Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[N:14][CH:15]=1.C[O:22][C:23](=[O:36])[CH:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31](O)=[CH:32][CH:33]=2)[CH:28]=[CH:27]1)[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Li+].[OH-]>C(Cl)Cl>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH:24]([CH3:25])[C:23]([OH:36])=[O:22])[CH:27]=[CH:28]3)=[N:14][CH:15]=1
Reactant: COC(=O)C(C)n1ccc2cc(O)ccc21
Reactant: OCCCOc1ccc(-c2nc3c(s2)CCCC3)cn1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C(=O)O)n1ccc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.7 %

Procedure:
To a solution of 3-[5-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol (Example 78, 0.098 g, 0.34 mmol) and 2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (Example 7, 0.067 g, 0.31 mmol) in CH2Cl2 (10 mL) were added triphenylphosphine (0.161 g, 0.61 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.155 g, 0.61 mmol). The yellow reaction mixture was stirred at rt for 18 h, then diluted with 20 mL hexanes, and filtered through a short pad of silica gel. The filtrate was concentrated under reduced pressure, and the residue (0.065 g) dissolved in 5 mL of a mixture of methanol/THF/water (2:2:1). LiOH (9.1 mg, 0.37 mmol) was added. The mixture was stirred at rt for 18 h and concentrated under reduced pressure. The residue was taken up in water and washed with ether. The aqueous layer was acidified to pH 3.5 and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound (7 mg, 4%). 1H NMR (400 MHz, acetone-d6) δ 8.20 (dd, 1H), 7.90 (dd, 1H), 7.35 (s, 1H), 7.29 (dd, 1H), 7.11 (s, 1H), 6.85 (dd, 1H), 6.50 (dd, 1H), 6.39 (s, 1H), 5.25-5.35 (m, 1H), 4.31 (t, 2H), 4.31 (t, 2H), 4.08 (t, 2H), 2.95-3.05 (br s, 1H), 2.70-2.78 (m, 4H), 2.30-2.35 (m, 2H), 1.70-1.94 (m, 4H). LC/MS m/z 478.2 (M+H)+, RT 2.90 min.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[C:58]([CH3:59])=[C:57]([C:60]2[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]3[C:76]([C:77]([F:80])([F:79])[F:78])=[CH:75][N:74]=[C:73]([NH:81][C:82]4[CH:96]=[CH:95][C:85]([CH2:86][P:87](=[O:94])([O:91]CC)[O:88][CH2:89][CH3:90])=[CH:84][C:83]=4[O:97][CH3:98])[N:72]=3)=[CH:62][CH:61]=2)[CH:56]=[N:55]1>>[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[C:58]([CH3:59])=[C:57]([C:60]2[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]3[C:76]([C:77]([F:80])([F:78])[F:79])=[CH:75][N:74]=[C:73]([NH:81][C:82]4[CH:96]=[CH:95][C:85]([CH2:86][P:87](=[O:91])([OH:94])[O:88][CH2:89][CH3:90])=[CH:84][C:83]=4[O:97][CH3:98])[N:72]=3)=[CH:62][CH:61]=2)[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C)nc3C(=O)NC)n2)c(OC)c1
Yield: 107.2 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(3-hydroxypropyl)-5-methyl-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 35B, 270 mg, 382 μmol) to afford 278 mg of the title compound (100%). 1H NMR (400 MHz, CD3OD) δ 8.95-9.04 (m, 1H), 8.26 (s, 1H), 7.96-8.01 (m, 1H), 7.71-7.80 (m, 1H), 7.51 (d, J=9.1 Hz, 1H), 7.08 (s, 1H), 6.83-6.90 (m, 1H), 4.25 (t, J=7.1 Hz, 2H), 3.81-3.92 (m, 5H), 3.55-3.60 (m, 2H), 2.97 (d, J=21.0 Hz, 2H), 2.92 (s, 1H), 2.61 (s, 3H), 2.03 (t, J=6.7 Hz, 2H), 1.17 (t, J=7.1 Hz, 3H). MS (ESI): m/z=679.67 [M+H]+. UPLC: tR=1.15 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8]C)=[O:7].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[Cl:17][C:4]1[C:3]([CH2:2][O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g (2.93 mmol) of methyl 3-bromomethyl-2-chloro-4-methylsulfonylbenzoate and 0.28 g (2.93 mmol) of phenol were dissolved in 20 ml of dimethylformamide and treated with 0.14 g (3.51 mmol) of 60% strength sodium hydride. The mixture was stirred overnight at room temperature and then concentrated in a high vacuum on a rotary evaporator. The residue was dissolved in 16 ml of tetrahydrofuran and 8 ml of water and the solution was refluxed for 4 h together with 0.23 g of NaOH (5.85 mmol). It was then allowed to cool and was largely concentrated on a rotary evaporator, and the aqueous residue was then treated with 2 M HCl. It was then extracted with methylene chloride, and the combined organic phase was dried over MgSO4 and completely concentrated on a rotary evaporator.
Reaction SMILES: C(O)(=O)C.Cl[CH2:6][C:7]([C:9]1[CH:10]=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])=[O:8]>O.C(O)C.[Zn]>[C:7]([C:9]1[CH:10]=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])(=[O:8])[CH3:6]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(O)c(O)c1
Reaction time: 2 h

