Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:10](O)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[CH:1]1([CH2:10][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
150 mg (0.92 mmol) of indan-1-carboxylic acid compound was dissolved in 9 mL of tetrahydrofuran, and then 105 mg (2.77 mmol) of lithium aluminum hydride was added at 0° C. and stirred at room temperature for 2 hours. Water was slowly added to quench the reaction, and when a gel was formed by adding ethyl acetate, the celite was filtered. Then, the residue was dissolved again in 20 mL of ethyl acetate and the organic layer was washed with distilled water three times. The organic layer was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 124 mg of colorless oil (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)/[CH:5]=[N:6]/[OH:7].ClC1C(F)=[C:15]([CH:18]=[CH:19]C=1)[CH:16]=[O:17].Cl.N[OH:24].[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:5]2[C:18]([CH3:19])=[C:15]([C:16]([OH:24])=[O:17])[O:7][N:6]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NO
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O/N=C/c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2cccc(Cl)c2F)noc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
(E)-3-Chloro-2-fluorobenzaldehyde oxime: To the solution of 3-chloro-2-fluorobenzaldehyde (1.3 g, 8.20 mmol) and hydroxylamine hydrochloride (0.695 g, 10.00 mmol) in EtOH (6.83 mL)/water (6.83 mL) was added 1 N NaOH (10.00 mL, 10.00 mmol). The reaction was stirred at rt for 4 h, then it was acidified to pH 6 with 1 N HCl which gave a white suspension. The reaction mixture was filtered, and the solid was rinsed with water, and air-dried to afford the desired product (1.31 g, 92%) as a white solid. MS(ESI) m/z: 174.0 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 7.74 (s, 1H), 7.66 (ddd, J=7.8, 6.3, 1.7 Hz, 1H), 7.42 (ddd, J=8.0, 7.2, 1.7 Hz, 1H), 7.13-7.07 (m, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:25][CH:24]=[CH2:23])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (50.0 g) in N,N-dimethylformamide (500 ml) were added potassium carbonate (60.3 g) and allyl bromide (28.3 ml), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water (600 ml), and the mixture was extracted with ethyl acetate (600 ml). The organic layer was sequentially washed with water (600 ml) and saturated aqueous sodium chloride solution (400 ml). The separated aqueous layer was extracted with ethyl acetate (300 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the resulting residue in n-hexane/ethyl acetate (4/1, 400 ml) was added silica gel (70 g), and the mixture was stirred at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the titled compound (62.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C1C=CC=CC=1>[CH:13]([NH:16][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)([CH3:15])[CH3:14]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: c1ccccc1
Product: CC(C)NC(=O)Nc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C

Procedure:
6-Amino-3,4-dihydrocarbostyril (1.6 g) is suspended in dry benzene (16 ml), and thereto is added dropwise a solution of isopropyl isocyanate (1.2 ml) in dry benzene (10 ml) with stirring at room temperature. The mixture is reacted at 50° to 60° C. for 3 hours. After the reaction, the resulting precipitate is separated by filtration, purified by silica gel column chromatography (solvent; chloroform:methanol=50:1), and recrystallized from ethanol to give 6-(3-isopropylureido)-3,4-dihydrocarbostyril (1.2 g) as colorless prisms, m.p. 252°-254° C.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[N:8]([CH3:13])[C:9]([CH2:11][OH:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:17].[K+]>>[C:1]([C:4]1[CH:15]=[CH:14][C:7]2[N:8]([CH3:13])[C:9]([C:11]([OH:17])=[O:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)nc(CO)n2C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CC(=O)c1ccc2c(c1)nc(C(=O)O)n2C

Procedure:
In a manner analogous to that described in Example 12, 4.1 g of 5-acetyl-1-methyl-benzimidazole-2-methanol can be oxidised with 4 g of potassium permanganate to give 5-acetyl-1-methyl-benzimidazole-2-carboxylic acid with a melting point above 135°.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[CH:3]=1.CCO[CH2:15][CH3:16].[NH4+].[Cl-]>>[CH3:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([C:5]2[CH:10]=[CH:9][C:15]([CH3:16])=[CH:7][CH:6]=2)=[CH:3]1
Reactant: Cn1cc(Br)c2ccccc21
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccc(-c2cn(C)c3ccccc23)cc1

