Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC(C)C)(C)C.[F:54][C:55]1[C:60](O)=[C:59]([F:62])[C:58]([F:63])=[C:57]([F:64])[C:56]=1[F:65].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27]([O:29][C:60]1[C:55]([F:54])=[C:56]([F:65])[C:57]([F:64])=[C:58]([F:63])[C:59]=1[F:62])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1.5 g (2.27 mmol) of Fmoc-Gln(Trt)-OH×0.5 diisopropyl ether and 0.46 g (2.5 mmol) of pentafluoro-phenol are dissolved in 35 ml of ethyl acetate, cooled to 0° and, while stirring, 0.52 g (2.5 mmol) of dicyclohexylcarbodiimide is added. The mixture is stirred at 0° for 1 hour and at room temperature for 3 hours, and insoluble material is filtered off and washed with tetrahydrofuran. The filtrate is evaporated to dryness, and the residue is dissolved in 30 ml of tetrahydrofuran. Slow addition of petroleum ether while stirring results in crystallization of Fmoc-Gln(Trt)-OPfp; m.p. 185°-187°, [α]D20 =-16.4° (THF).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)C.C(=O)=O.C([N-]C(C)C)(C)C.[Li+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:38])([F:37])[F:36])[C:29]#[N:30]>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]2[N:30]=[C:4]([OH:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH:1]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:37])([F:38])[F:36]
Reactant: Cc1ncccc1C(=O)O
Reactant: N#Cc1ccc(OC(F)(F)F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1nc(-c2ccc(OC(F)(F)F)c(F)c2)cc2ncccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
300 mg 2-methyl-nicotinic acid was suspended in 10 mL of tetrahydrofuran, and cooled to −70° C. with a bath of ethanol/dry ice. 3.3 mL lithium diisopropylamide (2.0 M in tetrahydrofuran/n-heptane/ethylbenzene) was added dropwise over 10 min and the mixture was stirred for 1.5 h at 0° C. After this time, it was cooled again to -70° C. and 0.9 g 3-fluoro-4-trifluoromethoxy-benzonitrile (4.1) was added quickly. Then the reaction mixture was stirred for 2 h at −70° C. and then warmed overnight to ambient temperature. The solvent was distilled off, diluted with ethyl acetate, 10 mL phosphate buffer and 5 mL 2N aqueous hydrochloric acid solution (pH 6-7). The formed precipitate was collected and dried. The resulting liquid phase was separated and the water phase extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate, concentrated and the residue suspended in ether and ethyl acetate. The precipitate was collected, dried and combined with the first precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:22]=2[F:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc(F)cc1F
Product: O=C(Nc1ccc(F)cc1F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2,4-difluoroaniline (50 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 47% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.53 (1H, s), 8.99 (2H, s), 8.68 (1H, m), 7.54 (1H, m), 7.40 (1H, m), 7.12 (1H, m). MS m/z: 460.05, 462.03 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:39][CH3:40])[C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:26]=2)[CH2:21][C@H:20]1[C:36](O)=[O:37])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[F:42][C:43]([F:47])([F:46])[CH2:44][NH:45][C:36]([CH:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[N:19]1[C:17](=[O:18])[C@@H:16]([NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:39][CH3:40])=[O:37]
Reactant: NCC(F)(F)F
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2C[C@H]1C(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C

