Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:19]N1C(=O)CCC1=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37]3=[N:40][C:41]([CH2:43][O:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[CH:42][N:36]3[C:35]2=[O:51])=[CH:30][CH:29]=1>ClCCCl>[Br:19][C:42]1[N:36]2[C:35](=[O:51])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[CH2:39][CH2:38][C:37]2=[N:40][C:41]=1[CH2:43][O:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)cn21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)c(Br)n21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.6 %

Procedure:
Benzoyl peroxide (7.2 mg, 0.03 mmol) was added to a stirred solution of N-bromosuccinimide (30.58 mg, 0.33 mmol) and 6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.3 mmol) in DCE (5 mL). The mixture was stirred at RT for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-bromo-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (57 mg, 35% yield) as a white solid.
Reaction SMILES: CS[C:3](=[N:8][CH:9]([CH3:11])[CH3:10])[S:4]([O-:7])(=[O:6])=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:15][CH:14]=1>C(#N)C>[CH:9]([NH:8][C:3]([S:4]([OH:7])(=[O:6])=[O:5])=[N:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:17][CH:18]=1)([CH3:11])[CH3:10]
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CSC(=NC(C)C)S(=O)(=O)[O-]
Solvent: CC#N
Product: CC(C)NC(=Nc1ccc(-c2c[nH]cn2)cc1)S(=O)(=O)O
Reaction time: 8 h

Procedure:
A solution of 1-methylthio-1-isopropylimino-methanesulfonate (6.8 g) in acetonitrile (150 ml) was added slowly to a solution of 4-(4-amino phenyl)-1-H-imidazole (5 g) in acetonitrile (250 ml) at room temperature. The reaction mixture was stirred overnight, and the product which crystallized out was collected by filtration to give the crude title compound, which was purified via its maleate in 95% ethanol. M.p. 209° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)C(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:46]=[CH:45][C:33]([CH2:34][NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.O>CN1CCCC1=O>[CH2:15]([C:13]1[N:14]=[C:3]2[C:2]([N:35]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:46][CH:45]=3)[CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[CH:12]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CC(C)Cc1cn2c(n1)c(Cl)nc1ccccc12
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3n3cc(CC(C)C)nc23)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of the 4-chloro-2-isobutylimidazo[1,2-a]quinoxaline (130 mg, 0.50 mmol) in 2 mL of 1-methylpyrrolidin-2-one was added N,N-diisopropylethylamine (129 mg, 1.0 mmol) and followed by bis(4-methoxybenzyl)amine (154 mg, 0.60 mmol). The reaction mixture was stirred at 120° C. overnight. And then 10 mL of water was added. The resulting mixture was extracted with ethyl ether (50 mL×3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (195 mg, 81%). MS: MH+=481 1H NMR (300 MHz, CDCl3): δ 7.72 (s, 1H), 7.65 (m, 2H), 7.21-7.39 (m, 6H), 6.84 (d, 4H), 5.34 (brs, 4H), 3.79 (s, 6H), 2.63 (d, 2H), 2.06 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH2:12])=[CH:5]2.[CH3:13][O-:14].[Na+]>CS(C)=O>[CH3:13][O:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH2:12])=[CH:5]2
Reactant: Nc1cc2cc(Br)ccc2cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2cnc(N)cc2c1
Temperature: 150 °C
Yield: 53.8 %

