Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][CH2:36][CH2:37][CH2:38][OH:39]>O1CCCC1.O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(C=Cc1cccnc1)NCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 4.5 g of 3-(3-pyridyl)acrylic acid, 3.5 g of N-hydroxysuccinimide, 6.8 g of dicyclohexylcarbodiimide, and 80 ml of dioxane is stirred at room temperature overnight. The reaction mixture is filtered, and the filtrate is concentrated to give a brown oil. The product is dissolved in 100 ml of tetrahydrofuran, and 2.3 g of 3-amino-1-propanol is added. The mixture is stirred at room temperature overnight and concentrated. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give 4.2 g of N-[3-(3-pyridyl)acryloyl]-3-amino-1-propanol. The product is converted into the hydrochloride with 35 w/v % ethanolic hydrogen chloride. To the hydrochloride is added 4.6 g of thionyl chloride, and the mixture is stirred at 100° C. for 2 hours. The remaining thionyl chloride is distilled off, and 50 ml of water is added. The resulting solution is neutralized with 10% aqueous sodium carbonate solution and extracted with three 50-ml portions of chloroform. The combined extracts are dried over magnesium sulfate, and the chlorofom is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give 3.2 g of N-[3-(3-pyridyl)acryloyl]-3-amino-1-chloropropane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][NH2:15])=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1ccc(NN)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-aminophenyl)propionic acid ethyl ester (14 g, 72.5 mmol) in conc. HCl (200 mL) was added aqueous (10 mL) NaNO2 (5 g, 72.5 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (33 g, 145 mmol) in conc. HCl (150 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with EtOH and Et2O to yield 3-(4-hydrazinophenyl)propionic acid ethyl ester as a white solid, which was used for the next reaction without further purification. MS (ESI): m/z: 209 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([C:17]4([CH3:20])[O:19][CH2:18]4)=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[CH2:18][OH:19])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cc2c(=O)c3cc(C4(C)CO4)ccc3oc2nc1N
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(=O)c3cc(C(C)CO)ccc3oc2nc1N
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of ethyl 2-amino-7-(1,2-epoxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (800 mg), 5% palladium-carbon (700 mg), ethanol (50 ml) and tetrahydrofuran (150 ml) was subjected to catalytic reduction for two hours at room temperature under ordinary pressure. Then, the catalyst was filtered off, and the filtrate was concentrated to dryness. The concentrate was purified by means of a silica-gel (80 g) column chromatography using chloroform-acetone-formic acid (9:1:0.1). The solvent was evaporated off, and the residue was recrystallized from chloroform to yield colorless prisms (499 mg) of ethyl 2-amino-7-(2hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine-3-carboxylate, m.p. 255°-256° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[C:22]([O:27][CH:28](Cl)[CH3:29])(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][C@H:28]([O:27][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH3:29])=[O:19])[CH2:15]1
Reactant: CC(Cl)OC(=O)C(C)C
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: C=CCOC(=O)N1COC(=O)[C@]12C1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O[C@@H](C)OC(=O)C(C)C
Yield: 15.5 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 1.43 g) and 1-chloroethyl isobutyrate (1.80 g) were treated in the same manner as in Example A-1 (3) to give (1S,2S,3S,5R,6S)-3′-allyl 6-(1-(isobutyryloxy)ethyl) 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (A-8-1, 307 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:60]([CH3:59])[CH2:61][C:62]3[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: CNCc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccncc1)C(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Yield: 63.5 %

Procedure:
A solution of 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (60 mg, 0.17 mmol), HATU (76 mg, 0.20 mmol), DIEA (0.035 mL, 0.20 mmol) and N-methyl-1-(pyridin-4-yl)methanamine (20.39 mg, 0.17 mmol) in DMF (1 mL) was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 5→80% ethyl acetate/hexane) to give the title compound (50 mg, 0.108 mmol, 65%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:23][O:24][CH2:25][CH2:26]Br>>[CH3:23][O:24][CH2:25][CH2:26][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:2]([CH3:22])([CH3:1])[CH2:3][O:4][C:5]=3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: COCCBr
Reactant: CC1(C)COc2ccc(C#Cc3ccc(O)cc3)cc2OC1
Product: COCCOc1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound was prepared according to the general procedure described in example 18 by alkylation of 4-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-phenol (Example 6) with 2-methoxyethyl bromide as brownish solid, MS (ESI) 353.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([NH:3][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:9]([OH:11])=[O:10])=[O:20]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
An aqueous NaOH (1M, 2.6 mL) solution is added, while stirring, to L-Leucine (4 g, 30.5 mmol) in a round bottom flask (250 mL). To this solution was added sodium carbonate (1.62 g, 15.2 mmol). The flask is cooled to 0° C. in an ice-water bath. Methyl chloroformate (2.6 mL, 33.5 mmol) is added drop wise and the reaction mixture is allowed to stir for 15 hours and reach room temperature. The reaction mixture is separated with ether (3×50 mL), and the aqueous layer is contained in a round bottom flask and cooled over an ice-water bath. Concentrated HCl(aq) is added drop wise until pH 2. The reaction mixture is brought to room temperature and extracted with 2-Me-THF (3×50 mL). The organic layers are pooled, dried (MgSO4), the solids removed by filtration, and the solvents of the filtrate removed under reduced pressure. The compound was purified by silicagel chromatography with gradient elution from CH2Cl2 to CH2Cl2/MeOH/acetic acid 17/2/1. Fractions containing product were combined and the solvent were removed in vacuum, resulting in N-methoxycarbonyl-L-leucine (1.9 g, 32%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9].C(N(CC)CC)C.[C:23](#[N:26])[CH:24]=[CH2:25]>O>[C:23]([CH2:24][CH2:25][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9])#[N:26]
Reactant: NCCCCNC(=O)C(O)C(O)C(=O)O
Reactant: C=CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: N#CCCNCCCCNC(=O)C(O)C(O)C(=O)O

Procedure:
2.01 Grams (9.127 mmoles) of N-(4-aminobutyl)tartaric acid monoamide (IX) obtained in 1. was dissolved in 40 ml of water, and after adding 1.273 ml of triethylamine and then 0.726 ml of acrylonitrile, the resulting mixture was stirred for 27 hours at room temperature. The reaction solution was then dried to solid under reduced pressure. After adding 20 ml of water to the residual solid, the resulting solution was passed through a column packed with 300 ml of Dowex® 1×4(OH-), and after washing with 1.2 liters of water, eluted with 0.5N aqueous acetic acid solution. The fractions containing the objective compound were collected and concentrated under reduced pressure to obtain 2.235 g of a syrup-form N-[4-(2-cyanoethyl)aminobutyl]tartaric acid monoamide (XI) (yield, 89.6%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH:13]2[C:18]([CH3:20])([CH3:19])[C@H:17]3[CH2:21][C@:14]2([CH3:22])[CH2:15][CH2:16]3)=[O:11])=[CH:8][C:7]=1[S:25]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH:13]2[C:18]([CH3:20])([CH3:19])[C@H:17]3[CH2:21][C@:14]2([CH3:22])[CH2:15][CH2:16]3)=[O:11])=[CH:8][C:7]=1[S:25]([N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: COCC#Cc1ccc(C(=O)NC2C(C)(C)[C@@H]3CC[C@@]2(C)C3)cc1S(=O)(=O)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc(C(=O)NC2C(C)(C)[C@@H]3CC[C@@]2(C)C3)cc1S(=O)(=O)N1CCOCC1
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution of 4-(3-methoxy-prop-1-ynyl)-3-(morpholine-4-sulfonyl)-N-((1S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide 6.1 (220 mg, 0.46 mmol) in ethanol (20 mL) under nitrogen was added palladium on carbon (10 mg, 0.08 mmol). The reaction mixture was stirred under a hydrogen atmosphere for 2 hours then filtered through celite washing with ethanol. The solvent was evaporated and the residue was purified by silica gel chromatography using hexane/ethyl acetate (0-50%) to give the product 85 as a white solid (120 mg, 54% yield).
