Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:21]1[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:39]C)[CH:35]=2)[CH2:30]1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.CO.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:20])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:10]=1)[C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:38][CH2:37][C:36]2[CH:35]=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=2[CH2:30]1)[CH3:2]
Reactant: CCN(Cc1ccc(N(C)CCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN(Cc1ccc(N(C)CCN2CCCCC2)cc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{4-[methyl(2-piperidin-1-ylethyl)amino]benzyl}amine (108 mg) in dichloromethane (5 ml) was added boron tribromide (1.0 M solution in dichloromethane) (1.0 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then methanol (2 ml) was added thereto on an ice bath. A saturated aqueous solution of sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The resulting residue was purified by NH silica gel column chromatography (chloroform-methanol system) to provide the title compound (58 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[F:17][C:18]([F:30])([F:29])[C:19]1[N:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([NH:24][NH:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[N:28][C:19]=1[C:18]([F:17])([F:29])[F:30])=[O:8]
Reactant: NNC(=O)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)NNC(=O)c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of 3,4-dimethoxy-5-nitrobenzoic acid (0.53 g, 2.34 mmol) and 1,1-carbonyldiimidazole (0.42 g, 2.59 mmol) was heated in tetrahydrofuran (10 mL) at reflux for three hours and then cooled to room temperature. 2-Trifluoromethyl-nicotinic acid hydrazide (0.53 g, 2.57 mmol) was added in one portion and the yellowish mixture was stirred at reflux overnight and then allowed to cool to room temperature. The mixture was poured onto cold water (100 mL) and the copious precipitate was filtered off, washed with water and dried to give 2-trifluoromethyl-nicotinic acid N′-(3,4-dimethoxy-5-nitro-benzoyl)-hydrazide (0.71 g, 73%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].I[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1ncc2ccc(C(=O)OC)cc21
Temperature: 60 °C

Procedure:
To a mixture of methyl 1H-indazole-6-carboxylate (0.95 g) in DMF (10 mL) was added 60% NaH (0.216 g). The mixture was heated to 60° C. and 1-iodobutane (0.61 mL) was added. The mixture was heated at 60° C. for 72 h and 1-iodobutane (0.61 mL) was added every 24 h. The mixture was removed from heat and cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 5% ethyl acetate in hexanes as eluent to give 0.356 g of the title compound: 1H NMR (CDCl3) δ 0.938, 1.34, 1.92, 3.97, 4.43, 7.73, 7.79, 8.03, 8.18.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccccc1F
Product: O=C(O)Cc1ccccc1Nc1ccccc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoroaniline to yield 2-[(2-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])([O:3]CC)=O.[OH:16][CH2:17][CH2:18][NH2:19]>>[OH:16][CH2:17][CH2:18][N:19]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:15])[C:8]=2[CH2:7][CH2:6][C:1]1=[O:3]
Reactant: CCOC(=O)CCC1C(=O)CCCC1=O
Reactant: NCCO
Product: O=C1CCCC2=C1CCC(=O)N2CCO

Procedure:
Prepared analogously to Example 27 from 2-(2-carbethoxy-ethyl)-cyclohexan-1,3-dione and 2-hydroxy-ethylamine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[CH2:12]([N:14]([CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:19])([F:20])[F:18])[C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])[CH3:13]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1F

Procedure:
Prepared similarly to Example 48 from 2,6-difluorobenzoyl chloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])/[CH:12]=[CH:13]\[C:14]([O:16]C)=[O:15])=[CH:5][CH:4]=1.[OH-].[K+].P([O-])([O-])([O-])=O.C(OCC)(=O)C>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)/C=C\C(=O)/C=C/c1ccc(OC)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(/C=C/C(=O)/C=C\C(=O)O)cc1
Reaction time: 1 h

Procedure:
A solution of 1.70 g (6.9 mmol) of methyl (2Z,5E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoate in 20 ml of ether was treated while cooling with ice and stirring vigorously within about 15 minutes with 20 ml of 5% potassium hydroxide solution. The reaction mixture was stirred at 4° for 1 hour and then treated with 15 ml of phosphate buffer (pH=6.5) and 30 ml of ethyl acetate, whereupon the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and evaporated. The solid residue was recrystallized from ethyl acetate/hexane and there was obtained (2Z,5E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoic acid as an orange colored powder of melting point 103.5°-104°.
Reaction SMILES: O[NH:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[S:8]\1.[H][H].O>C(O)(=O)C.[Pt](=O)=O>[NH2:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[S:8]\1
Reactant: [H][H]
Reactant: O=C1/C(=C(\NO)c2ccccc2)Sc2ccccc21
Agent: O=[Pt]=O
Solvent: O
Solvent: CC(=O)O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1

