Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)=[CH:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: NCCCCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 63.9 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and putrescine (3.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(4-aminobutylamino)-cholest-7-en-3β-ol as a white solid (6.9 g, 64%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 23% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[CH:10](O)[C:11]4[CH:12]=[CH:13][C:14]([Br:21])=[CH:15][C:16]=4[CH:17]([OH:20])[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[CH2:10][C:11]4[CH:12]=[CH:13][C:14]([Br:21])=[CH:15][C:16]=4[C:17](=[O:20])[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26]
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(O)c1cc(Br)ccc1C3O
Agent: Cl
Product: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1cc(Br)ccc1C3
Reaction time: 5 h
Yield: 939.8 %

Procedure:
2,9-Dibromo-13,13-dimethyl-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (15 g, 1 eq, 0.003 mol) was placed in a flask, and 5N HCl (100 ml) was added thereto. The reaction mixture was stirred for five hours while heating. The resultant solid was filtered, several times washed with distilled water and dried to give 2,9-dibromo-13,13-dimethyl-6H-indeno[1,2-b]anthracen-11(13H)-one (13.2 g, yield=92%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH:11]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:3]=2[O:2]1.[Na].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27]Cl>C(O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][C:11]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:14][NH:13][C:12]1=[O:15]
Reactant: CCOC(=O)C1C(=O)NCC1c1ccc2c(c1)OCO2
Reactant: COc1ccc(CCl)cc1OC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=O)NCC1c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A solution of 9.9 g of ethyl 4-(3,4-methylenedioxyphenyl)-2-oxo-3-pyrrolidinecarboxylate in 40 ml of absolute ethanol is added to a solution of 0.9 g of sodium in 50 ml of absolute ethanol at room temperature with stirring. The stirring is continued for one hour. To the mixture is added 8 g of 3,4-dimethoxybenzyl chloride. The resulting mixture is held at room temperature with stirring for one hour and then refluxed for an additional two hours. The ethanol is then removed under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 11.5 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-methylenedioxyphenyl)-2-oxo-3-pyrrolidinecarboxylate, melting at 167°-168°C.
Reaction SMILES: [C:1]1([S:7][C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[N:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.NC1CC2CCN1CC2>C(Cl)Cl.CO>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[C@@H:23]([NH:22][C:13]([C:11]1[S:12][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][N:10]=1)=[O:15])[CH2:24]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1nnc(Sc2ccccc2)s1
Agent: NC1CC2CCN1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1nnc(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acid (3.76 mmol) is placed in a flask and put under nitrogen. The acid is chilled in an ice bath. Oxalyl chloride (9 mL) that has also been cooled in an ice bath is added drop wise to the acid. The excess oxalyl chloride is removed under reduced pressure. The acid chloride is dissolved in about 5 mL CH2Cl2. The freebase of (R)-3-aminoquinuclidine (0.5 g, 2.52 mmol, 0.67 eq) is also dissolved in CH2Cl2 (5 mL), and the solution containing the acid chloride is cannulated into the flask containing the aminoquinuclidine. The reaction is stirred overnight at room temperature. The reaction mixture is diluted with MeOH, and poured through a Dowex 50AGWX2 CH+ column. The impurities are removed by washing the column with MeOH, and the product is eluted by washing the column with a solution containing 5% TEA in MeOH. The solvent is removed under reduced pressure, and the product is further purified by silica gel chromatography using a Biotage Flash 40M column (5% MeOH/CH2Cl2). This gives Example 64 (0.289 g, 22%) as a tan oil. MS (ESI) for C16H18N4OS2 m/z 347.2 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[NH:12][C:11](=[O:20])[N:10]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:9]2=[O:26])(=[O:5])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O.Cl>C1COCC1.CO.CCOC(C)=O>[OH:5][CH:1]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16]([F:18])([F:17])[F:19])[NH:12][C:11](=[O:20])[N:10]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:9]2=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
To a solution of N-(6-butyryl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (131 mg, 0.333 mmol) in THF (3 mL) and MeOH (3 mL) was added NaBH4 (131 mg, 3.32 mmol) portionwise over 10 min at r.t. The reaction mixture was stirred at r.t. for 18 h, poured onto a mixture of water and EtOAc then adjusted to pH 3-4 by addition of 1N aq HCl. The organic phase was washed twice with brine, dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (10 g silica gel, DCM/MeOH (1:0→9:1) to afford the title compound (94 mg, 71%) as colorless crystals. m.p.: 223-226° C., ESI-MS: m/z 396 [M+H]+, m/z 394 [M−H]−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]([O:24]C(C)C)=[O:23])[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)(=[O:4])=[O:3].O.[Li+].[OH-].CO>C1COCC1.ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23])[N:16]=2)[CH:8]=[C:9]([C:11]([F:13])([F:12])[F:14])[CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(-c2ncn(/C=C\C(=O)O)n2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.1 %

Procedure:
In a 1-neck 25 mL round-bottomed flask, (Z)-isopropyl 3-(3-(3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (0.350 g, 1.0 eq.), was dissolved in THF (3.5 mL, 5 vol.), added water (3.5 mL, 3.5 Vol) and added LiOH (0.053 g, 1.5 eq.). Reaction mixture was stirred at RT for 2-3 hrs. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol: dichloromethane as mobile phase and visualization with UV, SM Rf=0.35 and Product Rf=0.15. Reaction mixture was quenched into the acidic ice-water slurry (30 mL) and extracted in the ethyl acetate (25 mL×3). Organic layer was washed with sodium bicarbonate solution (50 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 270 mg of crude compound. The resulting crude compound off white was used for further stage, yield (83%); Mass: (ES+) 361.8 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][C:24]2[S:23][C:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:21][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1nc(-c2ccccc2)sc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccccc3)nc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with (4-methyl-2-phenyl-thiazol-5-yl)-methanol in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-[3-fluoro-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-[3-fluoro-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>ClCCl>[N+:18]([C:21]1[CH:22]=[C:23]([S:27]([O:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:13]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCOS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: -25 °C
Yield: 47 %

Procedure:
2-[4-(tert-butoxycarbonylamino)phenyl]-1-ethanol dissolved in dichloromethane. The reaction mixture was cooled to −25° C. and 9.34 g (42 mmole) 3-nitrobenzenesulfonyl chloride was added in portions. The reaction mixture was poured on to icewater, the phases were separated and the organic phase was dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using dichloromethane as eluent to give 8.3 g (yield 47%) 4-(tert-butoxycarbonylamino)-phenethyl 3-nitro-benzenesulfonate as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH:8]=2)[N:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[OH:25])[CH:8]=2)[N:3]=1
Reactant: Nc1nc2ccc(-c3ccccc3C(=O)C3CCOCC3)cc2cc1N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2ccc(-c3ccccc3C(O)C3CCOCC3)cc2cc1N1CCOCC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
(2-(2-Amino-3-morpholinoquinolin-6-yl)phenyl)(tetrahydro-2H-pyran-4-yl)methanone (0.164 g, 0.393 mmol, see Example 11) was dissolved in MeOH (20 mL) and treated with sodium borohydride (0.021 mL, 0.589 mmol). After 10 min, the solution was heated to 40° C. for an additional 15 minutes, then evaporated to dryness under reduced pressure. The crude material was partitioned between water (20 mL), saturated sodium bicarbonate (20 mL), and ethyl acetate (40 mL). The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure and the crude material was purified by silica chromatography (10-100% hexane in ethyl acetate gradient. The product peak which eluted was concentrated to give (2-(2-amino-3-morpholinoquinolin-6-yl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol. MS (ESI, pos. ion) m/z: 420 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].Cl[C:16]([O:19]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][N:5]1[CH2:6][C:7]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:13][C:16]1=[O:19]
Reactant: COC(=O)CNCc1ccccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CN1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2-Amino-benzylamino)-acetic acid methyl ester (0.50 g, 2 mmol) and bis(trichloromethyl)carbonate (0.54 g, 2 mmol) are dissolved in dioxane (5 ml) and stirred at RT for 24 hours. The reaction mixture is treated with water and extracted with EtOAc, the organic phase is dried over MgSO4, filtered and is concentrated in vacuo. Purification by flash column chromatography on silica, eluting with DCM:MeOH (10:1) affords the title compound. [M+H]+ 221.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Reactant: Fc1cccc(CBr)c1
Product: CC(C)(C)C(=O)Nc1cccc(COCc2cccc(F)c2)n1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(6-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.73 g) and 3-fluorobenzyl bromide as a yellow solid(0.66 g). MS (ESI): 317.1 (MH+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18]2.CI.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH:19]([CH3:1])[CH2:18]2
Reactant: CC(C)NC(C)C
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)CC(C)C2=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of diisopropylamine (5.2 mL, 36.9 mmol), in THF (20 mL) is added n-BuLi (14.8 mL, 36.9 mmol, 2.5 M in hexane) at −78° C. After 30 min, 5-methoxyindan-1-one (5.0 g, 30.8 mmol) in THF (35 mL) is added. After it is stirred at −78° C. for 1 h, the mixture is warmed to 10° C. for 30 min. The mixture is cooled again to −78° C. and methyl iodide (2.3 mL, 36.9 mmol) is added. The mixture is then warmed to RT over 1 h. NH4Cl solution is added and extracted with EtOAc. The organic extract is dried with MgSO4, concentrated and purified by chromatography to give the title compound (2.38 g): (M+H)+=177.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:13])[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>CN(C=O)C>[NH:30]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[O:13])[N:3]=2)=[N:31]1
Reactant: Nc1cc[nH]n1
