Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CO>[CH:1]([C@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[C@H:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: COc1ccc(CN[C@@H]2C[C@@H](C(c3ccccc3)c3ccccc3)OC[C@@H]2O)cc1

Procedure:
(1R,4S,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28b (0.021 g, 0.079 mmol) was reacted with p-methoxybenzylamine (0.22 g, 1.58 mmol) (Procedure E) to yield (3R,4R,6S)-6-benzhydryl-4-(4-methoxy-benzylamino)-tetrahydropyran-3-ol, (−)-29g 0.02 g (63%, [α]D=(−)63.75, c=1, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.I[CH2:17][CH3:18]>CN(C)C=O>[CH2:17]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: CCI
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
(washed beforehand with petroleum ether) and of 15 g (72.4 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 100 ml of dimethylformamide is stirred for 2 h at room temperature. 7.5 ml (93.7 mmol) of iodoethane, in solution in 20 ml of dimethylformamide, are subsequently added. After stirring for 10 h at room temperature, the reaction mixture is poured onto ice-cold water. It is extracted with diethyl ether. The organic phase is washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. 17 g (72 mmol) of a yellow oil are obtained, which oil is used as is in the following stage.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=4)=[C:14]([CH2:16][S:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)=[C:14]([CH2:16][S:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(CSc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2c(CSc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 34b (347 mg, 0.627 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added and the solid dissolved. TFA (2 mL) was added dropwise and then the reaction was stirred at rt for 4 h. The solvent was removed under reduced pressure and then the residue was dissolved in DCM (10 mL) and MeOH (3 mL) and the solvent was removed under reduced pressure. The residue was triturated with MeOH (10 mL) to afford a white precipitate that was isolated by filtration. The residual solvent was removed under reduced pressure to afford the title compound 116. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 13.05 (br. s., 1H), 8.12-8.20 (m, 2H), 8.06 (d, J=8.6 Hz, 2H), 7.89 (d, J=8.1 Hz, 3H), 7.59-7.71 (m, 2H), 7.47-7.53 (m, 1H), 7.43 (d, J=8.6 Hz, 1H), 6.40 (d, J=5.6 Hz, 1H), 4.82 (s, 2H), 3.85-3.98 (m, 4H), 3.66-3.78 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H23N5O3S: 498.2 (M+H). Found: 498.4.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:25]([N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:5]([C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[C:3](=[O:4])[C:2]([F:23])([F:1])[F:24])[CH2:8][CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccc(I)cc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N(CC1CCN(Cc2ccccc2)CC1)[C@@H]1C[C@H]1c1ccc(I)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (250 mg, 0.553 mmol) in 1,2-dichloroethane (DCE) (4 mL) were added benzaldehyde (0.067 mL, 0.663 mmol) and sodium triacetoxyborohydride (176 mg, 0.829 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (4 ml) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 194 mg of product as pale yellow viscous oil. MS: (M+H)+=543.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.29-1.52 (m, 3H), 1.57-1.93 (m, 4H), 2.04-2.25 (m, 2H), 2.37-2.51 (m, 1H), 2.91-3.22 (m, 3H), 3.40-3.66 (m, 4H), 6.89-7.07 (m, 2H), 7.27-7.40 (m, 5H), 7.64 (d, J=8.34 Hz, 2H).
Reaction SMILES: [N:1]([CH:4]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=2)=[CH:38][CH:37]=1)[CH2:5][C:6]1[N:7]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[C:9]([CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[N:10]=1)=[N+]=[N-]>CO.[Pd]>[CH3:15][C:12]([CH3:16])([CH2:13][CH3:14])[CH2:11][C:9]1[N:10]=[C:6]([CH2:5][CH:4]([C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:40][CH:41]=2)[NH2:1])[N:7]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:8]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N=[N+]=[N-])c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 8 h