Procedure:
0.5 gm (0.00186 mol) of (E)-2-[(hydroxyamino) phenylmethylene]-benzo[b]thiophen-3(2H)-one, dissolved in 10 cc of glacial acetic acid, was catalytically hydrogenated for 21/2 hours at a hydrogen pressure of 5 bar in the presence of 0.2 gm of platinum(IV) oxide. At the end of the hydrogen uptake, the catalyst-free solution was stirred into 100 cc of water, exhaustively extracted with ether, the combined ether extracts are successively washed with water, saturated aqueous sodium bicarbonate solution and then again with water, followed by drying over sodium sulfate. The crystalline residue left behind after expelling the solvent was recrystallized twice in the presence of activated carbon from a mixture of petroleum ether and ethyl acetate (2:1). 0.37 gm (79% of theory) of egg-yellow crystals, m.p. 121°-122° C., were obtained which, on the basis of the thin-layer chromatogram, mixed melting point and IR spectrum, were found to be identical to the product obtained according to Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of 2-amino-5-bromonicotinic acid (2.0 g, 9.20 mmol), HOBT (1.40 g, 11.2 mmol), EDCI (3.52 g, 18.4 mmol), Et3N (4.68 g, 46.0 mmol) and NH4Cl (2.48 g, 46.0 mmol) in DMF (100 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, suspended in water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the product of 2-amino-5-bromonicotinamide (1.80 g, yield: 80%), which was used for the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 8.14 (dd, J=4.4 Hz, 2.4 Hz, 2H), 8.04 (s, 1H), 7.46 (s, 1H), 7.37 (s, 2H). MS (M+H)+: 216/218.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]#[N:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].C([Li])CCC.C[Si]([CH:51]=[N+:52]=[N-:53])(C)C>C1COCC1.CCCCCC.[Cl-].[NH4+]>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40]4[N:41]=[N:53][NH:52][CH:51]=4)[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:4])[CH3:5])[N:7]=[CH:8]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)C(O)(c1ccc2cc(C#N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(-c3c[nH]nn3)ccc2c1)c1c[nH]cn1
Reaction time: 0.33 h

