Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3].O.S.[Na]>CO.C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)[NH2:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: S
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cc(N)cc([N+](=O)[O-])c1
Yield: 57 %

Procedure:
A solution of 1-(methylsulfonyl)-3,5-dinitro-benzene (1 g; 4 mmol) in methanol (80 ml) and toluene (20 ml) was treated with a solution of sodium hydrogensulfide-hydrate (227 mg; 4 mmol) in 20 ml methanol. The mixture was then refluxed for 3 hours additional 500 mg sodium hydrogensulfide-hydrate were added and refluxed for an additional hour. After cooling, the precipitate was filtrated and the filtrate concentrated. The residual was crystallized from methanol. 500 mg (2.31 mmol; 57% yield) of a yellow solid were obtained.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=3)[CH2:14]2)=[CH:3]1.O>ClCCl>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[CH2:14]2)=[CH:3]1
Reactant: COc1cccc(C2CCCN(CCc3c[nH]c4ccccc34)C2)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(C2CCCN(CCc3c[nH]c4ccccc34)C2)c1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of 1-[2-(1H-indol-3-yl)ethyl]-3-(3-methoxy phenyl) piperidine hydrochloride (1.4 g) in dichloromethane (500 ml) at -78° C. was treated dropwise with borontribromide (8 g) and the solution was allowed to warm up to room temperature over 2.5 hour. Water (5 ml) was added cautiously and the precipitate was filtered, washed with dichloromethane and water, dissolved in 10% sodium hydroxide solution (25 ml), acidified to pH 10 with 5N hydrochloric acid. The precipitate was collected, washed with water, to give 3-(1-[2-(1H-3-indolyl) ethyl]-3-piperidyl) phenol 1.2 g, m.p. 130°-135° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1([OH:26])[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1([OH:26])[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1(O)CCCC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC1(O)CCCC1C(=O)O
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of benzyl 2-(2-(t-butoxycarbonylamino)ethyl)-2-hydroxycyclopentanecarboxylate (from step D, 70 mg, 0.193 mmol) in MeOH (3 mL) was added palladium (10% wt Pd/C, 20.50 mg, 0.019 mmol). The resulting mixture was stirred under a hydrogen balloon for 30 min. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to yield 2-(2-(tert-butoxycarbonylamino)ethyl)-2-hydroxycyclopentanecarboxylic acid (50 mg, 0.183 mmol, 95% yield) as an oil. MS=273 (M+H)+
Reaction SMILES: C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1.[NH2:42][C:43]1[CH:44]=[C:45]([C:49]2[C:57]([C:58]3[CH:63]=[CH:62][N:61]=[C:60]([NH:64][C:65]4[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=4)[N:59]=3)=[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][N:51]3[N:50]=2)[CH:46]=[CH:47][CH:48]=1.[CH3:72][O:73][C:74]1[CH:82]=[CH:81][CH:80]=[CH:79][C:75]=1[C:76](Cl)=[O:77]>>[F:71][C:67]1[CH:66]=[C:65]([NH:64][C:60]2[N:59]=[C:58]([C:57]3[C:49]([C:45]4[CH:44]=[C:43]([NH:42][C:76](=[O:77])[C:75]5[CH:79]=[CH:80][CH:81]=[CH:82][C:74]=5[O:73][CH3:72])[CH:48]=[CH:47][CH:46]=4)=[N:50][N:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=34)[CH:63]=[CH:62][N:61]=2)[CH:70]=[CH:69][CH:68]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: COc1ccccc1C(=O)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1

