Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[N:16]([CH2:21][CH2:22]O)[S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][CH2:21][N:16]([C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(N(CCO)S(C)(=O)=O)c(OCC2CC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(N(CCBr)S(C)(=O)=O)c(OCC2CC2)c1
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of methyl 3-(cyclopropylmethoxy)-4-(N-(2-hydroxyethyl)-methylsulfonamido)benzoate (0.690 g, 2.009 mmol) in dry DCM (15 ml), CBr4 (0.866 g, 2.61 mmol) was added, followed by triphenylphosphine (0.685 g, 2.61 mmol), and stirring was continued for 2 hours at RT. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (eluent: EtOAc/petroleum ether 2/8) to give methyl 4-(N-(2-bromoethyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate as a colorless oil (0.630 g, 1.551 mmol, 77% yield, MS/ESI+ 405.8, [MH]+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:15][CH2:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18]>ClC1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:20][CH2:19][N:17]([CH3:18])[CH2:16][CH2:15]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(CCCl)CCCl
Reactant: CCCCOc1ccccc1N
Agent: Cl
Solvent: Clc1ccccc1
Product: CCCCOc1ccccc1N1CCN(C)CC1
Yield: 99 %

Procedure:
A stirred solution of 2-butoxybenzenamine (6.50 g) in chlorobenzene (50 ml) was treated with 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (7.70 g) according to the method of Intermediate 40. Concentration in vacuo of the dichloromethane extracts gave the title compound as a red oil (9.67 g).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:18])[C:12]([CH3:17])=[CH:13][C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][C:14]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:13]=[C:12]([CH3:17])[C:11](=[O:18])[C:10]([CH3:9])=[CH:15]1
Reactant: CC1=CC(=O)C=C(C)C1=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C(C)=C1
Yield: 80 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,6-dimethyl-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.60 g of the desired product (yield 80%).
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH2:30][CH2:29]1
Reactant: COC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reaction time: 1 h

Procedure:
A solution of (S)-6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (127.7 mg, 0.200 mmol) in THF (2.00 mL) at room temperature was treated with Pd(OH)2 (20 wt %, 42.2 mg, 0.060 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction mixture was stirred under hydrogen atmosphere for 1 h. The reaction mixture was opened to air and was filtered through a pad of Celite™, eluting with EtOAc and MeOH. The filtrate was concentrated under reduced pressure to give (S)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine, as a TFA salt, as a yellow oil, which was carried forward without additional purification. ESI-MS m/z [M+H]+434.5.
Reaction SMILES: C[Al](C)C.[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=CC=1.[OH:12][CH:13]([CH3:18])[CH2:14][C:15]([O-:17])=[O:16].Cl>ClCCl>[S:11]1[CH:8]=[CH:9][CH:10]=[C:5]1[O:17][C:15](=[O:16])[CH2:14][CH:13]([OH:12])[CH3:18]
Reactant: Sc1ccccc1
Reactant: CC(O)CC(=O)[O-]
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(O)CC(=O)Oc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry flask on ice, 6 ml of dehydrated dichloromethane was stirred and 2 ml of 2M trimethyl aluminum was slowly added thereto under a nitrogen stream. After that, 2 mmol of thiophenol was slowly added thereto. The mixture was stirred at room temperature for 30 minutes and then 3-hydroxybutyrate dissolved in 6 ml of dehydrated dichloromethane was added thereto. The reaction was monitored by a TLC. To this mixed solution was added 20 ml of dichloromethane and, until generation of bubbles stopped, 20 ml of 3% hydrochloric acid solution was added. The mixed solution was transferred to a separating funnel, washed with 3% hydrochloric acid solution for two times and with saturated saline for two times, dried over magnesium sulfate and evaporated in vacuo to give 532 mg of crude oily 3-hydroxybutyrate thiophenyl ester in dark yellow color. This was purified by a column chromatography (20 cm×1 cm diameter; eluent was hexane:ethyl acetate=2:1) using silica gel 60 to give 125 mg of pure 3-hydroxybutyrate thiophenyl ester as a transparent oil. The yield to the unpurified substance was 24%. Result of NMR analysis of this compound is as follows.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:55][C@H:54]([CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=1)[CH2:56][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)c3n[nH]c4ccccc34)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: O=C(c1n[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 32 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(1H-indazol-3-yl)methanone (0.20 g, 0.55 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.222 g, 0.55 mmol) according to Procedure G to give the title compound (0.093 g, 0.176 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:36][C:32]2[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=2)[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc12
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C)cccc23)n[nH]1
Temperature: 100 °C
Yield: 13 %