Procedure:
To an solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthonitrile in THF (15 mL) was added a solution of n-butyllithium in hexane (1.6M:2.57 mL) under ice cooling, and the mixture was stirred for 20 min. A solution of trimethylsilyldiazomethane in THF (10% wt.:6.0 g) was added dropwise to the mixture and stirred for 90 min under ice cooling. The reaction mixture was diluted with saturated aq. ammonium chloride and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=1:1) and crystallized from ethyl acetate-hexane (1:1) to give the titled compound (881 mg) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12](O)=[O:13])([O-:3])=[O:2].C([N:25](CC)CC)C.ClC(OCC)=O.N>C(Cl)Cl>[N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12]([NH2:25])=[O:13])([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(N)=O
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
In 100 ml of methylene chloride were dissolved 6.15 g of 2-[3-(2-nitrophenoxy)phenoxy]propionic acid and 4.2 g of triethylamine, followed by dropwise addition of 2.5 g of ethyl chloroformate at a temperature not exceeding 0° C., and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was poured into previously ice-cooled methylene chloride (120 ml) saturated with ammonia gas and the mixture was then stirred at room temperature for 30 minutes. The methylene chloride layer was washed with water (twice), dried and concentrated and the residue was crystallized from methanol and isopropyl ether to give 3.3 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:44]4[CH2:45][CH2:46][CH:41]([O:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)[CH2:42][CH2:43]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: c1cc(OC2CCNCC2)ccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(Oc5ccncc5)CC4)c3)n2)n1
Yield: 50.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with 4-(piperidin-4-yloxy)-pyridine [CAS-no. 224178-65-8] (0.365 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 50%) as a white foam. MS (ISP) 631.3 [(M+H)+].
Reaction SMILES: [Si]([O:8][CH2:9][C@@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@]1(C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@]1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
The compound (110 mg, 0.23 mmol) obtained in Example 3-3) was dissolved in methanol (3 mL). A 4 M solution (0.54 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (20 mL) and methanol (1 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (89 mg, 43%) in a white solid form.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[CH:16][C:17](N)=[N:18][CH:19]=1.[OH-:21].[Na+]>S(=O)(=O)(O)O.CCO>[F:5][C:6]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[CH:16][C:17]([OH:21])=[N:18][CH:19]=1
Reactant: CSc1ccc(-c2cnc(N)cn2)c(F)c1
Reactant: [OH-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Sodium nitrite (1.73 g, 25.1 mmol) was added portionwise to concentrated sulfuric acid (20 mL) at 0° C. The mixture was stirred at 45° C. until homogeneous, cooled to 0° C., and charged with a solution of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinamine (4.37 g, 18.6 mmol) in concentrated sulfuric acid (55 mL) at 0° C. The reaction was allowed to warm to 25° C., stirred for 15 min, then at 45° C. for 1 h. The reaction was poured onto ice and the pH was adjusted to ˜4 with 10N NaOH. The resulting tan precipitate was filtered, washed with water, and air-dried to afford a tan solid. The solid was refluxed in EtOH (300 mL), hot-filtered, and the filtrate concentrated to afford 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (3.16 g, 72% yield, purity=87%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ8.14 (d, 1H, J=1.2 Hz), 7.72-7.86 (m, 2H), 7.24-7.15 (m, 2H), 2.52 (s LRMS (ESI), m/z 237 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:18][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:17])=[O:5]
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C(C)(C)CCl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2,2-dimethylpropionyl chloride (7.0 g) in dichloromethane (50 ml) was added dropwise to a stirred solution of 1-(4-chlorophenyl)ethylamine (7.0 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) at 0°-5° C. under nitrogen. After the addition, the mixture was stirred at 0° C. for 0.5 hours and then stirred at ambient temperature for 2 hours. The mixture was washed with 5M hydrochloric acid and then with water. The mixture was dried and evaporated. The residue was recrystallised from petroleum ether (b.p. 60°-80° C.) to give 3-chloro-N-[1-(4-chlorophenyl)ethyl]-2,2-dimethylpropionamide, m.p. 95°-96° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[C:22]([O-])(O)=[O:23].[Na+]>CO.CCOC(C)=O>[CH3:22][O:23][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cncc(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (2 g, 7.6 mmol) in MeOH (26 mL) was added a solution of NaOMe (1.3 g, 23 mmol) in MeOH (40 mL). The mixture was heated at reflux for 24 hr. Additional NaOMe (1.3 g) was added. Continue heating at reflux for 24 hr, and then add additional NaOMe (1.3 g). Continue heating at reflux for 24 hr and cool to rt. Dilute with EtOAc and was with sat. aq. NaHCO3. The solids were removed by filtration. Separate phases and wash organic extract with additional sat. aq. NaHCO3. Dry organic extracts over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 25% ethyl acetate/hexanes) to afford 1.4 g (71%) of (1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as an oil: 1H NMR (CDCl3) δ 3.04-3.08, 3.23-3.29, 3.91, 4.75-4.78, 5.18, 5.42-5.45, 7.25-7.34, 7.57-7.61; MS (ESI+) for C14H15N3O2 m/z 258 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1O
Yield: 80 %

Procedure:
A solution of 15 gm (0.1 mole) of 2-hydroxyphenylacetic acid in 500 ml methanol and 2 ml concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was heated to reflux for 72 hours, and the sieves were exchanged at 24-hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3×100 ml portions of water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 13 gm (80% yield) of a yellow oil. The NMR spectrum was consistent with the assigned structure and this material was used in the next reaction step.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][NH:17][NH2:18]>C(O)C>[NH2:10][C:6]1[NH:18][N:17]([CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cccc(Cl)c1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(Cl)c2)[nH]1
Yield: 42 %

Procedure:
35 g (10% excess) of β-amino-β-ethoxyacrylic acid ethyl ester are introduced into 100 ml of ethanol. 32 g of 3-chlorobenzylhydrazine in 50 ml of ethanol are added while stirring. The mixture is worked up as above. 18.9 g of the compound identified above, as colorless felted needles of melting point 132°, are obtained. (Yield: 42% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>ClCCl>[C:30]([CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)=[O:34])#[N:31]
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1

Procedure:
Using the method for the preparation of the side chain acid in Example 1, 9.2 g (40 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 16.8 ml (120 mmol) of triethylamine, 16 ml (126 mmol) of chlorotrimethylsilane, 400 ml of dichloromethane, and 5.0 (45 mmol) of cyanoacetyl chloride [Org. Syn. Col. Vol. V, p. 171] gives 12.3 g of 2-[4-(cyanoacetylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid as the monohydrate; mp>280°.