Procedure:
Triethylamine (4.9 mL, 33 mmol) was added to the solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(S)-carboxylic acid (2.6 g, 5.72 mmol) and 2,2,2-trifluoroethylamine hydrochloride (1.55 g, 11.4 mmol) in dried dichloromethane (50 mL) at 0° C. under nitrogen, followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.902 g, 11.4 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for twenty-four hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was purified by column chromatography (silica gel, 8:2 diethyl ether: petroleum spirit) to provide a white solid as the desired product.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([Br:3])=[CH:5][CH:6]=1
Reactant: CN
Reactant: O=Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
800 ml of an 8% solution of methylamine in toluene are added, whilst cooling with ice, to 100 g of 4-bromobenzaldehyde and 300 g of molecular sieve (3 Angstroms). The mixture is stirred overnight at ambient temperature, suction filtered to remove the molecular sieve and the solvent is evaporated off. The residue is dissolved in 1.4 litres of ice cold methanol and 48 g of sodium borohydride are added in batches whilst cooling with ice. Then the mixture is stirred for 30 minutes at 0° C., for one hour at 10° C. and for two hours at ambient temperature, then evaporated to dryness, the residue is taken up in ice water, acidified with half concentrated hydrochloric acid and extracted twice with ether. The ether is discarded, the aqueous phase is made alkaline with concentrated sodium hydroxide solution whilst cooling and then extracted three times with ether. The organic phase is washed with water and saturated saline solution, dried and evaporated down. 96.8 g of N-methyl-4-bromobenzylamine are obtained in the form of a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11](Cl)=[O:12].Cl>ClCCl.C(N(CC)CC)C>[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromoaniline (1.73 g) in dichloromethane (40 ml), triethylamine (2.8 ml) and a solution of 2,4-dibromobutyryl chloride (3.2 g) in dichloromethane (10 ml) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After addition of 1 N hydrochloric acid to the reaction solution, the mixture was separated into two layers. The aqueous layer was subjected to extraction with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound, which was used in the next reaction without being purified.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-2,6-dimethoxypyridine gave 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.57 (d, 1H, J=8.7 Hz), 8.02 (d, 1H, J=2.7 Hz), 6.40 (d, 1H, J=8.1 Hz), 4.03 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3): −344640; LCMS: purity: 90%; MS (m/e): 285 (M+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[C:10]([F:20])=[C:11]([C:16]([F:19])=[CH:17][CH:18]=2)[C:12](=[N:14][OH:15])[NH2:13])[S:5][CH:6]=1.[CH3:21][O:22][C:23]1[S:24][C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:26][N:27]=1.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:10]1[C:9]([O:8][CH2:7][C:4]2[S:5][CH:6]=[C:2]([C:25]3[S:24][C:23]([O:22][CH3:21])=[N:27][CH:26]=3)[N:3]=2)=[CH:18][CH:17]=[C:16]([F:19])[C:11]=1[C:12](=[N:14][OH:15])[NH2:13]
Reactant: NC(=NO)c1c(F)ccc(OCc2nc(Br)cs2)c1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(OC)s1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(-c2csc(COc3ccc(F)c(C(N)=NO)c3F)n2)s1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
To a solution of 3-((4-bronnothiazol-2-yl)methoxy)-2,6-difluoro-N′-hydroxy benzimidamide (0.20 g, 0.55 mmol) in DMF (4.0 ml) was added 2-methoxy-5-(tributylstannyl)thiazole (0.23 g, 0.55 mmol) and the resulting reaction mixture was purged with nitrogen for 15 min. Tetrakis(triphenylphosphine) palladium (0) (0.06 g, 0.05 mmol) was then added and the reaction mixture was heated at 100° C. for 3 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (60-120 M, 35% EtOAc-Hexane) yielding the title compound as white solid (0.06 g, 27%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7].S(O)(O)(=O)=O.CS[C:32](=[NH:34])[NH2:33].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:1]([CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7])[C:32]([NH2:34])=[NH:33]
Reactant: NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: N=C(N)NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Yield: 85.9 %

Procedure:
In 30 ml of a 60% methanol/water solution (volume ratio) was dissolved 2 g of N-(3-amino-2-phenylpropyl)-5-isoquinolinesulfonamide obtained Referential example 2, 2.05 g of S-methylisothiourea sulfate and 1.67 g of potassium carbonate, and the mixed solution was heated at reflux for two hours. After the reflux, the methanol was distilled therefrom under reduced pressure and the white crystalline residue the obtained was separated by filtration under reduced pressure. The residue was recrystallized from methanol to give 1.93 g of N-(3-guanidino-2-phenylpropyl)-5-isoquinolinesulfonamide, i.e., Compound (31) in a yield of 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:9]1[N:10]=[C:11]([NH2:13])[S:12][C:8]=1[CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:21]=1[S:28]([NH:13][C:11]1[S:12][C:8]2[CH2:7][CH2:6][C:5]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[N:10]=1)(=[O:30])=[O:29]
Reactant: COc1cc2c(cc1OC)-c1nc(N)sc1CC2
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: COc1cc2c(cc1OC)-c1nc(NS(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)sc1CC2

Procedure:
The title compound was prepared from 7,8-dimethoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 6,7-dimethoxytetralone) and 2,4,6-trichlorobenzenesulfonyl chloride (213 mg) as described in the synthetic METHOD A to give a yellow powder (6.5 mg) with a purity of 86%: MS-ES (neg) m/z 505.1
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].CC(O)=O.CN.Cl.[BH3-][C:17]#[N:18].[Na+]>CO>[CH3:17][NH:18][CH:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:8])[CH2:3]1
Reactant: [BH3-]C#N
Reactant: O=C1CCNC(=O)C1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCNC(=O)C1
Reaction time: 2 h
Yield: 81 %

Procedure:
Piperidine-2,4-dione (2.0 g, 25.126 mmol, 1.0 eq.) was dissolved in MeOH (20 ml); AcOH (0.1 ml) and CH3NH2.HCl (2.37 g, 35.398 mmol, 2.0 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.29 g, 53.097 mmol, 3.0 eq.) was added in portions at 0° C. and the mixture was stirred for 14 hours at RT. After monitoring by TLC, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was used in the next stage without being purified further. Yield: 81% (1.814 g, 14.173 mmol)
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccco1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccco2)N1
Yield: 78.6 %