Procedure:
A mixture of 4.31 g (0.02 mol) of 3-bromo-1-methyl-1H-indole and 0.22 g (0.0004 mol) of NiCl2dppp was added to a solution of p-TolylMgBr in ether (prepared from 0.6 g of Mg (0.025 mol) and 4.21 g of TolylBr (0.024 mol) in 40 mL of ether) under stirring. The reaction mixture was stirred overnight. The resulting mixture was treated with 10% aqueous NH4Cl, the organic layer was separated, washed with 10% aqueous NH4Cl and then dried over anhydrous Na2SO4. The solution was evaporated to give an oil that crystallized. The product was washed with methanol and dried. Yield 2.2 g (49%) of colorless crystalline solid.
Reaction SMILES: [OH2:1].[OH:2]O.[CH3:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:4][S:5]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:2])=[O:1]
Reactant: CSc1ccc(O)cc1
Reactant: OO
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a water bath, methyl iodide (18.5 ml) and potassium carbonate (28.7 g) were added to an acetone (250 ml) solution of 4-hydroxythiophenol (25 g), and stirred at room temperature for 5 hours. The salt was removed by filtration, the solvent was evaporated away under reduced pressure, diethyl ether was added, and extracted with aqueous 2 N sodium hydroxide solution. The obtained aqueous layer was made acidic with aqueous 6 N hydrochloric acid solution, extracted with diethyl ether, and the organic layer was washed with aqueous saturated sodium chloride solution. After dried, the solvent was evaporated away under reduced pressure to obtain 4-(methylsulfanyl)phenol (27.3 g) as a pale yellow solid. In a water bath, 30% hydrogen peroxide water (67 ml) was gradually and added dropwise to an acetic acid (130 ml) solution of 4-(methylsulfanyl)phenol (27.3 g). After the addition, this was gradually heated up to 100° C., and stirred for 1 hour. The reaction solution was restored to room temperature, and neutralized with saturated sodium bicarbonate water. This was extracted with ethyl acetate, and washed with saturated sodium bicarbonate water and saturated saline water. After dried, the solvent was evaporated away to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35](F)[CH:36]=5)[C:31]([CH3:39])=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:41][O-:42].[Na+].CO.O.C(Cl)(Cl)Cl>CO>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:42][CH3:41])[CH:36]=5)[C:31]([CH3:39])=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3cc4c(cn3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(F)cnc12
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2c(C)cc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 72 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 2.5 mL of methanol, 77 mg of a 28% sodium methoxide/methanol solution was added at room temperature, and the mixture was heated under reflux while stirring for 2 hours. After cooling to room temperature, water and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform to obtain 82 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Product: CC(C)(F)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1

Procedure:
3-Bromo-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine was coupled to 2,4-difluoro-3-(pyridin-3-yl)phenylboronic acid as described in Example 65 to afford 3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine as a white solid: δH (360 MHz, CDCl3) 1.80 (6H, d, J 22), 7.21-7.29 (2H, m), 7.46 (1H, dd, J 8 and 5), 7.50-7.57 (1H, m), 7.85 (1H, d, J 8), 7.92 (1H, s), 8.31 (1H, dd, J 7 and 3), 8.70 (1H, dd, J 5 and 1), 8.79 (1H, s); m/z (ES+) 369 (M++H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH:19][CH:18]=1
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 63.8 %

Procedure:
First, 5 g of 6-bromo-1-hexanol, 5.7 g of 2,3difluoro-4'-hydroxybiphenyl, 7.6 g of potassium carbonate, and 70 ml of methyl ethyl ketone were placed in a 100 ml flask. Then, the mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water, and an organic layer was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 5.4 g of 2,3-difluoro-4'-(6-hydroxyhexyl)oxybiphenyl (Y: 63.5%). The compound thus obtained had a purity of 99.9% by GC.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.C([Li])CCC.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)[CH:42]=O>CCOCC>[CH3:48][O:47][C:45]1[CH:44]=[C:41]([CH:42]=[CH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:40]=[C:39]([O:38][CH3:37])[CH:46]=1
Reactant: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C=CCCCOc2ccccc2)cc(OC)c1
Yield: 60 %

