Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([O:9][CH2:10][C:11](N)=[O:12])=[C:7]([Cl:14])[N:6]=[C:5](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1.[CH2:23]([OH:25])[CH3:24]>>[NH2:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:25][CH2:23][CH3:24])=[O:12])=[C:7]([Cl:14])[N:6]=[C:5](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1
Reactant: CCO
Reactant: NC(=O)COc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Agent: Cl
Product: CCOC(=O)COc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Temperature: 100 °C
Yield: 84 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of 2-({4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}oxy)acetamide (0.6 g, 1.97 mmol) in ethanol (20 mL). The resulting mixture was heated at 100° C. for 3 h. The mixture was evaporated under reduced pressure to give the desired product as a solid (0.55 g, 84%) which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[CH2:13]([S:25]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+].O>C(#N)C.C(O)(C)C>[NH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[NH:28][S:25]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:27])=[O:26])=[C:3]([OH:12])[CH:4]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: CCCCCCCCCCCCS(=O)(=O)Nc1ccccc1C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Solvent: CC#N
Product: CCCCCCCCCCCCS(=O)(=O)Nc1ccccc1C(=O)Nc1cc(Cl)c(N)cc1O
Yield: 52 %

Procedure:
28.2 g of 2-amino-4-chloro-5-nitrophenol was refluxed in 150 ml of acetonitrile and to the mixture, a solution containing 52.7 g of 2-dodecansulfonamidobenzoyl chloride obtained in Step (i) above dissolved in 50 ml of acetonitrile was added. After refluxing for 4 hours, the reaction mixture was cooled to deposit crystals. The crystals were collected by filtration, washed with acetonitrile, and dried to yield 56 g thereof. These crystals were refluxed with stirring for 1 hour together with 60 g of reduced iron powder, 2 g of ammonium chloride, 50 ml of water, and 500 ml of isopropanol. After removing the iron powder by filtration, the filtrate was poured into 2 liters of water to deposit crystals. The crystals were collected by filtration and recrystallized from acetonitrile to obtain 36 g of the 5-amino-4-chloro-2-(2-dodecansulfonamidobenzoylamino)phenol compound.
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH3:4].[ClH:14]>[Pd].C(O)C>[ClH:14].[NH2:2][CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CC(=NO)c1cccc(C(=O)O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(N)c1cccc(C(=O)O)c1
Yield: 94 %

Procedure:
3-(1-(Hydroxyimino)ethyl)benzoic acid (2.28 g, 12.73 mmol) and palladium on carbon (10 wt. %, 1.355 g, 12.73 mmol) in ethanol (170 mL) and 12M aqueous HCl (2.1 mL, 24.2 mmol) were stirred under an atmosphere of H2 at 40 psi for 6 hours. The reaction mixture was purged with nitrogen for 30 minutes then filtered through a pad of Celite washing with methanol. The filtrate was concentrated in vacuo and the residue triturated from Et2O to give the sub-title compound as a white (2.4 g, 94% Yield). 1H NMR (400 MHz, CD3OD) δ 1.66 (d, 3H), 4.55 (q, 1H), 7.58 (t, 1H), 7.70 (d, 1H), 8.07 (d, 1H) and 8.16 (s, 1H); MS (ES+) 166.5.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([C:36]2([C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[OH2:11].[ClH:27].[CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])[CH2:37][CH2:38]2)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N1CCCC1)C1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C(=O)CO1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1COC(CCN2CCC(C(=O)N3CCCC3)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Temperature: 80 °C
Yield: 58.2 %

Procedure:
A mixture of 0.98 g of the compound obtained in step B of EXAMPLE 14, 0.645 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine and 0.69 g of K2 CO3 in 3 ml of DMF is heated at 80° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and extracted with an AcOEt/ether mixture, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/2; v/v) as the eluent. The product obtained is dissolved in the minimum amount of DCM and acidified to pH 1 by the addition of a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.42 g of the expected product. M.p.=155°-178° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:29](F)(F)C(O)=O.C[C@H](OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.BrCCCBr.O1CCCC1CN>>[CH3:29][C@H:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Agent: BrCCCBr
