Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:19][CH2:18][CH2:17][N:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: C1CCCNCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN1CCCCCCC1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of azocane (5.59 g, 49.4 mmol) and triethylamine (6.53 g, 64.7 mmol) in DCM (50 mL) at room temperature was added (2-bromoethoxy)(tert-butyl)dimethylsilane (13.0 g, 54.4 mmol). The mixture was stirred overnight, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed (brine (2×)), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure, and the residue was purified on a silica gel column (eluting with PE/EA=10/1) to afford 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azocane (11.8 g, 88%). LCMS: 272 (M+H)+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH:20]([OH:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C)C=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH:20]([O:22][CH3:25])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(C)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 1 h

Procedure:
4.0 g (69.5 mmol) of freshly powdered potassium hydroxide was stirred for 10 minutes in 40 ml of N,N-dimethylformamide and cooled to 10°. 5.48 g (17.3 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 4.94 g (35 mmol) of methyl iodide were added thereto in succession, the ice-bath was removed and the mixture was stirred for a further 1 hour. The reaction mixture was poured into 200 ml of water and extracted five times with methylene chloride. The combined organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-methoxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 139°-141°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:11])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cc(Cl)ccc2F)sc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 5-chloro-2-fluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 22% yield. m.p. 175-178° C.; 1H NMR (CDCl3, 300 MHz) δ 8.12 (dd, J=2.8, 6.6 Hz, 1H), 7.53 (ddd, J=2.8, 4.4, 8.8 Hz, 1H), 7.38-7.24 (m, 6H), 7.17 (dd, J=8.8, 11.3 Hz, 1H), 6.01 (t, J=4.7 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 404.1 (M+1).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:17])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Solvent: O=CO
Product: CCOC(=O)C(=NO)c1csc(NC=O)n1
Yield: 76.7 %

Procedure:
Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (126.4 g.), formic acid (81.3 g.) and acetic anhydride (180 g.) were treated in a similar manner to that of Preparation 20 (5) to give ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (109.6 g.).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[O:7]=[P:8](Cl)([Cl:10])[Cl:9]>>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][P:8]([Cl:10])([Cl:9])=[O:7]
Reactant: NCCCBr
Reactant: O=P(Cl)(Cl)Cl
Agent: Br
Product: O=P(Cl)(Cl)NCCCBr

Procedure:
To a three-necked flask fitted with a thermometer, distillation column and a nitrogen tube was added 3-bromopropylamine hydrobromide (12 g, 0.055 mol) and 20 mL of POCl3 (0.22 mol). The reaction mixture was heated to reflux under nitrogen overnight. Excess POCl3 was removed at the pump at room temperature (attempted distillation resulted in decomposition). The crude dichloridate, 15.4 g, was used directly in the procedure of the following Example V.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39]S(C)(=O)=O)[C:25]=1[CH2:44][CH2:45][CH3:46].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:25]=1[CH2:44][CH2:45][CH3:46]
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCCCCCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Yield: 76.6 %