Procedure:
Pd (10 wt % on activated carbon) (10 mg, cat.) was added to a degassed solution of 2-(4-{1-azido-2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]ethyl}phenyl)-5-fluoropyridine (110 mg, 0.17 mmol) in methanol (6 mL). After stirring under an atmosphere of hydrogen overnight, the reaction mixture was filtered through celite rinsing with methanol. The filtrate was concentrated to afford 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:26]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([O:20][CH3:26])=[O:19])=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)(CCCOc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: COC(=O)C(C)(C)CCCOc1ccc(OCc2ccccc2)cc1

Procedure:
In 100 ml of tetrahydrofuran was dissolved 9 g of 5-(p-benzyloxyphenoxy)-2,2-dimethylpentanoic acid. The resulting solution was treated with a diazomethane-ether solution in a conventional manner to give methyl 5-(p-benzyloxyphenyloxy)-2,2-dimethylpentanoate. The thus obtained ester was dissolved in 200 ml of methanol and 10% palladium-carbon was added to the solution. The mixture was reacted with stirring in a hydrogen atmosphere under normal pressure until a theoretical amount of hydrogen was absorbed. Palladium-carbon was removed by filtration and the solvent was removed by distillation under reduced pressure to give the desired product, methyl 5-(p-hydroxyphenoxy)-2,2-dimethylpentanoate as crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[CH3:26][C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49]O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(Br)(Br)(Br)[Br:55]>C1COCC1>[CH3:26][C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49][Br:55])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCO)cc2)C1(C)C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCBr)cc2)C1(C)C(N)=O
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of 2.123 g (8.093 mmol) of triphenylphosphine and 0.373 mL (4.61 mmol) of pyridine in 40 mL of dry THF under nitrogen was added 1.73 g (4.046 mmol) of methyl 4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide. The solution was cooled in a water bath and 1.34 g (4.046 mmol) of carbon tetrabromide was added and the resulting mixture was stirred for 3 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:8) to provide 1.726 g (87%) of methyl 4-({4-[(5-bromo-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide as a pale yellow oil. Electrospray Mass Spec: 492.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+].S(=O)(=O)(O)O.[Cl-].[Na+]>C(O)C.O>[OH:11][CH:4]([CH2:3][CH:2]([OH:1])[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC(O)CCc1cccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(O)CC(O)CCc1cccc2ccccc12
Temperature: 25 °C
Yield: 58.4 %

Procedure:
4.0 g (0.013 mole) of ethyl 5-hydroxy-7-(1-naphthyl)3-oxoheptanoate, prepared as described in step (a) above, dissolved in a small quanity of anhydrous ethanol were added dropwise to 0.57 g (0.015 mole) of sodium borohydride in 20 ml of absolute ethanol, with ice-cooling and stirring. When the addition was complete, cooling was immediately stopped and the mixture was allowed to warm to room temperature and was stirred for 30 minutes. After adding 200 ml of water, the mixture was acidified by the addition of sulphuric acid, saturated with sodium chloride and extracted three times, each with 50 ml of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate. The solvent was then evaporated off under reduced pressure and the resulting residue was adsorbed on a silica gel column chromatograph. The fractions eluted with a 9:1 by volume mixture of benzene and ethyl acetate were concentrated to dryness to give 2.4 g (yield 23%) of the desired Compound No. 3 in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Br:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Br:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:31]([C:30]1[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Br)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of N-[6-(3-amino-4-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (582 mg, 1.50 mmol) in N-methylpyrrolidone (5 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (310 mg, 1.95 mmol), and the mixture was stirred at room temperature for 18 hr. A 5% aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the mixture was stirred with heating under reflux for 15 min. After allowing the reaction mixture to cool to room temperature, the precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (658 mg, yield 86%) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH2:5][C:6](Br)([F:10])[CH:7]=[CH:8][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+].[CH3:37][C:38]([CH3:46])([CH2:43][CH:44]=[CH2:45])[C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1/[CH:45]=[CH:44]/[CH2:43][C:38]([CH3:46])([CH3:37])[C:39]([O:41][CH3:42])=[O:40])[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)C1=CC=CC(F)(Br)C1
Reactant: C=CCC(C)(C)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/CC(C)(C)C(=O)OC)c(F)c1
Temperature: 130 °C

