Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmoles) in dry dichloromethane (15 ml) and pyridine (4 ml) was cooled to 0° C. and treated dropwise with ethyl chloroformate (1.2 ml, 12.0 mmoles) under argon. After the addition was completed, the cooling bath was removed and the reaction was allowed to stir at room temperature for 1 hour. It was then diluted with ethyl acetate and the resulting solution was washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was coevaporated with toluene to remove residual pyridine. The colorless solid obtained was subjected to high vacuum and used in the next reaction without further purification (3.81 g). For analytical purposes, a small amount of the compound was recrystallized from ether-hexanes to provide colorless solid, melting point 61.5°-64.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([Br:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:17]O>>[NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([Br:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: Cc1cc(Br)c(C(=O)O)cc1N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)c(C)cc1Br
Yield: 99 %

Procedure:
To a cooled solution (5° C.) of 5-amino-2-bromo-4-methylbenzoic acid (100.0 g, 0.434 mmol) in anhydrous methanol (1.6 L) was added dropwise thionyl chloride (112.4 g). The reaction mixture was refluxed and monitored by TLC. After refluxing for 6 h, the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was diluted with ice water (1.2 L) and neutralized with 5% NaHCO3 to pH 7.5. The aqueous layer was extracted with EtOAc (3×600 mL), and the combined organic layers were washed with brine (2×500 mL), and dried over anhydrous Na2SO4. Concentration under reduced pressure provided the title compound as a pale solid. Yield: 99%. 1H-NMR (DMSO-d6, 300 MHz): δ 7.25 (s, 1H), 7.14 (s, 1H), 3.30 (s, 3H), 2.15 (s, 3H); MS ESI (m/z) 244 [M+1]+, calc. 243.
Reaction SMILES: Cl.[NH2:2][OH:3].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20](=O)[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C@@H:14]([C:34]([O:36][CH3:37])=[O:35])[CH2:13]1>N1C=CC=CC=1.O>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20](=[N:2][OH:3])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C@@H:14]([C:34]([O:36][CH3:37])=[O:35])[CH2:13]1
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=NO)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 7.6 %

Procedure:
0.32 g of hydroxylamine hydrochloride is added, with stirring and under an inert atmosphere, to a mixture of 1.27 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 13 cm3 of pyridine at a temperature in the region of 20° C. The mixture is stirred for 1 hour at a temperature in the region of 20° C. The resulting reaction mixture is diluted with 130 cm3 of distilled water and the mixture thus obtained is extracted with 50 cm3 of ethyl acetate and then two times with 30 cm3 of ethyl acetate. The combined organic phases are washed two times with 50 cm3 of distilled water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under a pressure of 50 kPa of nitrogen on a column of silica gel (particle size 20-45μ; weight of silica 160 g, diameter of the column 3.5 cm), elution being carried out with a mixture of ethyl acetate and cyclohexane (90/10 by volume). Fractions 20 to 22 are combined and then concentrated to dryness under the above conditions. 0.1 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-hydroxyimino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[N:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2nc3ccc(Cl)nn3c2-c2ccnnc2)cc1
Reactant: OCCN1CCNCC1
Solvent: CCCCCO
Product: OCCN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnnc4)n3n2)CC1
Temperature: 130 °C

Procedure:
The mixture of 0.26 g (0.8 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine and 0.425 g (3.2 mmol) of 2-hydroxyethylpiperazine in 4 ml of pentanol is heated in a sealed tube at 130° C. for 32 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[N:29]=[CH:30][NH:31][CH:32]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:31]3[CH:32]=[C:28]([CH3:27])[N:29]=[CH:30]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1c[nH]cn1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3cnc(C)c3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 4-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([OH:10])[CH:8]=[C:7]([CH3:11])[S:6]1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])=[O:4]
Reactant: COC(=O)C1SC(C)=CC1O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1sc(C)cc1O
Yield: 75 %

Procedure:
17.4 Parts of 3-hydroxy-5-methyldihydrothiophene-2-carboxylic acid methyl ester are dissolved in 100 parts by volume of methylene chloride. 14.9 parts of sulfuryl chloride in 20 parts by volume of methylene chloride are added in the course of 30 minutes at 10° C., whilst passing nitrogen into the mixture. The mixture is then distilled. 12.9 parts (75% of theory) of 3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester of boiling point 67°-70° C./0.3 mbar are obtained.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:7][CH:8]([CH3:12])[C:9](O)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH:1]1([O:6][C:9](=[O:10])[CH:8]([SH:7])[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(S)C(=O)O
Reactant: OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC(S)C(=O)OC1CCCC1

Procedure:
Into a 250 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 86 grams of cyclopentanol; 25 grams of 2-mercaptopropionic acid; and 1 gram of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 8 hours. At the end of the 8 hour reflux period, the reaction mass is cooled and admixed with 200 ml diethylether followed by washing with two 100 ml volumes of 10% aqueous sodium carbonate and one 100 ml volume of water. The reaction mass is dried over anhydrous sodium sulfate and the solvent is recovered on a Buchi apparatus. The reaction mass is then micro distilled yielding the product having the structure: ##STR135##
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8](=[N:14][O:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]=1.[NH3:19]>>[NH2:19][C:3]1[O:7][N:6]=[C:5]([C:8](=[N:14][O:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]=1
Reactant: N
Reactant: CCOC(=O)C(=NOC)c1noc(C(Cl)(Cl)Cl)n1
Product: CCOC(=O)C(=NOC)c1noc(N)n1

