Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].O.NN>C(O)COCCOCCO>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH3:10])=[CH:3][C:2]=1[NH2:1]
Reactant: CC(=O)c1ccc(F)c(N)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCc1ccc(F)c(N)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a stirred mixture of 3'-amino-4'-fluoroacetophenone (7.56 g, 49.4 mmol) in triethylene glycol (60 mL) was added 4.94 g of sodium hydroxide. Neat hydrazine hydrate (7.2 mL) was added to the mixture in one portion via a syringe. This addition resulted in a slight exotherm (temperature around 50°). The reaction flask (three neck, equipped with claisen adapter and receiving flask) was then equipped with a heating mantle and the reaction heated to 100° C. for 1 hour, then 150° C. At the higher temperature distillate began to collect in the receiving flask. After 1 hour at 150° C. the reaction mixture was then heated to 180° C., while still collecting distillate. After 45 minutes at 180° C. thin layer chromatography indicated the complete absence of starting material and the appearance of a single major product. The reaction mixture was cooled to room temperature with an ice bath and poured into 100 mL of water. The aqueous mixture was extracted three times with ether (125 mL). The combined organic extracts were washed once with water, once with brine and then dried over potassium carbonate. Concentration of the organic extracts in vacuo afforded 2-fluoro-5-ethylaniline (6.82 g) as an amber liquid. This material was further purified by column chromatography (silica gel, hexanes/ethyl acetate: 2/1) to give 7.11 grams of product as a viscous liquid.
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:21]([CH2:23][C:24]([NH2:26])=[O:25])#[N:22].CO.[H-].[Na+]>CN(C=O)C>[OH:25][C:24]1[N:26]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][C:23]=1[C:21]#[N:22]
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(/C(=C\N(C)C)C(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C#N)c(O)nc2-c2ccccc2)cc1
Temperature: 95 °C

Procedure:
A solution of (E)-3-(dimethylamino)-1-phenyl-2-p-tolylprop-2-en-1-one (Compound 113, 500 mg, 1.9 mmol), cyanoacetamide (175 mg, 2.1 mmol) and MeOH (0.2 ml, 2.2 mmol) in DMF (4 ml) was cannulated into a suspension of NaH (119 mg, 4.7 mmol, 95% in mineral oil) in DMF (2 ml) at room temperature. After the addition was completed, the reaction was heated to 95° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, concentrated in vacuo. The solid residue was triturated with diethyl ether, filtered and dried under high vacuum to yield the title compound as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:24])[C:22]=3[CH3:23])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:24])[C:22]=3[CH3:23])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cnn1C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cnn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of N-tert-butyl-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 98.3 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (224 mg, 152 μL, 1.97 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1.5 mL), methanol (0.75 mL) and ammonium hydroxide (0.2 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated then purified by chromatography (silica, 10-45% of a 1:4 methanol:dichloromethane solution in dichloromethane) to give N-tert-butyl-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 55.0 μmol, 56%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.10 (s, 1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.86 (s, 1H), 7.85 (d, J=3.3, 1 H), 3.71 (s, 3H), 2.16 (s, 3H), 1.30 (s, 9H); MS (EI/CI) m/z: 328.2 [M+H].
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].[CH2:24]([N:31]1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)[C:25]1C=CC=[CH:27][CH:26]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.CCCCCCC>[O:21]=[C:18]1[NH:31][CH:24]=[C:25]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:26]=[CH:27]1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 90 °C
Yield: 94.9 %

