Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[N:3]([C:6]1[N:11]=[C:10]([O:12]P(OC)(OC)=S)[CH:9]=[C:8]([CH3:19])[N:7]=1)CC.CCN(C1N=C(OP(OCC)(OCC)=S)C=C(C)N=1)CC.NC(N)=N.C=C1OC(=O)C1.C(=O)(O)O.NC(N)=N>>[NH2:3][C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:19])[N:7]=1
Reactant: CCN(CC)c1nc(C)cc(OP(=S)(OC)OC)n1
Agent: C=C1CC(=O)O1
Agent: CCOP(=S)(OCC)Oc1cc(C)nc(N(CC)CC)n1
Agent: N=C(N)N
Product: Cc1cc(O)nc(N)n1
Yield: 14 %

Procedure:
4-Hydroxypyrimidines bearing an amino group at the 2-position are intermediates for the preparation of various fungicidal and insecticidal products, including for example, the insecticides pirimiphos-methyl and pirimiphos-ethyl. They have been made by the condensation of an acetoacetic ester with a guanidine under basic conditions. Since acetoacetic esters may be prepared from diketene it was thought that synthesis of 4-hydroxy-pyrimidines from diketene itself would be possible. Various attempts to do this have been reported in the literature. Thus Lacey (J. Chem. Soc., 1954, 839-44) reacted diketene with guanidine carbonate in alkaline solution at the ambient temperature and obtained 2-amino-4-hydroxy-6-methylpyrimidine in 14% yield. Using the guanidine hydrochloride the yield was increased to 28%. However when methylguanidine hydrochloride was used the yield of product was only 8%, and investigation showed that the product was 1,6-dihydro-1,4-dimethyl-2-amino-pyrimidine-6-one and not a hydroxypyrimidine. Similarly Iwakura et al (J. Chem. Soc. Japan, Ind. Chem. Sect., 1954, 57, 947) found that 2-amino-4-hydroxy-6-methylpyrimidine was only obtained in 4% yield when diketene was reacted with guanidine nitrate in the presence of aqueous potassium hydroxide. We have now discovered that substantially higher yields of 2-amino-4-hydroxy-6-alkyl pyrimidines may be obtained by carrying out the reaction of a diketene with a guanidine in strongly acidic media. Furthermore the rate of reaction is sufficiently fast for the process to be operated in a continuous manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=1)[C:30]#[N:31].[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:33][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=4)[CH2:10][CH2:11]3)[C:16]2=[O:20])=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: N#Cc1cc(CBr)ccc1Cl
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4ccc(Cl)c(C#N)c4)C3=O)CC2)cc1

Procedure:
To a mixture of 3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (70 mg, 0.232 mmol) and 5-(bromomethyl)-2-chlorobenzonitrile (80 mg, 0.347 mmol) in THF (1 mL) and DMF (0.1 mL) was added NaH (46.3 mg, 1.16 mmol, 60%). The reaction was concentrated in vacuo then taken up in dichlormethane and MeOH and filtered through a short plug of silica gel. The pooled fractions containing the title material were pooled, concentrated and neutralized with NaHCO3. MeOH was added and the solution was cooled in a freezer. The title compound was obtained by collecting the white solid via filtration (45 mg). HRMS calculated for C25H26ClN3O3 451.1671. found (ESI, [M+H]+) 452.1744.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)OC(C)(C)O2
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)Oc2ccc(C(=O)CBr)cc2O1
Reaction time: 15 h

Procedure:
Bromine (1.5 cc) is added in the course of 5 minutes at a temperature in the region of 20° C. to a stirred solution of 5-acetyl-2,2-dimethyl-1,3-benzodioxole (5.8 g) in carbon tetrachloride (100 cc), and the mixture is left with stirring for 15 hours at the same temperature. The reaction mixture is taken up with water (150 cc). The organic phase is separated off after settling has taken place, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). 5-(2-Bromoacetyl)-2,2-dimethyl-1,3-benzodioxole (7.1 g) is obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)(O)=[O:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50]>>[C:49]([NH:48][CH2:47][CH2:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[NH:39][C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:7]1)=[O:2])(=[O:51])[CH3:50]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Reactant: CC(=O)NCCc1ccccc1N
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)Nc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Example 3a, 0.138 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.061 g of N-[2-(2-aminophenyl)ethyl]acetamide. The title compound is obtained as a yellow oil. Rf=0.21 (95:5 dichloromethane-methanol); Rt=5.22.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11]=[C:12]([CH3:14])[CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]>CO.[Pd]>[CH2:11]([C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)=Cc1c(C)cccc1C(=O)O
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(=O)O)c1CC(C)C
Yield: 91.6 %

