Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10](=O)[CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26].[CH3:31][Mg]Br.CCOCC>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10]([CH3:31])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26]
Reactant: C[Mg]Br
Reactant: CCCN1C(=O)N(Cc2ccc(C)c(C)c2)C(=O)C1CCCc1ccc(OC)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCn1c(CCCc2ccc(OC)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of 3-(3,4-dimethyl-benzyl)-5-[3-(4-methoxy-phenyl)-propyl]-1-propyl-imidazolidine-2,4-dione (0.155 g, 0.379 mmol) in THF (6 mL) was treated dropwise with a 3 molar solution of methyl magnesium bromide in Et2O (0.76 mL, 2.28 mmol) and then stirred at 0° C. under N2 for 1 h. The reaction was quenched with 1 N HCl (5 mL) and stirred at room temperature for 15 minutes to effect elimination and then was worked up extractively with EtOAc and water. The organic layer dried (MgSO4), and the solvent removed in vacuo to afford 0.155 g (100%) 1-(3,4-dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one that was utilized without purification. MS (ES+) Calc'd for C26H35N2O2 (M+1) 407. Found m/z 407 (100%). 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)CC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (v) (2.23 g), 1M aqueous sodium hydroxide (10 ml) and THF (20 ml) was stirred at RT for 3 h. The mixture was acidified with 2M hydrochloric acid, extracted with diethylether and the organics washed with water, dried, and evaporated under reduced pressure. The residue was recrystallised from ethylacetate/isohexane, yield 0.45 g.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:2]1[NH:16][N:17]=[N:18][C:1]=1[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nn[nH]n2)CC1
Temperature: 100 °C
Yield: 51.8 %

Procedure:
A mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (2.1 g), sodium azide (1.95 g) and ammonium chloride (1.6 g) in dimethylformamide was heated to 100° C. for 18 hours. The mixture was cooled and partitioned between 1N HCl and dichloromethane. The organic layer was washed with water, dried (MgSO4) and evaporated to give a gum which was purified by column chromatography eluting with MeOH/dichloromethane (1:99) to give tert-butyl 4-(2H-tetrazol-5-yl)piperidine-1-carboxylate (1.31 g); NMR (CDCl3): 1.5 (s, 9H), 1.9 (m, 2H), 2.15 (m, 2H), 3.0 (m, 2H), 3.3 (m, 1H), 4.2 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([NH2:20])=[CH:14][C:15]([F:19])=[C:16]([F:18])[CH:17]=1)(C(C)(C)C)(C)C.CN(C=O)C.OOS([O-])=O.[K+].[F:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([CH:40]=1)[CH:38]=O>O>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]2[N:11]([CH2:10][CH2:9][OH:8])[C:38]([C:37]3[CH:36]=[N:35][CH:34]=[C:33]([F:32])[CH:40]=3)=[N:20][C:13]=2[CH:14]=1
Reactant: O=Cc1cncc(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1cc(F)c(F)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCn1c(-c2cncc(F)c2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-difluorobenzene-1,2-diamine (38; 0.09 g, 0.0003 mol) in the mixture of DMF (3 ml) and water (0.3 ml) was added OXONE® (0.218 g, 0.0004 mol) and followed by 5-fluoronicotinaldehyde (0.041 g, 0.0003 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated and diluted with cold water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product 2-[5,6-difluoro-2-(5-fluoropyridin-3-yl)-1H-benzimidazol-1-yl]ethanol as an off white solid. 1H NMR (400 MHz, DMSO-d6), δ: 8.93 (s, 1H), 8.77 (m, 1H), 8.33 (m, 1H), 7.96 (m, 1H), 7.81 (m, 1H), 5.09-5.11 (t, J=5.2 Hz, 1H), 4.35-4.38 (t, J=5.0 Hz, 2H), 3.75-3.76 (m, 2H). LCMS (ES) m/e MS (M+1=294) Purity 99.33%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1(C)[CH2:27][O:26][C:25]2=[CH:28][C:29]3OC[C:32]4([C:42]=3[CH:43]=[C:24]12)C1C(=CC=CC=1)NC4=O.ClCC1C=CC(OC)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:27][O:26][C:25]1[CH:28]=[CH:29][C:42]([CH2:32][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:43][CH:24]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: COc1ccc(CCl)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(chloromethyl)-4-methoxybenzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (56%) as a white solid: mp 120-121° C.; MS (ES+) m/z 400.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([O:23]CC)=O)[N:9]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:23])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: CN1CCN(CCN)CC1
Solvent: CCO
Product: CN1CCN(CCNC(=O)Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)CC1