Procedure:
In a dry box, to the microwave test tube (20 ml volume) was added the 6-bromoisoquinolin-3-amine (1.0 g, 4.5 mmol) and the NaOMe (242.0 mg, 4.5 mmol) in 10 ml of DMSO. The microwave test tube was capped and moved from the dry box. The test tube was place into Microwave station to heat at 150° C. for 30 min. The crude residue was purified by a silica gel column to give 420 mg (yield 53.8%). 1H NMR (400 MHz, DMSO-d6) ppm 2.44 (s, 3H), 7.94-8.11 (m, 2H), 8.17 (d, J=8.56 Hz, 2H), 8.82 (s, 1H). MS m/z, (APCI); 175.1 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O1CCCC1.C1([Li])C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[N:38]/[S:39]([C:41]([CH3:44])([CH3:43])[CH3:42])=[O:40])=[CH:33][CH:32]=1.CO.C(O)(=O)C>>[C:41]([S:39]([NH:38][CH:37]([C:34]1[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=1)[C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][C:5]=1[C:14]([OH:16])=[O:15])=[O:40])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Cl)cc1
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1I
Agent: [Li]c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(Cl)cc1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylic acid (1.44 g, 3.96 mmol, prepared as in WO2009/154741) was suspended in anhydrous tetrahydrofuran (80.0 mL, 986 mmol), sonicated under nitrogen atmosphere for 10 min, and cooled in an acetone-dry ice bath for 10 minutes. Phenyllithium (1.8M in n-butyl ether, 8.81 mL, 15.9 mmol) was added dropwise over 7 minutes. The suspension was stirred with cooling for 5 minutes, at which point the cooling bath was removed and the suspension was stirred without cooling for 7 minutes. Reaction mixture was recooled in an acetone-dry ice bath for 10 minutes, at which point a solution of N-[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide (2.91 g, 11.9 mmol) in anhydrous tetrahydrofuran (20.0 mL, 246 mmol) was added dropwise over 8 minutes, and the mixture was stirred with cooling for 30 minutes. The mixture was quenched with methanol (5.0 mL, 120 mmol) and then acetic acid (1.0 mL, 18 mmol), and allowed to warm to room temperature. The volatiles were removed in vacuo, and the residue was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with 2×EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via column chromatography (gradient elution: AcOH/MeOH/DCM, 0/0/100 to 0.5/4.5/95) afforded 3-{[(tert-butylsulfinyl)amino](4-chlorophenyl)methyl}-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a mixture of diastereomers. Major diastereomer: 1.19 g, yield 62.2%. (FA) ES+ 482; ES− 480; 1H NMR (400 MHz, CDCl3) δ 7.31-7.33 (m, 2H), 7.15-7.17 (m, 2H), 6.14 (br s, 2H), 3.87-3.89 (m, 4H), 3.60-3.63 (m, 4H), 1.21 (s, 9H). Minor diastereomer: (0.292 g, yield 15.3%). (FA) ES+ 482; ES− 480; 1H NMR (400 MHz, CDCl3) δ 7.26-7.34 (m, 4H), 6.29-6.38 (m, br, 2H), 3.84-3.86 (m, 4H), 3.56-3.60 (m, 4H), 1.35 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[C:9]([CH3:14])=[N:10][O:11][C:12]=1[CH3:13])[C:3]([O:5]C)=[O:4].[Li+].[OH-].C(Cl)(Cl)Cl.CO.N.C([O-])(O)=O.[Na+].[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44](Cl)=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([NH:1][C@@H:2]([CH2:7][C:8]3[C:9]([CH3:14])=[N:10][O:11][C:12]=3[CH3:13])[C:3]([OH:5])=[O:4])=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)[C@@H](N)Cc1c(C)noc1C
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: N
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1noc(C)c1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 8 h

Procedure:
Methyl (S)-2-amino-3-(3,5-dimethyl-4-isoxazolyl)propionate (1.3 g, 6.6 mmol) was mixed with 2M LiOH (3.3 ml, 6.6 mmol) and dioxane (3.3 ml) at 0° C. and stirred overnight under N2. The next day a TLC control (CHCl3 /MeOH/NH3 aq 1/1/0.1) of the reaction mixture showed no ester present. 1M NaHCO3 (10 ml, 10 mmol) and 9-fluorenylmethyloxycarbonyl chloride (2.6 g, 10 mmol) dissolved in dioxane (10 ml) were added to the above solution and the stirring continued for a further hour. Dioxane was removed under reduced pressure and the aqueous solution acidified with a 10% KHSO4 solution to pH 2. The solution was extracted with CHCl3 (3×20 ml), dried (MgSO4) evaporated and purified by flash chromatography (Hexane/ethyl acetate/acetic acid 10/10/1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1>CN(C=O)C>[C:18]1([C:10]2[N:9]=[C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(N3CCNCC3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.7 %

Procedure:
Piperazine (3.22 g) was dissolved in DMF (830 mL), and 4-chloro-2-phenylquinazoline (3 g) was added thereto. The mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue and an insoluble material was filtered off. The organic layer of the filtrate was separated and extracted with 1 mol/L hydrochloric acid. The aqueous layer was basified with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure to give 1-(2-phenyl-4-quinazolinyl)piperazine (2.27 g) as a white solid.
Reaction SMILES: [F:1][C:2]1([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][NH:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:21]([O:30]N1C(=O)CCC1=O)([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=O>CC#N>[C:16]([O:15][C:14]([NH:13][C@@H:9]([CH2:8][C:2]1([F:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[CH2:10][N:11]([CH3:12])[C:21](=[O:30])[O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])=[O:20])([CH3:19])([CH3:17])[CH3:18]
Reactant: CNC[C@H](CC1(F)CCCCC1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: CN(C[C@H](CC1(F)CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
Crude (S)-tert-butyl 1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate and TeocOSu (137 mg, 0.5 mmol) were dissolved in 1:1 CH3CN/10% aqueous K2CO3 (20 mL). The mixture was stirred for 2 h. After this time all of the free amine was consumed. The CH3CN was removed in vacuo and the aqueous residue extracted with EtOAc (3×10 mL). The combine organic extracts washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography on silica, eluting with 0-27% EtOAc in hexanes, afforded (S)-2-(trimethylsilyl)ethyl 2-(t-butoxycarbonylamino)-3-(1-fluorocyclohexyl)propyl(methyl)carbamate (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl>CN(C=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 6 h
Yield: 60.5 %