Procedure:
In a manner analogous to Example 66, the title compound may be obtained by reacting 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 2-methoxybenzoyl chloride. HRMS: calc. C28H20N6OFS calcd for C31H23FN6O2: 530.1867, found: 531.1941 (M+H)+ 507.1403 found 507.1427+).
Reaction SMILES: [C:1]1([C:7]2[O:16][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:8]1[C:9]2[C:14]([NH2:15])=[N:13][CH:12]=[N:11][C:10]=2[O:16][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncnc2oc(-c3ccccc3)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ncnc2oc(-c3ccccc3)c(Br)c12
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Heat 80 g (378.7 mmol) 6-phenylfuro[2,3-d]pyrimidine-4-amine in 770 ml carbon tetrachloride to 60° C. Add 84.3 g (473.4 mmol) N-bromosuccinimide, and stir the mixture overnight under reflux. After cooling, filter, mix the filter cake successively with dichloromethane and acetonitrile, and filter again. Then dry the filter cake under vacuum. 86 g of the target product (78.2% of theor.) is obtained.
Reaction SMILES: C(O)=O.[C:4](OC(=O)C)(=O)C.[S:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:25].C(OCC)(=O)C.[ClH:32]>O1CCCC1>[ClH:32].[CH3:4][NH:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][C:16]([C:12]1[S:11][CH:15]=[CH:14][N:13]=1)=[CH:24]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CNc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Under ice-cooling, formic acid (6.0 mL) was added dropwise to acetic anhydride (12.5 mL). After dropwise addition, the reaction mixture was stirred at 60° C. for 2 hr. Tetrahydrofuran (10 mL) was added to the reaction mixture, and a solution of 2-(1,3-thiazol-2-yl)-1H-indole-7-amine (10 g) in tetrahydrofuran (10 mL) was added dropwise under ice-cooling. The reaction mixture was stirred for 30 min and concentrated. Tetrahydrofuran (10 mL) was added to the obtained residue, and borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution, 30 mL) was added. The reaction mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, and methanol (5 mL) was added. The reaction mixture was stirred with heating under reflux for 1 hr, concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1). To the obtained a yellow oil was added 4N hydrogen chloride-ethyl acetate solution (30 mL). The obtained yellow crystals were collected by filtration, and washed with diethyl ether and hexane to give the title compound (10 g, yield 70%) as yellow crystals. melting point 89° C.
Reaction SMILES: N1(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)C=CC=N1.Cl.[F:32][C:33]([F:48])([F:47])[C:34]1[N:35]=[CH:36][C:37]([NH:40][C@H:41]2[CH2:45][CH2:44][CH2:43][C@@H:42]2[NH2:46])=[N:38][CH:39]=1.[F:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)[C:51]=1[C:52](O)=[O:53]>>[F:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)[C:51]=1[C:52]([NH:46][C@H:42]1[CH2:43][CH2:44][CH2:45][C@@H:41]1[NH:40][C:37]1[CH:36]=[N:35][C:34]([C:33]([F:32])([F:47])[F:48])=[CH:39][N:38]=1)=[O:53]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(F)cccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1186050-58-7; 172 mg, 0.83 mmol) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.[NH:24]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC.CCO>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([C:27]3[CH:28]=[N:24][NH:25][CH:26]=3)[CH:3]=2)[N:8]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:9]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: Fc1ccccc1-c1nn(C2CCCCO2)c2cnc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1nn(C2CCCCO2)c2cnc(-c3cn[nH]c3)cc12

Procedure:
A microwave tube charged with 5-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (376 mg, 1 mmol), 1H-pyrazol-4-ylboronic acid (224 mg, 2 mmol), Pd(dppf)Cl2 (50 mg, 0.0625 mmol), saturated solution of Na2CO3 (0.5 mL), and DME/EtOH (5 mL/0.5 mL) was irradiated under microwave at 140° C. for 1 h. After cooling down, ethyl acetate was added. The mixture was washed with water twice (2×20 mL), dried over anhydrous Na2SO4 and concentrated to afford the crude product. The crude product was purified by silica-gel column chromatography eluting with 50% ethyl acetate in heptane to afford 3-(2-fluorophenyl)-5-(1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as a white solid (300 mg, 82%, ESI MS m/z=364 (M+1) which was treated with HCl/dioxane (4 mL, 3 mol/L) and stirred for overnight. The crude product was received by filtration and washed with a little dioxane. It was further purified by prep-HPLC eluting with 5 to 95% CH3CN in aqueous 10 mmol NH4HCO3 solution to afford 136 as a white solid (180 mg, 72%). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.16 (s, 2H), 8.02 (m, 1H), 7.87 (m, 1H), 7.54 (m, 1H), 7.38 (m, 2H). ESI MS m/z=280 (M+1)
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[CH3:17][O:18][C:19]([C:21]1([CH:24]([OH:35])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][O:22]1)=[O:20]>C(Cl)Cl.C(OCC)C>[CH3:17][O:18][C:19]([C:21]1([C:24](=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][O:22]1)=[O:20]
Reactant: COC(=O)C1(C(O)CCCCc2ccccc2)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1(C(=O)CCCCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
To a suspension of 7.6 g (35.4 mmol) of pyridinium chlorochromate and 2.90 g (35.4 mmol) of anhydrous sodium acetate in 100 ml of methylene chloride is added 1.55 g (5.9 mmol) of 2-(5-phenyl-1-hydroxypentyl)-2-oxiranecarboxylic acid methyl ester. The mixture is stirred at room temperature for 3 hours and then is diluted with ethyl ether. Filtration through Florisil and rotoevaporation gives an oil which is subjected to preparative column chromatography on silica gel (hexane:ethyl ether (3:2)). The appropriate fractions are combined and rotoevaporated to give 670 mg (43.3%) of the title compound: IR (film) 1757, 1723 cm-1 ; NMR (CDCl3) δ 1.65 (4H, m), 2.48-2.65 (4H, mc), 3.06 (1H, d, J=6 Hz), 3.33 (1H, d, J=6 Hz), 3.83 (3H, s), 7.21 (3H, m), 7.30 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][N:11](C(OC(C)(C)C)=O)[C:10](=[O:20])[CH:9]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([F:34])[CH:22]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[C:23]([F:34])[CH:22]=2)=[CH:4][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:20])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(C3=CC(=O)N(C(=O)OC(C)(C)C)C3)cnc2N)cc1F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2=CC(=O)NC2)cc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(6-amino-5-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyridin-3-yl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (158 mg, 0.337 mmol) was added TFA (2 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 1 h. After toluene was added, the volatile solvents were evaporated. The crude product was used for the next step. LCMS(m/z): 314.2 (MH+), 0.382 min.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.CC(=O)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:12][CH2:13][O:14][CH:1]1[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11]
Reactant: OCCO
Reactant: Cc1cc(C(=O)O)sc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)sc1C1OCCO1
Yield: 97.9 %

