Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[C:41]([F:44])([F:43])[F:42])=[CH:28][CH:27]=1>>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][NH:19][C:17]([C:15]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=1)=[C:2]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[C:41]([F:44])([F:42])[F:43])=[CH:28][CH:27]=1)[CH:11]=[CH:10][N:9]=3)=[O:18]
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccc(NC(=O)c5ccc(F)cc5C(F)(F)F)cc4)c3c2c1
Yield: 48.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 296 (40 mg, 0.12 mmol), and N-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl)benzamide (36 mg, 0.12 mmol) to provide 297 (35 mg, 50% yield) as a solid. LC-MS (M+H=607, obsd.=607).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH3:17])([S:7]([CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:9])=[O:8])[CH3:6])C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[CH3:17][C:5]([S:7]([CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 123 g (0.44 mol) of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid ethyl ester in THF (450 mL) are added 663 mL of 2M aqueous sodium hydroxide solution (1.33 mol). The reaction is stirred at room temperature for 1 h. To the reaction mixture is added TBME (1.25 L) and the layers are separated. The aqueous layer is cooled in an ice bath and then acidified with 37% aqueous HCl solution (123 mL). The resulting precipitate is isolated by filtration, washed with water (200 mL) and dried under reduced pressure at 50° C. to afford 101 g of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid as white crystalline solids. Yield: 91%; ES-MS: m/z 251 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.45 (2H, m), 1.49 (6H, s), 1.70-1.79 (2H, m), 2.13-2.28 (1H, m), 3.24 (2H, d, J=6.60 Hz), 3.28-3.38 (2H, m), 3.76-3.85 (2H, m), 13.65 (1H, br. s.)
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](Cl)=[O:27]>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:27]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4(R)-phenyl-2-oxazolidinone (340 g, 2.08 mol) in THF (8000 mL), is added n-BuLi (2.5 M, 920 mL, 1.1 eq). The reaction mixture is stirred for 20 minutes and 2-fluorobenzeneacetyl chloride (358 g, 2.08 mol) is added. After 2 hours the reaction mixture is quenched with saturated NH4Cl solution (1×1000 mL). The organic layer is separated, washed with H2O (1×1000 mL), saturated NaCl solution (2×1000 mL) and then concentrated in vacuo. This procedure yields 3-[(2-fluorophenyl)-acetyl]-4(R)-phenyl-2-oxazolidinone.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:31][CH3:32])[CH:23]=2)[CH2:18][CH2:17]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:31][CH3:32])[CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1ccc2c(c1)C1(CCNCC1)C(=O)CC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1)C1(CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC1)C(=O)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,4-dihydro-2-oxo-7-methoxyspiro[naphthalene-1(2H),4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 55% overall yield. FDMS m/e=434 (M+ of free base). α[D]589 =-5.55 (c=0.54, methanol).
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27].[CH2:31]=O>C(O)(=O)C>[CH2:26]([N:28]([CH2:31][C:22]1[O:23][C:17]2[CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:25][CH:24]=3)[CH2:20][CH2:19][C:18]=2[CH:21]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: C=O
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: CCNCC
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.527 g (1.590 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.20 ml (1.9 mmol) of diethylamine and 0.15 g (1.9 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=9/1) to yield the desired product.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27]1.[CH2:34]([S:36]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH:47]=O)[C:42]#[N:43])(=[O:38])=[O:37])[CH3:35].[F:49][C:50]([F:62])([F:61])[C:51]1[CH:52]=[C:53]([NH:57][C:58]([NH2:60])=[O:59])[CH:54]=[CH:55][CH:56]=1>COC(C)(C)C>[O:59]=[C:58]1[NH:60][CH:47]([C:46]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=2[S:36]([CH2:34][CH3:35])(=[O:37])=[O:38])[C:27]2[C:26](=[O:33])[CH2:31][CH2:30][CH2:29][C:28]=2[N:57]1[C:53]1[CH:54]=[CH:55][CH:56]=[C:51]([C:50]([F:49])([F:61])[F:62])[CH:52]=1
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOP(=O)(OCC)OCC
Solvent: COC(C)(C)C