Procedure:
The triphenyl(4-phenoxybutyl)phosphonium bromide was converted to an ylide using n-butyllithium and refluxing with 3,5-dimethoxybenzaldehyde in ether for 3 hours gave 1-(3,5-dimethoxyphenyl)-5-phenoxy-1-pentene as a 2:1 mixture of E:Z isomers. Purification was by column chromatography and gave a 60% yield. Subsequently, hydrogenation of 1-(3,5-dimethyoxypheny)-5-phenoxy-1-pentene over palladium on carbon (10%) under 50 psi of hydrogen gas resulted in the quantitative reduction of the pentene carbon-carbon double bond in to yield 1-(3,5-dimethoxyphenyl)-5-phenoxy-1-pentane. This phenoxy-1-pentane was then contacted with boron tribromide in benzene for 72 hours at 25° C. to deprotect the methoxy groups of the compound and substitute the phenoxy moiety with bromide to form 5'-bromo olivetol. After purification, an 80% yield was achieved.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18]>>[OH:18][C@@H:17]([C:16]([CH3:20])([CH3:19])[CH3:15])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CC(C)(C)C=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@@H](O)C(C)(C)C

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with trimethylacetaldehyde. Rapid addition of the aldehyde to the enolate solution at 0° C. gave a 1:1 ratio of the (2R*,3S*) and (2R*,3R*) isomers. The desired isomer was isolated by silica gel chromatography, then crystallized. 1-NMR (CDCl3, 400 MHz): δ 8.05 (m, 1 H), 7.20–7.27 (m, 4 H), 4.24 (dq, J=7, 4 Hz, 1 H), 3.82 (br t, J=4 Hz, 1 H), 2.33 (br d, J=4 Hz, 1 H), 1.36 (d, J=7 Hz, 3 H), 0.99, (s, 9 H). 13C-NMR (CDCl3, 100 MHz): δ 175.3, 150.8, 142.2, 127.9, 125.4, 124.9, 116.2, 109.9, 77.6, 40.3, 35.8, 29.7, 26.7, 12.7.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[CH3:9][CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])[N:4]=1)[CH3:10]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 60-63° C.; 1H NMR (300 MHz, CDCl3) δ7.28-7.21 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06-6.98 (m, 2H), 6.92 (s, 1H), 6.50 (s, 1H), 6.26 (s, 1H), 5.15 (d, J=16.2 Hz, 1H), 4.95 (d, J=16.2 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H), 3.37-3.22 (m, 1H), 1.39 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ178.5, 177.2, 155.2, 150.2, 144.6, 142.1, 138.3, 132.2, 128.8, 123.7, 123.4, 121.1, 114.1, 111.6, 109.7, 99.4, 80.1, 64.5, 63.9, 58.1, 40.6, 33.3, 23.1; MS (ES+) m/z 434.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
A suspension of 100 g (0.52 moles) of 3-nitrocinnamic acid in 800 ml glacial acetic acid and 100 ml of methanol was hydrogenated at 50 pounds per square inch over 2.5 g 10% palladium on carbon until four equivalents of hydrogen were absorbed. The catalyst was filtered off, the filtrates combined and the solvent was concentrated in vacuo leaving a brown glass of 3-aminobenzenepropanoic acid. To this was added 1 liter of ethanolic hydrochloric acid which was brought to reflux for five hours. The solvent was evaporated off in vacuo leaving a purple solid. Recrystallization from ethyl acetate yielded 88.0 g of ethyl 3-aminobenzenepropanoate, hydrochloride, mp 132°-135° C., (74% yield).
Reaction SMILES: C(NCC([NH:10][C@H:11]([C:19]([NH:21][CH2:22][CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(=O)C(C)=C.NCCC1N=CNC=1>>[NH2:10][C@H:11]([C:19]([NH:21][CH2:22][CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1c[nH]cn1
Agent: NCCc1c[nH]cn1
Product: N[C@@H](Cc1ccccc1)C(=O)NCCc1c[nH]cn1
Reaction time: 1.33 h

