Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl>[N:21]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: CCC(=O)Cl
Reactant: NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1

Procedure:
A solution of 2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidine (0.5 g), propionic chloride (0.18 ml) and triethylamine (0.3 ml) in methylene chloride (20 ml) was stirred at room temperature for 2 hr. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a pale-yellow substance (0.8 g). The obtained pale-yellow substance was crystallized from hexane/ethyl acetate (1:1, 50 ml) to give the title compound (0.5 g) as pale-yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:5])[CH3:4].Cl[CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>O1CCCC1.CN(C)C=O>[C:3]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][CH:13]=1)(=[O:5])[CH3:4]
Reactant: COCCOCCl
Reactant: CC(=O)OCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(COC(C)=O)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
0.53 g (132 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 20 g (120 mmol) of (4-hydroxy-phenyl)-methyl acetate diluted in 100 ml of tetrahydrofuran and 100 ml of dimethylformamide. The reaction mixture is stirred at room temperature, and then 15 ml (132 mmol) of 1-chloromethoxy-2-methoxy-ethane is added dropwise. After stirring at room temperature for 2 hours, then adding water, the reaction mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. After evaporation of the solvents, 25 g (86%) of [4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate is obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18]CC4CC4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:29]1(N)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:29]4[CH2:31][CH2:30]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NCC4CC4)CC3)cc2n1
Reactant: NC1CC1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NC4CC4)CC3)cc2n1

Procedure:
Prepared according to the method used in the preparation of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-cyclopropylmethyl-amine using cyclopropylamine in place of cyclopropanemethylamine. The title compound was obtained as a pale yellow solid (38 mg, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[BrH:11]>CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: Br
Solvent: CCOCC
Product: COc1ccc(CBr)cc1

Procedure:
A solution of 4-methoxybenzylalcohol (10 g) in ether (300 ml) was shaken with hydrobromic acid, 48%, (150 ml). The organic phase was washed with saturated sodium bromide, dried (K2CO3) and the solvents removed in vacuo to give 4-methoxybenzylbromide (113.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:20]([N:23](CC2C=CC(OC)=CC=2OC)[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(Cl)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 92.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 3-chloro-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (123 mg, 0.211 mmol) prepared in Example 23b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (85.0 mg, 54%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([C:20]([CH3:35])([CH3:34])[CH2:21]/[C:22](=[N:27]/S(C(C)(C)C)=O)/[C:23]([F:26])([F:25])[F:24])[CH:19]=1>C1COCC1.CCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([C:20]([CH3:34])([CH3:35])[CH2:21][C:22]([NH2:27])([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:23]([F:26])([F:25])[F:24])[CH:19]=1
Reactant: Cc1ccccn1
Reactant: COc1ccc(F)cc1C(C)(C)C/C(=N/S(=O)C(C)(C)C)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1ccccn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
To a chilled (−78 C.) solution of 0.05 mL (0.514 mmol) of 2-methylpyridine in 3 mL of dry THF was added 0.23 mL (0.4 mmol) of a 1.7 M solution of t-BuLi in pentane. The mixture turned a bright orange. After 10 min, a solution of 98 mg (0.257 mmol) of 2-methyl-propane-2-sulfinic acid [3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amide in 0.5 mL of anhydrous THF was added. The reaction was then warmed to room temperature, quenched with aqueous ammonium chloride, stirred for 30 min and extracted with diethyl ether.(3×) The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was dissolved in 2 mL of methanol, 3 drops of concentrated HCl were added and the reaction was warmed at 75° C. in a sealed tube. After 1 h, the reaction was cooled to room temperature, concentrated in vacuo, neutralized with aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were dried over (MgSO4), filtered and concentrated to afford an oil. The residue was purified by preparative thin layer chromatography eluting with hexanes-EtOAc (95:5) to afford 24 mg (25%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][C:23]=1[CH3:30].[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:30])[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc([Mg]Br)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A stirred solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 11.02 mmol) in 30 mL THF was cooled to 0° C., then (4-methoxy-3-methylphenyl)magnesium bromide (6.21 g, 27.5 mmol) was added dropwise via a syringe under N2 and the reaction mixture was stirred at the same temperature for 1.5 h, then gradually warmed up to room temperature over 1 h when the reaction was judged complete by LCMS. To the reaction mixture was slowly added 40 mL of saturated aqueous NH4Cl then the aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed to yield the crude product. Purification by flash chromatography gave the title compound as a white solid (1.97 g, 5.62 mmol, 51% yield). MS (ESI) m/z 334.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) retention time=1.57 min. 1H NMR (400 MHz, CDCL3) 8 ppm 1.48 (s, 9H) 1.62-1.91 (m, 4H) 2.27 (s, 3H) 2.78-3.02 (m, 2H) 3.27-3.46 (m, 1H) 3.91 (s, 3H) 4.12-4.27 (m, 2H) 6.87 (d, J=8.59 Hz, 1H) 7.77 (t, J=8.10 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[CH:16]=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[C:13]([Cl:12])[CH:18]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOc1ccccc1Cl
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1Cl

