Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[F:5][C:6]([F:18])([F:17])[C:7]([C:13]([F:16])([F:15])[F:14])([OH:12])[CH2:8][C:9]([CH3:11])=[CH2:10].[OH-:19].[Na+]>C1COCC1>[F:5][C:6]([F:17])([F:18])[C:7]([C:13]([F:14])([F:15])[F:16])([OH:12])[CH2:8][CH:9]([CH3:11])[CH2:10][OH:19]
Reactant: C=C(C)CC(O)(C(F)(F)F)C(F)(F)F
Reactant: [OH-]
Agent: B
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: CC(CO)CC(O)(C(F)(F)F)C(F)(F)F
Yield: 83.3 %

Procedure:
To a 3-necked, 500 mL round bottomed flask equipped with an overhead stirrer, digital thermometer and a 125 mL constant-pressure addition funnel with a nitrogen inlet was added 27 mL (0.27 mol) of borane-dimethylsulfide complex (10.0M in THF). The addition funnel was charged with a solution of 50 g (0.23 mol) of 1,1,1-trifluoro-2-trifluoromethyl-4-methyl-pent-4-en-2-ol (1) in 140 mL of anhydrous THF. The flask was cooled and the olefin was added slowly with stirring while maintaining a temperature below 15° C. The mixture was stirred at room temperature overnight after which time it was recooled and 100 mL (0.3 mol) of 3M NaOH (aq) was added carefully. The reaction mixture was reduced in volume on a rotary evaporator and subsequently co-evaporated with two 500 mL portions of diethyl ether. The resulting heavy oil was taken up in 50 mL of THF and the solution transferred to a 250 mL 3-necked round bottomed flask equipped with a 125-mL addition funnel, a digital thermometer, and a magnetic stirbar. The addition funnel was charged with 70 mL of 30% hydrogen peroxide. The flask was cooled and the hydrogen peroxide added slowly with stirring. After stirring overnight at room temperature, the solution was diluted with 500 mL of diethyl ether and adjusted to pH 6 (wet litmus) with 5% HCl. The ether layer was separated and the aqueous layer was extracted with 2×250 mL of ether. The combined organic phases were washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4, and evaporated to a yellow oil. The oil was purified by distillation through a Vigreux column, bp 57° C.@1.0 mm Hg to yield 46 g (85%) of (2) as a low melting solid. The identity of the product was confirmed using 1H NMR spectroscopy and HRMS.
Reaction SMILES: [CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:13]=O)[CH:8]=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH2:3][CH3:4])[CH3:2].[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[CH:1]([C:5]1[CH:12]=[C:9]([CH:10]=[O:11])[CH:8]=[C:7]2[C:6]=1[O:15][C:16](=[O:23])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(C)c1cc(C=O)cc(C=O)c1O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C=O)cc(C(C)CC)c2oc1=O

Procedure:
A solution of 5-sec-butyl-4-hydroxyisophthalaldehyde of formula I (0.5 g, 2.42 mmol), diethyl malonate (0.38 g, 2.42 mmol) in ethanol (20 mL) was treated with piperidine (0.3 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with acetic acid. To this residue water (20 mL) was added and extracted 3-fold with 20 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides ethyl 8-sec-butyl-6-formyl-2-oxo-2H-chromene-3-carboxylate (General Formula II). (0.47 g, 65% yield). White solid, m. p. 89-90° C.; 1H NMR (CDCl3, 300 MHz): δ 10.05 (s, 1H), 8.60 (s, 1H), 8.05 (brs, 1H), 8.01 (brs, 1H) 4.44 (q, 2H, J=7.1 Hz), 3.51-3.40 (m, 1H), 1.78-1.69 (m, 2H), 1.43 (t, 3H, J=7.1 Hz), 1.33 (d, 3H, J=7 Hz), 0.88 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz): δ 190.2, 162.7, 156.5, 155.8, 148.5, 137.3, 132.9, 131.7, 129.9, 119.2, 118.0, 62.2, 33.4, 29.6, 20.4, 14.2, 12.0; ESI-MS (m/z): 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](CC3C=CC(OC)=CC=3)[N:9]=[CH:10][C:3]=12.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: COc1ccc(Cn2ncc3c(Cl)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccnc2[nH]ncc12