Procedure:
400 ml of a mixture of 1:8 v/v glacial acetic acid in water was added in two portions to a stirred mixture of 35 g of 4-(chloroacetyl)catechol in 300 ml of ethanol. At 10-minute intervals, four 10 g portions of 90% zinc dust were added, the mixture being held below about 45° C. The mixture then was stirred for 2 hours at 30°-40° C. and allowed to stand over a weekend. The liquid phase was decanted and stripped to a quarter of its volume under reduced pressure. The residue was extracted with ether. The ether extract was washed with sodium bicarbonate solution. The solvent was evaporated. The solid residue was recrystallized from toluene to give 4-acetylcatechol (1A), mp: 118°-119° C.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][NH2:25]>CS(C)=O.O>[CH3:21][CH:18]1[CH2:17][NH:16][C:15](=[O:22])[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:11]=[C:2]([NH:25][CH3:24])[C:3]([CH3:23])=[N:4]4)[NH:20][C:19]1=2
Reactant: CN
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: O
Product: CNc1nc2c(-c3cc4c([nH]3)C(C)CNC4=O)cccc2nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 32.7 mg, 0.105 mmol) and methylamine (2.0M in THF; 0.158 mL, 0.316 mmol) in DMSO (0.8 mL) was stirred under argon in a sealed flask at 25° C. for 10 min, then at 60° C. for 1 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-7-methyl-2-(2-methyl-3-(methylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (21.0 mg, 0.065 mmol, 62% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.24 (1H, br. s.), 7.93 (1H, d, J=7.4 Hz), 7.57 (1H, d, J=7.8 Hz), 7.45 (1H, d, J=4.3 Hz), 7.32 (1H, t, J=7.8 Hz), 7.04 (1H, s), 6.99 (1H, br. s.), 3.43 (1H, dt, J=11.0, 4.0 Hz), 3.09-3.21 (2H, m), 3.07 (3H, s), 2.52 (3H, s), 1.30 (3H, d, J=6.5 Hz). m/z (ESI, +ve) 322.1 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C[O:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[S:32][C:31]3[N:33]=[CH:34][CH:35]=[N:36][C:30]=3[N:29]([CH2:37][O:38][CH3:39])[C:28]=2[CH:40]=1)=O.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:39][O:38][CH2:37][N:29]1[C:28]2[CH:40]=[C:24]([C:22]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:21])[CH:25]=[CH:26][C:27]=2[S:32][C:31]2[N:33]=[CH:34][CH:35]=[N:36][C:30]1=2
Reactant: Cc1ccccn1
Reactant: COCN1c2cc(C(=O)OC)ccc2Sc2nccnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COCN1c2cc(C(=O)Cc3ccccn3)ccc2Sc2nccnc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
0.15 ml of diisopropylamine in tetrahydrofuran (10 ml) was ice-cooled and 1.0 ml of a 1.6 M solution of n-butyllithium in hexane was added thereto. After stirring for 10 minutes, the reaction mixture was cooled to −78° C. After adding 0.15 ml of 2-methylpyridine, the mixture was stirred for 30 minutes and then a solution of 303 mg of methyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxylate in tetrahydrofuran (5 ml) was dropped thereinto. The reaction mixture was brought back to room temperature and distributed into an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was extracted, dried over anhydrous sodium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 30 mg of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-2-ylmethyl)ketone as yellow crystals. This ketone was further treated by the same method as the one of Example 119 to thereby give 13 mg of the title compound as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([O:1][C:2]2[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCSc1ccc(C(=O)OC)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CCSc1ccc(C(=O)OC)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 46 %