Procedure:
A solution of hydantoin (10 g), fused sodium acetate (20 g), and freshly distilled furfural (12 g) in acetic acid (40 ml) was heated under reflux for 11/4 hours. The dark solution was poured into cold water (400 ml) to precipitate the dark green/yellow product, which was washed with water until neutral and then with cold ethanol to give 14 g (80% theoretical yield) of 5-furfurylidenehydantoin m.p. 232°-5° (decomp.) (H. L. Wheeler and C. Hoffman, Amer. Chem. J., 1911, 45, 368, quote m.p. 232°.) The material was used without further purification.
Reaction SMILES: CO[CH2:3][N:4]1[C:8]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:7][C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:5]1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](CCl)[CH:34]=1>CN(C=O)C>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:3][N:4]2[C:8]([C:9]3[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=3)=[CH:7][C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:5]2)[CH:34]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(COC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(Cc2cccnc2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 1-methoxymethyl-5-(3,4,5-trimethoxyphenyl)-pyrazole-3-carboxylate (820 mg) was dissolved in DMF (4 mL), and to the solution potassium carbonate (325 mg) and 3-picolyl chloride hydrochloride (193 mg) were added, and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the diluted residue, the resultant residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2 to 0:1) to obtain the title compound.
Reaction SMILES: [Br:1]Br.[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[Br:1][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[F:18])[CH:13]=[O:14])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Solvent: ClCCl
Product: O=Cc1ccc(F)c(Oc2ccc(Br)cc2)c1
Reaction time: 1 h

Procedure:
A solution of bromine (9.60 g, 0.06 mmole) in methylene chloride (10 ml) was added dropwise to a solution of 3-phenoxy-4-fluorobenzaldehyde (10.8 g, 0.05 mmole) in methylene chloride (40 ml) at 20° C. taking a period of 1 hour with stirring. After the addition was finished, the reaction was continued for further 3 hours at the same temperature. The resulting solution was washed with water and then dilute aqueous potassium sulfite solution to remove the remaining bromine in the organic layer. The organic layer obtained was washed with a dilute aqueous sodium carbonate solution and then a dilute aqueous sodium chloride solution, and dried over anhydrous sodium sulfate and concentrated.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O>[F:14][C:13]([F:15])([F:16])[C:9]1[CH:8]=[C:7]([NH:6][CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: C=CC(=O)O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Water (150 mL) and acrylic acid (48 g) were added to 3-aminobenzotrifluoride (75 g). The reaction mixture was stirred at 100° C. for one hour. The solution was cooled to room temperature. The pH of the solution was then adjusted to 10 with a 1 N aqueous sodium hydroxide solution. The solution was washed with diethyl ether, and the pH of the solution was then adjusted to 3 with 1 N hydrochloric acid. The solution was extracted with diethyl ether. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=2:1). The title compound (82 g) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:5]([O:7]C)=[O:6].C(=O)([O-])[O-:15].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]([OH:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(CC(C)C)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(O)(CC(C)C)C(=O)O
Reaction time: 24 h
Yield: 73.6 %

Procedure:
Air was bubbled for 1 hour at room temperature through a suspension of 0.5 g (3 mmol) dimethyl-(2-methylpropyl)malonate and 1.73 g (5 mmol) cesium carbonate in 7 ml dimethylformamide. Stirring was continued at room temperature for 24 hours. 25 ml water was added and the mixture was extracted with diethylether. Acidification with aqueous 1 N hydrochloric acid to pH=1 and extraction with ethylacetate yielded 0.42 g (83%) (R/S)-2-hydroxy-2-isobutyl-malonic acid monomethyl ester, MS (m/e): 189.4 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:34]3=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]3[CH:32]=[N:31]2)[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:24]4[CH2:29][CH2:28][CH:27]([N:30]5[C:34]6=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]6[CH:32]=[N:31]5)[CH2:26][CH2:25]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CC1
Yield: 41.9 %

Procedure:
300 mg (1 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde and 306 mg (1.20 mmol) 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine were reacted for four days (additional NaBH(OAc)3 has been added after four, six, eight, 24 and 28 hours (two equivalents each)) at room temperature and purified as previously described. 210 mg of the desired compound were obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 2.2 g of 4-(4-acetamidophenylmercapto)-3-benzylamino-5-sulfamoylbenzoic acid and 22 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. After cooling it is filtered, the filtrate acidified with glacial acetic acid to pH = 4. The precipitate formed is filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-benzylamino-5-sulfamoylbenzoic acid melting at 254°-256°.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=4[F:37])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[F:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([F:37])[C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4c(F)cccc4F)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3c(F)cccc3F)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-(4-{2-[2-(2′, 6′-difluoro-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1 N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the product as a solid. 1H NMR (400 MHz, CDCl3) δ8.05 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.34-7.28 (m, 1H), 7.02-6.98 (m, 2H), 6.91-6.78 (m, 4H), 4.17 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.39 (s, 3H), 1.53 (s, 6H); MS (EI) 494.5 (M+H)+.