Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17]OCC)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: CCOC=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Solvent: CCO
Product: CCN(C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21)CC
Reaction time: 24 h

Procedure:
1-(3-Chlorophenyl)-3-(ethoxymethylene)2(1H, 3H)-indolone (0.15 g, 0.5 mmole), diethylamine (5 ml, 48 mmole) and ethanol (30 ml) were combined and stirred 24 hours at 25°. The reaction mixture was concentrated in vacuo to an oil. The oil was taken up in ethyl acetate, washed with H2O and then brine, dried over MgSO4 and evaporated to yield title product which crystallized on cooling and trituration with ether/pentane, 96 mg. m.p. 74°-75.5°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](OC(=O)N)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]1[CH2:11][CH2:10][N:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:21]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cn2)C1

Procedure:
With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared by the hydrogenation of (R)-1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1.[C:22]([CH2:24][C:25](O)=[O:26])#[N:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][N:14]([C:25](=[O:26])[CH2:24][C:22]#[N:23])[CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)CC#N)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of 6-bromo-4-((3S,4S)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydrogen iodide salt prepared as previously described in Step 1 of Example 158 (200 mg, 0.429 mmol), 2-cyanoacetic acid (43.8 mg, 0.515 mmol) and BOP (285 mg, 0.644 mmol) in DMF (2 mL) was added DIPEA (0.225 mL, 1.288 mmol) and the resulting mixture was stirred at rt for 4 h. The reaction mixture was added to water (˜5 volumes) and the pH was adjusted to ˜7 with 1 N HCl and the resulting cloudy mixture was extracted with EtOAc (150 mL×2). The combined organic extracts were washed with water, brine, dried over anhyd. magnesium sulfate, filtered and concentrated to afford the title compound which was used directly in the next transformation. HPLC (method B) retention time=2.55 min. LCMS (m+1)=405.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[C:26]3([CH2:27][CH2:28][N:29]([C:6](=[O:7])[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)[CH2:30][CH2:31]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: COc1cc(C(=O)N2CCC3(CC2)C(=O)NCN3c2ccccc2)cc(OC)c1OC

Procedure:
The title compound, MS: m/e=426.4 (M+H+), was prepared in accordance with the general method of example 1 from 3,4,5-trimethoxybenzoyl chloride and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:3]2[C:2]([Cl:1])=[CH:13][C:6]([C:7](=[O:8])[N:9]([O:11][CH3:12])[CH3:10])=[CH:5][N:4]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CON(C)C(=O)c1cnc(Cl)c(Cl)c1
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1

Procedure:
5,6-Dichloro-N-methoxy-N-methyl-nicotinamide from step (a) above (3.2 g, 1.36 mmol) reacted with piperazine-1-carboxylic acid tert-butyl ester (2.53.g, 1.36 mmol, Aldrich) under the conditions of Example 3a to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 385 (M+1).
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:28]([O:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1=C[C@H]2CC(OC(=O)c3ccccc3)O[C@H]2C1
Temperature: 25 °C