Procedure:
To ethyl 2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (syn isomer) (3.4 g) was added liquid ammonia (17 ml). After giving homogenous solution, it was poured into a petri dish, followed by removing liquid ammonia by ventilation. To the residue were added water and ethyl acetate, and the separated ethyl acetate solution was washed with an aqueous sodium chloride and dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diisopropyl ether to obtain ethyl 2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (syn isomer) (1.75 g), mp 143°-146° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][N:1]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[CH:2]=1
Reactant: N#Cc1cccc(F)c1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2ccc(-c3ccccn3)c2)c1
Temperature: 25 °C

Procedure:
2-(1H-Pyrrol-3-yl)pyridine (0.144 g, 11.0 mmol), 3-fluorobenzonitrile (1.21 g, 10 mmol), and potassium carbonate (0.0.276 g, 2 mmol) were heated at 145° C. in DMF (0.5 mL) for 14 h. After this time, the reaction mixture was cooled to rt and quenched with H2O (30 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the residue was chromatographed on silica gel eluting with EtOAc:hexane (2:3) to afford a white solid which was recrystallized from dichloromethane-hexane to give 3-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile as white crystals. 1H NMR (CD3Cl, 300 MHz) δ 8.59 (ddd, 1H), 7.78˜7.71 (m, 3H), 7.68 (dd, 1H), 7.62˜7.53 (m, 3H), 7.17˜7.11 (m, 2H), 6.89 (dd, 1H). MS (ES) 246.1 (M++H).
Reaction SMILES: Br.[N:2]1[C:3](=[O:11])[CH2:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([CH:22]=[C:4]2[N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]3=[N:2][C:3]2=[O:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CN2C=CC=CC2=N1
Reactant: O=Cc1cccc2ccccc12
Agent: Br
Solvent: CCO
Product: O=C1N=C2C=CC=CN2C1=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1 g (4.7 mmol) of imidazo[1,2-a]pyridin-2-one hydrobromide salt and 726 mg (4.7 mmol) of 1-naphthaldehyde in 20 mL of ethanol is heated at reflux for 1 h and then cooled to room temperature. The precipitate is collected. The isolated solid is suspended in 40 mL of 2M potassium carbonate solution and the resulting mixture is stirred for 48 h at room temperature. The precipitated solid is collected and washed with water to give the desired compound.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:18]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1

Procedure:
By substantially following the procedures of Example 1,A, 25.0 g (194 mmol) of nipecotic acid was protected with benzylchloroformate under basic conditions to afford 18.0 g (68 mmol; 35%) of analytically pure N-Cbz-nipecotic acid as a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH:13](OC(OC)=O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24].C([O-])(O)=O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH:13]([P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])[O:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: COC(=O)OC1CSC(COC(=O)c2ccccc2)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OP(=O)(OC(C)C)C1CSC(COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzoyloxymethyl-5-(methyloxycarbonyloxy)-1,3-oxathiolane (4.80 g, 16.11 mmol) and triisopropyl phosphite (4.77 ml, 19.33 mmol) in dry dichloromethane (100 ml) at 0° C. was added dropwise titanium tetrachloride (1.77 ml, 16.11 mmol). After 2 h at 0° C., the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into saturated NaHCO3 (100 ml). The mixture was then filtered and the filtrate was partitioned. The aqueous layer was further extracted with dichloromethane (2×) and the combined extracts were washed with brine (1×), dried and concentrated. Chromatography eluting with 25-50% EtAc in hexanes yielded the title compound as a 1:1 cis trans mixture (4.958 g, 79%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([N:12]1[C:17]([CH3:18])=[N:16][C:15](=[O:19])[C:14]([CH:20](C)C(NN)=O)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>O.Cl>[NH2:1][CH2:20][C:14]1[C:15](=[O:19])[NH:16][CH:17]([CH3:18])[N:12]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:13]=1
Reactant: O=N[O-]
Reactant: Cc1nc(=O)c(C(C)C(=O)NN)nn1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1NC(=O)C(CN)=NN1Cc1ccccc1
Reaction time: 2 h
Yield: 108.1 %

Procedure:
Sodium nitrite (1.29 g) in water (25 ml) was added to a stirred solution of 2-benzyl-2,5-dihydro-3,α-dimethyl-5-oxo-1,2,4-triazine-6-acetic acid, hydrazide (5.0 g) in conc. hydrochloric acid (3.3 ml) and water (75 ml) keeping the temperature at -1° to -2°. The azide separated as a white solid which rapidly became a thick gum. Conc. hydrochloric acid (5 ml) was added and the mixture was raised to 65° over 30 minutes and left at this temperature for 2 hours. During this period the gum gradually dissolved to give a clear yellow solution. This was cooled and brought to pH 8 by the addition of sodium bicarbonate. Water was removed by rotary evaporation and the residual solid was extracted with boiling isopropanol (6×100 ml). The extract was filtered and concentrated to give the amine as a gum (4.37 g) which failed to crystallise.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35]Br)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:35][CH2:34][CH2:33][NH:32][C:31]([O:30][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:37])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 60 °C