Procedure:
A solution of the 3-methyl-2-(2-methyl-1-propenyl)benzoic acid (291) (2 g, 10.5 mmol) in MeOH (40 mL) is hydrogenated using 10% palladium/carbon catalyst at 40 bar/30° C. using the Thales nanotechnology H-cube for 48 h. The MeOH is concentrated in vacuo to give the product as colorless oil (1.85 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:11][C:12]([O:14][CH3:15])=[O:13].CC([O-])(C)C.[K+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccnc1
Reactant: COC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
3-Nitropyridine (5.00 g, 40.3 mmol) and methyl chloroacetate (7.30 g, 67.3 mmol) were dissolved in THF (50 mL) and added drop-wise to a slurry of KOtBu (18.1 g, 161 mmol) in THF (50 mL) at 0° C. The reaction mixture was stirred at RT for 1 h, cooled to 0° C. and quenched with sat aq NH4Cl (100 mL). The THF was removed in vacuo and the reaction mixture was diluted with DCM (75 mL). The aq fraction was extracted with DCM (3×40 mL) and the combined organic fractions were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a dark brown oil (3.94 g, 50%). LCMS (ES+): 196.9 [MH]+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Si]([N:12]=[N+:13]=[N-:14])(C)(C)C>CCOCC>[CH2:5]([C:6]1[N:12]=[N:13][NH:14][CH:7]=1)[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C#CCCCCC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCc1c[nH]nn1
Temperature: 155 °C

Procedure:
##STR10## 1-heptyne (9.6 g) and Me3SiN3 (7.8 g) were sealed into a heavy-walled glass reactor at -70° C. and 0.6 mm Hg. The mixture was heated at 155° C. for 48 hrs., cooled and dissolved in Et2O. The Et2O was treated exactly as in Example 2. The product was distilled, bp 89-94/0.2 mm to give 7.2 g (76%) water white liquid whose NMR spectrum and elemental analysis confirm its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:5]2[CH2:19][CH2:20]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>C1COCC1>[Br:41][CH2:20][CH2:19][C:5]1[C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCBr
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole was prepared according to method D Step III with 2-(5,6-dichloro-2-(triethylsilyl)-1H-indol-3-yl)ethanol (1.7 g; 4.94 mmol) in THF (6 mL) and triphenyl phosphine (2.59 g; 9.87 mmol) and perbromomethane (3.27 g; 9.87 mmol) in THF (40 mL) pre-stirred for 30 minutes. The crude mixture was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 0.548 g (27%) of 3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=[O:44]>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][C:40]3=[O:44])[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: NCCCN1CCCC1=O
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCCN3CCCC3=O)n2)s1
Yield: 37 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.29 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.60 ml, 4.3 mmol) the title compound was obtained (0.070 g, 37% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.65-7.79 (m, 1H), 7.35-7.49 (m, 2H), 7.19-7.34 (m, 4H), 6.11-6.26 (m, 1H), 3.22 (t, J=6.8 Hz, 4H), 2.21 (t, J=8.1 Hz, 2H), 1.91 (quin, J=7.6 Hz, 2H), 1.63-1.74 (m, 2H), 1.36 (d, J=6.9 Hz, 6H). MS (ES+): 631 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20](O)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([NH:34][CH2:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=4)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Product: COc1cccc(CNC(=O)CC2NC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 50 %

