Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=O)[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[ClH:23].Cl.[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30][NH2:31])[CH2:26]1>O>[ClH:23].[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30][N:31]=[C:17]2[CH2:16][CH2:15][C@@:14]3([CH3:21])[CH:19]([C@@H:2]([CH3:1])[CH2:3][C@@H:4]4[C@@H:13]3[CH2:12][CH2:11][C@@:9]3([CH3:10])[C@H:5]4[CH2:6][CH2:7][C:8]3=[O:22])[CH2:18]2)[CH2:26]1
Reactant: NO[C@@H]1CCNC1
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Agent: Cl
Solvent: O
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=NO[C@@H]3CCNC3)CC12
Yield: 70 %

Procedure:
Prepared in 70% yield as described in Example 1 starting from 6α-methylandrostane-3,17-dione (II-ai, Prepn. 19) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (III-e, Prepn. 5). The crude product was dissolved in H2O and freeze-dried to give the title compound I-ax. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.03 (2H, bb), 4.73 (1H, m), 3.30-3.02 (5H, m), 2.45-0.56 (22H, m), 0.87 (3H, m), 0.84 (3H, s), 0.78 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(C)c1
Yield: 93.8 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (203 mg, 1 mmol) and of 1,1′-thiocarbonyldi-2(1H)-pyridone (263 mg, 1.1 mmol) in dichloromethane (10 mL) was stirred at 20° C. for 16 h to yield an orange solution. The solution was concentrated under reduced pressure to ¼ of its volume and subjected to column chromatography on silica gel using dichloromethane/methanol (95:5 v/v) as eluent to yield the title compound (230 mg, 94%) as a yellow oil which solidified on standing.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].[Br:14]N1C(C)(C)C(=O)N(Br)C1=O.CCOC(C)=O.CCCCCC>C(O)(C(F)(F)F)=O>[Br:14][C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:11])[F:12])[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CCOc1ncccc1C(F)(F)F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CCOc1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
2-Ethoxy-3-trifluoromethyl-pyridine (900 mg, 4.71 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (1.35 g, 4.71 mmol) were placed in a round-bottom flask. To this mixture was slowly added 10 mL trifluoroacetic acid. The mixture was stirred at ambient temperature for overnight. More 1,3-dibromo-5,5-dimethylhydantoin (540 mg, 1.9 mmol) was added and the reaction mixture was stirred at ambient temperature for another day. After the completion of the reaction, TFA solvent was evaporated in vacuo and the resulting residue was neutralized to pH 7 by the addition of saturated NaHCO3. The aqueous layer was extracted with dichloromethane three times and the combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a mixture of oil and white solid. The residue was redissolved into 20% EtOAc/Hexane, and the unsoluable white solid was filtered out. The filtrate was concentrated and then purified by column chromatography on silica gel (10% EtOAC/Hexane) to give 5-bromo-2-ethoxy-3-trifluoromethyl-pyridine as a colorless liquid (1.0 g, 79% yield). 1H-NMR (400 MHz, CDCl3): δ 1.41 (t, 3H, J=7.07), 4.46 (q, 2H, J=7.07), 7.94 (dd, 1H, J=0.51, J=2.53), 8.34 (dd, 1H, J=0.51, J=2.53).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](O)=[O:12].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:18]([O:17][C:15](=[O:16])[NH:14][C@@H:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH2:9]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To an ice cold solution of (S)-3-(2-amino-phenylamino)-2-tert-butoxycarbonylamino-propionic acid (4 g, 13.54 mmol) in DMF (40 mL) was added EDCI.HCl (2.86 g, 14.89 mmol), HOBT (2.01 g, 14.89 mmol) and DIPEA (7.19 mL, 40.63 mmol). The resulting mixture was stirred for 16 h at RT. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated and the resulting material was purified by silica gel chromatography using to afford the title compound (2.9 g, 77%) as an off white solid. LC-MS: 278 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][CH:13]=O.[BH3-]C#N.[Na+]>[NH4+].[Cl-]>[Cl:11][CH2:12][CH2:13][NH:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCl
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Product: ClCCN[C@@H]1C[C@H]1c1ccccc1
Temperature: 0 °C
Yield: 72 %