Procedure:
To a mixture of the title compound of Example 113 (0.250 g) and triethylamine (0.09 mL) in 100 mL of 3:1 CH2Cl2MeOH is added 10% Pd/C (0.050 g). The mixture is hydrogenated at 30 psi H2 for 6 h. The reaction is filtered through celite and the filtrate is condensed. The crude product is dissolved in DMF (~25 mL) and acidified with 1 N HCl (25 mL). The resulting solid is collected, dried and recrystallized from EtOH to yield 0.152 g of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[CH3:8].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][C:2]=1[O:16][CH2:15][C:14]([F:18])([F:17])[F:13]
Reactant: COC(=O)c1cnc(Cl)c(C)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of methyl 5-chloro-6-methylpyrazine-2-carboxylate (3.00 g, 16.1 mmol), 2,2,2-trifluoroethanol (32.2 g, 322 mmol), and potassium carbonate (3.33 g, 24.1 mmol) in DMF (30 mL) is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is filtered off, and the filtrate is diluted with EtOAc (300 mL). The organic layer is washed with water (100 mL×3) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting EtOAc to give 3.91 g (97% yield) of the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[C:20]([F:31])[C:19]=2[CH3:32])=[C:14]([F:33])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)C)=[O:7].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[C:20]([F:31])[C:19]=2[CH3:32])=[C:14]([F:33])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
To a solution of isopropyl 2-[2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)-2-methyl-phenyl]methylamino]phenoxy]acetate (300 mg, 0.65 mmol, 1.0 eq) in a mixture of THF (10 mL) and MeOH (10 mL) was added NaOH (2M aqueous solution, 10 mL). The reaction mixture was stirred at room temperature for 3 h. The THF was evaporated in vacuo and the pH of the aqueous phase adjusted pH 3 with diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried to give the title compound as a white solid (104 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[C:3]=1[N+:12]([O-:14])=[O:13].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[C:4]([F:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1F
Reaction time: 2 h

Procedure:
To 4-chloro-2-fluoro-3-nitro-benzoic acid (5.0 g, 22.8 mmol) suspended in dry DCM (60 mL), was added DMF (0.5 mL) followed by the slow addition of oxalyl chloride (2.4 mL, 27.3 mmol, 2M in DCM). The mixture was stirred for 2 hrs, then concentrated to yield 4-chloro-2-fluoro-3-nitro-benzoyl chloride as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[O:34].ClC([O-])=O>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH2:37][O:38][CH3:39])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Yield: 54.5 %

Procedure:
At RT, triethylamine (260 mL, 1.87 mmol) was added to a mixture of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (300 mg, 0.94 mmol) in THF (9 mL). The mixture was cooled to −70° C. external temperature and 2-methoxyethyl chloroformate (0.1 mL, 0.89 mmol) was added dropwise. Once the addition of the chloroformate was complete, the reaction was quenched with H2O, and extracted three times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 2-10% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-2-methoxyethyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 14) (205 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.41 (m, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.72 (d, J=6.0 Hz, 1H), 7.58 (s, 1H), 7.38-7.32 (m, 2H), 6.94-6.90 (m, 2H), 4.25-4.01 (m, 6H), 3.88-3.85 (m, 1H), 3.49-3.47 (m, 2H), 3.23 (s, 3H), 2.49 (s, 3H), 2.26-2.17 (m, 1H), 2.07-2.01 (m, 1H) ppm. LC/MS: m/z 423.3 (M+H)+ at 2.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1>>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(I)cc1
Reactant: COCOc1cccc(B(O)O)c1
Product: CCOC(=O)Cc1ccc(-c2cccc(O)c2)cc1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 543 mg (3.6 mmol) of 3-methoxymethoxyphenylboronic acid with 700 mg (2.4 mmol) of ethyl 4-iodophenylacetate, 630 mg (68%) of the expected ethyl ester are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[N:9](OC(C)C)=[O:10].C(OCC)C.[ClH:20]>C(O)(C)C>[ClH:20].[OH:10][N:9]=[C:4]([C:5](=[O:7])[CH3:6])[CH2:3][N:2]([CH3:8])[CH3:1]
Reactant: CC(=O)CCN(C)C
Reactant: CC(C)ON=O
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(=O)C(CN(C)C)=NO
Reaction time: 0.5 h