Reactant: O=C(c1cccc(F)c1)c1nc(Cl)c2ccccc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(F)c1)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of (4-chloroquinazolin-2-yl)(3-fluorophenyl)methanone from Example 1 (57 mg, 0.20 mmol) in DMF (3 mL), DIEA (0.069 mL, 0.4 mmol) and 1H-pyrazol-3-amine (83 mg, 1 mmol) were added. The mixture was stirred at 50° C. for 2 h. The reaction was quenched by adding water and the precipitate was filtered. The crude solid was purified on preparative TLC using DCM/MeOH as mobile phase to afford (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)(3-fluorophenyl)methanone (18 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ 6.80 (s, 1H), 7.67-7.61 (m, 4H), 7.92-7.84 (m, 4H), 8.78 (m, 1H), 10.82 (s, 1H), 12.54 (s, 1H); LC-MS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4]([O:7][C@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([C:14]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])=O)[CH2:9]1)(=[O:6])=[O:5].CO>O1CCCC1.C(OCC)(=O)C>[CH3:3][S:4]([O:7][C@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([CH2:14][N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:9]1)(=[O:5])=[O:6]
Reactant: CN1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCNC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNC1=O
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a solution of sodium borohydride (0.60 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride ether complex (5.8 ml) under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. To the mixture was added a solution of (2S,4R)-4-methanesulfonyloxy-1-methyl-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (2.3 g) in tetrahydrofuran (15 ml) and the mixture was stirred at the same temperature for 5 hours. To the reaction mixture was added dropwise methanol (15 ml) under ice-cooling. The mixture was filtered off and the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (50 ml) and conc. hydrochloric acid (2 ml) and the solution was stirred at ambient temperature overnight The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.89 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH2:4].Cl.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Cl)[CH:7]=1>>[CH3:3][NH:4][CH2:12][C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1cccnc1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To 25 ml of a 20% aqueous solution of NaOH stirred under cooling with ice-water, a 40% aqueous solution of methylamine (13.6 g, 0.175 mole) was added dropwise over 5 minutes, followed by further dropwise addition of an aqueous solution (10 ml) of 8.2 g (0.05 mole) of 3-pyridylmethyl chloride hydrochloride over 10 minutes. The mixture was further stirred at room temperature for 2 hours and, then, extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove the solvent. The residue was subjected to vacuum distillation to give 2.6 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (tert-butyl)(phenylsulfonyl)amine (17.43 g, 81.83 mmol) in 180 ml dry THF in an ice bath was added nBuLi (66 ml, 2.5M in hexanes) via addition funnel. Then triisopropyl borate (33 ml, 143.06 mmol) was added via addition funnel. The mixture was warmed to room temperature and allowed to stir for 4 hr. The reaction mixture was then cooled in an ice bath before HCL (82 ml, 3M) was added dropwise. This was allowed to stir at room temperature for 3 hr. The mixture was then put in the freezer over the weekend. The reaction was then warmed to room temperature and extracted with ether. The aqueous layers were washed twice more with ether. The combined organic layers were washed three times with 5M NaOH aqueous solution. The combined basic layers were acidified to pH=1 with 6M HCL solution. These acidified layers were then extracted three times with ether. These ether layers were then dried over MgSO4, filtered, then concentrated in vacuo to about 50 ml solution. To this solution was added hexanes and a minimal amount of ethyl acetate. A white precipitate is observed and the mixture in stored in the freezer to allow for crystallization. The white solid is then filtered and collected (14.65 g, 57 mml, 70%) ES-MS(M+H)+=258.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C1(O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(#N)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[O:16][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
To a 200 gallon reactor was added 582 pounds (%Wt/Wt Phenol to Solvent--14.1%) of acetonitrile, followed by 82 pounds (0. 323 mole--1.0 equiv.) of 87% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, 72.4 pounds (0.717 mole--2.22 equiv.) of triethylamine, and 99.0 pounds (0.717 mole--2.22 equiv.) of potassium carbonate. The mixture was heated to 70° C., and 90.1 pounds (0.539 mole--1.67 equiv.) of methyl 2-bromopropanoate was added during a two hour period a rate to maintain the reaction temperature at 65-70° C. Upon completion of addition, the reaction mixture was stirred at to 65-70° C. for seven hours. After this time, the reaction mixture was analyzed by GC, which indicated that 8% of the phenol starting material remained. An additional 9.0 pounds (0.054 mole--0.16 equiv.) of methyl 2-bromopropanoate, 8.0 pounds (0.058 mole--0.17 equiv.) of potassium carbonate, and 4.0 pounds (0.040 mole--0.12 equiv.) of triethylamine were added. Upon completion of addition, the reaction mixture is stirred at 65-70° C. for an additional hour. At the conclusion of this period, the reaction mixture is filtered, and the filtrate was concentrated under vacuum at 70° C. to yield an oil. The oil was taken up in 213 pounds of toluene and 185 pounds of a 2.5% aqueous sodium carbonate solution. The organic layer is separated from the aqueous layer and concentrated under vacuum at 90° C., yielding 106.0 pounds of 86.2% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]propanoate (92% yield).