Procedure:
Methyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydro1quinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoate was prepared following general procedure B, substituting methyl 5-[4-(chlorocarbonyl)-2-fluorophenyl]-2,2-dimethylpentanoate for 6-trifluoromethyl nicotinyl chloride. (Methyl 5-[4-(chlorocarbonyl)-2-fluorophenyl]-2,2-dimethylpentanoate was prepared in five steps from 4-bromo-3-fluorobenzoic acid. To a solution of 3-bromo-3-fluorobenzoic acid in toluene/methanol was added dropwise a 2M solution of trimethylsilyl diazomethane until slight yellow coloration persists indicating reaction had gone to completion. Reaction mixture was concentrated to give methyl-3-bromo-3-fluorobenzoate. To a solution of methyl-3-bromo-3-fluorobenzoate in dimethylformamide was added sequentially palladium acetate, triphenylphosphine, tetrabutylammonium chloride, potassium acetate and methyl 2,2-dimethylpent-4-enoate. Reaction mixture was heated under microwave irradiation at 130° C. for 10 m. to give methyl 3-fluoro-4-[(1E)-5-methoxy-4,4-dimethyl-5-oxopent-1-en-1-yl]benzoate. Hydrogenation of this diester gave methyl 3-fluoro-4-(5-methoxy-4,4-dimethyl-5-oxopentyl)benzoate which benzoic ester was selectively hydrolyzed using lithium hydroxide to give 3-fluoro-4-(5-methoxy-4,4-dimethyl-5-oxopentyl)benzoic acid. Subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF afforded methyl 5-[4-(chlorocarbonyl)-2-fluorophenyl]-2,2-dimethylpentanoate in decent yield). The rest of the procedures were followed as indicated in general procedure H to afford methyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoate.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1.[CH3:24][NH2:25]>>[F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:17]=[CH:18][C:19]([CH2:20][NH:25][CH3:24])=[CH:22][CH:23]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1
Reactant: CN
Reactant: O=Cc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1
Product: CNCc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1

Procedure:
The title compound was prepared following the procedure described in Example 32 from aldehyde 97a and methylamine (2M/MeOH) to give 0.069 g (42%) of a white solid: mp=204-208° C. (dec); Rf=0.03 (7% methanolic ammonia/CHCl3); IR (KBr) 1655, 1609, 1470, 1437 cm−1; 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 3.54-3.55 (m, 2H), 3.75 (s, 2H), 4.45-4.46 (m, 2H), 7.52 (d, 2H, J=8.2 Hz), 7.57-7.61 (m, 1H), 7.73-7.76 (m, 1H), 7.80 (d, 2H, J=8.2 Hz), 8.59-8.63 (m, 1H). HRMS calcd for C18H17N4OF 324.1386 (M+), found 324.1378. Anal. (C18H17N4OF.0.3H2O) C, H, N.
Reaction SMILES: CO[C:3](=[O:14])/[C:4](=[N:11]\[O:12][CH3:13])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:15][NH2:16]>O>[CH3:15][NH:16][C:3](=[O:14])[C:4](=[N:11][O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CN
Reactant: CO/N=C(\C(=O)OC)c1ccccn1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccn1

