Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1.CO.Cl.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:35]=[C:36]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[N:37]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH:38]=2)=[CH:30][C:29]=1[C:50]([F:53])([F:52])[F:51]>>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:37]1[CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([C:50]([F:52])([F:51])[F:53])[CH:30]=2)[N:35]=[C:36]1[CH:44]1[CH2:45][CH2:46][N:47]([C:2]2[C:3]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=4[O:21][CH3:22])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:48][CH2:49]1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)c(OC)c1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: Cl
Solvent: CO
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)c(OC)c1
Yield: 60 %

Procedure:
Combine a mixture of 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.10 equiv; 868.3 mmol; 277.63 g) in methanol (62.44 mol; 2.53 L) at RT, a solution of 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (1.00 equiv; 789.35 mmol; 361.0 g) and TEA (9077 mmol; 1265 mL) in methanol (62.44 mol; 2.53 L) and stir the mixture overnight at 55-60° C. Partition the reaction mixture between water (10 L) and EA (10 L). Extract the organic layer with 2 N HCl (5 L). Separate and extract the aqueous layer with EA (5 L). An oil separates in the aqueous layer. Decant the aqueous liquid and hold the oil for recovery of product. Stir the decanted aqueous layer with EA (5 L) and adjust the pH of the mixture to 10-11 with 2 N NaOH. Separate the organic layer, wash with brine, and dry over Na2SO4. Filter and evaporate the solvent to give the title compound (473.3 mmol; 316.0 g; 60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][C:8]([F:20])=[CH:7][CH:6]=2.[CH:22](O)=[O:23]>>[OH2:23].[CH2:13]([N:12]1[C:11]2[C:10]3[CH:9]=[C:8]([F:20])[CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([CH3:21])[C:2]=2[N:1]=[CH:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc2ccc(F)cc2c(NCc2ccccc2)c1N
Reactant: O=CO
Product: Cc1nc2ccc(F)cc2c2c1ncn2Cc1ccccc1
Product: O

Procedure:
Using the method of Example 138, 3-amino-4-benzylamino-6-fluoro-2-methylquinoline (from Example 45) was reacted with formic acid to provide 1-benzyl-8-fluoro-4-methyl-1H-imidazo[4,5-c]quinoline hydrate, m.p. 178°-181° C. Analysis: Calculated for C18H14FN3.0.25H2O: %C, 73.1; %H, 4.9; %N, 14.2; Found: %C, 73.0; %H, 4.7; %N, 14.3.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:15][CH2:16][CH:11]2[CH2:10]1)(C(C)(C)C)(C)C.F[Si-2](F)(F)(F)(F)F.[H+].[H+]>C(#N)C.C(OCC)(=O)C>[OH:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:15][CH2:16][CH:11]2[CH2:10]1
Reactant: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Agent: [H+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(-c2cccc(C34CC(O)CC3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of racemic N-((4aRS,6RS,7aSR)-6-(tert-butyldimethylsilyloxy)-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (1.47 g, 2.31 mmol) in acetonitrile (6 mL) is added 20-25% aqueous fluorosilicic acid (2.82 g, 4.62 mmol) and the resulting mixture is stirred at room temperature for 3 h. The reaction is diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The mixture is washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 10% to 60% ethyl acetate in hexanes over 40 minutes to give the title compound as a racemic mixture (0.709 g, 64%). ES/MS m/e: 459 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[CH:13]=O>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[C:13]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: COc1ccc(OC)c(C=O)c1
Product: COc1ccc(OC)c(-c2nc3ccccc3s2)c1

Procedure:
2-Aminothiophenol (6.3 g., 0.05 mole) and 8.3 g (0.05 mole) of 2,5-dimethoxybenzaldehyde were combined and mixed thoroughly. After a few minutes the mixture evolved heat, became cloudy, and slowly crystallized. The mixture was then warmed for a few minutes to complete the reaction. The product was then recrystallized from ethanol yielding 8.0 g (59%), mp. 96°-99°.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[C:13]3[CH2:20][C@@H:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:22][C@@H:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C([Li])CCC>>[C:18]([C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@H:11]3[CH2:22][C@H:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:20][C:13]=1[C:12]=23)#[N:19]
Reactant: CCCN(CCC)[C@@H]1Cc2c(C#N)ccc3c2[C@H](C1)CN3C(=O)c1ccccc1
Agent: [Li]CCCC
Product: CCCN(CCC)[C@@H]1Cc2c(C#N)ccc3c2[C@@H](CN3)C1
Yield: 86.9 %