Procedure:
Prepared as in Example 10-48 from 3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) and (3-methoxyphenyl)methanamine. Yield: 50%. LC/MS; expected 453. found 453.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.7 μM.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](O)=O)=[CH:7]2.CS(Cl)(=O)=O.[N:20]1C=CC=CC=1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]#[N:20])=[CH:7]2
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Agent: CS(=O)(=O)Cl
Product: N#Cc1ccc2c(Br)cccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-naphthoic acid (4.3 g, 17 mmol)) in dry pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (1.4 mL, 18 mmol). After stirring at 0° C. for 1 h, ammonia gas was bubbled through the solution for 10 min, whilst maintaining the temperature below 5° C. During the gas addition the solution became viscous, so additional dry pyridine (˜30 mL) was added. Excess ammonia was removed in vacuo, the solution again cooled to 0° C., then treated with additional methanesulfonyl chloride (12.5 mL) and allowed to warm to room temperature overnight. The solution was poured onto ice cold water, the mixture stirred for 30 min and the brown precipitate collected by filtration, washed on the sinter with ice cold water, then dried in vacuo. The crude product was dissolved in hot chloroform (˜35 mL) and insoluble material filtered off. The chloroform was removed and the residue dissolved in a minimum volume of ether at reflux. Hexane was added until the solution remained turbid at reflux, the solution filtered rapidly into a pre-heated flask, and allowed to cool slowly to room temperature. The precipitate was collected by filtration, washed with hexane, and dried in vacuo, to yield 5-bromo-2-naphthonitrile. Further crops were obtained by cooling the filtrate at −18° C. overnight.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[ClH:38].FC(F)O[C:42]1C=C(C2C=C(C(NC3C=CC([C@@H]4OCCNC4)=CC=3)=O)NN=2)C=C[CH:47]=1.Cl.N1CCO[C@@H](C2C=CC(NC(C3C=C(C4C=CC=CC=4)NN=3)=O)=CC=2)C1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCCCCCC.O.CN(C=O)C>[ClH:38].[F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH2:42][CH3:47])[N:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(-c4cccc(OC(F)F)c4)n[nH]3)cc2)C1
Reactant: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1cc(-c2cccc(OC(F)F)c2)n[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCCCCCC
Solvent: O
Product: CCn1nc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2)cc1-c1cccc(OC(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
(S)-Tert-butyl 2-(4-(3-(3-(difluoromethoxy)phenyl)-1H-pyrazole-5-carboxamido)phenyl)morpholine-4-carboxylate: In a 25 mL round-bottomed flask, 3-(3-(difluoromethoxy)phenyl)-1H-pyrazole-5-carboxylic acid (515 mg, 2.03 mmol, Eq: 1.1) (preparation described in example 40), (5)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (513 mg, 1.84 mmol, Eq: 1.00) (preparation described in example 1), N-Methylmorpholine (559 mg, 608 μl, 5.53 mmol, Eq: 3) and HBTU (1.05 g, 2.76 mmol, Eq: 1.5) were combined with DMF (2 ml) to give a yellow solution. The reaction mixture was stirred overnight at 60° C. The mixture was poured into water (10 ml) and extracted twice with EtOAc. The organic layers were washed with NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to give a brown crude mixture. This mixture was diluted with Heptane, stirred for 15 minutes and the suspension was filtered. The resulting solid was washed several times with Heptane to afford the desired compound as a brown solid (550 mg, 58.0%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11](C2OC=CC=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1.[O:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1>>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:39]2[CH:40]=[CH:41][O:37][CH:38]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1
Reactant: OB(O)c1ccoc1
Reactant: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccco1
Product: COc1c(-c2ccoc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 45 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with furan-3-yl boronic acid (7.2 mg, 0.064 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (10.6 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1H) 7.84 (d, J=8.09 Hz, 1H) 7.80 (t, J=1.84 Hz, 1H) 7.68-7.75 (m, 2H) 7.54-7.64 (m, 2H) 7.50 (t, J=6.07 Hz, 1H) 7.35 (d, J=2.57 Hz, 1H) 7.08 (d, J=1.47 Hz, 1H) 6.57 (s, 1H) 5.68 (d, J=8.09 Hz, 1H) 3.47 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[N:17]=[C:16]2[S:18][CH:19]=[CH:20][C:15]2=[CH:14][C:13]=1[C:21]([OH:23])=[O:22])=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].OS(O)(=O)=O>O>[CH:5]([C:4]1([CH3:8])[NH:9][C:10]([C:12]2[N:17]=[C:16]3[S:18][CH:19]=[CH:20][C:15]3=[CH:14][C:13]=2[C:21]([OH:23])=[O:22])=[N:2][C:1]1=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1nc2sccc2cc1C(=O)O)C(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(C)NC(c2nc3sccc3cc2C(=O)O)=NC1=O
Temperature: 80 °C

