Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
3-Methoxybenzenesulfonyl chloride (0.04 mL, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 38 (50 mg, 55% yield) as a yellow solid. LC-MS (M+H=379, obsd.=379).
Reaction SMILES: [OH-].[K+].ClC1C=CC=CC=1C[C:7]1[CH:17]=[CH:16][CH:15]=[C:9]2C([NH:12][C:13](=O)[C:8]=12)=O.[ClH:22]>O>[Cl:22][C:7]1[CH:17]=[CH:16][CH:15]=[CH:9][C:8]=1[CH2:13][NH2:12]
Reactant: O=C1NC(=O)c2c(Cc3ccccc3Cl)cccc21
Reactant: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NCc1ccccc1Cl
Temperature: 130 °C
Yield: 98 %

Procedure:
A 250 mL, round-bottomed, 3-necked flask was charged with 82.5 g of 20% aqueous potassium hydroxide and 20 g (73.6 mmol) of 2-chlorobenzylphthalimide. The reaction mixture was refluxed (bath temperature 130° C.) for 18.3 h with stirring, and then allowed to cool to room temperature. A mixture containing 50 mL of water and 50 mL of concentrated hydrochloric acid was then added dropwise and the reaction mixture was heated under reflux for a further 22.5 hours. The reaction mixture was then allowed to cool, and the cooled reaction mixture was filtered, and the collected solids were washed with 5×10 mL of water, and dried in a vacuum oven. NMR, IR and GC analysis indicated these to be mainly phthalic acid contaminated with 2-chlorobenzylphthalamic acid (11.2 g, 92%). The filtrate was rendered basic (pH 10) by the addition of potassium hydroxide pellets, and was then extracted with 4×100 mL of methylene chloride. After stripping of the solvent, a 98% yield (10.23 g) of 2-chlorobenzylamine was obtained (purity 99% by GC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:13])[CH2:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>ClCCl.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:13][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2c(c1)CC(N)CC2
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.49 g) in dichloromethane (5 ml) were added in turn pyridine (0.29 ml) and 4-fluorobenzoyl chloride (0.33 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 4-fluoro-N-(7-methoxy-1,2,3,4-tetrahydronaphthalene-2-yl)-benzamide (497 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[F:10].[C:11]([O-:14])(=[O:13])[CH3:12].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:11]([O:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:10])[CH:4]=1)(=[O:13])[CH3:12]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(Br)c(F)c1
Temperature: 80 °C
Yield: 15 %

Procedure:
To a room temperature solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene from Step 1 (11.8 g) in DMF (150 mL) was added sodium acetate (10.8 g). The mixture was heated at 80° C. for 16 hours. It was cooled to room temperature and poured into ice and saturated aqueous sodium bicarbonate (200 mL), and extracted with diethyl ether (2×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The crude material was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:25 to 1:10) to yield 4-bromo-3-fluorobenzyl acetate (containing about 15% of 4-bromo-3-fluorobenzaldehyde). The residue was dissolved in methanol (100 mL), cooled at 0° C. and sodium methoxide (250 mg) was added. The reaction mixture was stirred at room temperature for 2 hours. It was cooled to 0° C. and sodium borohydride was added (1.5 g). Stirred at 0° C. for 1 hour and poured into ice and saturated aqueous ammonium chloride (200 mL). Extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:5 to 1:3) to yield the title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[CH3:30])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:64][CH:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:26])=[CH:23][C:22]=4[CH3:30])=[N:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
A mixture of 0.02 g (0.00005 mole) of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methyl-benzoic acid (I-7), 0.023 g (0.00006 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.018 mL (0.0001 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.0085 g (0.000075 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.009 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-8) as a white solid.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH:7]1[CH2:10][N:9]([C:11]2[C:20]([F:21])=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:24][CH2:23]3)=[CH:13][C:12]=2[F:29])[CH2:8]1)=O.C(O)(=O)C>[OH-].[Na+]>[NH2:5][CH2:6][CH:7]1[CH2:8][N:9]([C:11]2[C:20]([F:21])=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:24][CH2:23]3)=[CH:13][C:12]=2[F:29])[CH2:10]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(CNC(=O)C(F)(F)F)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A solution of 0.8 g (1.6 mmoles) of 7-(3-trifluoroacetamidomethyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 9) in 30 ml of 1N sodium hydroxide is maintained at 80° C. for 3 hours, cooled and acidified with acetic acid. Filtering and washing yield 0.41 g (65%) of 7-(3-aminomethyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 190°-195° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](OC2C=CC=CC=2)=[N:25][C:26]#[N:27])=[CH:19][CH:18]=1>C(#N)C>[C:20]1([O:23][C:24]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)=[N:25][C:26]#[N:27])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: N#CN=C(Oc1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (1.3 g; 5.98 mmol) in acetonitrile was added diphenyl N-cyanocarbonimidate (1.56 g; 6.55 mmol; 1.1 equiv). The reaction mixture was stirred at 60° C. for 48 h under nitrogen atmosphere and then concentrated under reduced pressure. The crude product was suspended in ethyl acetate (50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL) and stirred overnight at room temperature. The solid was collected by filtration and dried to give N-cyano-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboximidic acid phenyl ester (1.85 g; 85%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl>C(OCC)(=O)C>[ClH:27].[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 196.4 %

Procedure:
To 1-(tert-butoxycarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine (2.0 g) were added methanol (10 ml)and 4 N hydrochloric acid in ethyl acetate solution (20 ml), and the solution was stirred at room temperature 30 minutes. The reaction solution was concentrated, and the residue was treated with acetone to give amorphous powder which was dried under reduced pressure to give the title compound (1.66 g).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCN(CC)CC>>[CH3:17][S:18]([O:1][CH:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]1)[CH3:3])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 98.7 %