Agent: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: NCC1CCCO1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane, and (tetrahydro-2-furanylmethyl)amine.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[CH2:27]([O:29][C:30]([C:32]1[O:33][C:34]([CH2:37]Br)=[CH:35][CH:36]=1)=[O:31])[CH3:28]>>[CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:37][C:34]4[O:33][C:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])=[CH:36][CH:35]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(CBr)o1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(CC)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of step (vi) (0.6 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807)(0.47 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 0.19 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](S(N)(=O)=O)[CH:5]=[N:6][C:7]=1Cl.BrC1C=CC(S(Cl)(=O)=O)=NC=1Cl.C[N:26](C)[CH2:27][CH2:28][N:29](C)C>>[NH:26]1[C:2]2[CH:3]=[CH:4][CH:5]=[N:6][C:7]=2[NH:29][CH2:28][CH2:27]1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: CN(C)CCN(C)C
Agent: O=S(=O)(Cl)c1ccc(Br)c(Cl)n1
Product: c1cnc2c(c1)NCCN2

Procedure:
The 5-bromo-6-chloro-3-pyridinesulfonamide derivative (lix) (prepared from the commercially available 5-bromo-6-chloropyridine sulfonyl chloride as shown in Scheme 18) is condensed with diamine (lxxix), (lxxx) or N1,N1,N2,N2-tetramethylethane-1,2-diamine to form tetrahydropyridopyrazine derivative (I-e), (I-f) or (I-d), respectively, as shown.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][OH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].[H-].[Na+].CI.[C:48](=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)[C:22]([CH2:40][O:41][CH3:48])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(COC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxymethylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in tetrahydrofuran (4 ml), then thereto are added sodium hydride (12 mg) and methyl iodide (0.02 ml) under ice-cooling, and the mixture is stirred at room temperature for 3 hours and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→3:2) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxymethylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (92 mg). MS (m/z): 628 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:32]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1.[ClH:52]>>[ClH:52].[ClH:52].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:32]=[N:31][NH:30][CH:29]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:16][CH2:17]1
Reactant: CS(=O)(=O)c1ccc(F)c(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(F)c(N2CCN(c3ncnc4ccc(-c5cn[nH]c5)cc34)CC2)c1

Procedure:
211 mg 4-[4-(2-fluoro-5-methylsulfonylphenyl)piperazin-1-yl]-6-(1-trityl-1H-4-pyrazolyl) quinazoline obtained in Example 730 was subjected to deprotection of the trityl group and converted into the corresponding hydrochloride by the same method as in Example 163, to give 108 mg of the title compound as pale yellow crystals.
Reaction SMILES: C(O)(=O)C.C([O:9][C:10](=[O:36])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:15][C:14]=1[CH2:34][NH2:35])(C)(C)C.[C:37]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C:46]1=O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.[Pd].O.C(Cl)Cl>[C:37]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:35][CH2:34][C:14]1[CH:15]=[C:16]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:10]([OH:9])=[O:36])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(CNc2ccccc2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.2 %

Procedure:
A solution of 3-{2-aminomethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid tert-butyl ester acetic acid salt (290 mg, 0.665 mmol, Example 1, Step B) and 2-benzoyl-cyclohexanone (161 mg, 0.797 mmol) in anisole (20 mL) was treated with a slurry of Pd/C (60 mg) in anisole (2 mL). The mixture was refluxed at 200° C. with azeotropic removal of water for 2 h and cooled to room temperature. The catalyst was filtered and a fresh slurry of Pd/C (60 mg) in anisole was added. The mixture was heated at 110° C. for 72 h and filtered through a pad of Celite. The filtrate was concentrated, purified by silica gel chromatography-(25% EtOAc/hexanes) to afford a mixture of starting material and desired tert butyl ester intermediate. The mixture was treated with TFA (1.0 ml)/CH2Cl2 (1.0 ml)/H2O (0.1 mL), stirred for 3 h, and concentrated. The residue was and purified using silica gel chromatography (MeOH/EtOAc 1/9) to give the title compound (38 mg, 10%). MS (ESI) m/z 561.