Procedure:
The (trans)-2-phenylcyclopropanamine previously obtained was added to activated and dried molecular sieves (3 A), proceeding with several vacuum and argon cycles. DCM (120 mL) was added and stirred before adding chloroacetaldehyde (1.5 mL, 12.0 mmol) and stirring for 4 hours. The reaction was cooled to 0° C. and NaBH3CN (0.88 g, 14.0 mmol) was added. The mixture was stirred at room temperature overnight. NH4Cl (20 mL) was added and the organic layer was extracted, dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (Hexane-MTBE 70:30) affording 1.68 g (8.56 mmol) of N-(2-chloroethyl)-N-[(trans)-2-phenylcyclopropyl]amine. Yield: 72%. 1HNMR (CDCl3) δ (ppm): 1.01 (q, 1H), 1.08 (quin, 1H), 1.93 (m, 1H), 2.37 (quin, 1H), 3.08 (t, 2H), 3.67 (t, 2H), 7.04 (d, 2H), 7.15 (t, 1H), 7.25 (t, 2H). MS (M+H): 195.88
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:19][OH:20])=[C:13]([C:15](O)([CH3:17])[CH3:16])[CH:14]=1)(C(C)(C)C)(C)C.C([Li])CCC.CCCCCC.CC1C=CC(S(Cl)(=O)=O)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:17][C:15]1([CH3:16])[C:13]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:14]=2)[CH2:19][O:20]1
Reactant: CC(C)(O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OCc2ccc(O)cc21
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
To a solution of 2-[5-[tert-butyl(dimethyl)silyl]oxy-2-(hydroxymethyl)phenyl]propan-2-ol (Intermediate 10, 1.344 g, 4.533 mmol) in THF (5 mL) at 0° C. butyllithium 1.6M in hexane (3.116 ml, 4.98 mmol) was added and the reaction mixture was stirred for 5 minutes at the same temperature. 4-methylbenzenesulfonyl chloride (1.04 g, 5.44 mmol) dissolved in 1 ml of THF was added followed by the addition of butyllithium 1.6M in hexane (3.116 ml, 4.98 mmol). After 10 minutes at the same temperature tetrabutylammonium fluoride (9.066 ml, 9.066 mmol) was added and the reaction mixture stirred for additional 10 min. Then, it was quenched with ammonium chloride (50 ml) and extracted with ethyl acetate (100 ml). The organic phase was washed with brine (2×100 ml), dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 70:30 to afford the title compound (500 mg) as white solid
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)([CH3:3])=[CH2:2].CN1C=CN=C1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[CH3:3][C:1]1([C:4]2[CH:9]=[N:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=2)[CH2:2][CH:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(C)c1ccc(C(F)(F)F)nc1
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1(C)c1ccc(C(F)(F)F)nc1
Yield: 62.9 %

Procedure:
A toluene (2 ml) solution of 5-isopropenyl-2-(trifluoromethyl)pyridine (219 mg, 1.17 mmol), Co(TPP) (26 mg, 0.039 mmol) and 1-methyl-1H-imidazole (320 mg, 3.9 mmol), ethyl diazoacetate (208 mg, 1.8 mmol) were treated in the same procedure as described in Example 2H. The crude residue (201 mg, 63% yield of the title compound as a black oil) was used in a further reaction without purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[OH-].[Na+].C(=O)([O-])O.[Na+]>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: COc1ccc(-c2cccnc2)c([N+](=O)[O-])c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(O)ccc1-c1cccnc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
1.235 g of 3-(4-methoxy-2-nitrophenyl)pyridine was dissolved in 100 ml of a 47% aqueous solution of hydrogen bromide, and the solution was stirred at a bath temperature of 120° C. for 8 hours. After cooling, the reaction mixture was adjusted to pH 3-4 with a 50% aqueous solution of sodium hydroxide, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The solvent was evaporated, and the crude crystals were recrystallized from ethyl acetate to give 477 mg of 3-(4-hydroxy-2-nitrophenyl)pyridine. The recrystallization mother liquor was subjected to silica gel column chromatography, and the column was eluted with a 50:1 mixture of chloroform and ethanol. The solvent was evaporated to give 331 mg of the above compound. The total amount of the above compound was 808 mg (yield 69.7%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:34]=[CH:33][C:32](Br)=[CH:31][C:28]=1[C:29]#[N:30]>>[NH2:26][C:27]1[N:34]=[CH:33][C:32]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N#Cc1cc(Br)cnc1N
Product: N#Cc1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 2-amino-5-bromo-nicotinonitrile (example C.23 step 1) (200 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (280 mg, 59%). MS (ISP) 473.2 [(M+H)+]; mp 264° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH:10]([CH3:18])[C:11](=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=4)[CH:10]([CH3:18])[C:11](=[N:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: CC1C(=O)c2c([nH]c3ccc(Cl)cc3c2=O)CC1c1ccc(C(F)(F)F)cc1
Product: CC1C(=NCCCN(C)C)c2c([nH]c3ccc(Cl)cc3c2=O)CC1c1ccc(C(F)(F)F)cc1