Procedure:
Purified lactol 7 (591.5 mg, 3.84 mmol, 1 eq.), was dissolved in CH2Cl2 (7 ml) and stirred at r.t. Dimethylaminopyridine (23.5 mg, 0.19 mmol, 5 mol %) was added as a solid. Triethylamine (647.5 μl, 4.61 mmol, 1.2 eq.) and benzoyl chloride (534.5 μL, 4.61 mmol, 1.2 eq.) were added via syringe. The reaction mixture was stirred at r.t. for 36 h, filtered over basic alumina and the organic phase was concentrated to give the crude material. The material was purified by column chromatography eluting with petrol/EtOAc (3:1) to give the benzoyl acetal 55 (as an approximately 1.3:1 mixture of diasteroisomers, 706.7 mg, 71%) as pale yellow solid.
Reaction SMILES: Cl[CH:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1.[C:30]([O-:33])(=[O:32])[CH3:31].[K+]>C(O)(=O)C>[C:30]([OH:33])(=[O:32])[CH3:31].[OH:32][C@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To the solution of 3-chlorocholest-5-en-24-one in glacial acetic acid (3 ml) was added anhydrous potassium acetate (0.2 g) and the solution was refluxed for 4 hours. The reaction mixture was concentrated and extracted with diethyl ether. The ether layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel to give 81.1 mg of 3β-hydroxycholest-5-en-24-one acetate having a melting point of 125°-127° C. after recrystallization from methanol.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccccn2)C[C@H](C)N3C(C)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A solution of ethyl 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (for a preparation see Intermediate 27)(240 mg, 0.557 mmol) in ethanol (5 mL) was treated with aqueous lithium hydroxide (1N, 1.115 mL, 1.115 mmol) and the resulting mixture was stirred at room temperature. After 1 h most of the ethanol was removed in vacuo, the residue was diluted with water (ca 2 mL) and the “cloudy” mixture was treated with acetic acid (0.064 mL, 1.115 mmol). The precipitate formed was isolated by filtration, washed with Et2O and dried at 60° C. for 16 h to give 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotin ic acid (150 mg, 0.373 mmol, 66.9% yield) as a pale yellow solid which was used in the next step without further purification. LCMS (HpH, 2 min), Rt=0.61 min, MH+=403.
Reaction SMILES: [Cl-].[NH4+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:32])[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)#[N:4]>CC(O)C.O.[Fe]>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:32])[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)#[N:4]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc([N+](=O)[O-])c2)c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(N)c2)c1=O
Yield: 80.2 %

Procedure:
Iron powder (180 mg) and 342 mg of ammonium chloride were added to a solution of 317 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-nitrophenyl)-1,2-dihydropyridin-2-one in a mixture of 10 ml of 2-propanol and 5 ml of water followed by refluxing for 4 hours. The reaction mixture was concentrated, partitioned in ethyl acetate-water, the organic layer was washed with water, dried and concentrated and the residue was purified by a silica gel column chromatography (ethyl acetate/hexane system) to give 235 mg of the title compound as a pale yellow solid.
Reaction SMILES: [C@H:1]12[CH2:7][CH:4](CC1)[CH2:3][C:2]2=[O:8].[C:9]([O-:12])(=[O:11])[CH3:10].[Na+].OO>C(O)(=O)C>[OH:8][C:2]1([CH2:10][C:9]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:7][CH2:1]1
Reactant: CC(=O)[O-]
Reactant: O=C1CC2CC[C@@H]1C2
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CC1(O)CCCC1
Yield: 66.7 %

Procedure:
This product is oxidized by the Baeyer-Villiger procedure. (1R)-Norbornanone (81, 18 mmol) is stirred with sodium acetate (9 g, water-free), hydrogen peroxide (27 ml, 30%), and acetic acid (9 ml) at 5° C. in the dark for 40 hours. The reaction is quenched by the addition of sodium sulfite (50 ml of a 10% aqueous solution) at 0° C. The product is extracted twice with EtOAc (600 ml). The extract is washed with the sodium sulfite solution, then with sodium bicarbonate solution (50 ml, saturated), then with sodium chloride solution (saturated), dried and evaporated. The product is chromatographed on silica (380 g, ether) to yield the lacton of 3 hydroxycyclopentane-1-acetic acid (82, 12 mmol, 67%).
Reaction SMILES: C([O:3][C:4](=[S:24])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH3:23])=[N:10][CH:9]=1)[NH2:6])C.C(O)C.[OH-].[K+].Cl>O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[S:24])[NH2:6])=[CH:9][N:10]=[C:11]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1ncc(C[C@H](N)C(=S)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1ncc(C[C@H](N)C(O)=S)n1Cc1ccccc1Cl
Yield: 79.9 %