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:16][C:15](=O)[CH2:14][C:13](=[O:18])[CH2:12]1.[Cl:19][C:20]1[CH:31]=[C:24]2[C:25](OC(=O)[NH:29][C:23]2=[CH:22][CH:21]=1)=[O:26].Cl>CN(C)C=O>[Cl:19][C:20]1[CH:31]=[C:24]2[C:23]([NH:29][C:15]3[CH2:16][CH:11]([C:5]4[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=4[Cl:3])[CH2:12][C:13](=[O:18])[C:14]=3[C:25]2=[O:26])=[CH:22][CH:21]=1
Reactant: O=C1CC(=O)CC(c2ccc(Cl)cc2Cl)C1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(c2ccc(Cl)cc2Cl)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.96 g of 50% sodium hydride in 10 ml of N,N-dimethylformamide at -10° C. is added dropwise a solution of 5.14 g of 5-(2,4-dichlorophenyl)cyclohexan-1,3-dione in 40 ml of N,N-dimethylformamide. During the addition frothing occurs and the temperature rises to 10° C. The mixture is then stirred at room temperature for 1 hr and cooled to 5° C. A solution of 3.96 g of 5-chloroisatoic anhydride in 40 ml of N,N-dimethylformamide is added and stirring is continued at room temperature for 18 hrs and then at 85°-90° C. for 5 hr. The mixture is poured into 1300 ml of ice water containing 10 ml of concentrated hydrochloric acid. The solid is collected, washed with water, and suspended in 200 ml of methanol. The suspension is heated on a steam bath for 0.5 hr, cooled and filtered. The solid is washed with methanol and then with ether and dried in vacuo at 60° C. for 18 hrs to give 7-chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)-acridinedione; mp 308°-310° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]2[C:12](=[O:17])[NH:13][NH:14][C:15]=2[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([N:14]1[C:15]([CH3:16])=[C:11]([CH2:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:12]([OH:17])=[N:13]1)(=[O:20])[CH3:19]
Reactant: COc1ccc(Cc2c(C)[nH][nH]c2=O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Cc2c(O)nn(C(C)=O)c2C)cc1F
Temperature: 135 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
A mixture of 1,2-dihydro-4-[(3-fluoro-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (synthesized as described in WO0236602; 4.11 g, 0.0174 mol), acetic anhydride (41 mL) and acetic acid (41 mL) was stirred at 135° C. for 8 hours and at room temperature for 12 hours. After being concentrated, the reaction mixture was diluted with toluene and then concentrated again. To the resulting residue, methanol (400 mL) and a 25 wt % methanol solution of sodium methoxide (0.37 mL) were added and stirred for 20 hours. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to give 1-acetyl-4-[(3-fluoro-4-methoxyphenyl)methyl]-3-hydroxy-5-methyl-1H-pyrazole (960 mg, 20%) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:29][CH2:30][NH2:31]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:29][CH2:30][NH:31][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:13][C@@H:11]3[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH2:15]2)[CH:17]=[N:18][CH:19]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCCc4ccc(Cl)c(Cl)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3,4-dichlorophenethylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 505 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[CH3:34])[CH2:23][CH2:22]2)=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:73]1([C:76]2[O:77][CH:78]=[C:79]([C:81](O)=[O:82])[N:80]=2)[CH2:75][CH2:74]1>O.C(OCC)(=O)C>[Cl:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:81]([C:79]2[N:80]=[C:76]([CH:73]3[CH2:75][CH2:74]3)[O:77][CH:78]=2)=[O:82])=[C:3]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[CH3:34])[CH2:25][CH2:26]2)[CH:4]=1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCCCN4CCCC4=O)cc3N)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCCCN4CCCC4=O)cc3NC(=O)c3coc(C4CC4)n3)CC2)c1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 5-amino-2-chloro-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 12d (158.70 mg, 0.33 mmol) was taken up in clean, dry N,N-dimethylformamide (3.00 ml, 38.74 mmol) and the mixture was stirred at room temperature under an inert nitrogen atmosphere until