Procedure:
To a solution of piperidin-4-yl-carbamic acid benzyl ester (15 g, 58.4 mmol, crude product from Boc-deprotection step) in dimethylformamide (60 mL) at 23° C. was added potassium carbonate (12.1 g, 87.6 mmol, 1.5 equiv), potassium iodide (4.85 g, 29.2 mmol, 0.5 equiv) and (3-bromo-propyl)-carbamic acid tert-butyl ester (13.9 g, 58.4 mmol, 1 equiv). The resulting mixture was warmed to 60° C. (oil bath). After 90 min at 60° C. the reaction mixture was cooled to 23° C. then partitioned between ethyl acetate and water (100 mL each). The organic layer was separated, washed with saturated brine solution (150 mL), dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 330 g silica gel column as a solution in dichloromethane (25 mL) then eluted with 2 M ammonia in methanol in dichloromethane (0-12.5% 2 M ammonia in methanol linear gradient over 12 column volumes at a flow rate of 100 mL/min) to give 16.9 g (43.2 mmol, 74% over 3 steps) of the title compound as a clear
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][OH:21])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.[H-].[Na+].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][O:21][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=4)(=[O:38])=[O:37])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1
Reactant: OCc1cc2nc(-c3cc(F)cc4[nH]ccc34)nc(N3CCOCC3)c2s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2cc3nc(-c4cc(F)cc5c4ccn5S(=O)(=O)c4ccc(C)cc4)nc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
To a suspension of [2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-methanol (0.54 g, 1.41 mmol) in anhydrous THF (20 mL) and DMF (5 mL) was added sodium hydride (60% suspension in mineral oil, 0.34 g, 8.5 mmol). The resulting mixture was stirred at RT for 10 min, then p-toluenesulfonyl chloride (1.08 g, 5.66 mmol) was added and the reaction mixture was heated at 40° C. for 3 h. The resulting solution was partitioned between EtOAc and a saturated aqueous solution of ammonium chloride. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (0.60 g, 62%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]([NH2:20])=[O:19])[S:16][CH:17]=2)=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([C:18]([NH2:20])=[O:19])[S:16][CH:17]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2csc(C(N)=O)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1nc(-c2ccc(O)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Boron tribromide (3.7 ml) was added dropwise under nitrogen to a suspension of 4-(4-methoxyphenyl)-thiazole-2-carboxamide (3 g) in dichloromethane (45 ml). The mixture was stirred at room temperature for 2 h, then under reflux for 2 h and then cooled, after which water (60 ml) was added cautiously. The precipitate was filtered and the collected solid was dried under vacuum at 50° C., and recrystallised from methanol to give 4-(4-hydroxyphenyl)-thiazole-2-carboxamide (2.03 g), m.p. 223°-227° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10](OC)=[O:11])[S:5][CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][N:16]=2)[S:5][CH:6]=1
Reactant: COC(=O)c1ccnc(-c2nc(C)cs2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1csc(-c2cc(CO)ccn2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl 2-(4-methylthiazol-2-yl)isonicotinate (2.400 g; 10.20 mmol) in anh. MeOH (50 ml) was treated with NaBH4 (775 mg; 20.50 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 17 h. After concentration to dryness under reduced pressure, the resulting residue was treated with water, and extracted with DCM. The organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (2-(4-methylthiazol-2-yl)pyridin-4-yl)methanol as a yellow solid. LC-MS (conditions A): tR=0.47 min.; [M+H]+: 207.05 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:17])[CH:6]=[CH:5]2.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]=[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[N:8]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(=O)ccc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 80 °C

Procedure:
Methyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.67 mmol), CuI (0.67 mmol) and PdCl2(PPh3)2 (0.40 mmol) were dissolved in triethylamine (3 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 5 minutes. Ethynyltrimethylsilane (3.5 mmol) was added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 80° C. for 8 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min)=2.759, method [1], MS(ESI) 314.1 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11][C:12]1[N:13]=[C:14](Br)[C:15]2[N:16]([CH:18]=[CH:19][N:20]=2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:14]3[C:15]4[N:16]([CH:18]=[CH:19][N:20]=4)[CH:17]=[C:12]([Br:11])[N:13]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2ncoc2c1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cn2ccnc2c(Nc2ccc3ncoc3c2)n1

Procedure:
A quantity of 0.13 g (1 mmole) of Benzooxazol-6-ylamine is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford benzooxazol-6-yl-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:13]([F:32])=[CH:12][N:11]=1>>[F:32][C:13]1[C:14]([NH:16][CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[N:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Fc1cnc(Cl)nc1NC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(NC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and N-(2-chloro-5-fluoro-pyrimidinyl)-1,1-di(4-chlorophenyl)methylamine produced 5-fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamine. LCMS: ret. time: 25.59 min.; purity: 91%; MS (m/e): 421 (MH+—Cl).