Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:49][C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[C:52]([O:54][CH3:55])=[O:53]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][C:50]2[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=2[C:52]([O:54][CH3:55])=[O:53])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(Cc2ccccc2C(=O)OC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 72 %

Procedure:
By the procedure of Example 3, Step A, 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) was alkylated with methyl 2-(bromomethyl)benzoate [R. M. Scrowston and D. C. Shaw, J. Chem. Soc. Perkin Trans. I, 749 (1976)] to give a 72% yield of the titled compound as a foam, homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 766 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]([NH:32][CH2:33][CH2:34]O)[CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][CH2:30][NH:32][CH2:33][CH3:34])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CCNCCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCNCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(ethylamino)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(ethylamino)ethanol following General Procedure K.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1ccc(Br)cc1Cl

Procedure:
Following the procedures described in Example 36: 4-bromo-2-chlorobenzoic acid and oxalyl chloride were reacted to provide 4-bromo-2-chloro-benzoyl chloride, which was reacted with 3-methylamino-but-2-enoic acid methyl ester to provide 2-(4-bromo-2-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester. 2-(4-Bromo-2-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester and hydroxylamine hydrochloride were then reacted to provide 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester. Following Example 36, Step 4, 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester was hydrolyzed to 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid. 5-(4-Bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid and (R)-1-(2-chloro-phenyl)-ethanol were then reacted as described in Example 36, Step 5 to provide [5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:25]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:7][CH:8]=2)[CH3:24])=[CH:27][CH:28]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1cccs1
Reactant: CNc1ccc(Cl)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2cccs2)cc1)c1ccc(Cl)cc1
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}thiophene-2-sulfonamide, and N-methyl-4-chloro aniline, the title compound was isolated as a yellow solid in 69% yield (94% purity by HPLC).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:16][C:17]3([C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=4)[CH2:19][CH2:18]3)=[O:15])[CH:12]3[CH2:30][CH2:31][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.O[Li].O>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:16][C:17]3([C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=4)[CH2:18][CH2:19]3)=[O:15])[CH:12]3[CH2:30][CH2:31][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3C4CCC(CC4)N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)C3C4CCC(CC4)N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 108.8 %

Procedure:
The title compound (E40) (8.03 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-(1-(2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxamido)cyclopropyl)benzoate (D156) (7.6 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.C1COCC1.[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH3:22])[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc2c(O)nc(Cl)nc2c1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N(C)C)nc2c1
Temperature: 100 °C

Procedure:
2-chloro-7-methoxyquinazolin-4-ol (288 mg, 1.368 mmol) was dissolved in Dimethylamine 2 M in THF (2 ml, 4.00 mmol) and heated to 100° C. for 1 h in a sealed tube. The reaction was cooled and the volatiles were removed under vacuum. The crude solid was collected and washed with water, filtered and dried to give 2-(dimethylamino)-7-methoxyquinazolin-4-ol which was carried to the next step without further purification. MS: MS m/z 220.1 (M++1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(C)(C)C.[Li]CCCC.[CH3:23][C@H:24]1[C@@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[O:35])[NH:25]1.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>C1COCC1.C(N(CC)CC)C>[C:1]1([CH2:7][C:8]([N:25]2[C@@H:24]([CH3:23])[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][C:26]2=[O:35])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mechanically stirred solution of phenylacetic acid at -78° C. is treated with one part pivaloyl chloride then one part triethylamine. The mixture is stirred at -78° C. for 15 minutes, at 0° C. for 45 minutes, then recooled to -78° C. In a separate flask, one part 2.5M nBuLi is added to a solution of (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone in THF at -78° C. The solution is stirred for 15 minutes then transferred to the flask containing pivalic anhydride via cannula. The mixture is stirred for 15 minutes at -78° C. and 9 hours at room temperature. The mixture is quenched with 2M KHSO4 and, after evaporation of the THF, is extracted 3 times with ethyl acetate. The combined ethyl acetate extracts are dried over MgSO4, filtered and concentrated to provide the crude title compound which is purified by column chromatography eluting with ethyl acetate-hexane.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]([C:12]1[CH:21]=[C:20]([F:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[CH:13]=1)(=[O:11])[CH3:10].O>C(COC)OC>[F:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([C:9]([OH:11])=[CH:10][C:3](=[O:5])[CH3:4])[CH:21]=1
Reactant: COc1ccc2cc(C(C)=O)cc(F)c2c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2cc(C(O)=CC(C)=O)cc(F)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of sodium hydride (0.048 mol) and ethyl acetate (4.22 g, 0.048 mol) in dry dimethoxyethane (10 ml) under nitrogen, was treated over 30 minutes at room temperature with a solution of 2-acetyl-4-fluoro-6-methoxynaphthalene (5.33 g, 0.024 mol) in dry dimethoxyethane (25 ml). The reaction mixture was then stirred at 50° C. for 31/2 hours. After cooling it was treated with water (50 ml) then dilute hydrochloric acid (50 ml) and the orange precipitate collected by filtration, washed with petrol and dried. Recrystallisation from methanol/ether gave 3.2 g product m.p. 107°-8° C.
Reaction SMILES: [NH2:1][C:2]([C:6]1([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:8][CH2:7]1)([CH3:5])[CH2:3][NH2:4].O.[ClH:17]>>[ClH:17].[ClH:17].[NH2:1][C:2]([C:6]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)([CH3:5])[CH2:3][NH2:4]
Reactant: CC(C)(C)OC(=O)C1(C(C)(N)CN)CC1
Agent: Cl
Solvent: O
Product: CC(N)(CN)C1(C(=O)O)CC1
Reaction time: 0.5 h