Procedure:
The procedure of Example 7E was followed using 2.5 g (6.5 mmol) of (2aS,4S)-1-benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole and 8.1 ml (13 mmol) n-butyl lithium to provide 1.6 g of an oil. Chromatography of the oil over silica gel with EtOAc as eluent gave 1 g (54%) of product as an oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(NC(=O)C(COC1=CCC(c2ccccc2)C=C1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
A solution of 2 M Na2CO3 (4 mL) was added at room temperature under an atmosphere of Argon to a mixture of the compound obtained in Example 22, step f (401 mg, 0.848 mmol), Pd(PPh3)2Cl2 (154 mg, 0.22 mmol) and phenylboronic acid (145 mg, 1.1872 mmol) in toluene (10 mL) and the reaction was heated to reflux. After 5 h, the reaction was cooled to room temperature. The mixture was diluted with EtOAc, and washed with brine. The combined organic layers were dried over anhydrous NaSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography which gave the title compound as a white solid (255 mg, 64%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21]Br)=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1.C[NH2:33].C1COCC1>CN(C=O)C>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21][NH2:33])=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CBr)c1cccc(C(F)(F)F)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CN)c1cccc(C(F)(F)F)c1
Yield: 44 %

Procedure:
A solution of 5-bromomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (50 mg, 0.091 mmol) in DMF (2 mL) is treated with methylamine in THF (2.0 N solution, 49 μL, 0.091 mmol) and the resultant solution is heated in a microwave at 125° C. for 5 min. The crude reaction mixture is concentrated in vacuo and purified by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) to afford 5-aminomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (20 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[Br:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(#N)C>[Br-:15].[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N+:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[F:1])[CH:6]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Fc1ccccc1Oc1cccnc1
Solvent: CC#N
Product: CCOC(=O)C[n+]1cccc(Oc2ccccc2F)c1
Product: [Br-]

Procedure:
To a solution of 1 g of 3-(2-fluorophenoxy) pyridine in 40 ml of acetonitrile is added 0.9 g of ethyl bromoacetate and the solution is refluxed 16 hours. The solvent is removed in vacuo to yield 1-(2-ethoxy-2-oxoethyl)-3-(2-fluorophenoxy) pyridinium bromide; mp 133°-135° C.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=2)[CH:23]=[C:24]([CH3:26])[CH:25]=1>O1CCCC1>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:28]=[C:29]([NH:32][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:30][N:31]=2)[CH:21]=[C:20]([CH3:19])[CH:25]=1
Reactant: Cc1cc(C)cc(-c2cc(N)[nH]n2)c1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c1

Procedure:
The named compound is prepared by substituting 5-(3,5-dimethyl-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2381 gms. 5-(3,5-dimethyl-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) over the weekend.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[CH:8]=[CH:9][CH:10]=[C:3]12.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C1COCC1>[CH3:1][CH:2]1[N:7]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:6][CH2:5][N:4]2[CH:8]=[CH:9][CH:10]=[C:3]12
Reactant: CC1NCCn2cccc21
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CC1c2cccn2CCN1C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A solution of (190 mg, 1.4 mmol) of 1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (A21) in THF (10 ml) was added dropwise in the course of 30 min to a suspension of (558 mg, 5.6 mmol) of succinic anhydride in THF (10 ml). The mixture was then stirred for 2 h at RT and concentrated in vacuo. The residue was taken up in chloroform, washed with water and brine, dried over MgSO4 and concentrated in vacuo. 257 mg (0.92 mmol, 54%) of 4-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4-oxobutanoic acid (S4) were obtained.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1.I[CH3:35].[H-].[Na+]>CN(C=O)C>[CH3:35][O:1][CH:2]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(Cn1ncc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1=O)c1ccccc1
Yield: 34.8 %

Procedure:
A mixture of the product from Example 441, 2-(2-hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (210 mg, 0.45 mmol), iodomethane (56 μL, 0.90 mmol), and an 80% oil dispersion of sodium hydride (18 mg, 0.59 mmol) in anhydrous DMF (16 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and 2 N aqueous hydrochloric acid. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a yellow oil which was purified by column lo chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions containing product were combined and concentrated in vacuo , and the residue was triturated with hexanes to provide the title compound (yield: 75 mg, 34.7%). mp 135-137° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 3.26 (s, 3H), 4.33-4.52 (m, 2H), 4.91 (dd, J=9 Hz, 3 Hz, 1H), 6.99 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 3 Hz, 2H), 7.31-7.50 (m, 7H), 7.87 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 479 (M+H)+. Anal. calc. for C26H23FN2O4S: C, 65.25; H, 4.84; N, 5.85. Found: C, 64.98; H, 4.83; N, 5.81.
Reaction SMILES: [CH3:1][Mg]Cl.[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](N(OC)C)=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.O.Cl>O1CCCC1>[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](=[O:15])[CH3:1])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Reactant: C[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(Cl)cccc2s1
Reaction time: 0.5 h