Procedure:
(±)-1,1-Dimethylethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.74 g, 49%) was prepared as a light brown oil from (±)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (0.56 g, 2.44 mmol), methanesulfonyl chloride (0.23 mL, 2.93 mmol) and Et3N (0.69 mL, 4.88 mmol) in a manner similar to Example 150, Step 1. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.70-4.55 (m, 1H), 4.20-4.10 (m, 2H), 2.99 (s, 3H), 2.70-2.55 (m, 2H), 1.80-1.60 (m, 3H), 1.43 (s, 9H), 1.38 (d, 3H, J=6.4 Hz), 1.35-1.15 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[C:4]1[N:3]=[C:2]([N:28]2[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (700 mg, 2.42 mmol) in 10 ml CH2Cl2 at 0° C. was added triethylamine (0.67 mL, 4.8 mmol) followed by the addition of tert-butyl piperidin-4-ylcarbamate (630 mg, 3.14 mmol) under an N2 atmosphere. The reaction was gradually warmed to room temperature and stirred overnight. The reaction mixture was then quenched with water, and the layers were separated. The aqueous layer was extracted twice with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to obtain tert-butyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate (1.05 g, 96%) LC/MS: m/z 453.3 (M+H)+ at 2.60 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7].[C:42]([O:46][C:47](=[O:55])[NH:48][CH2:49][CH2:50][NH:51][CH:52]1[CH2:54][CH2:53]1)([CH3:45])([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:42]([O:46][C:47]([NH:48][CH2:49][CH2:50][N:51]([CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7])[CH:52]1[CH2:53][CH2:54]1)=[O:55])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCCNC1CC1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CCNC(=O)OC(C)(C)C)C5CC5)c4)sc4c3CCCC4)cc2)cc1
Yield: 97.7 %

Procedure:
By using 2.0 g of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 1.0 g of tert-butyl[2-(cyclopropylamino)ethyl]carbamate, 0.76 g of potassium carbonate, and 40 mL of DMF, 2.5 g of methyl 4-(2-{4-[({2-[(3-{[{2-[(tert-butoxycarbonyl)amino]ethyl}(cyclopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate was obtained by the method similar to Preparation Example 9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=C)=[CH:14][CH:13]=1.C(N(C)C)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Yield: 46.1 %

Procedure:
0.112 mg (0.5 millimols) of palladium acetate, 10.97 g (50 millimols) of 4-bromobenzoyl chloride, 10.17 g (50 millimols) of 4-bromostyrene and 6.76 g (50 millimols) of N-benzyldimethylamine in 100 m of o-xylene are stirred for 1 hour at 130° C. After having filtered off the amine salt which has precipitated, the filtrate is concentrated and the crude product is recrystallised twice from toluene. 7.8 g (46% of theory) of 4,4'-dibromostilbene are obtained in the form of white flakes; melting point 213.3° C.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14]C)=O)[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28])(=[O:20])=[O:19]>CO>[Br:1][C:2]1[N:11]=[C:10]([C:12]([NH:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:18]([CH3:17])(=[O:20])=[O:19])=[O:14])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: CS(=O)(=O)c1ccccc1CN
Solvent: CO
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Reaction time: 96 h

Procedure:
Methyl 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (500 mg, 1.77 mmol, prepared as in Example 113) and 1-[2-(methylsulfonyl)phenyl]methanamine (491 mg, 2.65 mmol) were suspended in 10 mL methanol in an oven-dried Schlenck tube. The solution was purged with Argon for 1 minute and capped. The solution was heated to 80 deg C. with stirring over 4 days. Upon cooling a white solid precipitated out of the methanol. LCMS analysis indicated that the precipitate was the desired product. Filtration and subsequent washing with methanol (10 mL) afforded the desired material as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:41])([CH3:39])[CH3:40])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Trifluoroacetic acid (0.10 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-3-fluoro-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 60-(1); 13.5 mg, 0.0209 mmol) in dichloromethane (0.50 mL) at room temperature, and the mixture was stirred at room temperature for two hours. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (8.5 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35]>C(#N)C.O>[CH:34]([NH:37][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([O:28][CH2:29][C:30]([F:31])([F:32])[F:33])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:36])[CH3:35]
Reactant: CC(C)N
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v) is added 885 μL (10.4 mmol) of isopropylamine. The reaction mixture is stirred for 16 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 4:6) affords 60 mg (10% over two steps) of the product as a white solid; LC/MS:536/538 (M+H)+, m.p.: 247-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[CH2:30][CH2:31]2)=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccncc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.100 g (0.29 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 47 mg (0.29 mmol) of 1-Pyridin-4-yl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 1 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate, and ethyl acetate/MeOH (10/1).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]([CH2:33][CH2:34][CH3:35])[CH:24]([C:26]1[O:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=1)[OH:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([CH2:7][CH:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:22][CH:23]([CH:24]([C:26]2[O:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=2)[OH:25])[CH2:33][CH2:34][CH3:35])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCC(N)C(O)c1nnc(CC)o1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1nnc(CC)o1
Reaction time: 14 h
Yield: 102.2 %

Procedure:
To a stirred mixture of 2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (84.9 mg, 0.3 mmol), 2-amino-1-(5-ethyl-1,3,4-oxadiazole-2-yl)-1-pentanol HCl salt (70.5 mg), prepared as in reference 21, and HOBt (55.1 mg, 0.36 mmol) in MeCl2 (5 ml), was added EDC (86.4 mg, 0.45 mmol) and N-methylmorpholine (0.25 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 142 mg of 2-cyclohexylmethyl-N-{1-[(5-ethyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-butyl}-4-morpholin-4-yl-4-oxo-butyramide; MS: 463.5(M−1), 465.3(M+1).