Procedure:
At room temperature, 0.82 g (3.83 mmol) of the crude product of tert-butyl 1-(1,2-diamino-1-methylethyl)-1-cyclopropanecarboxylate was dissolved in concentrated hydrochloric acid (5 mL), and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added water, subsequently the solvent was removed under reduced pressure. And then the solution was subjected to azeotropy with ethanol (twice). As a result, 0.82 g of a crude product of the target compound (3.55 mmol, 930) was obtained as a light yellow foam-like solid. The obtained crude product was used for the subsequent reaction without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[CH2:12]([S:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([CH2:12][S:19][C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH2:22][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCc1ccccc1SCc1ccccc1
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2ccccc2Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 9.9 g of potassium t-butoxide in 100 ml of DMF under a N2 atmosphere was added portion wise 6 g of 1,2,4-triazole. After stirring at ambient temperature for one hour, a solution of 20 g of 2-benzylmercaptobenzyl chloride in 15 ml of DMF was added dropwise and the suspension was heated at 70° C. for 4 hours, then stirred at 25° C. 16 hours. After pouring the suspension into excess ice-water the residue was extracted with methylene chloride, dried (MgSO4), and the solvent was evaporated in vacuo to an oil residue which solidified to 14.5 g of the subject compound when triturated with 1-chlorobutane; m.p. 65°-68° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([CH2:13][CH:14]=O)[C:8]([O:10]CC)=O)=[C:4]([Cl:18])[CH:3]=1.Cl.[NH:20]1[C:28]2[CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24][C:23]=2[CH:22]=[N:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]2[CH2:13][CH2:14][N:29]([CH:26]3[CH2:27][C:28]4[C:23](=[CH:22][NH:21][N:20]=4)[CH2:24][CH2:25]3)[C:8]2=[O:10])=[C:4]([Cl:18])[CH:3]=1
Reactant: NC1CCc2cn[nH]c2C1
Reactant: CCOC(=O)C(CC=O)Cc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCc2c[nH]nc2C1
Yield: 37.4 %

Procedure:
Combine ethyl 2-(4-bromo-2-chlorobenzyl)-4-oxobutanoate (0.92 g, 2.8 mmol), 4,5,6,7-tetrahydro-1H-indazol-6-amine hydrochloride (preparation 80) (490 mg, 2.8 mmol) and sodium triacetoxyborohydride (886 mg, 4.2 mmol) in dichloroethane (50 mL) and stir for 48 hours at room temperature. Add water and extract with CH2Cl2. Dry the organic layer over magnesium sulfate, filter and concentrate. Purify the residue by silica gel chromatography affords the title compound (428 mg, 68%): MS (m/z): 410 (M+2).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][C@@H:44]([CH3:46])[N:43]([CH:47]4[CH2:50][O:49][CH2:48]4)[CH2:42][C@@H:41]3[CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH3:51][C@H:41]1[CH2:42][N:43]([CH:47]2[CH2:50][O:49][CH2:48]2)[C@H:44]([CH3:46])[CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][C:22]5[N:21]6[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]6)=[CH:15][C:14]=5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of 126a (150 mg, 0.20 mmol) and lithium hydroxide (72 mg, 3.0 mmol) in i-propanol/THF (5:3, 8.0 mL) and water (2.0 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford 126 (45 mg, 33%) as a white solid. MS: [M+H]+ 682.9. 1H NMR (500 MHz, CHCl3) δ 8.60 (dd, J=2, 5 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.37-7.35 (m, 1H), 7.14-7.12 (m, 1H), 6.96-6.94 (m, 1H), 6.82-6.80 (m, 1H), 6.31 (s, 1H), 4.77-4.71 (m, 2H), 4.67-4.62 (m, 2H), 4.58-4.55 (m, 1H), 4.41-4.40 (m, 1H), 4.29-4.25 (m, 1H), 4.13-4.09 (m, 1H), 3.91-3.80 (m, 3H), 3.77-3.74 (m, 1H), 3.70 (s, 3H), 3.18 (d, J=5.0 Hz, 1H), 3.06-3.01 (m, 1H), 2.98-2.90 (m, 2H), 2.83 (m, 2H), 2.77-2.70 (m, 2H), 2.47 (m, 1H), 2.06-2.01 (m, 2H), 1.97-1.93 (m, 1H), 1.88-1.87 (m, 2H), 0.91-0.89 (m, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]2)=[O:18])[C:12]2[C:7](=[CH:8][C:9]([CH3:25])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[OH:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:17](=[O:18])[CH2:16][O:15][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH3:25])=[CH:10][CH:11]=3)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)[CH2:20]1
Reactant: COC(=O)c1cc(OCC(=O)N2CC[C@@H](O)C2)c2ccc(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(OCC(=O)N3CC[C@@H](O)C3)cc(C(=O)O)nc2c1
Reaction time: 2 h