Procedure:
Using a method similar to Example 1-D, methyl 2-hydroxy-4-(ethylthio)benzoate and 1-Boc-4-hydroxy-piperidine gave the title compound (5.0 g, 12.64 mmol 46%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=3)(=[O:35])=[O:34])=[N:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2snc(NCCCN)c12
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2snc(NCCCNS(=O)(=O)c3cccc(C(F)(F)F)c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
N1-(4-methylbenzo[d]isothiazol-3-yl)propane-1,3-diamine (100 mg, 0.45 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.12 mL, 0.63 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 3-trifluoromethylbenzenesulfonyl chloride (0.09 mL, 0.54 mmol) in methylene chloride (5 mL) was added drop-wise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(4-methylbenzo[d]isothiazol-3-ylamino)propyl)-3-(trifluoromethyl)benzenesulfonamide (23 mg). 1H NMR (300 MHz, DMSO-d6): 7.75 (d, 1H), 7.30 (m, 2H), 7.25 (m, 2H), 6.92 (t, 1H), 6.28 (t, 1H), 3.22 (t, 2H), 2.98 (t, 2H), 2.81 (s, 3H), 2.15 (t, 2H), 1.80 ppm (m, 2H). MW=429 confirmed by LC-MS, tr=3.92 min (Method E) MH+=430.
Reaction SMILES: CC(C)N=C=NC(C)C.[CH2:10]([O:13][C:14]([NH:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:18]([OH:20])=O)=[O:15])[CH:11]=[CH2:12].[CH2:29]([O:31][CH:32]([O:38][CH2:39][CH3:40])[CH2:33][NH:34][CH:35]([CH3:37])[CH3:36])[CH3:30].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH:17]([NH:16][C:14](=[O:15])[O:13][CH2:10][CH:11]=[CH2:12])[C:18](=[O:20])[N:34]([CH2:33][CH:32]([O:31][CH2:29][CH3:30])[O:38][CH2:39][CH3:40])[CH:35]([CH3:36])[CH3:37])=[CH:23][CH:24]=1
Reactant: C=CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(CNC(C)C)OCC
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: C=CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N(CC(OCC)OCC)C(C)C
Reaction time: 12 h

Procedure:
7.8 ml of DIC are added dropwise to a solution of 5.7 g of 2-allyloxycarbonylamino-3-(4-chlorophenyl)propionic acid, 3.5 g of (2,2-diethoxyethyl)isopropylamine, 6.8 g of HOAt in 30 ml of DMF and the solution is stirred for 12 h. The reaction solution is concentrated under reduced pressure and purified by flash chromatography on silica gel (eluent ethyl acetate/n-heptane=1/3). The desired product is obtained with MW=440.97 (calculated monoisotopic); measured value (M+H)+: 441.15
Reaction SMILES: [CH3:1][N:2]([C:17]1[C:18]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:19]=2[N:20]=[CH:21][N:22]=1)[CH:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl.C(=O)([O-])[O-]>CO.O1CCOCC1.C(Cl)Cl>[CH3:1][N:2]([C:17]1[C:18]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:19]=2[N:20]=[CH:21][N:22]=1)[CH:3]1[CH2:9][O:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4COCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CNCCOC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.5 %