Reaction SMILES: C([N:8]1[C@@H:17]2[C@:12]([OH:18])([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[C:20]1([NH:19][CH:11]2[C@:12]3([OH:18])[C@H:17]([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:8][CH2:9][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O[C@]12CCCC[C@@H]1N(Cc1ccccc1)CCC2Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O[C@]12CCCC[C@@H]1NCCC2Nc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of (4aS,8aS)-1-benzyl-4-(phenylamino)octahydroquinolin-4a(2H)-ol (0.280 g, 0.832 mmol) in MeOH (5 mL) was added NH4COOH (0.840 g, 13.3 mmol) and 10% Pd/C (0.280 g). The resulting mixture was heated at 60° C. for several hours. The reaction was cooled to rt, filtered through a syringe filter, washed with EtOH, and concentrated to give the title compound. LRMS M+H calc'd: 247.34. found 247.34
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH2:57]O)[CH2:53][CH2:52]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>O1CCCC1.[Cl-].[Na+].O>[O:24]=[C:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH2:57][CH:54]3[CH2:55][CH2:56][N:51]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:52][CH2:53]3)[CH:15]=2)[NH:20]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Diethylazodicarboxylate (40% solution in toluene, 3.3 mL, 7.4 mmol) was added to a mixture of 6-hydroxy-3,4-dihydro-2(1H)-quinolinone (2) (1.0 g, 6.1 mmol), triphenylphosphine (1.607 g, 6.1 mmol), and N-Boc-4-piperidinemethanol (1) (1.32 g, 6.1 mmol) in anhydrous tetrahydrofuran (25 mL) at 0° C. After the addition, the mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with brine (20 mL) and stirred for 30 min. The mixture was extracted with ethyl acetate (2×30 mL), and washed with brine. The combined organic extract was dried over Na2SO4, and later evaporated on a rotavap. The residue was purified by flash column chromatography on silica gel (230-400 mesh; 8 g) using hexane:ethylacetate solvent mixture. Yield: 3.02 g (some phosphorus side products were present, used without further purification for subsequent step). 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 6.70 (b.s, 1H), 6.67 (m, 2H), 3.74 (d, 2H), 2.91 (t, 2H), 2.70 (b.t, 2H), 2.59 (m, 2H), 1.93 (b.s, 1H), 1.80 (b.d, 2H), 1.44 (m, 9H), 1.24 (m, 2H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([C:32]1([C:39]2[C:48]3[O:47][CH2:46][CH2:45][O:44][C:43]=3[C:42]([O:49][CH3:50])=[CH:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)#[N:31].O>C1COCC1>[CH3:50][O:49][C:42]1[C:43]2[O:44][CH2:45][CH2:46][O:47][C:48]=2[C:39]([C:32]2([C:30]#[N:31])[CH2:37][CH2:36][C:35](=[CH:2][O:3][CH3:4])[CH2:34][CH2:33]2)=[CH:40][CH:41]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1OCCO2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (34 g, 99 mmol) in THF (320 mL) was added potassium tert-butoxide (11 g, 99 mmol). The mixture was stirred at room temperature for 15 minutes, and a solution of Compound 1 (15 g, 52 mmol) obtained in Example 1 in THF (150 mL) was added dropwise, followed by stirring at room temperature for 45 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=3/1) to give Compound 6 (14 g, 82%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH3:22]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(Br)cc1

Procedure:
Reaction of 4-bromobenzoyl chloride with 2-(o-aminophenethyl)-1-methylpiperidine according to the procedure of Example 114 affords 4-bromo-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p. 137.5°-138.5° C. (corr.), from ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[O:34](S(C(F)(F)F)(=O)=O)[S:35]([C:38]([F:41])([F:40])[F:39])(=O)=[O:36].CCOC(C)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([O:19][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:36])=[O:34])=[C:10]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2c(O)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 1-benzyl-6-chloro-4-hydroxy-3-(3-methyl-isoxazol-5-yl)-1H-quinolin-2-one (1.00 g, 2.73 mmol) and Et3N (0.57 ml, 4.10 mmol) in 20 ml of DCM under at −78° C. was added Tf2O (0.50 ml, 3.0 mmol) slowly under Ar. The mixture was warmed to rt. Treated with 150 ml of EtOAc, the mixture was washed with H2O (4×50 mL), brine (40 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure gave 1.35 g (99%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 7.95 (d, 1H, J=2.3 Hz), 7.55 (dd, 1H, J=9.0, 2.3 Hz), 7.27-7.37 (m, 4H), 7.21 (d, 2H, J=8.3 Hz), 7.17 (s, 1H), 5.60 (s, 2H), 2.42 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H14ClF3N2O5S, 499.0 (M+H), found 499.0.