Procedure:
A suspension of 5-formyl-4-methyl-thiophene-2-carboxylic acid (3.00 g, 17.6 mmol), ethylene glycol (3.28 g, 52.9 mmol) and p-toluene sulfonic acid hydrate (61 mg, 0.353 mmol) in toluene (80 mL) is refluxed for 3 h in a Dean-Stark apparatus. The clear solution is diluted with EA and washed twice with water. The washings are extracted back with EA. The combined organic extracts are dried over Na2SO4, filtered, concentrated and dried to give 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acid (3.69 g) as a pale yellow resin, LC-MS: tR=0.46 min, [M+1]+=215.15. b) To a mixture of 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acid (3.00 g, 14.0 mmol), HOBt (2.52 g, 16.8 mmol) and EDC (2.95 g, 15.4 mmol) in isopropanol (240 mL), hydrazine hydrate (1.50 g, 29.4 mmol) is added at 0° C. The suspension is stirred at 0° C., diluted with DMF and warmed to rt. Stirring is continued at rt for 2 h before the solvent is evaporated. The residue is dissolved in acetonitrile and separated by prep. HPLC (XBridge C18, 50×50 +100×50 mm, 10 μm, gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give the title compound (2.43 g) as a colourless solid; LC-MS: tR=0.57 min, [M+1]+=228.96; 1H NMR (D6-DMSO): δ2.20 (s, 3H), 3.90-3.99 (m, 2H), 3.99-4.08 (m, 2H), 4.43 (s, 2H), 6.06 (s, 1H), 7.43 (s, 1H), 9.69 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][CH3:14].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:13]([CH3:14])[CH3:12])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CNC
Agent: CCP(=O)(C#N)CC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-amino-5-bromonicotinic acid (0.35 g, 1.61 mmol) in tetrahydrofuran (5 mL) was added dimethylamine (0.8 mL of a 2M solution in tetrahydrofuran, 1.60 mmol), diethylphosphoryl cyanide (0.29 g, 1.77 mmol), and triethylamine (0.34 g, 3.38 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then at room temperature for 4 h. Concentration and purification by column chromatography on silica (5-10% methanol in dichloromethane) gave the title Compound as a white solid. MS (EI) for C8H10BrN3O: 244 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.S(=O)(=O)(O)O.[C:19](=O)([O-])O.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:19])=[O:12])=[CH:5]2
Reactant: O=C([O-])O
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2cc(C)ccc2[nH]1

Procedure:
5-Methylindole-2-carboxylic acid (0.9 g, 5.13 mmol) was dissolved in methanol (25 ml) and treated with sulphuric acid (0.5 ml). The mixture was refluxed for 4 h. The volume of solvent was reduced and the residue treated with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic fractions were dried and concentrated to give the desired ester.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[N+:22]([O-])=O)[C:13]3=[O:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[CH:21][N:12]([CH2:11][C:9]1[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=1)[C:13]2=[O:25]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc2c(c1)OCCO2
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12

Procedure:
2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-5-nitro-2H-isoquinolin-1-one (0.9 g, 0.002 mol), tin dichloride dihydrate (2 g, 0.009 mol) were stirred in tetrahydrofuran (10 mL, 0.1 mol) at room temperature for 20 hours. The volatiles were removed and the residue was purified via flash column chromatography (40 g of silica gel, 50% EtOAc/Hexanes) gave a red oil. MS m/z (M+H) 309.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[CH:6]2.P(Br)(Br)([Br:16])=O>>[Br:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1ccc2[nH]c(=O)ccc2c1
Product: COc1ccc2nc(Br)ccc2c1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 49.3 %