Procedure:
A solution of tert-butyl 6-(methyl-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1,4-oxazepane-4-carboxylate (0.142 g, 0.283 mmole) 107.4 in MeOH (5 mL) was treated with 4 M HCl in 1,4-Dioxane (0.28 mL (1.13 mmol) and stirred at rt for 24 hr. An additional of 4 M HCl in 1,4-dioxane (0.4 mL) was added and the mixture stirred for an additional 24 hr and then heated at 50° C. for 2 hours. The mixture was cooled to rt and concentrated in vacuo to give a residue was dissolved in DCM (10 mL) and 5 mL MeOH and neutralized by addition of 0.43 g of polymer-supported carbonate resin (3.5 mmol/g) and stirring at room temperature for 2 hours. The resin was removed by filtered through celite, and the filtrate was concentrated to dryness to yield 125.6 mg of N-methyl-N-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-amine 107.5 as a yellowish solid glass that was used without further purification. LCMS (ESI) m/z: 402.20 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[C:14]([C:15]([O:17]C)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:22])[CH:7]=1.[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[C:14]([C:15]([OH:17])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:22])[CH:7]=1
Reactant: CCCc1nn2c(OCc3c(F)cccc3F)cc(C)cc2c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCc1nn2c(OCc3c(F)cccc3F)cc(C)cc2c1C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 116.2 %

Procedure:
A solution of 169 mg (0.43 mmol; about 95% purity) of methyl 7-[(2,6-difluorobenzyl)oxy]-5-methyl-2-propylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 96A in 4.5 ml of dioxane was admixed with 2.6 ml (2.6 mmol) of 1 N sodium hydroxide solution and reacted at 90° C. for 24 h. Subsequently, another 0.5 ml (0.5 mmol) of 1 N sodium hydroxide solution were added and the mixture was stirred at 90° C. for 1 h. The reaction solution was cooled and adjusted to pH 2 with 1 N hydrochloric acid. The solids that precipitated out were filtered off and dried under high vacuum. 180 mg of the title compound (72% by LC-MS, 84% of theory) were obtained and were converted without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[NH4+:13]>C(O)CCC>[CH3:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:13])[C:3]=2[S:10][CH:9]=1
Reactant: [NH4+]
Reactant: Cc1csc2c(Cl)ncnc12
Agent: [OH-]
Solvent: CCCCO
Product: Cc1csc2c(N)ncnc12
Temperature: 25 °C
Yield: 78.2 %

Procedure:
In a sealed tube was added 4-chloro-7-methylthieno[3,2-d]pyrimidine (2.0 g, 10.83 mmol) and ammonium hydroxide (12.65 mmol, 325 mmol) in butanol (7 ml). The reaction was heated to 90 C for 4 hours and then cooled to room temperature. The resulting white precipitate was collected to give 7-methylthieno[3,2-d]pyrimidin-4-amine (1.4 g, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, s), 7.74 (1H, s), 7.34 (2H, s), 2.34 (3H, d, J=1.00 Hz).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:26][C:27]1[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:44][CH2:45]4)=[O:42])[N:39]=3)[N:36]=2)[CH:28]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C)Oc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 67.3 %

Procedure:
Using 3-tert-butoxybenzoic acid (110 mg, 0.58 mmol), oxalyl chloride (63 μL, 0.73 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (4.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (4.0 mL) as starting materials and in the same manner as in Example 335, the title compound (160 mg, 57%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](O)=[O:20])[C:14]=1[CH3:22].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH2:45])[CH3:41]>CN(C=O)C.CN(C)C1C=CN=CC=1.CO.O>[CH3:41][CH2:40][N:42]([CH2:43][CH2:44][NH:45][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2/[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]/2=[O:11])[NH:17][C:16]=1[CH3:18])=[O:20])[CH2:46][CH3:47]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: CCN(CC)CCN
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 17 °C
Reaction time: 1.25 h