Procedure:
4-Chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (5) 19 g (69.4 mmol) in neat TFA (30 mL, 389 mmol) was stirred at 80° C. for 4 hr. The resulting RM was concentrated and MeOH was added and the obtained precipitate was filtered and washed with MeOH. The crude solid was treated with EtOAc, saturated NaHCO3 and dried over Na2SO4, to yield the desired product as a half white solid. 1H NMR (400 MHz, CDCl3): δ 13.23 (br s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.32 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:19][CH3:20].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:19][CH3:20])=[C:2]([F:1])[CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(N3CCOCC3)c[nH]c(=O)c2cc1F
Product: COc1cc2c(N3CCOCC3)cnc(Cl)c2cc1F
Yield: 46.8 %

Procedure:
A solution of 7-fluoro-6-methoxy-4-morpholinoisoquinolin-1(2H)-one (0.25 g, 0.898 mmol) in POCl3 (5 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get desired compound (0.13 g, 46.8%) as solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.98-7.95 (m, 2H), 7.56-7.54 (d, J=8 Hz, 1H), 7.45-7.40 (m, 2H), 4.08 (s, 3H), 3.89-3.86 (m, 4H), 3.11-3.09 (m, 4H); MS: MS m/z 297.07 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Si:11]([O:28][CH2:29][CH:30]([CH2:43]O)/[CH:31]=[CH:32]/[P:33](=[O:42])([O:38][CH:39]([CH3:41])[CH3:40])[O:34][CH:35]([CH3:37])[CH3:36])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[Si:11]([O:28][CH2:29][CH:30](/[CH:31]=[CH:32]/[P:33]([O:38][CH:39]([CH3:41])[CH3:40])([O:34][CH:35]([CH3:36])[CH3:37])=[O:42])[CH2:43][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(C)OP(=O)(/C=C/C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(/C=C/C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(Cl)ncnc21)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
To a solution of 6-chloropurine (213 mg, 1.37 mmol), diisopropyl (E)-3-(t-butyldiphenylsilyloxy)methyl-4-hydroxybut-1-enylphosphonate (694 mg, 1.37 mmol) and triphenyl phosphine (540 mg, 2.06 mmol) in N,N-dimethylformamide (22 ml) stirred at 0° C. under dry nitrogen was added diethyl azodicarboxylate (358 mg, 2.06 mmol). The solution was stirred at room temperature for 16 h. The solvent was removed and the residue purified by column chromatography on silica gel eluting with acetone-hexane (1:4, 1:2) then ethyl acetate-methanol (99:1, 9:1) to give (E)-9-[2-(t-butyldiphenylsilyloxy) methyl-4-(diisopropoxyphosphoryl)but-3-enyl]-6-chloropurine as a colourless gum (244 mg, 28%); λmax (EtOH) 265 (9,215nm; υmax (film) 2980, 2930, 1590, 1560, 1425, 1385, 1335 and 1245 cm-1 ; δH (CDCl3) 1.10 (9H, s, CH3), 1.20 (12H, m, CH (CH3)2), 3.07 (1H, m, CH), 3.69 (2H, d, J 6 Hz, CH2O ), 4.50 (4H, m, CH2N and CH(CH3)2), 5.57 (1H, pseudo-t, J 17 Hz, PCH=CH), 6.66 (1H, ddd, J 8 Hz, 17 Hz and 26 Hz, PCH=CH), 7.30-7.70 (10H, m, Ph), 8.00 (1H, s, H-2/H-8), 8.73 (1H, s, H-2/H-8) (Found: M+ 641.2459. C32H42N4ClO4PSi requires M+ 641.2479).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:30][CH2:31][CH3:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>C(OCC)(=O)C.CN(C)C=O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:30][CH2:31][CH3:32])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 8.5 %