all solids were taken up in solution. To this mixture was then added the HATU (188.20 mg, 0.49 mmol) followed by the N,N-diisopropylethylamine (0.17 ml, 0.98 mmol) and the mixture was again stirred until all solids were in solution. The 2-cyclopropyl-oxazole-4-carboxylic acid 1h (65.70 mg, 0.43 mmol) was then added to the reaction mixture and the reaction was allowed to stir under nitrogen at room temperature overnight. The reaction mixture was diluted with 15 ml of water and 15 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous solution using ethyl acetate (3×20 ml) and the organic phases were combined, washed with brine (1×25 ml) and saturated aqueous lithium chloride solution (2×25 ml). The solution was dried over Na2SO4; the product solution was decanted and the solvent was removed under reduced pressure. The resultant brown semi-solid was purified using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. The product, 2-cyclopropyl-oxazole-4-carboxylic acid {4-chloro-2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide 12e (81.80 mg, 0.13 mmol), was isolated as an off-white solid and was submitted for testing.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]([CH3:37])([CH3:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C>[CH3:27][C:28]([CH3:37])([CH3:36])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:31]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CC(C)(C)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)CN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
7.15 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 2.9 gm of potassium carbonate and 4.5 gm of 1-(2,2-dimethyl-propyl)-piperazine were refluxed for 5 hours in 100 ml of absolute ethanol. Then, the hot reaction mixture was suction filtered. The crystals which precipitated out of the filtrate were then recrystallized from isopropanol in the presence of activated charcoal.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:51])[CH2:17][C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25]([CH2:26][C@@H:27](OC4CCCCO4)[CH2:28][C@@H:29]2OC2CCCCO2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:14]>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16](=[O:51])[CH2:17][C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:14]
Reactant: CCOC(=O)C[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C[C@H]1CC[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 mL of diisopropylamine in 3 mL of tetrahydrofuran at -30° C. was added 3.82 mL (0.0061 mol) of 1.6 M of butyllithium in hexane. After stirring for 0.5 hr, 3.03 g (0.0056 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]pregn-5-en-21-oic acid ethyl ester in 30 mL of tetrahydrofuran was added dropwise to yield the lithium enolate of [1α,3β]-1,3-bis[tetrahydro-2H-pyran-2-yl)oxy]pregn-5-en-21-oic acid ethyl ester. The mixture was stirred for 1 hr at -30° C. and cooled to -70° C. A solution of 2.30 g (0.0068 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-1-iodo-4-methylpentane in 5 mL of hexamethylphosphoramide was added dropwise. The mixture was stirred at -70° C. for 1 hr and was allowed to warm to 25° C. and stir for 1 hr. The mixture was then diluted with 9:1 hexane-ether. The solution was washed with water, and saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to give [1α,3β]-1,3-bis[(tetrahydro-2H-yran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-oic acid ethyl ester, [α]D20 +10° (c 1, CHCl3).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][N:24]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1c(C2CCN(S(C)(=O)=O)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Methanesulfonyl chloride (4 μL, 0.05 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (17.0 mg, 0.05 mmol) and triethylamine (0.02 mL, 0.14 mmol) in dichloromethane (1.0 mL), and the reaction stirred at room temperature overnight. The reaction solution was purified directly via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-0% hexanes in ethyl acetate) to afford (S)-1-(2-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (14 mg, 72%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.04 (m, 6H), 1.19-1.26 (m, 1H), 1.58-1.81 (m, 6H), 2.02 (s, 3H), 2.17-2.30 (m, 2H), 2.68-2.85 (m, 3H), 2.89 (s, 3H), 2.89-2.99 (m, 1H), 3.60-3.76 (m, 4H), 4.57 (br d, J=6.45 Hz, 1H), 7.09 (br s, 2H). MS (ESI, pos. ion) m/z 409 [M+H]+.