Procedure:
By following the procedure of Example 3, and using 7-chloro-2-methyl-3-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1,9(2H,10H)-acridinedione instead of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)acridinedione and N,N-dimethyl-1,3-propanediamine instead of N,N-diethylenediamine one obtains 7-chloro-1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro2-methyl-3-[4-(trifluoromethyl)phenyl]-9(2H)-acridinone; mp 169°-170° C. after chromatography on silica eluted with chloroform/methanol 7:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17][NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:18][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=CC1(c2ccc(F)c(Cl)c2)CCCCC1
Reactant: CN
Product: CNCC1(c2ccc(F)c(Cl)c2)CCCCC1
Yield: 55 %

Procedure:
The title compound was synthesized from 1-(3-chloro-4-fluorophenyl)-cyclohexanecarbaldehyde and methyl amine using General Procedure H1 and was obtained in 55% yield. LCMS Rt=7.73 min, m/z=256 (M+1). 1H NMR (CDCl3, δ): 7.37 (dd, J=2.4, 7.1 Hz, 1H), 7.22 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.09 (t, J=8.7 Hz, 1H), 2.58 (s, 2H), 2.29 (s, 3H), 2.0 (m, 2H), 1.7-1.2 (m, 8H). 13C NMR (CDCl3, δ, mult): 157.4(0), 154.9(0), 142.9(0), 129.2(1), 126.8(1), 126.7(1), 120.8(0), 120.6(0), 116.3(1), 116.1(1), 64.2(2), 42.1(0), 37.3(3), 34.6(2), 26.4(2), 22.1(2).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]1=[O:20])[CH2:4][CH2:5][CH3:6].[CH:21](OCC)=[O:22]>C(COC)OC>[CH:21]([CH:14]([CH2:13][C:10]1[CH:11]=[CH:12][N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:20])[CH:9]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:22]
Reactant: CCOC=O
Reactant: CCCCn1ccc(CCC(=O)OCC)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCn1ccc(CC(C=O)C(=O)OCC)cc1=O
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a stirred suspension of 50% sodium hydride in oil (13.89 g) in dimethoxyethane (100 ml) at -2° C., was added dropwise over 90 minutes, a mixture of ethyl β-(N-n-butyl-2-oxo-4-pyridyl)propionate (58.19 g) and ethyl formate (25.73 g), the reaction temperature being maintained below 5° C. The reaction mixture was then allowed to warm to room temperature overnight, poured on to ice and extracted successively into petroleum ether (40°-60°) (150 ml) and diethyl ether (3×100 ml). The combined organic extracts were washed with water (40 ml); and the aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid. A brown oil came out of solution which was extracted into ethyl acetate (3×150 ml). The combined ethyl acetate extracts were washed with water (2×30 ml), dried over MgSO4 and evaporated under reduced pressure. The residue was washed with petroleum ether (40°-60°) and dried in vacuo to afford as a pale brown solid, ethyl α-formyl-β-(N-n-butyl-2-oxo-4-pyridyl)propionate (54.84 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=3)=[O:25])=[C:19]([C:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.CCO.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=3)=[O:25])=[C:19]([C:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CN)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of [2-(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 0.41 g, 0.77 mmol) in CH2Cl2 (20 mL) was treated with EtOH (0.2 mL) and TFA (6 mL). The mixture stirred at room temperature for 45 min, and the solvents were evaporated in vacuo. The crude material was used directly in the next step. LC-MS (ESI, m/z): Calcd. for C24H28N6O2 433.2 (M+H). found 433.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([C:34]([F:37])([F:36])[F:35])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[C:11]([F:13])([F:14])[F:12])[O:8][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([C:34]([F:35])([F:37])[F:36])[CH:27]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(c1ccc(Oc2ccc(C=O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 214, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one(Example 151, step 7) was reacted with 4-fluoro-2-(trifluoromethyl)benzaldehyde in the presence of cesium carbonate to give the title compound as a colorless oil. MS (m/e, ISP neg. ion)=532.0 [M−H+].
Reaction SMILES: Cl[C:2]1([F:12])[C:5]([F:7])([F:6])[C:4]([F:9])([F:8])[C:3]1([F:11])Cl>[Zn]>[F:6][C:5]1([F:7])[C:2]([F:12])=[C:3]([F:11])[C:4]1([F:9])[F:8]
Reactant: FC1(F)C(F)(F)C(F)(Cl)C1(F)Cl
Agent: [Zn]
Product: FC1=C(F)C(F)(F)C1(F)F