Procedure:
IMS (50 mL) and water (16 mL) were degassed thoroughly. tert-Butyl 4-bromophenethylcarbamate (3.52 g, 11.7 mmol), sodium carbonate (5.0 g, 46.9 mmol), palladium tetrakis (1.35 g, 1.2 mmol) and 1-benzyl-1H-pyrazole-4-boronic acid pinacol ester (5.0 g, 17.6 mmol) were added and the reaction mixture heated to 90° C. overnight. The reaction was partitioned between ethyl acetate (500 mL) and water (250 mL) and brine (250 mL), then dried (MgSO4). Filtration and removal of the solvent gave the crude residue which was subject to column chromatography (50% ethyl acetate/heptane) to give tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (4.2 g, 11.1 mmol, 95% yield).
Reaction SMILES: [CH:1](OCC)=O.[C:6](#[N:11])[CH2:7][CH2:8][C:9]#[N:10].C[O-].[Na+].[F:15][C:16]([F:22])([F:21])[C:17]([CH3:20])([NH2:19])[CH3:18].C(O)(=O)C>C1(C)C=CC=CC=1>[F:15][C:16]([F:22])([F:21])[C:17]([NH:19][CH:1]=[C:8]([CH2:7][C:6]#[N:11])[C:9]#[N:10])([CH3:20])[CH3:18]
Reactant: N#CCCC#N
Reactant: CCOC=O
Reactant: CC(C)(N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(NC=C(C#N)CC#N)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl formate (330 mg, 4.46 mmol) and succinonitrile (300 mg, 3.75 mmol) in toluene (1561 μl) was added dropwise to a suspension of sodium methanolate (215 mg, 3.97 mmol) in toluene (1561 μl) at 0° C. After being stirred at RT for 3 h, the reaction mixture was treated with 1,1,1-trifluoro-2-methylpropan-2-amine (486 mg, 3.82 mmol) and acetic acid (255 μl, 4.46 mmol) then heated at 120° C. for 3 h. After being cooled to RT, the reaction mixture was washed with brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a brown oil, which was used without further purification.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=O)=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>C(#N)C.N12CCCN=C1CCCCC2>[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=[CH:9][C:8]4[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=4[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)c1ccccc1C=Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Yield: 65 %

Procedure:
To a solution of 2-ethoxycarbonylbenzyltriphenylphosphonium bromide (605 mg) and 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (285 mg) in acetonitrile (5.00 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.317 ml) was added. The resulting solution was heated under reflux for 10 hours. After concentration under reduced pressure, diisopropyl ether was added to the residue. The resulting insoluble material was removed by filtration. After concentration of filtrate under reduced pressure, n-heptane was added to the residue. The resulting insoluble material removed again by filtration. After concentration of filtrate, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-[5-{2-(2-ethoxycarbonylphenyl)ethenyl}benzofuran-2-yl]thiazole (280 mg) as a mixture of E and Z isomer as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:26]3[C:22](=[O:32])[C:23]4[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:25]3=[O:27])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C

Procedure:
4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (4.0 g, 11.5 mmol) and potassium phthalimide were combined and dissolved in DMF (30 mL), and the mixture was heated at 50° C. for two days. The mixture was then cooled to room temperature and the reaction quenched with water (30 mL). The mixture was then extracted with EtOAc, and washed with a 10% aqueous lithium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated to obtain intermediate (22a) (4.8 g). MS m/z: [M+H+] calcd for C26H23NO4, 414.5; found 414.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:21]1([C:27]2[N:32]=[N:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]1[N:31]3[N:32]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:28]=[CH:29][C:30]3=[N:33][N:34]=1)=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cl
Product: COc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (148 mg) and 1-(6-phenylpyridazin-3-yl)hydrazine (126 mg) in HCl (conc., 0.3 mL) was heated at 100° C. for 5 min and was subject to microwave heating (180° C., 15 min) The yellow sludge was quenched with NaOH (5N, 1 mL). The pink mixture was filtered and washed with NaOH (1 N, 1 mL), H2O (2 mL). The solid was suspended in DMF (2 mL)-DCM (2 mL). MeI (0.2 mL) was added followed by the addition of NaOH (2N, 1 mL). After 2 h, the mixture was partitioned between DCM (10 mL) and aqueous Na2SO3 (5 mL). The organic was dried over MgSO4, concentrated, and purified in silica (1-15% MeOH in DCM) to give the product as a yellow powder.
Reaction SMILES: [C:1]1(N2C(S(CCC)(=O)=O)=NN=N2)[CH:6]=CC=C[CH:2]=1.[K].C[Si](C)(C)N[Si](C)(C)C.[CH:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1)=O.O>COCCOC>[CH:28](/[C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1)=[CH:2]\[CH2:1][CH3:6]
Reactant: CCCS(=O)(=O)c1nnnn1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: COCCOC
Solvent: O
Product: CC/C=C/[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-phenyl-5-propylsulfonyl-1H-tetrazole (3.34 g) and anhydrous ethylene glycol dimethyl ether (60 ml) at −60° C. was added 0.5 M hexamethyldisilazane potassium solution (in toluene, 26.6 ml), and the mixture was stirred for 30 minutes. Under the same condition, a solution of t-butyl trans-4-formylcyclohexylcarbamate (3.02 g) in anhydrous ethylene glycol dimethyl ether (15 ml) was added thereto and the reaction mixture was gradually warmed to 25° C. and stirred overnight. To the reaction mixture was added water, and the mixture was stirred for 1 hour, then extracted with diethyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.31 g of t-butyl trans-4-[(E)-1-butenyl]cyclohexyl-carbamate.
Reaction SMILES: [OH-:1].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#N)=[CH:27][CH:26]=3)[C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:15])[CH2:10]2.C[OH:34]>>[CH:3]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([OH:34])=[O:1])=[CH:29][CH:30]=3)[C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:15])[CH2:12]2
Reactant: N#Cc1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(F)(F)F)cc1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: O=C(O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(F)(F)F)cc1
Temperature: 65 °C
Reaction time: 45 h
Yield: 93 %