Procedure:
To a solution of 4-dimethylamino-2-butanone[34.5 g, 0.3 moles, described by E. C. du Feu et al., J. Chem. Soc., 56 (1937)] in dry isopropanol (120 ml), gaseous hydrogen chloride is introduced at 0° C. until the solution is acidic to congo red (ca. pH=4). Isopropanol saturated with hydrogen chloride (2 ml) is added. Isopropyl nitrite (29.4 g, 0.33 moles) is added dropwise with stirring while maintaining the reaction temperature at 30° to 35° C. After 30 min, diethyl ether (100 ml) is added and the mixture is stirred for 30 min. The precipitate is collected to obtain 47 g of the title compound, mp 188°-199° C. The latter precipitate is crystallized from ethanol-diethyl ether to obtain 32 g of title compound; mp 205°-206° C., nmr(DMSO-d6) δ 2.4(s), 2.75(s), 4.07(s) and 12.35(broad singlet).
Reaction SMILES: [C:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH2:6]1)(=[O:3])[CH3:2].O.[C:11]([O:15][CH2:16][CH:17]=[CH2:18])(=[O:14])[CH:12]=[O:13]>C1C=CC=CC=1>[CH2:16]([O:15][C:11]([CH:12]([OH:13])[N:8]1[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1=[O:9])=[O:14])[CH:17]=[CH2:18]
Reactant: CC(=O)SC1CC(=O)N1
Reactant: C=CCOC(=O)C=O
Solvent: c1ccccc1
Solvent: O
Product: C=CCOC(=O)C(O)N1C(=O)CC1SC(C)=O

Procedure:
4-Acetylthioazetidin-2-one (Annalen, 1974, p. 553) (1.4 g) and allyl glyoxylate hydrate (1.5 g) are refluxed for 2 hours in benzene to afford a solution of 1-(allyloxycarbonylhydroxymethyl)-4-acetylthioazetidin-2-one which is cooled and used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[C:14]([O:28][CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.BrC1N=C(NC2C=CC(N3CCN(C4COC4)CC3)=CC=2)C2N(C=CN=2)C=1.BrC1N=C(N(C2C=CC(N3CCN(C4COC4)CC3)=CC=2)[C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79])C2N(C=CN=2)C=1>>[Br:1][C:2]1[N:3]=[C:4]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:22][CH2:23]3)=[C:14]([O:28][CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:13]=2)[C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Nc2ccc(N3CCN(C4COC4)CC3)c(OCCOC3CCCCO3)c2)n1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCN(C3COC3)CC2)cc1)c1nc(Br)cn2ccnc12
Agent: Brc1cn2ccnc2c(Nc2ccc(N3CCN(C4COC4)CC3)cc2)n1
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1)c1nc(Br)cn2ccnc12

Procedure:
6-Bromo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)imidazo[1,2-a]pyrazin-8-amine XXV (1.2 g, 2.4 mmol) was reacted according to the analogous method described in Intermediate Example 1.01 (conversion of III to IV) to provide tert-butyl (6-bromoimidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)carbamate XXVI.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=[O:7].[C:13]([OH:23])(=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O.[B]>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[O:23][C:13](=[O:22])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:7]1
Reactant: O=CCOc1ccc(Cl)cc1Cl
Reactant: O=C(O)C(O)c1ccccc1
Agent: [B]
Solvent: CCOCC
Product: O=C1OC(COc2ccc(Cl)cc2Cl)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A solution containing 5.1g (0.025 mole) of 2,4-dichlorophenoxyacetaldehyde, 4.25g (0.028 mole) of mandelic acid, and 10.0g (0.07 mole) of boron trifluoide etherate in 250 ml of ether was allowed to stir for 2 hours at ambient temperature, washed with aqueous sodium carbonate and water, dried and concentrated. The residual solid was purified by silica chromatography to give 2.7g of 2-(2,4-dichlorophenoxymethyl)-5-phenyl-1,3-dioxolan-4-one, trans isomer, having a melting point of 68°-71°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:8]([CH:7]([OH:12])[C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:19][CH:20]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C(=O)c1ccc(CO)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 2.7 grams (0.070 mole) of lithium aluminum hydride in 170 milliliters of dry tetrahydrofuran is cooled to 0° and treated by dropwise addition with 6.7 grams (0.035 mole) of p-pivaloyl benzyl alcohol in 70 milliliters of dry tetrahydrofuran. The resulting mixture is stirred for 5 hours at room temperature, and then cooled to 0° C. and treated by dropwise addition with saturated sodium sulfate solution. The mixture is filtered and the filter cake is washed thoroughly with tetrahydrofuran. The tetrahydrofuran is dried over magnesium sulfate, filtered and evaporated to give α-t-butyl-p-xylene-α,α'-diol, m.p. 91° to 95° C.