Procedure:
A solution of 3-[(2-chlorophenyl)methyl]-2-propylthiohistidine ethyl ester (Example 2 (i) ) (0.48 g, 1.26 mmol), ethanol (4 mL), water (4 mL) and potassium hydroxide (0.111 g, 1.97 mmol) was stirred at 25° C. for 1 hour. The mixture was treated with concentrated hydrochloric acid to pH 4.0 and cooled. The resulting precipitate was collected and triturated with ethanol to give 0.34 g (77%) of 3-[(2-chlorophenyl)methyl]-2-propylthiohistidine;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH:27]([F:29])[F:28])=[N:25][N:26]=2)[N:23]=1>>[F:29][CH:27]([F:28])[C:24]1[N:22]2[N:23]=[C:18]([N:14]3[CH2:13][CH2:12][N:11]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([CH3:10])[CH3:9])[CH2:16][CH2:15]3)[CH:19]=[CH:20][C:21]2=[N:26][N:25]=1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(c1ccc(F)cc1)N1CCNCC1
Product: CC(C)(c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 62 %

Procedure:
A mixture of 1-[1-(4-fluorophenyl)-1-methyl-ethyl]piperazine (obtained as described in J. Med. Chem. 2007, 50, 3528) and 6-chloro-3-(difluoromethyl)-[1,2,4]-triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 269 to give 3-(difluoromethyl)-6-[4-[1-(4-fluorophenyl)-1-methylethyl]piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 62% yield.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:24])[CH:23]=1)[C:20](=[O:25])[N:19]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:27]=1[CH2:28][O:29][C:30](=[O:32])[CH3:31])[N:18]=[CH:17]2)([CH3:13])([CH3:12])[CH3:11].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:24])[CH:23]=1)[C:20](=[O:25])[N:19]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([C:2]3[O:6][C:5]([C:7](=[O:8])[NH2:9])=[CH:4][CH:3]=3)[C:27]=1[CH2:28][O:29][C:30](=[O:32])[CH3:31])[N:18]=[CH:17]2)([CH3:11])([CH3:12])[CH3:13]
Reactant: NC(=O)c1ccc(Br)o1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2ccc(C(N)=O)o2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
In a microwave flask, a suspension of 5-bromofuran-2-carboxamide (200 mg, 1.05 mmol), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (Intermediate-5, 1.04 g, 2.11 mmol), X-PHOS (50.2 mg, 0.105 mmol), Pd2(dba)3 (48.2 mg, 0.052 mmol) and potassium phosphate (894 mg, 4.21 mmol) in dioxane (7 ml) and water (0.7 ml) was degassed with argon for 3-5 min. The mixture was set in a microwave at 125° C. for 30 min. Water was added and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash column chromatography (ethyl acetate in hexanes, gradient to 100% ethyl acetate) to obtain acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(5-carbamoyl-furan-2-yl)-benzyl ester (78.5 mg, 16%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C[O:17][C:18]1C=CC=C[C:19]=1N1CCN(CCO)CC1>>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:19][CH2:18][OH:17])[CH2:12][CH2:11]1
Reactant: COc1ccccc1N1CCN(CCO)CC1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Product: OCCN1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 97 %

Procedure:
2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]ethanol (35A) is prepared from 1-(2,3-dichloro-phenyl)-piperazine hydrochloride as described for 28A.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28]4(C)[CH2:30][O:29]4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:33])[CH2:4][CH2:5][C:6](=[O:32])[CH:7]=1.I(O)(=O)(=O)=O>O1CCCC1.O.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:29])[CH3:30])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:33])[CH2:4][CH2:5][C:6](=[O:32])[CH:7]=1
Reactant: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CO)CO1
Agent: [O-][I+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Yield: 22 %