Procedure:
3 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.5 g of 2-(4-methylpiperazin-1-yl)ethylamine are boiled under reflux for 20 h in 40 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-N-[2-(4-methylpiperazin-1-yl)ethyl]acetamide is obtained as a colorless foam. Rfvalue: 0.17 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 2.1 (s, 3H), 2.3 (m, 10H), 3.15 (m, 2H), 4.9 (s, 2H), 7.0 (m, 4H), 7.4 (m, 3H), 8.0 (m, 2H), 11.0 ppm (s, 1H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:50])[C@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:43]([O:44][CH3:45])=[CH:42][C:41]([CH2:46]O)=[CH:40][C:39]=2[O:48][CH3:49])=[CH:34][CH:33]=1)[NH:20][C:21](=[O:30])[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:70]1(=[O:76])[NH:74][C:73](=[O:75])[CH2:72][CH2:71]1>C1COCC1>[C:13]([O:17][C:18](=[O:50])[C@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39]([O:48][CH3:49])=[CH:40][C:41]([CH2:46][N:74]3[C:73](=[O:75])[CH2:72][CH2:71][C:70]3=[O:76])=[CH:42][C:43]=2[O:44][CH3:45])=[CH:34][CH:33]=1)[NH:20][C:21](=[O:30])[C:22]1[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=1[Cl:28])([CH3:15])([CH3:16])[CH3:14]
Reactant: O=C1CCC(=O)N1
Reactant: COc1cc(CO)cc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC(C)(C)C)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CN2C(=O)CCC2=O)cc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
DEAD (0.13 mL) was added to an ice-cooled solution of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(hydroxymethyl)phenyl]-L-phenylalanine tert-butyl ester (250 mg), triphenylphosphine (175 mg) and succinimide (90 mg) in THF (3 mL) under N2. The mixture was stirred at 0° C. for 30 min, and warmed to room temperature and stirred for 2 h. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAC. The combined organic layer was dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 1:1) to give N-(2,6-dichlorobenzoyl)4-[2,6-dimethoxy-4-(succinimidomethyl)phenyl]-L-phenylalanine tert-butyl ester (138 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:18]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1>ClCCl>[NH:22]1[CH2:21][CH2:20][CH:19]([CH:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:8])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3ccccc3NC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccccc2CC1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxylate (260 mg, 0.79 mmol) in dichloromethane (3 mL). Reaction stirred at room temperature for 1 hour. Reaction mixture was concentrated in vacuo. Residue was dissolved in methanol. Dowex 1×4-200 ion exchange resin was added to the mixture to create a slurry. Mixture stirred at room temperature for 30 minutes. Resin was filtered off and washed with methanol. Filtrate was concentrated. Title compound was obtained as dark foam in quantitative yield. MS m/e (M+H)+=231.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][CH2:18][F:19].O=O>>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([O:11][CH2:16][CH2:17][CH2:18][F:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCCBr
Reactant: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Agent: O=O
Product: CC(=O)c1cc(OCCCF)cc(C(C)(C)C)c1

Procedure:
1-(3-tert-Butyl-5-hydroxyphenyl)ethanone (O3.106; 500 mg) was reacted with 1-bromo-3-fluoropropane (239 μl) and worked up analogously to O2.105. 630 mg of the title compound were obtained. LC-MS rt: 1.16 min [M+H]+: 253.2 (met. b)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)=[O:20]
Reactant: OCCc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)COc1ccc(CCO)cc1

Procedure:
Prepared from 2-(4-hydroxyphenyl)-ethanol, potassium carbonate and methyl bromoacetate analogously to Example XXXVa.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8](O)([CH2:28][O:29]S(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([O:29][CH2:28]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@@]1(c2ccccc2F)CO1
Temperature: 40 °C
Yield: 72.2 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (100 mg) was dissolved in dimethylformamide (4 ml), to which potassium carbonate (42 mg) was added, and the mixture was heated at 40° C. for 1 hour. The resultant was diluted with ethyl acetate (20 ml) and washed with water (10 ml) and a saturated aqueous solution of sodium chloride (10 ) successively. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1/4). The desired fraction was concentrated and the residue was recrystallized from diisopropyl ether to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (58 mg) as a colorless crystalline powder.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si](O[CH2:27][C:28]1[C:29]([N+:40]([O-:42])=[O:41])=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])(C(C)(C)C)(C)C.C(N(CC)CC)C.[Br:50][C:51]([CH3:56])([CH3:55])[C:52](Br)=[O:53]>C1COCC1>[Br:50][C:51]([CH3:56])([CH3:55])[C:52]([CH2:27][C:28]1[C:29]([N+:40]([O-:42])=[O:41])=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])=[O:53]
Reactant: CC(C)(Br)C(=O)Br
Reactant: C#CCNC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1cccc(CC(=O)C(C)(C)Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
TBAF (4.19 mL of a 1.0 M solution in THF) was added dropwise to a stirring solution of Compound 11 (487 mg, 1.40 mmol) in THF (14 mL). TLC analysis showed complete reaction after 5 minutes, after which time the THF was removed on a rotary evaporator and the resulting oil was dissolved in EtOAC (50 mL), washed with saturated NH4Cl (2×20 mL), water (2×50 mL), dried over MgSO4, concentrated in vacuo. The resulting white solid (Compound 12) was dissolved in anhydrous THF (14 mL), triethylamine (184 mg, 1.81 mmol) was added, and the resulting solution was added dropwise to a stirring solution of □-bromoisobutyrylbromide (225 mg, 1.82 mmol) in THF (5 mL) at 0° C., A white precipitate formed immediately. The mixture was allowed to warm to room temperature and stirred overnight under argon atmosphere after which time the solid salts were filtered, and the solvent was removed on a rotary evaporator. The resulting yellow oil was dissolved in ethyl acetate (50 mL) and washed with water (3×20 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (50% EtOAc:hexane) to yield Compound 13 (321 rag, 60%) as a white solid.
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C:15]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(=O)C>[C:20]1([CH:17]2[CH2:16][C:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:14]([S:13]([OH:3])(=[O:2])=[O:1])[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O
Reactant: CCOC(=O)C1=C(S)CCC(c2ccccc2)C1
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCC(c2ccccc2)C1
Temperature: 52.5 °C
Reaction time: 3 h