Procedure:
To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methylquinazoline (0.255 g, 0.79 mmol) in DMA (2 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester prepared according to US2007/219195 (0.31 g, 1.58 mmol) and acetic acid (0.15 mL) and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and then was purified by reverse phase HPLC using an ammonium acetate modifier. Fraction 1 containing pure product were combined, treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM and the combined extracts were washed with saturated aq NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 12.15 (br s, 1H), 10.57 (s, 1H), 8.67 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.92-8.11 (m, 2H), 7.75 (d, J=7.0 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 5.96 (s, 1H), 2.59 (s, 3H), 2.17 (s, 3H); LC-MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[C:16](N)[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1)=[O:11].[ClH:21]>C(#N)C.[Cu](Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:21])[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1)=[O:11]
Reactant: COC(=O)c1cc(N)cc(OC)n1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(OC)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.25 mL (10.5 mmol) tert-butyl nitrite and 1.42 g (10.5 mmol) copper(II)chloride in 40 mL acetonitrile was added a solution of 1.20 g (6.59 mmol) 4-amino-6-methoxy-pyridine-2-carboxylic acid methyl ester in 10 mL acetonitrile dropwise at 40° C. This mixture was stirred at 80° C. for 1 h, then poured into ice water, acidified with 4 M aqueous HCl and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=3/1→2/1).
Reaction SMILES: [F:1][CH:2]([F:9])[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].O.[NH2:11][NH2:12]>O1CCCC1>[F:1][CH:2]([F:9])[C:3]1([OH:8])[NH:12][N:11]=[C:5]([CH3:6])[CH2:4]1
Reactant: NN
Reactant: CC(=O)CC(=O)C(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC1=NNC(O)(C(F)F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-difluoropentane-2,4-dione (2.5 g, 0.018 mol) in tetrahydrofuran (32 mL) was added hydrazine hydrate (0.98 mL, 0.020 mol) in tetrahydrofuran (32 mL) dropwise. The reaction was stirred at 25° C. for 16 hours and then concentrated in vacuo. The residue was used in the next reaction without further purification. 1H NMR (CDCl3): δ 5.68-5.96 (t, 1H), 5.50-5.80 (br s, 1H), 2.98 (dd, 1H), 2.68 (dd, 1H), 2.01 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Product: OC1CCN(c2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1
Yield: 61 %

Procedure:
1-(2,6-Diphenyl-pyrimidin-4-yl)-piperidin-4-ol was prepared from compound 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol and phenyl boronic acid by a procedure analogous to that disclosed in Examples 39 and 95, as described above. Yield: 61%.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([CH:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]([O:23]C)=[O:22])=[N:13]2)[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[C:4]1([CH:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]([OH:23])=[O:22])=[N:13]2)[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1nn(C(C)c2ccccc2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1nc(C(=O)O)c2ccccc21
Temperature: 45 °C
Reaction time: 12 h
Yield: 58.1 %

Procedure:
To a mixed solution of lithium hydroxide monohydrate (0.68 g, 16.8 mmol) in tetrahydrofuran (20 mL) and water (10 mL), methyl 1-(1-phenylethyl)-1H-indazole-3-carboxylate (2.3 g, 8.4 mmol) was added. The mixture was stirred at 45° C. for 12 hours. Then the organic solvent was removed under reduced pressure. To the residue, 1 N hydrochloride aqueous solution was added to adjust the pH to 3-4, and then the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to afford 1-(1-phenylethyl)-1H-indazole-3-carboxylic acid (1.3 g, 60%) as a white solid, which was directly used in next step. LRMS (M+H+) m/z: calcd 266.29. found 266.
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:6](=[O:10])([OH:9])([OH:8])[OH:7].[Zr:11]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:11].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:11].[Zr+4:11]
Reactant: O=P(O)(O)O
Reactant: [Zr]
Agent: O=P([O-])([O-])[O-]
Product: [Zr+4]
Temperature: 350 °C

Procedure:
A zirconium phosphate film was prepared by adding a stoichometric amount of phosphate in the form of phosphoric acid to a solution of zirconium bound to PEI. The solution was then spin coated onto a glass slide and thermally treated at 1° C. to 120° C. with a dwell time of 30 minutes followed by heating to 350° C. at 1° C./minute with a dwell time of 30 minutes followed by heating to 450° C. at 1° C./minute with a dwell time of 1 hour and then cooling to 25° C.
Reaction SMILES: Cl[C:2]1N=NC(NC)=C(C2C=CC=CC=2C)C=1.[Cl:17][C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:41])[C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:27]=2)=[C:20]([C:42]2[CH:47]=[CH:46][C:45](F)=[CH:44][C:43]=2OC)[CH:19]=1>>[Cl:17][C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:41])[C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([S:36]([CH3:39])(=[O:37])=[O:38])[CH:27]=2)=[C:20]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH3:2])[CH:19]=1
Reactant: CNc1nnc(Cl)cc1-c1ccccc1C
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Product: Cc1ccccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 1, intermediate d) after a reaction time of 18 hours, applying a second purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2). Colorless foam (23%). MS (ESI+): m/z=484.070 ([M+H]+).