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 50 °C

Procedure:
A mixture of triethyl phosphate (4.6 mL, 26.9 mmol) and phosphorous pentoxide (2.54 g, 17.9 mmol) is heated at 50° C. over night and dilutet with tert-butyl methyl ether (45 mL). Cyclohexane-1,3-dione (3.77 g, 33.6 mmol), 3-(ethylsulfonyl)-4-formylbenzonitrile (5.00 g, 22.4 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (4.57 g, 22.4 mmol) are added, and the mixture is heated at reflux for 4 h. The mixture is cooled at room temperature and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 930 mg; ESI mass spectrum [M+H]+=504; Retention time HPLC: 1.02 min (Z017_S04).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+].[F:13][C:14]([F:20])([CH3:19])[C:15]([F:18])([F:17])O.F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>>[F:13][C:14]([F:20])([CH:15]([F:18])[F:17])[CH2:19][O:2][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(F)(F)C(O)(F)F
Agent: [K+]
Agent: [Na+]
Product: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
138.2 g of potassium carbonate, 21.2 g of sodium carbonate, 198 g of tetrafluoropropanol and 124 g of 4-fluorobenzaldehyde are introduced at room temperature under argon protective gas and heated for 20 hours at 140° C. The boiling point of the reaction mixture is initially 125° C. As the reaction progresses, the internal temperature rises to 140° C. After 20 hours, the mixture is cooled to 25° C and filtered. This gives 229.6 g of filtrate containing 72% of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde. The filter cake is washed 3 times using in each case 100 ml of toluene. Filtrate and toluene used for washing are collected separately. After 63.9 g of 2,2,3,3-tetrafluoropropanol have been distilled off from the filtrate, the distillation residue is combined with the toluene used for washing. After the toluene has been distilled off under atmospheric pressure, the residue is fractionated in vacuo at 3 mbar and a bottom temperature of up to 135° C. and a head temperature of 109° C. to 110° C. As the main fraction, 188.7 g of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde with a purity (GC) of 98% to 99% are obtained.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Mg]Cl)(C)C.[CH:24](=[O:27])[CH2:25][CH3:26].[NH4+].[Cl-]>C1COCC1>[OH:27][CH:24]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH2:25][CH3:26]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: CCC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
124-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.2 g, 6.21 mmol) in dry THF (150 mL) was cooled to −78° C. under Ar, and a 2M solution of iPrMgCl in THF (18.6 mL, 37.3 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and propionaldehyde (3.61 g, 62.1 mmol) was then added. The mixture was stirred at −78° C. for another 30 min and then allowed to warm to RT overnight. The reaction mixture was poured onto a saturated aq. solution of NH4Cl and extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, heptane to AcOEt/MeOH 9:1) to give the title compound (231 mg). UPLC-MS: MS 287.2 (M+H+); UPLC rt 0.59 min.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:10]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[O:12][N:11]=1)([CH3:9])[CH3:8].[Cl:22][C:23]1[C:28]([CH3:29])=[C:27](Cl)[N:26]=[CH:25][N:24]=1>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([O:21][CH:18]2[CH2:17][CH2:16][N:15]([C:13]3[O:12][N:11]=[C:10]([CH:7]([CH3:9])[CH3:8])[N:14]=3)[CH2:20][CH2:19]2)[C:28]=1[CH3:29]
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Temperature: 30 °C
Reaction time: 20 h
Yield: 62.5 %

Procedure:
Potassium tert-butoxide (478 mg, 0.00426 moles) was added to a solution of 1-(3-iso-propyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (0.9 gm, 0.00426 moles) and 4,6-dichloro-5-methylpyrimidine (690 mg, 0.00426 moles) in dry THF (30 ml) at 0° C. and the reaction mixture was stirred for 20 hours at 30° C. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 900 mg product as off white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:16][C:15]3[C:10](=[C:11]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.Cl[C:39]1[N:47]=[CH:46][N:45]=[C:44]2[C:40]=1[NH:41][CH:42]=[N:43]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][NH:19][C:39]3[N:47]=[CH:46][N:45]=[C:44]4[C:40]=3[N:41]=[CH:42][NH:43]4)=[CH:16][C:15]3[C:10](=[C:11]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(C)(C)OC(=O)NCc1cc2cccc(S(C)(=O)=O)c2nc1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)nc12