Procedure:
6-[(1-Carbamoyl-1,2-dimethylpropyl)carbamoyl]thieno[2,3-b]pyridine-5-carboxylic acid (17.35 g, 0.052 mol) is added to water (225 mL) containing sodium hydroxide (10.35 g, 0.26 mol). The resulting basic solution is heated at 80° C. for two hours and 45 minutes, cooled in an ice-water bath and acidified with 6N H2SO4. The product 6-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)thieno[2,3-b]pyridine-5-carboxylic acid is filtered off, washed with water and air dried yielding 1.54 g, 70.3%, mp 221°-223° C.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.CC(C)([O-])C.[K+].[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH2:35])[N:28]=3)=[C:21]([F:42])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:2][CH2:35]2)[N:28]=3)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCCCC1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCCCC4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of trimethylsulfoxonium iodide (0.385 g, 1.75 mmol) and potassium tert-butoxide (0.196 g, 1.75 mmol) in 4 mL DMSO was added 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclohexylvinyl)thiazolo[5,4-b]pyridine (0.371 g, 0.874 mmol) rapidly as a solution in THF (8 mL min volume). The reaction mixture became a light purple color. The reaction was sealed and heated to 60° C. After 4 h, the reaction mixture was cooled, quenched with ice and sat'd aq. NH4Cl, diluted with EtOAc and the organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting orange oil/solid was purified by silica gel chromatography 40 g, 0-40% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclohexylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: calculated: 438.2; Observed: 439.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1CC([O-])=O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:18]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:18]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C([O-])Cc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-fluoro-4-iodophenylacetate (500 mg) in methanol (3 ml) was added 1.07 ml of 2N aqueous sodium hydroxide. The reaction solution was stirred at room temperature for 40 minutes, followed by vacuum concentration of the reaction solution. The residue obtained was diluted with water, acidified with 10% aqueous citric acid to pH 4, then extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C(F)(F)F)=[CH:14][C:13]=2[F:25])[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[CH3:36][N:37](C=O)C.O.[OH-].[Li+]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.[Zn].[C-]#N.[Zn+2].[C-]#N.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:4][CH:3]=[C:2]([C:36]#[N:37])[C:10]=23)=[C:13]([F:25])[CH:14]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cc4ccc(NC(=O)C(F)(F)F)cc4F)ccnc32)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2nccc(Cc3ccc(N)cc3F)c12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
1.70 g (2.98 mmol) of N-[4-({3-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-methyl)-3-fluorophenyl]-2,2,2-trifluoroacetamide, 219 mg (1.19 mmol) of zinc acetate, 78 mg (1.19 mmol) of zinc dust, 189 mg (1.61 mmol) of zinc cyanide, 50.0 mg (0.09 mmol) of bis(diphenylphosphino)ferrocene and 27.3 mg (0.03 mmol) of tris(dibenzylideneacetone)dipalladium are initially charged. Under argon, a degassed mixture of 17 ml of DMF and 0.17 ml of water is added, and the mixture is heated at 100° C. for 20 hours. 10 ml of water, 8 ml of THF and 1.21 g (50.3 mmol) of lithium hydroxide are added to the crude mixture, which is then stirred at RT for 20 h. The mixture is concentrated a little and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: dichloromethane:methanol 25:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[CH:18]=[CH:17][C:13]3=[N:14][O:15][N:16]=[C:12]3[CH:11]=2)=[O:9])[CH2:2]1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH3:21][N:7]([CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)[C:8]([C:10]1[CH:18]=[CH:17][C:13]2=[N:14][O:15][N:16]=[C:12]2[CH:11]=1)=[O:9]
Reactant: CI
Reactant: O=C(NC1CCCOC1)c1ccc2nonc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2nonc2c1)C1CCCOC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
N-(Tetrahydro-2H-pyran-3-yl)-[2,1,3]-benzoxadiazole -5-carboxamide (371 mg, 1.5 mmol) was added to a suspension of sodium hydride (216 mg, 9 mmol) in dry DMF (5 ml), followed by methyl iodide (1.0 ml) and the mixture was stirred at 20° C. for 1 hour. The solvent was evaporated under vacuum, dichloromethane (30 ml) was added and the organic phase was washed with 1N HCl (100 ml) and NaHCO3 solution (100 ml). The aqueous was re-extracted with dichloromethane (100 ml), the organics dried over magnesium sulfate and concentrated under vacuum to give the title compound as a white solid after trituration with diethyl ether (186 mg). Mp: 134-135° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, 1H, J=9.0 Hz); 7.83 (s, 1H); 7.40 (d, 1H, J=9.0 Hz); 4.70-3.20 (m, 4H), 3.01 (sb, 3H) and 2.10-1.50 ppm (m, 4H).