Procedure:
A solution of Sodium hydroxide (1.056 mL, 2.11 mmol) was added in one portion to a stirred solution of N-adamantan-2-yl-1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Intermediate#124) (250 mg, 0.60 mmol), in methanol (10 mL) under air. The resulting solution was stirred at 65° C. for 45 hours. The resulting mixture was evaporated to dryness and the residue dissolved in ice/water (25 mL) and the mixture was acidified with 2M HCl. The precipitate was collected by filtration, washed with water (25 mL) and dried under vacuum to afford 4-[4-(adamantan-2-ylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzoic acid (243 mg, 93%) as a white solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][CH2:17]2)=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29].C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[C:4]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[S:5][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)s2)CN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)c(-c3cccc(Cl)c3)s2)CN1
Temperature: 150 °C

Procedure:
Under argon, 70.0 mg of the compound from Example 24A having a purity of 76% (0.14 mmol) and 47.5 mg (0.27 mmol) of 3-chloro-4-fluorophenylboronic acid are provided in 2.6 ml of 1,2-dimethoxyethane, and 1.0 ml (0.91 mmol) of an aqueous sodium bicarbonate solution (10%) and 6.3 mg (0.005 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated in a closed glass vessel at 150° C. under microwave irradiation for 5 minutes. The reaction mixture is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient with addition of 0.1% formic acid) and additional preparative thin-layer chromatography (silica gel; mobile phase: ethyl acetate). 8.0 mg (13% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][NH:8][CH2:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>CO>[OH:5][CH2:4][CH2:3][CH2:2][C:1]([N:8]([CH2:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11])[CH3:7])=[O:6]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCO1
Solvent: CO
Product: CN(C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)C(=O)CCCO

Procedure:
500 ml (565 g, 6.56 mol) of gamma-butyrolactone are placed in 2.0 l of methanol. 1.28 kg (6.56 mol) of methylglucamine are added to the solution obtained. The mixture is then refluxed for 16 hours. The solution obtained is evaporated to dryness. The colourless syrup so initially obtained crystallises into a white solid after a few days at room temperature. (Melting point 78°-79° C.)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][C:7]2([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)[CH3:12].C([Li])(C)(C)C.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1.CCCCC>[NH:14]1[CH2:15][CH2:16][N:17]=[C:13]1[C:7]1([CH3:12])[C:8]2[C:3](=[C:2]([CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][O:6]1
Reactant: CC1(C2=NCCN2)OCCc2c(Br)cccc21
Reactant: CC(C)(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C2=NCCN2)OCCc2c(C(O)C(C)(C)C)cccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(5-bromo-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (Example 2, 0.075 g) in 2 ml of THF was added 0.33 ml of tert-butyl lithium solution in pentane (1.7M) at −78° C. followed by addition of 1.2 ml of 20.8M solution of trimethylacetaldehyde in THF. After stirring at −78° C. for 15 min, the reaction was quenched with ice. The title compound was isolated with separation methods A and G. (Yield 0.003 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[CH3:15][S:16]([CH3:18])=O.[OH-:19].[K+]>C(=S)=S>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][C:15](=[S:16])[NH:1][CH2:2]2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12].[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[S:16][C:18](=[O:19])[NH:1][CH2:2]2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: [OH-]
Reactant: CS(C)=O
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: [K+]
Solvent: S=C=S
Product: COc1ccc(C2CNC(=O)S2)cc1OC
Product: COc1ccc(C2CNC(=S)O2)cc1OC
Reaction time: 2.5 h
Yield: 6 %
Yield: 9 %