Procedure:
A mixture of 1.14 g (0.0059 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.87 g (0.0059 mole) of 6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester and 1.62 g (0.012 mole) of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 17 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 35% ethyl acetate-hexane to yield 2.65 g (77% yield) of 6-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:5][CH2:4][NH:3]1.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([N:3]1[CH2:4][CH2:5][CH:6]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:7][CH:2]1[CH3:1])=[O:42]
Reactant: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (40 mg, 0.08 mmol) in DMF (3 mL) were added 3-fluorobenzoic acid (12.51 mg, 0.0893 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (53.86 mg, 0.122 mmol) and triethylamine (0.0396 mL, 0.284 mmol). The mixture was stirred at room temperature overnight and purified by prep-LC-MS to give 20 mg of {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile as a white powder. LC/MS found: 629.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C([O-])(=O)C.[Na+].O.Br[CH:17]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[CH:18]=O>CO>[CH3:31][O:30][C:28](=[O:29])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:17]2[C:5]3[C:4](=[O:9])[NH:3][C:2]([NH2:1])=[N:7][C:6]=3[NH:8][CH:18]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CCC(Br)C=O)cc1
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To 1.69 g (13.4 mmol) of 2,4-diamino-6-hydroxypyrimidine, 2.20 g (26.8 mmol) of sodium acetate and 20 ml of water at 80° C. were added 3.82 g (13.4 mmol) of 2-bromo-4-(4-carbomethoxyphenyl)butanal, prepared in Preparation 2, in 7 ml of methanol over 5 minutes. The mixture was maintained at 80° C. for 5 minutes, cooled to room temperature and stirred for 30 minutes. The mixture was filtered, washed with water, and dried for 18 hours at 50° C. @10 torr to provide 3.32 g of 4-(2-[2-amino-4-oxo-3,7-dihydropyrrolo[2,3 -d]pyrimidin-5-yl]ethyl)benzoic acid methyl ester (m.p. >220° C.) in a yield of 79.4 percent. The remaining filtrate was cooled to 5° C. and filtered to provide an additional 0.069 g of the above product, for a combined yield of 81 percent. 1H NMR (DMSO-d6)δ2.80 (m, 2H), 2.93 (m, 2H), 3.78 (s, 3H), 5.97 (s, 2H), 6.26 (d, J =2.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 10.12 (s, 1H), 10.58 (s, 1H); FDMS 312 (M+), Anal. for C16H16N4O3, Calcd: C, 61.53; H, 5.16; N, 17.94; Found: C, 61.79; H, 5.33; N, 17.66.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][CH2:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:25]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:19])([CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:21][CH:22]=2)[CH3:25])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Reactant: C=O
Solvent: O=CO
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(C)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.9 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate are added 10 ml of formaldehyde and 20 ml of formic acid to prepare a solution, which is stirred at room temperature for 30 minutes and then at 50° C. for 1 hour. The formaldehyde and formic acid are distilled off from the reaction mixture under reduced pressure, and ethanol is added to the residue. After filtering off the insolubles from the resulting solution, the ethanol is distilled off from the filtrate. The resulting oily residue is dissolved in ether, washed with water and dried. The ether is distilled off from the dried solution to given an oily residue (2.8 g), which is purified by silica gel column chromatography, using chloroform as an eluent to give 2.3 g of ethyl 2-[4-{N-(4-chlorophenyl)-N-methylaminomethyl}phenoxy]-2-methylpropionate, an oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:19]([OH:21])=O)[CH:5]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[NH:36]1[C:35]([NH:34][C:19]([C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][CH2:17][CH3:18])=[CH:14][CH:15]=3)[N:7]=2)=[O:21])=[N:39][N:38]=[N:37]1
Reactant: Nc1nnn[nH]1
Reactant: CCNc1ccc(-c2cc(OCC)cc(C(=O)O)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCNc1ccc(-c2cc(OCC)cc(C(=O)Nc3nnn[nH]3)n2)cc1
Yield: 69.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-ethoxy-6-(4-ethylaminophenyl)-2-pyridinecarboxylic acid (0.28 g), carbonyldiimidazole (0.17 g) and 5-aminotetrazole (0.09 g) are reacted to give N-(5-tetrazolyl)-4-ethoxy-6-(4-ethylaminophenyl)-2-pyridinecarboxamide (0.24 g). M.P. 255°-257° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1)(O)=O>>[O:2]1[CH2:1][CH2:3][N:4]=[C:5]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1
Reactant: NCCO
Reactant: O=C(O)CCCCc1cn(-c2cccnc2)c2ccccc12
Product: c1cncc(-n2cc(CCCCC3=NCCO3)c3ccccc32)c1

Procedure:
A solution of 6.1 g of ethanolamine and 2.94 g of 3-(4-carboxybutyl)-N-(3-pyridyl)indole are heated at 170° for 3 hours. Excess ethanolamine is removed by distillation under reduced pressure to yield 3-[4-(4,5-dihydrooxazol-2-yl)butyl]-N-(3-pyridyl)indole.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][C:16]=2[Cl:26])[C:6]=1[CH3:27].[OH-].[Na+]>CO.C1COCC1>[Cl:26][C:16]1[CH:17]=[C:18]([S:21]([CH2:24][CH3:25])(=[O:22])=[O:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[C:6]1[CH3:27]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [1-(2-chloro-4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (3.32 g, 7.89 mmol) in methanol/THF (30 ml of a 1:1 mixture) is added 1M NaOH (15 ml). After stirring at room temperature overnight, the solvent is removed in vacuo and the residue is dissolved in water (20 ml). The solution is acidified to pH1 using 6M HCl and the resulting suspension is filtered and recrystallised from IPA/water to yield the titled product. (MH+ 407)
Reaction SMILES: C[O-].[Na+].[CH:4]([NH2:6])=[NH:5].C[O:8][C:9](=O)[CH:10]([C:14](=O)[CH3:15])[CH2:11][CH2:12][CH3:13].C(O)(=O)C>CO>[CH2:11]([C:10]1[C:9](=[O:8])[NH:5][CH:4]=[N:6][C:14]=1[CH3:15])[CH2:12][CH3:13]
Reactant: N=CN
Reactant: CCCC(C(C)=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1c(C)nc[nH]c1=O
Reaction time: 0.25 h