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and 2-chlorophenetole.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[NH:18][N:17]=3)=[N:13][C:12]=2[CH:26]=1.C=O.[BH3-][C:30]#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH3:30])[CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[NH:18][N:17]=3)=[N:13][C:12]=2[CH:26]=1
Reactant: C[C@H]1CNCCN1c1ccc2[nH]c(-c3n[nH]c4cc(Cl)ccc34)nc2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1CN(C)CCN1c1ccc2[nH]c(-c3n[nH]c4cc(Cl)ccc34)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[6-((2S)-2-methylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole (1 equivalent) is dissolved in a mixture of MeOH and acetic acid (10: 1), on molecular sieves. Paraformaldehyde (10 equivalents) is added in one portion. The reaction mixture is stirred at room temperature overnight then solid NaCNBH3 is added in small portions. The reaction mixture is refluxed for 5 hours, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue is dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic solution is dried over Na2SO4, and the solvent removed under reduced pressure to afford the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:16]1([CH2:15][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A reaction mixture of methyl 3-(4-hydroxyphenyl)propanoate (commercially available, from Aldrich) (4.0 g, 22 mmol), 1-(bromomethyl)benzene (3.8 g, 22 mmol (commercially available from Aldrich)) and cesium carbonate (14.30 g, 44 mmol) in DMSO (20.0 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water (50.0 mL) and extracted with EtOAc (100.0 mL), and the organic layer was washed with water (3×30 mL) and brine (30 mL), and dried with MgSO4. The crude product was recrystallized with hexane/EtOAc (98/2) to the title compound 23.1. 1H NMR (500 MHz, CDCl3) δ ppm 2.65 (t, J=7.83 Hz, 2H) 2.94 (t, J=7.83 Hz, 2H) 3.71 (s, 3H) 5.08 (s, 2H) 6.95 (d, J=8.56 Hz, 2H) 7.16 (d, J=8.56 Hz, 2H) 7.34-7.50 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1nc2cc(CC(N)C(=O)O)ccc2o1
Product: Cc1nc2cc(CC(Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)ccc2o1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(2-methyl-benzooxazol-5-yl)-propionic acid to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23](Cl)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:25])[CH3:24])=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)cc(OC)c1
Temperature: 25 °C

Procedure:
After 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the ethyl acetate phase was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 249.1 mg.
Reaction SMILES: C([O:9][CH:10]1[O:42][C@@H:41]([CH3:43])[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]1[O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1>CO.C1COCC1>[C:13]([O:12][C@@H:11]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:41]([CH3:43])[O:42][CH:10]1[OH:9])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1OC(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1OC(O)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
The compound (V) (22.4 g, 38.6 mmol) is dissolved in MeOH:THF (3:7, 400 ml), and then NH3 gas is bubbled for 15 minutes at 0° C. and stirred at 0° C. for 1 hour. The reaction process is identified by thin layer chromatography while repeating the above process. The solvent is vacuum concentrated, and then the compound (VI) (16 g, 87%, α:β=14:1) is isolated using flash column chromatography (toluene/EtOAc, 10:1, v/v).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[C:10]([CH2:21][C:22]2([CH3:25])[CH2:24][O:23]2)=[C:9]([O:26]CC2C=CC=CC=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CO.[Pd]>[C:1]([O:5][C:6]([C:7]1[CH:12]=[C:11]([OH:13])[C:10]2[CH2:21][C:22]([CH2:24][OH:23])([CH3:25])[O:26][C:9]=2[CH:8]=1)=[O:34])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2(C)CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
A mixture of 3,5-bis-benzyloxy-4-(2-methyl-oxiranylmethyl)-benzoic acid tert-butyl ester (227b) (158 g, 0.343 mol), 10% Pd/C (15 g), Et3N (57.3 mL, 0.412 mol) and K2CO3 (56.94 g, 0.412 mol) in MeOH (1.5 L) was stirred under 760 mmHg of H2 at room temperature overnight. TLC (EtOAc/petroleum ether=1/3) showed that the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give a brown oil. The brown oil was further purified by prep. HPLC to give the title compound (18 g, 18.7% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.98 (s, 1H), 6.82 (s, 1H), 3.67 (d, 1H), 3.56 (d, 1H), 2.80 (d, 1H), 1.48 (s, 9H), 1.35 (s, 3H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:19]=[CH:18][C:17]2[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=2)[N:11]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:8][C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[C:12]2[C:17]=1[CH:18]=[N:19][C:10]([Cl:9])=[N:11]2
Reactant: Oc1cccc2cnc(Cl)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Oc1ccc(Br)c2cnc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Solid NBS (1 eq) was added to a stirred solution of 2-chloroquinazolin-8-ol (1 eq) (See example 1 for synthesis) in NMP at 0° C. under argon. After stirring at 0° C. for 30 min, LCMS showed that the reaction was complete. The formation of both 5-bromo (Major) and 7-bromo (Minor) isomers along with 5,7 dibromo product was observed. The reaction mixture was diluted with ethyl acetate and washed with satd. sodium bicarbonate, water and brine. Dried, filtered and concentrated. The crude was purified by flash chromatography (3-5% EtOAc/Hexane) to provide 5-bromo-2-chloroquinazolin-8-ol as a white solid in 60% yield. ES/MS m/z 259.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[C:11]([C:15]([O:17]C)=[O:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(=O)O)cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
A mixture of methyl 5-(benzyloxy)-1-methyl-1H-pyrazole-3-carboxylate (15.8 g, 64.0 mmol) and 8 M sodium hydroxide solution (20 mL) in tetrahydrofuran (100 mL) and methanol (100 mL) was stirred at 40° C. for 4 h. Solvent was removed and 6 M hydrochloric acid solution added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid (13.5 g, 91%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([O:10][C:11]([N:13]1[CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][NH:19][C:18](=O)[C:17]=3[C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([Cl:3])[C:17]=3[C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of phosphorous oxychloride (30 mL) was added triethylamine (30 mL) over 15 mins at 0° C. under argon. 4-oxo-3,5,6,8-tetrahydro-4H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (4.20 g, 14 mmol) was then added to the flask. The reaction mixture was stirred at 0° C. for 30 mins then heated at 65° C. for 2 h. The reaction mixture was cooled to rt before concentrated in vacuo. The residue was coevaporated with toluene (2×200 mL). DCM (50 mL) was added to the solid residue and the reaction mixture was quenched with ice/saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.08 g (12.5 mmol, 89%) of a light yellow solid. 1H-NMR (CD2Cl2-d2) δ 8.74 (s, 1H), 4.74 (s, 2H), 3.78 (t, 2H), 3.19 (t, 2H), 1.49 (s, 9H); LCMS RT=3.53 min, [M+H]+=326.0.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[C:6]([O:10][C:11](=[O:14])[NH:12][NH2:13])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([NH:12][N:13]=[CH:1][CH:2]([CH3:4])[CH3:3])=[O:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)C=NNC(=O)OC(C)(C)C

