)c(Cl)c2)cc1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]-2-chlorophenol (127) (0.38 g, 0.88 mmol), ethyl acrylate (0.96 mL, 8.80 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.062 g, 0.09 mmol), Et3N (0.61 mL, 4.38 mmol) and DMF (10 mL). The stirred reaction mixture was heated overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of water and EtOAc (100 mL). The layers were separated and the organic phase washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated to give reddish brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.26 g (66%) of compound 128 as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.92 (s, 6H), 0.94 (s, 6H), 1.30 (s, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.96 (s, 2H), 1.97 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 5.43 (s, 1H), 6.39 (d, J=15.9 Hz, 1H), 6.90-7.00 (m, 2H), 7.11 (d, J=1.8 Hz, 1H), 7.16 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65 (d, J=15.9 Hz, 1H). LCMS (ESI): m/z, 453 (M+H)+, 451 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[NH4+].[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].Cl>ClCCl>[C:11]([N:14]1[CH2:15][CH2:16][CH:17]([C:20](=[O:21])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])[CH2:18][CH2:19]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
67 g of 1,3-difluorobenzene and 133 g of ammonium chloride were added to 150 ml of dichloromethane, and then the mixture was cooled to room temperature. 98 g of 1-acetyl-4-piperidinecarbonyl chloride in 50 ml of dichloromethane was added thereto dropwise, and then the mixture was stirred at an elevated temperature for 3 hours. The reaction mixture was poured to a mixture of ice and hydrochloric acid, and the resulting mixture was extracted with 200 ml of dichloromethane. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed from the filtrate to obtain 55.9 g of the title compound (yield: 41%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[C:16]2=[O:31]>C(O)CCC>[CH3:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:30])[C:23]=1[N:17]1[C:16](=[O:31])[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([NH:12][C:2]3[N:11]=[C:10]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[CH:14]=2)[C:18]1=[O:22]
Reactant: Clc1ncc2ccccc2n1
Reactant: Cc1cccc(C)c1N1C(=O)c2ccc(N)cc2C1=O
Solvent: CCCCO
Product: Cc1cccc(C)c1N1C(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2C1=O
Yield: 42.5 %

Procedure:
A mixture of 2-chloroquinazoline (0.62 g, 2.6 mmol) and 5-amino-2-(2,6-dimethylphenyl)isoindoline-1,3-dione (0.69 g, 2.6 mmol) in n-butanol (10 mL) was heated at 120° C. until all of the butanol had evaporated. Additional butanol (10 mL) was added and the process repeated twice. After the reaction mixture was cooled, water was added (20 mL). A precipitate which formed was collected by suction filtration. N,N-Dimethylacetamide (5 mL) was added to dissolve the solid which was purified by preparative reverse-phase HPLC to give 2-(2,6-dimethylphenyl)-5-[(4-phenylquinazolin-2-yl)amino]-1H-isoindole-1,3(2H)-dione (0.26 g, 21%). 1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 8.80 (m, 1H), 8.42 (m, 1H), 7.96 (m, 1H), 7.90 (m, 2H), 7.85 (m, 1H), 7.81 (m, 2H), 7.65 (m, 3H), 7.50 (m, 1H), 7.32 (m, 1H), 7.25 (m, 2H), 2.10 (s, 6H). MS (EI) for C30H22N4O2: 471.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14]C=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Br[CH2:25][CH2:26][CH2:27][Cl:28]>>[CH2:19]([O:18][CH:15]([CH3:14])[CH2:16][CH2:17][CH2:12][S:9]([N:8]([CH2:25][CH2:26][CH2:27][Cl:28])[CH:4]([CH:5]([CH3:6])[CH3:7])[C:3]([O:2][CH3:1])=[O:23])(=[O:10])=[O:11])[C:20]#[C:21][CH3:22]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Reactant: ClCCCBr
Product: CC#CCOC(C)CCCS(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C
Yield: 76.1 %

Procedure:
According to the procedure of Example 5, 1.00 g (2.95 mmol) 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.88 mL (8.849 mmol) of 1-bromo-3-chloropropane provided 0.92 g of methyl 2-[{[4-(2-butynyloxy)pentyl]sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate as a white solid. Electrospray Mass Spec 416.2 (M+H)+.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+].[Na+].O(Cl)Cl.[Zr:11].Cl>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Zr+4:11].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: [Zr]
Agent: Cl
Agent: ClOCl
Agent: O=S(=O)([O-])[O-]
Product: [Zr+4]

Procedure:
141 g of a 25% sodium sulfate solution was heated to 85° C., 375 g of a 16% (by ZrO2 conversion) zirconium oxychloride solution which had been previously heated to 85° C. was added thereto, hydrochloric acid was added to achieve a free acid concentration of 1.5 N and this was maintained for 0.5 hours to produce basic zirconium sulfate (high-temperature reaction liquid).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1>CN(C=O)C.O>[I:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: BrCc1cccc(I)c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1cccc(I)c1
Temperature: 0 °C
Yield: 107.2 %