Procedure:
In a manner similar to that of Example 1(g), starting with 600 mg (1.3 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-propylcarbamate in 7 ml of ethyl acetate and 7 ml of dimethylformamide, 50 mg (10%) of the desired product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=O)[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[N:32]1([C:19]([C:18]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:14][C:13]=3[CH:15]=[CH:16][CH:17]=2)=[O:21])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)O)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carboxylic acid (125 mg, 0.426 mmol) and 1-hydroxybenzotriazole (57.6 mg, 0.426 mmol), morpholine (0.0743 ml, 0.852 mmol) in DMF (3 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (163 mg, 0.852 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give the desired product (130 mg, 84.4%) as a solid.
Reaction SMILES: C([N:3](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:25][C:26]1[N:31]=[C:30](C(O)=O)[C:29]2[C:35]([O:57][CH3:58])=[N:36][N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:28]=2[CH:27]=1>O1CCOCC1.O>[Cl:25][C:26]1[N:31]=[C:30]([NH2:3])[C:29]2[C:35]([O:57][CH3:58])=[N:36][N:37]([C:38]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:28]=2[CH:27]=1
Reactant: CCN(CC)CC
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(N)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Triethylamine (370 μl, 2.66 mmol) followed by diphenylphosphoryl azide (447 μl, 2.068 mmol) were added to 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (36B, 790 mg, 1.681 mmol) in 1,4-dioxane (16.5 ml) a 100 ml roundbottom flask attached to a reflux condenser. The mixture was allowed to stir at 100° C. overnight. Room temperature was attained and the reaction mixture was diluted with water and extracted into EtOAc. The organic layer was washed with NaHCO3, brine, dried over NaSO4, and concentrated in vacuo. The material was loaded onto silica gel and purified by MPLC 0-25% EtOAc/hexanes gave 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-amine MS: [M+H]+ m/z 441.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33]C)=[O:32].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:14][C:13]1[S:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([OH:33])=[O:32])=[CH:4][CH:5]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole (2.13 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (1.65 g) and N,N-dimethylformamide (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (10 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.19 g, 44%) of 2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH2:17])[CH:11]=1.[F:19][C:20]([F:31])([C:27]([F:30])([F:29])[F:28])[C:21]([F:26])([F:25])[C:22](Cl)=[O:23]>COCCOC>[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:22](=[O:23])[C:21]([F:25])([F:26])[C:20]([F:19])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:11]=1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)Cc1ccc(O)c(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Sodium bicarbonate (51 g, 0.607 mol) was suspended in 1,2-dimethoxyethane (180 ml), and methyl(3-amino-4-hydroxyphenyl)acetate (58.26 g, 0.32 mol) was added, followed by a further quantity of 1,2-dimethoxyethane (75 ml). To this mixture was added, dropwise, a solution of heptafluorobutyryl chloride (112.5 g, 0.48 mol) in 1,2-dimethoxyethane (140 ml), at such a rate that the reaction temperature was maintained at 19-20° C. Once the addition was complete, the mixture was stirred at room temperature for 1½ hours. The reaction mixture was filtered and the solid was taken up in ethyl acetate and washed with saturated aqueous bicarbonate solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was taken up in acetone (450 ml) and water (450 ml) was added. The mixture was stirred for 1½ hours, during which time an oil separated. The aqueous acetone was decanted and a further quantity (250 ml) of water was added to the oil. The mixture was stirred for 1 hour, during which time the desired product crystallised; it was collected by filtration, washed with water and dried to give methyl(3-heptafluorobutyramido-4-hydroxyphenyl)acetate (87.0 g).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[CH2:9][N:10]=[N+:11]=[N-:12])=[O:5])C.[OH-].[Na+]>CO.O>[N:10]([CH2:9][C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3])=[N+:11]=[N-:12]
Reactant: CCOC(=O)[C@@H]1C[C@H]1CN=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A solution of trans-ethyl-2-azidomethyl-1-cyclopropane carboxylate (7.282 g, 37.13 mmol) in a mixture of methanol (20 ml) and water (10 ml) was cooled to 0° C. and treated dropwise with 40.8 ml of 1M sodium hydroxide in water (40.8 mmol). After the addition was completed the bath was removed and the solution was stirred at room temperature for 3 h. The methanol was evaporated under reduced pressure and the aqueous solution was extracted with ether (2×10 ml). After acidification with dilute hydrochloric acid (3N), the aqueous phase was extracted with dichloromethane (4×25 ml) and the combined organic extracts washed with water (10 ml), brine (10 ml) and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation (bulb to bulb) of the residue under vacuum gave 4.830 g (92%) of a clear oil; bp 100°-108° C./0.6 mm Hg (air bath temperature); ir (film) νmax : 2095 (N3), 1695 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.25 (2H, d, J=6, CH2N3), 2.0~0.6 (4H, m, cyclopropyl), 12.3 (1H, s, COOH). Anal. calcd for C5H7N3O2 : C 42.55, H 5.00, N 29.77; Found: C 42.55, H 4.89, N 29.75.
Reaction SMILES: [Cl: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].[Br:13]N1C(=O)CCC1=O>Br.C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1Cl