Procedure:
Sodium peroxyborate tetrahydrate (35.2 g) was admixed with acetic acid (200 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-5-phenyl-1-cyclohexene-1-carboxylate synthesized in Reference Example 13 (20 g) in acetic acid (200 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (500 ml) and stirred at room temperature for 1 hour and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (20 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in a mixture of acetonitrile (500 ml) and methanol (500 ml) and stirred at room temperature for 2 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (500 ml) and the pellet which precipitated was isolated by a filtration to obtain ethyl 5-phenyl-2-sulfo-1-cyclohexene-1-carboxylate as a white powder (40.4 g) containing inorganic substances.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]4[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[O:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:35]1[CH2:36][CH:37]=[C:38]([C:2]2[CH:3]=[C:4]3[C:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:28]5[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:39][CH2:40]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Temperature: 80 °C

Procedure:
A vial was charged with tert-butyl 3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.105 g, 0.193 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.122 g, 0.580 mmol), potassium carbonate (0.134 g, 0.966 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.014 g, 0.019 mmol). The vial was flushed with Ar (g), then dioxane (1.288 mL) and water (0.644 mL) were added in sequence. The vial was sealed and heated at 80° C. overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-100% EtOAc:Hex) to afford tert-butyl 3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as an off-white solid. MS m/z=547.2. Calc'd for C29H27FN4O4S: 546.61.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=[CH:11][C:6]=2[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>O1CCOCC1>[F:15][C:12]([F:13])([F:14])[C:9]1[N:10]=[CH:11][C:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(C(F)(F)F)nc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NCCc2cnc(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Approximately 485 mg (1.53 mmol) of tert-butyl 8-oxo-2-(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate was treated with 10 mL of 4M HCl in anhydrous dioxane, and the solution was stirred at room temperature for 0.5 h, then concentrated to dryness. The residue was washed with diethyl ether and dried to give the title compound as a white solid. LC-MS 218 (M+1).
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][C@@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27](OC)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:20][CH2:21][C@@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](CO[C@@H](C)CO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: Nc1ccc(F)cn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Trimethylaluminium (2M in hexanes)(0.608 mL, 1.22 mmol) was added to 5-fluoropyridin-2-amine (130 mg, 1.16 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AO2) (552 mg, 1.06 mmol) in toluene (8 mL) was added and the reaction was heated to 100° C. for 5 hours in the microwave reactor. The reaction was allowed to cool to room temperature before adding EtOAc (30 mL) and 20% sodium potassium tartrate solution (30 mL), which was stirred vigorously for 16 hours. The phases were separated and the organic layer was washed with sat. brine (15 mL), dried (MgSO4) and evaporated to afford the product (638 mg, 100%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.05 (d, 6H), 0.87 (s, 9H), 1.17 (d, 3H), 3.51-3.58 (m, 1H), 3.60-3.69 (m, 2H), 4.18-4.22 (m, 2H), 6.00 (t, 1H), 7.40-7.49 (m, 2H), 7.98-8.03 (m, 1H), 8.13 (d, 1H), 8.22-8.28 (m, 1H), 8.44 (s, 1H), 8.60-8.64 (m, 2H), 8.94 (s, 1H); m/z (ES+), (M+H)+=602.55; HPLC tR=3.35 min
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]=[N+]=[N-])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reaction time: 3 h

Procedure:
To a solution of 1-5 (19.3 g, 0.076 moles) in THF (400 ml)/H2O (195 ml) was added triphenylphosphine (80.0 g, 0.305 moles) in one portion at room temperature. This was stirred for 3 hours and the solvent was then removed in vacuo. The residue was acidified to pH 2 with 10% KHSO4 solution and this was extracted with 4×100 ml portions of EtOAc. The organic extract was extracted with 2×100 ml portions of 10% KHSO4 and the aqueous phases were combined and the pH was adjusted to pH 10 with 2N NaOH. This solution was extracted with EtOAc and the organic phase was dried (MgSO4), and the solvent was removed to give 1-6 as a yellow liquid, Rf 0.3 (silica gel 10% CH3OH in CHCl3 /NH3),