Procedure:
The method of carrying out the reaction of zinc with 1,2-dichlorohexafluorocyclobutane in alcohol to obtain hexafluorocyclobutene is well known (G. Fuller and J. C. Tatlow, J. Chem Soc., 3198 (1961)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[C:19]4[N:11]([C:12](=S)[NH:13][C:14](=[O:20])[C:15]=4[CH:16]=[N:17]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].OO.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C)C=O.C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[C:19]4[N:11]([C:12]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH:34]=[CH:33][N:32]=[CH:31]5)=[N:13][C:14](=[O:20])[C:15]=4[CH:16]=[N:17]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCn1ccnc1
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(F)c1)=CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1nc(NCCCn2ccnc2)n2c3c1cnn3C(c1cccc(F)c1)=CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.0 g of 8-(3-fluorophenyl)-4,5-dihydro-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3one in 300 ml of N,N-dimethylformamide was added 18.75 ml of 1N sodium hydroxide. The reaction mixture was cooled to 0° C. in an ice bath for 30 minutes, then 6.25 ml of 30% hydrogen peroxide was added to the mixture dropwise. The mixture was stirred at 0° C. for one hour and 30 minutes then 12.5 ml of N(3-aminopropyl)imidazole was added in one portion. The mixture was allowed to warm to room temperature over 32 hours. The mixture was filtered to remove the solid which was washed with water. The filtrate and wash was evaporated in vacuo to give a yellow solid. The solid was dissolved in 250 ml of chloroform then 100 ml of water was added to give a precipitate. The layers were separated and the precipitate was collected by filtration to give a white solid. The solid was recrystallized from dimethylsulfoxide and dried in vacuo at 60° C. to give 1.1 g of the product of the example as a white solid, m.p. 256°-258° C.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][NH:13][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>COCCOC>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:13]3[C:7]4[N:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[C:8]=4[CH:11]=[CH:12]3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: CC(C)n1cnc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)n1cnc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Yield: 88.8 %

Procedure:
Under argon gas, 3-isopropyl-7H-pyrrolo[2,3-d]-pyrimidin-4-one (89 mg) was dissolved in anhydrous DME (2 ml) and, under ice-cooling and stirring, 60% sodium hydride-oil (22 mg) was added. The mixture was stirred for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (201 mg) in anhydrous DME (1 ml) was added. Then, the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel, 12 g; hexane: ethyl acetate =4:1-3:2) to provide the title compound as colorless powder (181 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18](=O)[CH2:19]Br)[O:17][C:13]=2[CH:12]=[C:11]([Cl:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][N:25]=1.CC(O)C>>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:29]=[C:27]4[N:26]([CH:19]=3)[N:25]=[C:24]([Br:23])[S:28]4)[O:17][C:13]=2[CH:12]=[C:11]([Cl:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1cc2c(OCc3ccccc3)cc(Cl)cc2o1
Reactant: Nc1nnc(Br)s1
Solvent: CC(C)O
Product: Clc1cc(OCc2ccccc2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A sealable vessel was charged with 1-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoethanone (Example 37F, 1.48 g, 3.51 mmol), 5-bromo-1,3,4-thiadiazol-2-amine (0.632 g, 3.51 mmol) and IPA (25 mL, 324 mmol). The reaction mixture was heated in an oil bath at 80° C. for 6 hours then heated in the microwave at 150° C. for 1 hour. The reaction mixture was allowed to stand for 1 hour and the insoluble material was filtered off and rinsed with MeOH to give the desired product as a brown solid (1.19 g, 2.58 mmol, 73.6% yield). LC (Method A): 2.549 min. LCMS (APCI) calcd for C19H12BrClN3O2S [M+H]+ m/z 459.95. found 460.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.74 (s, 1H), 7.55-7.50 (m, 2H), 7.45-7.34 (m, 4H), 7.17 (d, J=0.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 5.32 (s, 2H).
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([O:47][C:48](=[O:50])[CH3:49])[CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:18][O:17][C:14]1[N:15]=[CH:16][C:11]([NH:10][C:42](=[O:43])[C:41]2[CH:45]=[CH:46][C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])=[CH:39][C:40]=2[O:47][C:48](=[O:50])[CH3:49])=[CH:12][CH:13]=1
Reactant: COc1ccc(N)cn1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(OC)nc3)c(OC(C)=O)c2)=C(C)C1=O
Yield: 17.8 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (93 mg, 0.555 mmol), 5-amino-2-methoxypyridine (55 mg, 0.440 mmol) and triethylamine (44 mg, 0.440 mmol) were added to a methylene chloride solution (5 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (137 mg, 0.366 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (31 mg, 0.065 mmol, 18%).