Reaction SMILES: [CH2:1]=O.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C@H:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:29](=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[CH:8][CH:7]=1)[CH3:4]>ClC(Cl)C.ClCCl>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C@H:23]2[CH2:28][N:27]([CH3:1])[CH2:26][CH2:25][N:24]2[C:29](=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: C=O
Reactant: CCOc1ccc(-n2c([C@H]3CNCCN3C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ccccc3c2=O)cc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@H]3CN(C)CCN3C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ccccc3c2=O)cc1
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Formaldehyde (37% in water) (0.015 g, 0.18 mmol) was added to a solution of 20 (0.05 g, 0.09 mmol) in dichloroethane (5 mL), followed by Na(OAC)3BH (0.057 g, 0.27 mmol) at room temperature. The mixture was stirred overnight. The solution was diluted with dichloromethane, washed by saturated sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash column to afford a white solid (40 mg). 1H NMR (CDCl3) 1.42 (t, 3H, J=7.0 Hz), 2.01-2.26 (m, 4H), 2.89 (m, 2H), 3.77 (m, 4H), 4.04 (q, 2H, J=7.0 Hz), 4.46 (m, 1H), 5.41 (m, 1H), 7.01 (m, 3H), 7.06 (m, 1H), 7.41 (m, 5H), 7.71 (m, 1H), 8.21 (d, 1H, J=8.08 Hz). MS (ESI+) 569.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[N:13]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[C:14](=[O:18])OCC.[H-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:8][C:6]1[CH:5]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:3]2[N:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:14](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)N(c1ccc(Cl)cc1Cl)c1c(N)cc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1Cl
Yield: 79.3 %

Procedure:
Ethyl 2,4-diamino-6-(trifluoromethyl)phenyl(2,4-dichlorophenyl)carbamate (1.1454 g) was dissolved in ethanol (20 ml), and to the solution was added sodium hydride (112.2 mg). The reaction mixture was heated at reflux for 6 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (60 g, CHCl3:methanol=10:1→5:1) to give the title compound (0.8058 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[CH:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:2]
Reactant: CCOC(=O)COc1cc(OC)c(Cl)cc1C(O)c1ccccc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(=O)COc1cc(OC)c(Cl)cc1C(=O)c1ccccc1
Yield: 39.9 %

Procedure:
The above prepared [4-chloro-2-(hydroxy-phenyl-methyl)-5-methoxy-phenoxy]-acetic acid ethyl ester (1.91 g, 3.81 mmol, corrected for purity) was dissolved in 50 mL of CH2Cl2, treated with MnO2 (8.28 g, 25 eq.), and the reaction mixture vigorously stirred over night. Filtration over a pad of Celite, carefully rinsing, and evaporation of the solvent, followed by flash chromatography (SiO2, heptane/AcOEt=7/3) and crystallization from heptane/AcOEt gave 0.530 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[CH3:33][C:32]1[C:27]([NH2:26])=[N:28][CH:29]=[C:30]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:31]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1cc(Br)cnc1N
Product: Cc1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2-amino-5-bromo-3-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (140 mg, 30%). MS (ISP) 462.2 [(M+H)+]; mp 233–234° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[O:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC[C@@H]2CCCO2)cc1
Reaction time: 12 h

Procedure:
A mixture of 4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzoic acid methyl ester (9.8 g), sodium hydroxide solution (2 N; 80 ml) and MeOH (300 ml) was stirred for 12 hours. Organic volatile fractions were removed on a rotary evaporator. The remaining aqueous phase was extracted with methyl tert-butyl ether (MTBE) and then acidified with concentrated hydrochloric acid. The resulting precipitate was filtered off and dried. The product was thus obtained with the molecular weight of 222.24 (C12H14O4); MS (ESI): 223 (M+H+).