Procedure:
tert-Butyl (2-(3-fluorophenyl)-8-(methyl sulfonyl)quinolin-3-yl)methylcarbamate (18 mg, 0.042 mmol) was treated with 50% TFA in DCM (1 mL) for 30 min at rt and the reaction mixture was concentrated to driness. The resulted solid was treated with 6-chloropurine (7.1 mg, 1.1 eq) and hunig's base (0.04 mL, 4 eq) in BunOH (1 mL) at 90° C. HPLC on reverse phase gave a white solid. 1H-NMR (400 Hz, CD3OD) δ 8.47 (s, 1H), 8.38 (dd, J=8.0, 4.0 Hz, 1H), 8.24 (s, 1H), 8.18 (dd, J=8.0, 4.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.50-7.39 (m, 3H), 7.11 (t, J=8.0 Hz, 1H), 5.24 (s, 2H), 3.45 (s, 3H). Mass Spectrum (ESI) m/e=449 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].C1(NC2CCCCC2)CCCCC1.[OH:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29])[O:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of isobutyl chloroformate (26 ml, 200 mmole) in 600 ml of chloroform was added in portions the dicyclohexylamine (DCHA) salt of N-hydroxysuccinimide (HOSu, 49.28 g, 200 mmole). After stirring the resulting suspension overnight, the precipitated DCHA hydrochloride was filtered off and washed with chloroform. The concentrated filtrate (ca. 50 ml) and washings were diluted with 400 ml of ethyl acetate (EtOAc) and washed with 10% citric acid (4×100 ml), brine (2×100 ml), 10% sodium bicarbonate (3×100 ml), and brine (4×100 ml) and then dried (magnesium sulfate), filtered, and concentrated to ca. 100 ml. On diluting with ether and precipitating with hexane, 26.6 g (62% yield) of iBuOCO-OSu was obtained, mp 33°-35° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[O:16][CH:15](C3C=CC=CC=3)[CH2:14]2)[N:10]=[C:9]1SCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:38].[I-].N.CO>CO.CCO>[NH2:38][C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12](=[O:13])[C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[O:16][CH:15]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14]2)[N:10]=1
Reactant: [NH4+]
Reactant: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Agent: N
Agent: [I-]
Solvent: CO
Solvent: CCO
Product: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1Cc1ccccc1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg, 0.10 mmol) in MeOH/EtOH (1:1, 2 mL) in a 10 mL CEM microwave test tube was added NH4I (50 mg, 0.34 mmol) and NH3/MeOH (7 N, 2 mL). The resulting mixture was heated in a CEM microwave reactor at 120° C. for 60 min. The cooled mixture was concentrated in vacuo and the residue was purified by reversed phase. HPLC to give 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 34%) as a TFA salt. MS m/z 462 (M+H+).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:16])([O:3]C)=[O:2].O.[OH-].[Na+]>CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:16])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCCCC(=O)Nc1ccccc1OCCCC(=O)O
Yield: 96 %

Procedure:
To a stirred solution of (8) (1.0 g, 2.22 mM) in methanol (100 mL) is added 1 mL of water followed by dropwise addition of 2.5N sodium hydroxide solution (4.0 mL). The walls of the reaction flask are rinsed down with 10 mL of methanol and the mixture is stirred under a nitrogen atmosphere until TLC analysis shows no ester (mono- or di-) remaining. The methanol is removed in vacuo, the residue taken up in 100 mL of water, stirred for solution, filtered (20 mL water rinses), and the stirred filtrate acidified dropwise with 2N hydrochloric acid. Filtration of the resultant precipitate followed by copious water washing and drying gave 0.87 g (96%) of (9) as a chalk-like white solid. The compound was one component by TLC (silica gel, the eluant was 10 mL of 2% methanol in methylene chloride containing 4 drops of glacial acetic acid). mp 128.5°-130° C. uncorr.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=2)[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](Cl)=[CH:28][CH:27]=2)=[O:23])=[N:6][C:7]=1[C:8]1[NH:12][C:11]([C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][N:9]=1.[ClH:36]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=2)[C:22]([NH:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([Cl:36])[CH:31]=2)=[O:23])=[N:6][C:7]=1[C:8]1[NH:12][C:11]([C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][N:9]=1