Procedure:
A stirred mixture of 36.9 g. of methyl o-chlorophenylacetate, 36.0 g. of N-bromosuccinimide, and 2 drops of 48% hydrobromic acid in 500 ml. of carbon tetrachloride is refluxed for 20 hours and then filtered through magnesium silicate. Evaporation under reduced pressure gives methyl α-bromo-o-chlorophenylacetate as a straw-colored liquid.
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][CH:12]1[C:20](=O)[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH:20]([NH2:10])[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH2:14][CH2:13]1
Reactant: CC1CCc2sccc2C1=O
Reactant: NC1CCCc2occc21
Product: CC1CCc2sccc2C1N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.12-6.99, 4.13, 3.89, 3.51, 2.86-2.74, 2.13-1.98, 1.75, 1.65, 1.15, 1.07.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(S([N:51]2[C:59]3[CH:58]=[CH:57][N:56]=[C:55](Br)[C:54]=3[CH:53]=[CH:52]2)(=O)=O)C=CC=CC=1>O1CCOCC1.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.[Cu]I>[CH3:40][C:36]([N:33]1[CH2:32][CH2:31][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:55]4[C:54]5[CH:53]=[CH:52][NH:51][C:59]=5[CH:58]=[CH:57][N:56]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:35][CH2:34]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4nccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (150 mg, 0.22 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (90 mg, 0.27 mmol), Pd(PPh3)4 (25 mg, 10 mol %) and CuI (50 mg, 0.25 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH. The resulting residue was dissolved in IMS/dioxane (1:1 mL) and 12.5 M aqueous NaOH solution (0.1 mL) added. After stirring for 1 h the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 05:95) to give 106 (28 mg, 24%) as a pale yellow solid. LCMS (Method F) RT 4.86 min; [M+H]+ 521.3. 1H NMR (CDCl3, 400 MHz): δ 9.11 (s, 1 H); 8.54 (d, J=5.6 Hz, 1 H); 7.45 (s, 1 H); 7.41 (dd, J=3.3, 0.9 Hz, 1 H); 7.38 (dd, J=5.6, 0.95 Hz, 1 H); 7.36 (d, J=3.3 Hz, 1 H); 7.10 (d, J=5.3 Hz, 1 H); 5.25 (d, J=5.2 Hz, 1 H); 4.10 (t, J=4.75 Hz, 4 H); 3.91 (t, J=4.7 Hz, 4 H); 3.85 (s, 2 H); 2.60 (s, 8 H); 1.24 (s, 6 H)
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=Cc1c(F)ccc(F)c1Cl
Product: Fc1ccc(F)c(CNC2CC2)c1Cl

Procedure:
Synthesized according to typical procedure J from 2-chloro-3,6-difluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:21][CH2:22][CH2:23][Cl:24]>O>[Cl:24][CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccc(OCCCCl)cc1
Temperature: 5 °C
Yield: 82 %

Procedure:
10.5 kg of 4-hydroxybenzamide, 10.58 kg of potassium carbonate and 83 kg of acetonitrile are introduced into a reactor. The mixture is stirred and then there are added 24.14 kg of a solution of 1-bromo-3-chloropropane. The reaction mixture is heated at reflux for 4 hours. Water (105 L) is added in the hot state, the mixture is then cooled to 5° C. and filtered. The filter cake is washed with water and then with acetonitrile. The title product is obtained in the form of a powder in a yield of 82%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:13][OH:14]>[OH-].[Na+]>[CH3:13][O:14][C:7]1[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[C:9]([CH3:11])[N:8]=1
Reactant: CO
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: COc1nc(C)cc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of methyl-2-chloro-6-methylpyrimidine-4-carboxylate (5.0 g) in 2N aq. NaOH (67 mL) and methanol (67 mL) is stirred at rt for 24 h. Methanol is evaporated and the aq. phase is acidified with 25% aq. HCl at 0° C. A beige crystalline solid crushes out. It is filtered, rinsed with water and heptane and dried (3.0 g); LC-MS: tR=0.55 min, [M+H]+=169.01; 1H NMR (D6-DMSO): δ 2.50 (s, 3H), 3.94 (s, 3H), 7.52 (s, 1H), 13.7 (s br, 1H).