Procedure:
To a stirred solution of pyrrolidin-2-one (1.55 mL, 20.2 mmol) in DMF (25 mL) at 0° C. under N2 was added NaH (60% dispersion in mineral oil, 808 mg, 20.2 mmol) portion-wise over 10 min. The reaction mixture was maintained at 0° C. for 30 min and was then treated with 1-(bromomethyl)-3-iodobenzene (5.00 g, 17.0 mmol) over 10 min and afterwards was warmed to RT for 2 hr. The resulting mixture was diluted with water (100 mL) and extracted with DCM (2×100 mL). The combined organic extracts were washed with water (100 mL) and with brine (100 mL) and evaporated in vacuo to afford 1-(3-iodobenzyl)pyrrolidin-2-one as a yellow oil (5.49 g, 100%); Rt 1.85 min (Method 2, acidic); m/z 302 (M+H)+, (ES+).
Reaction SMILES: CC(C)CCN[CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[S:16][C:15]([C:17]([NH2:19])=[O:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[CH2:23]([CH:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24].[BH4-].[Na+]>CO>[CH2:23]([CH:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[S:16][C:15]([C:17]([NH2:19])=[O:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)[CH3:24]
Reactant: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)s2)cc1
Reactant: CCC(CC)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)CCNCc1ccc(Oc2ccc(C(N)=O)s2)cc1
Reaction time: 8 h

Procedure:
Place 5-(4-formylphenoxy)thiophene-2-carboxamide (Example 10, Part C) (0.235 g, 0.948 mmol), 3-ethylpentylamine (Part B) (0.115 g, 0.996 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.7 mL), cap and stir overnight. Add NaBH4 (0.0359 g, 0.948 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give the title compound: TOF MS ES+ 347.2 (M+H)+, HRMS calcd for C19H27N2O2S 347.1793 (M+H)+, found 347.1799, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.4 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=1.Cl[CH2:25][CH:26]1[O:30][C:29](=[O:31])[N:28]([CH3:32])[CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O.C(#N)C>[CH3:32][N:28]1[CH2:27][CH:26]([CH2:25][N:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([NH:13][C:14]4[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=4)[CH:3]=[C:2]([CH3:1])[CH:7]=3)[CH:12]=[N:11]2)[O:30][C:29]1=[O:31]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: CN1CC(CCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC3CN(C)C(=O)O3)c2)c1
Temperature: 140 °C

Procedure:
N-[3-Methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.31 mmol), 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (56.2 mg, 0.38 mmol), and cesium carbonate (122 mg, 0.38 mmol) were dissolved in DMA (1 mL). The mixture was then heated by microwave irradiation to 140° C. for 1.5 hours. Additional 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (30 mg, 0.19 mmol) was added and the mixture heated by microwave irradiation to 140° C. for 30 minutes. The reaction was cooled to room temperature, diluted with water (3 mL) and ACN (3 mL) then filtered through a syringe filter and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (45 to 80% ACN/water with 0.1% TFA modifier). The free base was liberated using PL-HCO3 cartridges (Stratospheres™, 0.9 mmol) and lyophilized to afford racemic 3-methyl-5-{[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one. MS ESI calcd. for C20H20F3N6O2 [M+H]+ 433. found 433. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.80 (d, J=3.9 Hz, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=3.4 Hz, 1H), 7.06 (s, 1H), 4.90-4.79 (m, 1H), 4.45-4.32 (m, 2H), 3.65 (t, J=8.9 Hz, 1H), 3.40 (dd, J=6.2, 9.0, 1H), 2.68 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [C:1]([C:3]([CH3:39])([CH3:38])[C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=4)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)#[N:2]>C1COCC1.[Pd]>[C:1]([C:3]([CH3:39])([CH3:38])[C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH2:20][CH:21]([C:28]4[CH:29]=[CH:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=4)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)#[N:2]
Reactant: CC(C)NC(=O)C(=Cc1cccc(-c2cc(C(C)(C)C#N)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)NC(=O)C(Cc1cccc(-c2cc(C(C)(C)C#N)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
A solution of 3-{3-[6-(cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamide from Step 3 (20 mg, 0.038 mmol) in THF (1 mL) containing Pd/C (10%, 9 mg) was stirred under H2 (50 psi) for 18 h. Filtration on celite, evaporation, and purification on HPLC (u-porasil ethyl acetate/hexane, 70:30 to 100:0, over 30 min.) afforded the 3-{3-[6-(cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-propionamide compound as a foam.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33].CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([CH2:2][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.8 %

Procedure:
To a mixture of 4-[2-(4-chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (0.85 g), methyl 2-(2-hydroxyphenyl)acetate (0.40 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.11 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]acetate as an oil (0.57 g, 57%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [C:1]([CH:4]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:5]([CH3:12])[CH2:6][C:7](OCC)=[O:8])(=O)[CH3:2].C([O-])(=O)C.[NH4+:23]>C(O)C>[CH3:12][CH:5]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:1]([CH3:2])[NH:23][C:7](=[O:8])[CH2:6]1
Reactant: [NH4+]
Reactant: CCOC(=O)CC(C)C(C(C)=O)c1ccncc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=C(c2ccncc2)C(C)CC(=O)N1
Yield: 9.8 %

Procedure:
A mixture containing 24 g of ethyl 4-acetyl-3-methyl-4-(4-pyridinyl)butanoate, 7 g of ammonium acetate and 50 ml of ethanol was refluxed for 8 hours with stirring. The reaction mixture was then concentrated to dryness in vacuo and the remaining white solid was collected, washed with ethanol and dried to produce 1.8 g of 3,4-dihydro-4,6-dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 184°-185° C. It's nmr and mass spectrum were consistent with the assigned structure.