Procedure:
To a solution of 996 mg 4-[2-((R)-3-Hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid methyl ester in 10 ml THF were added 2.8 ml aqueous NaOH (1 M) at 0° C. After 2 h the mixture was brought to pH 4 by using Amberlite IR-120 ion exchange resin. The reaction mixture was filtered and concentrated and the crude product obtained used in the next step without further purification. Yield: 700 mg
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46](Cl)(=[O:48])=[O:47]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[Cl:39])(=[O:48])=[O:47])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 2-Chlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 114 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (94 mg, 55%) as a white solid. MS cald. for C24H24ClFNO4S [(M+H)+]: 476, obsd. 476.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(Cl)nc(Nc3ccccc3)c2c1

Procedure:
In a procedure analogous to that of Example la 2,4-dichloro-6-methoxy-quinazoline (1.53 g) (prepared as described in J. Chem. Soc. 1948, 1759), aniline (0.8 g) (0.184 g) and N,N-diisopropyl-ethylamine (1.72 g) are reacted together to give 2-chloro-6-methoxy-4-phenylamino-quinazoline as light yellow crystals melting at 177-179° C., Rf (A2) 0.59.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:9]=[C:10]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1>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.[Cu]I.C(#N)C>[CH3:18][C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:9]=1)([CH3:17])[C:15]#[N:16]
Reactant: CC(C)(C#N)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CC(C)(C#N)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
Ethynyltrimethylsilane (4.0 mL, 28.9 mmol) was added to a mixture of ACN (100 mL), TEA (25 mL), 2-(3-bromophenyl)-2-methylpropionitrile (5.0 g, 22.3 mmol), (Ph3P)2PdCl2 (780 mg, 1.11 mmol) and copper(I) iodide (130 mg, 0.68 mmol) under nitrogen atmosphere. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, concentrated to a black residue and filtered through silica gel with 20% ethyl acetate in hexane. The filtrate was concentrated to a red oil and chromatographed on silica gel with 2% ethyl acetate in hexane. Obtained 2-methyl-2-(3-trimethylsilanylethynylphenyl)-propionitrile (4.00 g, 74%) as an orange oil. 1H NMR (DMSO-d6) δ: 0.24 (s, 9H), 1.69 (s, 6H), 7.43 (m, 2H), 7.56 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([NH2:24])[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH:35](OC)O[CH:33]2OC)=[CH:28][CH:27]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([N:24]1[CH:35]=[CH:36][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:27][CH:28]=2)=[CH:33]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:18])([CH3:19])[CH3:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)C(C)(C)C
Yield: 35 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octa-deca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester (prepared as described in Example 1(b))was condensed with 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) in 1,2-dichloroethane with trifluoroacetic acid to provide in 35% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (CDCl3): ∂ 7.63-7.57 (m, 6H), 7.44 (t, 2H, J=7.6 Hz), 7.35-7.25 (m, 6H), 7.09 (s, 1H), 6.80 (t, 1H, J=2.4 Hz), 6.61 (t, 1H, J=2.0 Hz), 6.28 (d, 1H, J=8.8 Hz), 5.99-5.71 (bm, 1H), 5.17-5.08 (m, 3H), 4.02 (d, 1H, J=8.0 Hz), 3.40 (dd, 1H, J=5.7, 16.7 Hz), 3.12 (dd, 1H, J=8.5, 16.9 Hz), 2.76 (d, 3H, J=4.8 Hz), 0.87 (s, 9H). Anal. Calculated for C34H37N3O4: C, 74.02; H, 6.76; N, 7.62. Found: C, 73.87; H, 6.93; N, 7.39.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:19])[C:12](=[CH:15]OCC)[C:13]#[N:14])[CH3:9]>N1C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:19])[C:12](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]#[N:14])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)=CNc1ccccc1
Yield: 49.9 %

Procedure:
0.91 ml (10 mmol) of aniline and 1.69 g (10 mmol of ethyl(ethoxymethylene)cyanoacetate were dissolved in 10 ml of pyridine and heated under reflux. After 3 h pyridine was removed under vacuum, and the residue was purified by chromatography (silica gel column, eluent 1% methanol in dichloromethane). 1.08 g (50%) of ethyl(anilinomethylene)cyanoacetate were obtained. The compound was cyclized by heating in a biphenyl/phenyl ether mixture. After cooling a precipitate was filtered and washed with diethyl ether to give 4-hydroxyquinoline-3-carbonitrile (49%). Following the procedure outlined in Step 3 of Example 1, but substituting 4-hydroxyquinoline-3-carbonitrile for 9-(10H)acridone, 4-chloro-3-cyanoquinoline (90%) was obtained, which was reacted with 4-(4-methylpiperazin-1-yl)aniline (according to the procedure of Step 4 in Example 1), to afford the title compound with 12% yield (overall yield 3%).