Procedure:
6-Methoxyquinolin-2(1H)-one (6.81 g, 38.9 mmol) was carefully added to POBr3 (18.9 g, 66.1 mmol) at 60° C., and the resulting solution was stirred at 140° C. for 2.5 h. The reaction mixture was cooled and poured onto crushed ice, and the solid was collected by filtration. Purification of this material on silica gel (gradient elution from 5 to 12% EtOAc in petroleum ether) afforded the title compound (4.57 g, 49.3%) as a solid. LCMS (ES+) m/z 238, 240 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH2:26][S:27][CH3:28])[CH:25]=1)[NH2:22]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([CH2:26][S:27][CH3:28])[CH:25]=[C:19]([CH3:18])[CH:20]=2)=[N:3][CH:4]=1
Reactant: CSCc1cc(C)cc(N)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cc(C)cc(CSC)c2)ncc1F

Procedure:
Intermediate 58.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-methyl-5-[(methyl-sulfanyl)methyl]aniline. The batch was purified by chromatography (hexane/ethyl acetate 5% to 32%) to give the desired product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[S-:9][C:10]#[N:11].[K+].NC1C(N)=CC=CN=1>CC(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:11]=[C:10]=[S:9])=[O:7]
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccco1
Agent: Nc1cccnc1N
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1ccco1
Temperature: 10 °C

Procedure:
2-Furoylisothiocyanate is prepared from 2-furoyl chloride (13 g., 0.1 moles) and potassium thiocyanate (9.7 g., 0.1 moles) in acetone (35 ml.). The mixture is stirred at 10° C. for fifteen minutes. 2,3-Diaminopyridine (2.8 g., 0.0257 moles) is added as a solid, the mixture stirred at 10° C. and allowed to warm to room temperature for three hours. The yellow solid is filtered, washed with acetone, slurried in 500 ml. water, filtered, washed with water and air dried. The product, 8.45 g. (80%) is purified by recrystallization from acetone giving 6.1 g. (57%) of desired product, as yellow crystals, m.p. 174° C. dec., of 2,3-bis[3-(2-furoyl)-2-thioureido]pyridine.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH-].[Na+].CC(OC)(C)C.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][OH:32])[CH2:26]1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][O:32][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:26]1
Reactant: OC[C@@H]1CCC[C@H](OC2CCCCO2)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COC[C@@H]1CCC[C@H](OC2CCCCO2)C1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
34 g of [(1R,3S)-3-(tetrahydropyran-2-yloxy)cyclohexyl]methanol, 100 g of tert-butyl bromoacetate, 16.2 g of tetrabutylammonium bisulfate and 5.9 g of tetrabutylammonium iodide are dissolved in 250 ml of toluene and, at 10° C. (ice-water bath), a solution of 63.5 g of sodium hydroxide in 80 ml of water is added, and the mixture is stirred vigorously (KPG paddle stirrer) at 10° C. for 8 h. Then MTBE and water are added, and the phases are separated. The aqueous phase is extracted twice with MTBE, and the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate gradient). This results in 36.4 g of tert-butyl [(1R,3S)-3-(tetrahydropyran-2-yloxy)cyclohexylmethoxy]acetate and 6.8 g of [(1R,3S)-3-(tetrahydropyran-2-yloxy)cyclohexyl]methanol as pale yellow oils.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:18][CH2:19][C:20]3([CH2:25][CH2:24][N:23]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:22][CH2:21]3)[CH2:26][CH2:27]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)CC#N)CC4)n2)nn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of 5-chloro-N2-(1,5-dimethyl-1H-pyrazol-3-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (200.5 mg, 0.5142 mmol) in dichloromethane (28 mL) and N,N-dimethylformamide (7 mL) were added 2-cyanoacetic acid (110.3 mg, 1.297 mmol), N,N-diethylethanamine (156.5 mg, 1.547 mmol) and HATU (585.4 mg, 1.540 mmol). The mixture was stirred at room temperature for 4 h and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the title compound as a white solid (128.5 mg, 54.68%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]([CH3:26])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.O>CN(C)C=O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]([CH3:26])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1nc2ccccc2nc1NCCN
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2nc1NCCNCC(O)COc1ccccc1
Temperature: 40 °C

Procedure:
5.6 g. Phenyl glycidyl ether and 15 g. 2-(2-aminoethylamino)-3-methylquinoxaline are dissolved in a little dimethylformamide and warmed to 40° C. for 32 hours. The reaction mixture is then poured into water, extracted with methylene chloride, dried and purified chromatographically on silica gel in the manner described in Example 25. There are obtained 4.2 g. (33% of theory) of the desired product in the form of a viscous oil.