Procedure:
N-(Phenylalanyl)histamine was prepared by the method described by H. Arold and L. Rietschel (Z. Chem. 1969, 9, 144) and used in the polymeranalogous reaction with the copolymer KoII described in Example 1. The copolymer (KoV) was obtained which contained 1.1% of N(N'-(methacryloyl)glycyl)-L-phenylalanylhistamine units. It was incubated with chymotrypsin by the method described in Example 1. The released histamine was determined according P. A. Shore, A. Burkhalter and V. H. Cohn, Jr. (J. Pharmacol. exp. theor. 127, 182, 1959). The initial concentration of the bonded histamine was 1×10-3M and the chymotrypsin concentration 0.5 mg/ml. The initial cleavage rate was constant for 80 minutes with the slope K = 1.2×10-6 mole min-1 mg-1. The limit cleavage was 28%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C@H:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20]([CH3:30])([CH3:29])[C:21]([NH:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[N:11]1)#N.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:40].[OH2:50]>>[S:25]1[CH:26]=[N:27][N:28]=[C:24]1[NH:23][C:21](=[O:22])[C:20]([CH3:30])([CH3:29])[C@H:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[C:1]([OH:40])=[O:50])[N:11]=[CH:12]2)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C(=O)Nc1nncs1)[C@@H](c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2C#N)c1
Product: CC(C)(C(=O)Nc1nncs1)[C@@H](c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2C(=O)O)c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A suspension of (3S)-3-(1-(2-cyano-4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide (35 mg, 0.072 mmol) and Na2O2 (77 mg, 1.1 mmol) in water (7 mL) was stirred under nitrogen at 70° C. for 30 min and at 90° C. for 1 day. The mixture was acidified with 10% aqueous citric acid solution to pH=2 and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate extracts were concentrated in vacuo. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 2-(5-((S)-3-(1,3,4-thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzoic acid; Example 157 (24 mg, 0.047 mmol, 64% yield) as a yellow solid. MS found: (M+H)+=516. 1H-NMR (500 MHz, METHANOL-d3) δ ppm 8.95 (s, 1H) 8.16 (s, 1H) 7.89 (s, 1H) 7.72 (dd, J=8.80, 3.02 Hz, 1H) 7.60 (dd, J=8.66, 4.81 Hz, 1H) 7.49 (td, J=8.25, 3.02 Hz, 1H) 7.39-7.43 (m, 3H) 7.15-7.27 (m, 4H) 4.82 (s, 1H) 1.46 (s, 3H) 1.44 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]([C:20]3[C:21](Cl)=[N:22][CH:23]=[CH:24][CH:25]=3)=O)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[NH2:28][NH2:29]>C(O)C>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:29][N:28]=3)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(c1cc(S(=O)(=O)NCCN2CCOCC2)c[nH]1)c1cccnc1Cl
Solvent: CCO
Solvent: O
Product: O=S(=O)(NCCN1CCOCC1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid (2-morpholin-4-yl-ethyl)-amide (100 mg) and hydrazine hydrate (excess) in ethanol (5 mL) was heated at 80° C. for 48 hours. The reaction was concentrated, diluted with water, acidified to pH 2 with 1N HCl and extracted with DCM. The aqueous layer was adjusted to pH 7 with NaHCO3, the precipitate was collected by vacuum filtration, washed with water to give the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]1[OH:56]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]1[OH:56])=[O:9]
Reactant: NC1CCCCC1O
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (75.0 g, 0.25 mol) was dissolved in DMF (850 mL). To the solution was added TBTU (91.0 g, 0.275 mol), N,N-diisopropylethyl amine (214 mL, 1.25 mol) and (1SR,2RS)-2-amino-cyclohexanol hydrochloride (41.7 g, 0.275 mol). The reaction mixture was stirred for 1.5 h at room temperature. The solvent was evaporated in vacuo, the residue was partitioned between ethyl acetate (2500 mL) and 1 N sodium hydroxide solution (2000 mL), the water phase was separated, extracted once more with ethyl acetate (1000 mL) and the organic phases were washed 2 times with water (2×1500 mL). Organic phases were pooled, dried with MgSO4 and concentrated to about 900 mL. The product precipitated upon stirring and cooling to 0° C. Filtration, washing with ethyl acetate/n-heptane (1:1) and drying in vacuo gave the title compound (81.1 g) as a white solid; MS (ISP) 397, 399 (M)+.