Procedure:
B-21a is prepared analogously to B-19a starting from isobutyraldehyde (1.26 mL, 13.9 mmol) and tert-butylcarbazate (1.83 g, 13.9 mmol). Yield: 2.56 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br.S([O-])([O-])=O.[Na+].[Na+].O>C(O)(=O)C>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(F)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(F)c(C(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
2-Fluoro-4-methoxybenzoic acid (10.0 g) was suspended in acetic acid (80 mL). To the suspension was slowly added dropwise bromine (20.7 g)/acetic acid (20 mL) solution. After completion of the dropwise addition, the mixture was stirred at 25° C. for 3 hr and further at 60° C. for 4 hr, the completion of the reaction was confirmed by HPLC. After cooling to room temperature, to the suspension was added dropwise an aqueous solution of sodium sulfite (9.63 g) and water (100 mL). After completion of the dropwise addition, the mixture was stirred at 25° C. for 2 hr, and then for 2 hr under ice-cooling. The precipitated crystals were collected by filtration, washed four times with water (30 mL), and vacuum dried to give 5-bromo-2-fluoro-4-methoxybenzoic acid as white crystals (14.5 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].C(OC([NH:29][C@H:30]1[C:34]2([CH2:36][CH2:35]2)[CH2:33][NH:32][CH2:31]1)=O)(C)(C)C>CS(C)=O>[NH2:29][C@H:30]1[C:34]2([CH2:36][CH2:35]2)[CH2:33][N:32]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[C@@H:13]3[CH2:15][C@@H:14]3[F:16])=[C:3]([CH3:21])[C:2]=2[F:1])[CH2:31]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Solvent: CS(C)=O
Product: Cc1c(F)c(N2C[C@@H](N)C3(CC3)C2)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of 200 mg of 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 287 mg of 7-(S)-t-butoxycarbonylamino-5-azaspiro[2.4]heptane, and 5 ml of anhydrous dimethyl sulfoxide was heated at 100° C. for 30 minutes with stirring. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated yellow crystals were collected by filtration and added to 5 ml of trifluoroacetic acid while stirring and cooling with ice, followed by stirring at room temperature for 30 minutes. The reaction mixture was further worked up in the same manner as in Example 7. Recrystallization of the crude crystal from ethanol gave 122 mg of the titled compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].CC(=CC)C.C([OH:18])(C)(C)C.[O-]Cl=O.[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:18])=[O:8]
Reactant: CC(C)(C)O
Reactant: O=Cc1scnc1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: O=C(O)c1scnc1Cl
Reaction time: 0.33 h

Procedure:
To a stirring mixture of 10.3 g (69.8 mmol) 4-chloro-thiazole-5-carbaldehyde (Journal of the Chemical Society, Perkins Transactions, 1992, 973-978), 296 ml (2792 mmol) 2-methyl-2-butene, and 200 mL tertiary butanol was added a solution of 50.5 g (558 mmol) NaClO2, 50.2 g (419 mmol) NaH2PO4 in 300 mL of water, dropwise over 20 minutes. The reaction was stirred for 1 hour then concentrated to 1/3 volume via rotary evaporation. The remaining solution was acidified with 6N HCl with rapid stirring. The precipitated solid was filtered and air dried under high vacuum overnight to give 10.6 g of white solid.