Procedure:
A solution of 1.54 g of 9-fluoro-11β ,17,21-trihydroxy-16α-[(2-methyl-oxiranyl)methoxy]pregn-4-ene-3,20-dione, 21-acetate in 50 ml of tetrahydrofuran is stirred for 270 minutes with a solution of 2.6 g of periodic acid in 20 ml of water. The solution is poured into water and extracted with chloroform. The chloroform solution is washed with 10% sodium bicarbonate solution, dried, and evaporated in vacuo to give an oily residue. This is dissolved in chloroform and chromatographed on a 40 g-silica gel column. Elution with chloroform gives 400 mg of slightly impure product followed by 990 mg of TLC homogeneous solid. The 990 mg is recrystallized twice from acetone-hexane to give 328 mg of 9-fluoro-11β ,17,21-trihydroxy-16α-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate, melting point 203°-208°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[CH:11][CH:12]=1
Reactant: Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 4-(3,4-difluorobenzyloxy)phenol (1.00 g, 4.2 mmol) in N,N-dimethylformamide (20 ml) was added potassium tert-butoxide (0.47 g, 4.2 mmol), followed by stirring at room temperature for 30 minutes. To the reaction solution was added 1-fluoro-2-nitrobenzene (0.60 g, 4.3 mmol), followed by stirring at 150° C. for 5 hours. After allowing to stand overnight, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 1-[4-(3,4-difluorobenzyloxy)phenoxy]-2-nitrobenzene (1.41 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:20])[C:18]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:20])[C:18]=1[N:8]1[CH2:7][CH2:6][CH:5]([C:3]([N:2]([CH3:11])[CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: CN(C)C(=O)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 80.9 %

Procedure:
General procedure C was followed using N,N-dimethylpiperidine-4-carboxamide 6 (43 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (66 mg, 80%), m.p. 120-122° C.; umax (CHCl3)/cm−1 3026, 2850, 1631, 1559, 1140, 1092, 934; m/z (ESI) C13H18Cl2N3O requires 302.0821, found [M+H]+ 302.0823.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([O-])=O.[N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=C[CH:10]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O.[N+]([O-])([O-])=O.[Ag+].C(Cl)(Cl)Cl>[N:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[N:9]=[CH:10][C:2]=1[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: c1cnc2c(n1)CCCC2
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(n1)CCCC2
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a solution of 1.0 g of monoethyl oxalate in 14 mL of dichloromethane, 0.47 g of 5,6,7,8-tetrahydroquinoxaline, 91 μL of concentrated sulfuric acid, 1.7 g of sodium persulfate, and a suspension of 60 mg of silver nitrate in 14 mL of water were added, and the mixture was heated under reflux while stirring for 1 hour 30 minutes. To the reaction mixture, 1.7 g of sodium persulfate and 60 mg of silver nitrate were further added, and the mixture was heated under reflux for 1 hour 50 minutes. The reaction mixture was charged with chloroform and adjusted to pH 7.5 with a saturated aqueous sodium hydrogen carbonate solution, the insoluble substance was filtered off, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=90:10 to 67:33 to obtain 0.16 g of ethyl 5,6,7,8-tetrahydroquinoxaline-2-carboxylate as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]([N:21]1[CH2:32][CH2:31][C:24]2([O:28][C:27](=[O:29])[O:26][C:25]2=[CH2:30])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1.CCCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:25]([OH:26])([CH3:30])[C:24]3([CH2:23][CH2:22][N:21]([CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:32][CH2:31]3)[O:28][C:27]2=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: COc1ccc(CCN2C(=O)OC3(CCN(Cc4ccccc4)CC3)C2(C)O)cc1OC
Reaction time: 8 h
Yield: 94 %

Procedure:
19.9 g of 2-(3,4-dimethoxyphenyl)ethylamine are portionwise added to a solution of 25.9 g of 8-benzyl-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane in 35 ml of anhydrous xylene under stirring. Meanwhile the temperature of the reaction mixture increases to 35° to 40° C. The reaction mixture is left to stand at room temperature overnight, then the crystalline reaction mixture is diluted with n-heptane and filtered. The solid precipitate obtained is recrystallized from ethanol to obtain the title compound in 94% yield, m.p.: 181°-183° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[S:20][C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[C:17]=2[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[CH:23][CH:24]=1
Reactant: Nc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 85 %

Procedure:
By essentially following the conditions described in Example 179, Part A, the free base of the title compound was prepared as an oil from 2-(4-aminophenyl)benzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part C) in 85% yield following MPLC (SiO2; 30% then 40% THF with 5% TEA in hexanes). The product was converted to the oxalate salt according to the conditions described in Example 1, Part G.