Procedure:
A mixture of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene) methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (70 g) in DMF (1050 mL) was cooled to 15-19° C. To this mixture p-toluene sulfonyl chloride (133.4 g) in DMF (350 mL) was added in 15 min. 4-dimethylamino pyridine (81.3 g) in DMF (350 mL) was added in 15 min and pyridine (36.9 g) was added in 15 min at 15-19° C. The reaction mixture was stirred at the same temperature over a period of 60-90 minutes. The reaction mass was cooled to 13-16° C. To the above reaction mixture N, N-diethyl ethylene diamine (81.3 g) in DMF (350 mL) was added in 10 min at 13-16° C. The reaction mass was maintained under stirring for a period of 30 minutes at the same temperature. The progress of the rection was monitored by HPLC with a limit of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid not more than 5.0%. After the completion of reaction 28 mL of water was charged and DMF was distilled off under vacuum. 1050 mL of 5% sodium bicarbonate solution was charged under stirring. The pH of the above solution was adjusted to 12-13 by 50% NaOH solution. Ethyl acetate was charged and it was stirred for 5 min. The organic layer were separated and treated with 1% NaOH, and brine solution followed by separation of the ethyl acetate fraction and distillation off under vacuum below 50° C. The residue was treated with 30% methanol in water to isolate the material. It was treated with methanol to obtain sunitinib base. The obtained solid was dried under vacuum at 55 -65° C. over for a period of 5 hrs. Yield: 65.6 g of Sunitinib base with ˜0.5% des ethyl sunitinib.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 137.8 %

Procedure:
Benzyl 4-hydroxyphenyl ketone (5.1 g; 24 mmol), 3.8 g (3.5 mL, 30 mmol) of benzyl chloride, and 16.6 g (120 mmol) of pulverized and flame dried K2CO3 were slurried in 75 mL dry Me2CO under Ar. The mixture was heated to reflux 16 h, cooled to room temperature, diluted with CH2Cl2 (100 mL), and filtered. The resulting filter cake was washed with C6H6 (50 mL) and EtOAc (50 mL). The combined filtrates were concentrated and the resulting orange oil was dissolved in C6H6, washed with 10% K2CO3 (100 mL), 5% NaOH (2×50 mL), and H2O (100 mL). The organic layer was dried (MgSO4), filtered, and concentrated to give 10 g of a light orange solid, which was purified on 60 g flash SiO2 (1:1 petroleum ether-CH2Cl 2) to give Benzyl 4-benzyloxphenyl ketone as a clear oil which was crystallized from C6H6 -EtOH to yield 3.1 g of white needles (43%). mp: 134.5°-136° C. NMR δ 8.03 and 7.03 (AA'BB', c, 4H, ArH), 7.43 (s, 5H, ArH), 7.31 (s, 5H, ArH), 5.15 (s, 2H, PhCH2O), 4.25 (s, 2H, COCH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14](OC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl trans-4-(4-chlorophenyl)cyclohexanecarboxylate (compound of formula (VIIa)) (25.3 g, 100 mmol) in dichloromethane (250 mL) at −78° C. under argon was added a 1M solution of diisobutylaluminium hydride (DIBAL) in dichloromethane (110 mL, 110 mmol) and the mixture was stirred for 90 minutes. A further 5 mLs of DIBAL was then added. Methanol (125 mL) was added with stirring and the mixture allowed to warm to −10° C. 1M aqueous hydrochloric acid (250 mL, 250 mmol) was then added with stirring. The aqueous layer was extracted with dichloromethane (250 mL) and the combined organics washed twice with water (2×125 mL). The organics were concentrated under vacuum to a volume of 75 mL, the residue was diluted by the addition ethyl acetate (125 mL) and the mixture was then concentrated under vacuum to a volume of 75 mL. The resulting mixture containing the title compound was used in the next step without analysis or purification.