Procedure:
Z-α-methoxyimino-2-pyridineacetic acid methylester (5 g) and a solution of methylamine in water (15 ml, 30%) were stirred at a temperature of 60° C. until the starting compound was completely dissolved. Water was evaporated under reduced pressure and the residue was recrystallized from toluene, yielding N-methyl-α-methoxyimino-2-pyridineacetamide (3.0 g), Z-isomer, m.p. 132°-133° C. The E-isomer was obtained in the same way, but starting from the corresponding E-ester. M.p. of the E-isomer 91°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4′-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI−): m/z=483.1 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1([C:22]([O:24]C)=[O:23])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Li+].CO>C1COCC1.O>[CH2:15]([O:14][C:12]([N:3]1[C:2]([CH3:1])([C:22]([OH:24])=[O:23])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1(C)Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C(=O)O)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
Step-3: To a solution of 2-benzyl 3-methyl 3-methyl-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate in THF (1.2 mL) was added lithium hydroxide (50.5 mg, 1.204 mmol) in water (0.6 mL). Methanol (0.72 mL) was added till homogeneous solution was obtained and the reaction was heated at 60° C. overnight. The reaction was concentrated, acidified to pH 2 using 2 N HCl, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford the crude product which was purified by preparative TLC using hexane/ethyl acetate mixture (1:1) to afford 2-((benzyloxy)carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. MS (ES+): m/z 326.15 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:10][C:8](=[O:9])[C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[N:5][CH:6]=3)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)COCCc1cccc(F)c1
Reactant: NC(=O)c1cncnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c(COCCc2cccc(F)c2)nc2ncncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
A suspension of the commercially available 4-amino-5-pyrimidinecarboxamide [4786-51-0] (150 mg, 1.09 mmol) and of [2-(3-fluoro-phenyl)-ethoxy]-acetic acid methyl ester (254 mg, 1.19 mmol) in THF (7 ml) was treated with LiHMDS (1M solution in THF, 2.17 ml) and stirred overnight at ambient temperature. The resulting yellow suspension was filtered and the filtrate was evaporated to dryness and triturated with EtOAc/MeOH 9:1. The yellow solid was filtered off, the mother-liquid was evaporated and the remaining residue was purified by column chromatography (silica gel, EtOAc/MeOH, 9:1) to give the title compound as a white solid (3 mg, 1%), MS: m/e=301.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[C:4]([C:33](=[O:36])[NH:34][CH3:35])[CH:3]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[C:4]([C:33](=[O:36])[NH:34][CH3:35])[CH:3]=1
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCC2(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCCC2(C)C

Procedure:
Intermediate 12, N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide was treated with trifluoroacetic acid, according to Method D to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm: 11.76 (1 H, br), 8.84 (1 H, t, J=5.9 Hz), 7.46 (1 H, dd, J=8.4, 5.5 Hz), 7.04–7.18 (2 H, m), 6.22 (1 H, s), 4.57 (2 H, d, J=6.6 Hz), 3.93 (2 H, t, J=6.4 Hz), 3.00 (3 H, d, J=4.8 Hz), 1.88–2.00 (2 H, m), 1.67–1.74 (2 H, m), 1.33–1.39 (6 H, m); HRMS (ESI) calcd for C20H24FN4O4 (M+H) 403.1782, found 403.1783.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:34][CH:35]=1.Cl>N1C=CC=CC=1>[F:43][C:29]([F:28])([F:42])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:37][CH2:38][N:39]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[C:3]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:40][CH2:41]2)=[N:34][CH:35]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide (0.1 g, 0.242 mmol) in pyridine (2 ml) was treated with 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (0.3 g, 0.68 mmol) and the reaction mixture was stirred for 1 hour at room temperature. Subsequently the reaction mixture was poured onto crushed ice containing two drops of concentrated hydrochloric acid, extracted with ethyl acetate (25 ml) and the organic layer was washed with brine and evaporated. The title compound was obtained by column chromatographic purification of the crude material with 30% ethyl acetate in hexane. 1H-NMR (DMSO-d6) δ: 3.33-3.37 (m, 4H), 3.56 (m, 4H), 6.86-6.88 (d, 1H), 7.10-7.12 (d, 2H), 7.22-7.29 (m, 3H), 7.35-7.37 (m, 1H), 7.44-7.48 (m, 1H), 7.74-7.79 (m, 3H), 8.38 (s, 1H). MS m/z: 608.8 (M+).