Procedure:
45 mmol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol is dissolved in 65 ml. of absolute dimethyl sulfoxide and combined in succession with 1.8 g. of pulverized potassium hydroxide and 1.4 ml. of carbon disulfide at 10°. The reaction mixture is then stirred under the exclusion of moisture for 2.5 hours. After withdrawing the dimethyl sulfoxide under vacuum, the residue is combined with 100 ml. of water and extracted three times with 100 ml. of chloroform. The combined chloroform phases are dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is chromatographed over 125 g. of silica gel with chloroform:methanol (96:4). After recrystallization of the corresponding fractions from methanol, a 9% yield of 5-(3,4-dimethoxyphenyl)-2-oxazolidinethione, m.p. 177°-178° is obtained in addition to a 6% yield of 5-(3,4-dimethoxyphenyl)-2-thiazolidinone, m.p. 167°-169°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:11])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:45]1[C:57]2[CH:56]([CH2:58][O:59][C:60](=[O:77])[NH:61][C:62]3[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([O:69][CH2:70][C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[CH:63]=3)[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]=2[CH:48]=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O>[CH:45]1[C:57]2[CH:56]([CH2:58][O:59][C:60](=[O:77])[NH:61][C:62]3[CH:67]=[CH:66][C:65]([NH:68][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[OH:11])=[C:64]([O:69][CH2:70][C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[CH:63]=3)[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]=2[CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
4-Fluoro-2-hydroxy-benzoic acid (74) (0.15 g, 0.961 mmol) was dissolved in DMF (6 mL), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.382 g, 1.01 mmol) was added followed by iPr2EtN (0.167 mL, 0.961 mmol) and the mixture was shaken in a Teflon septum capped 40 mL I-Chem vial at room temperature for 25 minutes. (4-Amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (0.419 g, 0.961 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (50 mL), washed with water (25 mL), aqueous saturated NaHCO3 (25 mL) and brine (25 mL) via extraction, dried over MgSO4. The organic layer was concentrated to give a yellow oil. Purification by flash chromatography using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane in 30 minutes) gave the desired product (75) upon concentration (0.192 g, 0.334 mmol, 35% yield). LC-MS (ESI): (exact mass: 574.19) m/e=575.2 [M+1]+ (100%), 1149.5 [2M+1]+ (25%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:18]([CH2:30][O:31][Si](C(C)(C)C)(C)C)=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.C(Cl)Cl.O>C(Cl)Cl>[CH:27]1([C:25]2[NH:24][N:23]=[C:22]([NH:21][C:19]3[C:18]([CH2:30][OH:31])=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:20]=3)[CH:26]=2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)c(Nc3cc(C4CC4)[nH]n3)n2)c1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)c1
Temperature: 20 °C
Reaction time: 30 h
Yield: 10.1 %

Procedure:
A mixture of N-tert-butyl-3-(5-((tert-butyldimethylsilyloxy)methyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)benzenesulfonamide (400 mg, 0.718 mmol), BCl3/CH2Cl2 (10 mL, 10 mmol, 13.9 eq, 1 M) in CH2Cl2 (10 mL) was stirred at 20° C. under a nitrogen atmosphere for 30 h. Water (50 mL) was added into the mixture. The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed (sat NaHCO3, brine), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (CH2Cl2/MeOH 500:1 to 15:1 as eluent) to afford compound 3-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl)pyrimidin-2-yl)benzenesulfonamide (Compound 124) (28 mg, 10%) as yellowish solid. LC-MS (m/z)=387.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.81-0.82 (m, 2H), 0.94-0.98 (m, 2H), 1.92-1.95 (m, 1H), 4.61 (d, J=5.2 Hz, 2H), 5.65 (t, J=5.2 Hz, 1H), 6.54 (s, 1H), 7.44 (s, 2H), 7.72 (t, J=8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.51 (d, J=7.6 Hz, 1H), 8.84 (s, 1H), 8.92 (s, 1H), 12.18 (s, 1H).