Procedure:
Methylmagnesium chloride (3M solution in tetrahydrofuran; 5.7 ml) was added under nitrogen to a stirred solution of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (4 g; prepared in a manner similar to that described in Example 18) in tetrahydrofuran (120 ml) then the mixture was allowed to stand at ambient temperature for 30 minutes, heated under reflux for 30 minutes and allowed to stand at ambient temperature for 30 minutes. Further methylmagnesium chloride (3M solution in tetrahydrofuran; 2.0 ml) was added and the mixture was allowed to stand at ambient temperature for 2 hours. Further methylmagnesium chloride (3M solution in tetrahydrofuran; 2.0 ml) was added and the mixture was allowed to stand at ambient temperature for 30 minutes. Water (200 ml) and 5M hydrochloric acid (15 ml) were added and the product was extracted into dichloromethane (3×80 ml). The combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 1-(4-chloro-benzo[b]thiophen-2-yl]ethan-1-one (1.8 g) as an off-white solid, m.p. 113-115° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C:61](Cl)=[O:62])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 56 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 56% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(O)[CH3:7])C.Cl.O=S(Cl)Cl>ClCCl>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH:6]([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 3.2 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester in 10 ml. of dichloromethane is saturated with dry HCl gas and 1 ml. of SOCl2 is added. The mixture is warmed to 50° for 2 hours and solvent is removed. The residue, 3'(2',4'-difluoro-4-biphenylyl)-3-chlorobutyric acid ethyl ester, is dissolved in 100 ml. of methanol and hydrogenated on 100 mg. of platinum oxide under normal pressure at 25°. The precipitate is filtered off. A solution of 0.4 g. of NaOH in 5 ml. of water is added to the filtrate. The mixture is heated under reflux for 2 hours and evaporated and the residue is dissolved in water and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11](C(O)=O)[C@H:10]([CH2:16][CH3:17])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1C=CC(P([N:32]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C[C:36]([OH:39])(C)C>>[CH2:16]([C@H:10]1[C@@H:11]([N:32]=[C:36]=[O:39])[CH2:12][C@@H:8]([NH:7][S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:5])=[O:6])[CH2:9]1)[CH3:17]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N=C=O
Temperature: 70 °C

Procedure:
To a mixture of (1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic acid (Preparation #Z.1, 1.00 g, 3.83 mmol) in t-BuOH (19.1 mL) was added DPPA (0.826 mL, 3.83 mmol) and TEA (1.17 mL, 8.42 mmol). The reaction mixture was heated at about 70° C. for about 45 min. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. The material was dried under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamide with 30 mol % of t-BuOH as an excipient (0.97 g, 98%) as a colorless oil: LC/MS (Table 1, Method n) Rt=0.56 min; MS m/z 259 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]1([CH:33]([O:35][C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=2)[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([O:35][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[CH:37][CH:38]=1
Reactant: CC(Oc1ccc(CN)cc1)c1ccccc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)c1ccccc1
Yield: 69.8 %

Procedure:
Use a method similar to the General Procedure 5-3, to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (851 mg, 2.0 mmol) and (±)-4-(1-phenyl-ethoxy)-benzylamine (721 mg, 2.6 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give (±)-7-chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (702 mg, 69%). MS (ES+) m/z: 503 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].FCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[C:32]([C:33]#[N:34])=[CH:31][NH:30][N:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[N:30]=[CH:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1F
Agent: O=C(CF)c1ccccc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccccc3F)nc12
Yield: 27.1 %

Procedure:
Reaction of 1-(2-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234 mg, 1.0 mmol), prepared from commercially available 2-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (83 mg, 27%). MS (ISP) 307.1 [(M+H)+]; mp 165° C.
Reaction SMILES: [C@@H:1]1([OH:7])[CH2:5][CH2:4][CH2:3][C@H:2]1[OH:6].Cl[C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(OCC)(=O)C.O1CCOCC1>[OH:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[O:7][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:18]=1
Reactant: C1CNCCN1
Reactant: O[C@@H]1CCC[C@H]1O
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O[C@@H]1CCC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Yield: 19.1 %

Procedure:
To a solution of trans-1,2-cyclopentanediol [manufactured by Aldrich Co., cf. J. Chem. Soc., 4026 (1952)] (5.39 g) and 2,4-dichloroquinazoline [cf. J. Am. Chem. Soc., 53, 3867 (1931)] (9.58 g) in dimethylformamide (50 ml) is added gradually 60% sodium hydride (in oil) (2.49 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for 1 hour and 20 minutes. The reaction mixture is diluted with ethyl acetate and washed with water 6 times. The resulting ethyl acetate solution is dried over anhydrous magnesium sulfate and is evaporated to dryness under reduced pressure, and the residue is briefly purified with medium pressure liquid column chromatography (eluent, chloroform) to give an oily substance. The oily substance thus obtained is dissolved in dioxane (27 ml), and the mixture is slowly added dropwise to a solution of piperazine (9.67 g) in dioxane (36 ml) with stirring at 70° C., and the mixture is stirred at the same temperature for one hour and 10 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The resulting solution is evaporated to dryness under reduced pressure, and the residue is washed with acetone, and the resulting crystals are recrystallized from acetone to give 4-[trans-(2-hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (2.89 g) as crystals.