Reactant: Cl
Reactant: Nc1ncc(-c2cccc(C(=O)NCc3ccc(Cl)cc3)c2)nc1-c1nnc([C@H]2CCCNC2)[nH]1
Product: Nc1ncc(-c2cccc(C(=O)NCc3cccc(Cl)c3)c2)nc1-c1nnc([C@H]2CCCNC2)[nH]1

Procedure:
3-(5-amino-6-{5-[(3S)-piperidin-3-yl]-4H-1,2,4-triazol-3-yl}pyrazin-2-yl)-N-[(4-chlorophenyl)methyl]benzamide): 1H NMR (400 MHz; DMSO-d6): 9.3 (t, 1H); 8.9 (m, 2H); 8.67 (s, 1H); 8.4 (d, 1H); 7.8 (d, 1H); 7.7 (m, NH); 7.6 (t, 1H); 7.2 (m, 4H); 4.5 (d, 2H); 3.6 (d, 1H); 3.4-3.1 (m, 3H); 3.0 (m, 1H); 2.1 (m, 1H); 1.8 (m, 3H); MS (EI) for C25H25N8OCl HCl: 489 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.CCN(CC)CC.Cl[CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:41]([CH:40]=[CH2:39])(=[O:43])=[O:42])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)Nc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.14 mL (1.0 mmol) of Et3N in 4 mL of THF was added 0.063 mL (0.6 mmol) of 2-chloroethanesulfonyl chloride. The solution was stirred 1 h, warming to ambient temperature. The solution was poured into 10% aq. citric acid and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO4), and concentrated under reduced pressure. The crude product was chromatographed (elution with 1:1 EtOAc-hexanes) to afford 221 mg (80%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. 1H NMR (300 MHz, DMSO) δ 12.47(br. s, 1H); 9.92(br. s, 1H); 7.97(s, 2H); 7.17(d, 2H, J=8.4 Hz); 7.02(d, 2H, J 8.4 Hz); 6.69(dd, 1H, J=16.5, 9.9 Hz); 6.04(d, 1H, J=16.5 Hz); 5.96(d, 1H, J=9.9 Hz); 3.78(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].O>CO>[Cl:3][C:4]1[C:5]([CH2:6][OH:7])=[CH:8][CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cccc(O)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of sodium borohydride (724 mg, 19.2 mmol) in anhydrous methanol (10 mL) was added a solution of 2-chloro-3-hydroxybenzaldehyde (1.0 g, 6.4 mmol) in anhydrous methanol (5 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, 2-chloro-3-(hydroxymethyl)phenol was obtained (710 mg, 70% yield) and used for next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 4.51 (d, J=5.8 Hz, 2H), 5.28 (t, J=5.8 Hz, 1H), 6.84-6.87 (m, 1H), 6.96-6.99 (m, 1H), 7.12 (t, J=7.8 Hz, 1H), 10.02 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[CH3:21])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][CH2:9][C@@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[CH3:21])[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1cc(Br)ccc1[C@@H](CO)COCc1ccccc1
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
To 16E (8.0 g, 22.91 mmol), 4-methylmorpholine (3.02 mL, 27.5 mmol) in THF (100 mL) at −20° C. was added ethyl chloroformate (2.420 mL, 25.2 mmol). The mixture was stirred for 20 min. The cloudy reaction mixture was filtered. The filtrate was treated with sodium borohydride (1.213 g, 32.1 mmol) and MeOH (30 mL) slowly from −20° C. The mixture was stirred at −20° C. for 15 min. and then at rt for 1 h. The reaction was quenched with addition of sat. ammonium chloride. Organic solvent was removed under reduced pressure. The residue was partitioned between EtOAc/water. The organic layers were collected, washed with sat. sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-40% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give 16F (5.93 g, 17.69 mmol, 77% yield). MS (ESI) (m/z): 357, 359.4 (M+Na)+. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.40 (m, 7H) 7.01 (d, J=8.34 Hz, 1H) 4.56 (s, 2H) 3.92-4.04 (m, 1H) 3.67-3.89 (m, 3H) 3.35-3.49 (m, 1H) 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.CC([O-])=O.[Na+].[Br:16]Br.[OH-].[Na+]>CC(O)=O.O>[Br:16][C:10]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1ccc(C=O)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ncc(C=O)cc1Br
Temperature: 90 °C
Yield: 39.2 %

Procedure:
To a mixture of 6-methoxynicotinaldehyde (3 g, 0.0219 mol) and NaOAc (3.5 g, 0.0427 mol) in HOAc (10 mL) was added a solution of bromine (1.64 mL, 0.031 mol) in HOAc (10 mL) over 30 mins via an additional funnel. The mixture was heated to 90° C. for 5 h, cooled to rt. The reaction was added iced water (100 mL), neutralized to pH=7.5 with aq. NaOH (5 N), extracted with ethyl acetate (4×50 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via flash column using dichloromethane as an eluent. The product containing fractions were collected and concentrated to give 5-bromo-6-methoxynicotinaldehyde (1.854 g, 39% yield).