Procedure:
NaOMe (1.30 g, 24 mmol) is added to a stirred solution of formamidine (12 mmol) in MeOH (75 ml) at room temperature. The mixture is stirred for 15 minutes. 2-Acetyl-pentanoic acid methyl ester (10 mmol) is added and the mixture is stirred at room temperature overnight. Acetic acid (0.72 g, 12 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and it is extracted with 2-butanone (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid (100), which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:13](=[O:27])[CH:12]([OH:28])[CH2:11]1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)[C:13](=[O:27])[CH:12]([OH:28])[CH2:11]1
Reactant: COc1cccc(F)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Product: O=C1C(O)CC(c2c(O)cccc2F)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (−78° C.) solution of rac-(3R*,5S*)-5-(2-fluoro-6-methoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (compound corresponding to example 293; 355 mg; 0.88 mmol) in anh. DCM (8 ml) was treated dropwise with a solution of boron tribromide BBr3 (1.0 M in DCM; 4.45 ml; 4.45 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Water was added dropwise to the cooled (0° C.) reaction mixture, and the separated aq. layer was extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered and concentrated to dryness under reduced pressure affording rac-(3R*,5S*)-5-(2-fluoro-6-hydroxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 386.05 g/mol.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][C:15]=1[CH:16]=[O:17].Cl>CO>[OH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:23])[CH3:24])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCCOCCOC2CCCCO2)c(C=O)c1
Agent: Cl
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1ccc(OCCOCCO)c(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above benzaldehyde was dissolved in methanol (400 ml) containing 1N hydrochloric acid (50 ml) and the mixture was stirred at room temperature for 3 hours. The methanol was removed by evaporation in vacuo, and the residue was extracted with dichloromethane. The extracts were evaporated in vacuo, to give the title compound as an oil (23.6 g).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:23]=5)[CH:17]=4)[N:12]([S:28]([C:31]4[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:11]=3)[N:7]=[C:6]([C:38](O)=[O:39])[CH:5]=2)[CH2:3][CH2:2]1.C[N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[OH-]>CN(C=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:26])[CH3:27])=[N:22][N:23]=5)[CH:17]=4)[N:12]([S:28]([C:31]4[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=4)(=[O:29])=[O:30])[CH:11]=3)[N:7]=[C:6]([C:38]([NH2:42])=[O:39])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(C(=O)O)cc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(C(N)=O)cc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxylic acid (50 mg) was treated with HATU (51.1 mg, 0.134 mmol) followed by DMF (3 mL) and Hunig's base (0.1 mL). The reaction was stirred for 30 min at RT then treated with NH4OH (0.1 mL) and stirred for 30 min. The reaction was quenched with H2O and extracted with EtOAc (50 mL) and washed with brine (3×20 mL), dried over MgSO4, filtered and concentrated. The crude residue was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:32]=[CH:31][C:19]3[NH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:22][C:18]=3[CH:17]=2)[CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:32]=[CH:31][C:19]3[NH:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:22][C:18]=3[CH:17]=2)[CH:10]=1
Reactant: COc1ccc(-c2nc3cc(-n4ccc(=O)c(OCc5ccccc5)c4)ccc3[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(-n4ccc(=O)c(O)c4)ccc3[nH]2)cc1
Temperature: 60 °C

Procedure:
3-(Benzyloxy)-1-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]pyridin-4(1H)-one (912 mg, 10 mmol) and 10% Pd/C (100 mg) in EtOH (300 mL) was stirred under an H2 balloon for 3 hours. After this time, LCMS indicated that the reaction was complete. After evacuation and purge with N2 (3×), the EtOH solution was heated at 60° C. for 1 h, filtered, and the catalyst was washed with EtOH (4×50 mL). The combined EtOH solution was concentrated to provide the desired product 3-hydroxy-1-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]pyridin-4(1H)-one as a slightly yellow solid. 1H NMR (500 MHz, DMSO): δ 13.05 (s, broad, 1 H); 8.15 (d, J=8.3 Hz, 2 H); 7.89 (d, J=6.9 Hz, 1 H); 7.71 (m, 3 H); 7.34 (d, J=7.9 Hz, 1 H); 7.13 (d, J=8.6 Hz, 2 H); 6.32 (d, J=7.3 Hz, 1 H); 3.85 (s, 3 H); LCMS (M+H)+ 334; HRMS Calcd for (C19H15N3O3+H)+ 334.1186. Found 334.1188.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: C1CNCCN1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCNCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and piperazine following the procedure outlined in Example 15 (modifications: 40° C., 8 h, purified by reverse-phase HPLC). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 11.79 (br, 1H), 10.51 (s, 1H), 9.81 (br, 1H), 9.73 (br, 1H), 9.25 (s, 1H), 8.82 (s, 2H), 8.02 (d, 1H), 7.17 (d, 1H), 4.97 (s, 1H), 4.01 (t, 2H), 3.95 (s, 3H), 3.68 (br d, 2H), 3.58-3.35 (br m, 4H), 3.26 (br, 2H), 3.13 (m, 2H), 1.84-1.70 (m, 4H), 1.50-1.32 (m, 4H); MS (ESI): 520.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:37][CH:38]=1)[CH3:47]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, ethyl 4-bromophenylacetate, and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.