Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N[C@H]2CC[C@H](O)CC2)nc(N)n1
Temperature: 160 °C

Procedure:
A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.18 g, 8.24 mmol), trans-4-aminocyclohexanol (1.00 g, 6.60 mmol), potassium carbonate (1.82 g, 13.2 mmol), and diisopropylethyl amine (1.44 mL, 8.24 mmol) in dimethylacetamide (20.0 mL) was heated at 160° C. in a sealed tube overnight. The reaction mixture was diluted with ethyl acetate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-5%) to afford the title compound as a foamy solid (1.47 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH:14]2[CH2:18][CH:17]([CH2:19][OH:20])[CH:16]([OH:21])[CH:15]2[OH:22])=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1Cl.[NH3:23].[C:24](OC(OCC)OCC)(=O)C>>[NH2:23][C:7]1[N:6]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:4]=[C:3]2[C:2]=1[N:1]=[CH:24][N:13]2[CH:14]1[CH2:18][CH:17]([CH2:19][OH:20])[CH:16]([OH:21])[CH:15]1[OH:22]
Reactant: CCOC(OCC)OC(C)=O
Reactant: N
Reactant: CCCSc1nc(Cl)c(N)c(NC2CC(CO)C(O)C2O)n1
Product: CCCSc1nc(N)c2ncn(C3CC(CO)C(O)C3O)c2n1
Reaction time: 24 h

Procedure:
The product of step v) (0.2 g) and diethoxymethyl acetate (10 ml) were stirred at ambient temperature under nitrogen for 1 hour, then at 80° for 24 hours. Evaporation afforded a residue which was treated with liquid ammonia (15 ml) in an autoclave at 60° for 16 hours. The ammonia was allowed to evaporate and the residue taken up in 0.5M hydrochloric acid (10 ml) at 60° for 45 min. The volatiles were removed in vacuo and the remaining material dissolved in water (10 ml). Upon neutralisation with concentrated ammonia the sub-title compound crystallised and was collected and dried (0.15 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>CCOCC>[CH2:28]([NH:31][C:32]([N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[N:14]=[N:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])=[O:33])[CH2:29][CH3:30]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: CCCN=C=O
Solvent: CCOCC
Product: CCCNC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 24 h

Procedure:
To a solution of 5.4 g. (0.014 mol.) of 1,3-bis(2cyano-5-trifluoromethylphenyl)triazene in 500 ml. of ether is added 15 ml. of propyl isocyanate. The reaction mixture is stirred at 25° for 24 hours after which time the precipitated product is collected by filtration and washed with ether to give 3-(N-propylcarbamoyl)-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene, m.p. 138°-140° (dec.).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:16][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(=O)O)nn1-c1ccccc1
Reaction time: 8 h
Yield: 38 %

Procedure:
600 mg (2.94 mmol) of 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid were dissolved in 30 ml of DMF, 1.92 (5.9 mmol) of cesium carbonate and 1.04 g (7.35 mmol) of iodomethane were added, and the resulting mixture was heated for 4 h to 80° C. The mixture was filtrated and the solvent removed in vacuo. The residue was dissolved in 20 ml of MOH and 5.9 ml of an aqueous 1 M solution of sodium hydroxide. After stirring overnight the reaction was complete. The solvent was removed and the residue subjected to preparative HPLC to give the title compound in a yield of 38%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(OC([NH:43][CH2:44][C:45]([O:47][CH2:48]Cl)=[O:46])=O)(C)(C)C>CN(C=O)C>[ClH:1].[NH2:43][CH2:44][C:45]([O:47][CH2:48][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)=[O:46]
Reactant: CC(C)(C)OC(=O)NCC(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)CN)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Product: Cl

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) in DMF (0.9 mL), KOH (23 mg, 0.4 mmol), a solution of chloromethyl 2-((tert-butoxycarbonyl)amino)acetate (46 mg, 0.2 mmol) in DMF (100 mL). The title compound was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) and was obtained as a white solid (46 mg, 33.3%). The title compound was characterized by
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]=[O:29]>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]([OH:29])[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=Nc1c(F)cccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N(O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 1,3-difluoro-2-nitrosobenzene (143 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])=[CH:16][CH:15]=[CH:14][C:13]=2[OH:28])(=[O:8])[CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[C:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])=[CH:16][CH:15]=[CH:14][C:13]=2[O:28][CH2:2][CH2:3][OH:4])(=[O:8])[CH2:6][CH3:7]
Reactant: OCCBr
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccc(F)cc1C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
A solution of 2-bromoethanol (5.75 ml, 42 mmol) in acetone (25 ml) was added dropwise to a refluxing mixture of 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (1.62 g, 5 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol) and acetone (25 ml) with vigorous stirring. Heating was continued for 18 hours, then water added, the product extracted into dichloromethane, dried and evaporated. Chromatography (silica gel, 2-5% methanol in dichloromethane) and recrystallisation from methanol yielded 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (0.89 g), m.p. 170°-1.72°.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[C:3]([F:2])([F:17])[F:18])[CH2:8][CH2:9]2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1)N1CCC(Oc2ccccc2C(F)(F)F)CC1

Procedure:
A solution of 4-(2-trifluoromethylphenoxy)piperidine hydrochloride (42 mg, 0.15 mmol), 3-chlorophenyl isocyanate (36 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 μL, 0.45 mmol) was stirred in dichloromethane (2 mL) at room temperature for overnight. The reaction mixture was diluted with dichloromethane and the solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine. The organic fraction was dried over MgSO4, filtered, and concentrated. The compound was purified by radial silica gel chromatography (1:20 to 1:2 ethyl acetate:hexanes) to afford the product which was 98% pure by LCMS analysis (15.7 mg, 26%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:12][S:11][C:10](=[S:13])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:15][C:16]([OH:18])=[O:17].[I-:19].[Na+]>CC(C)=O>[IH:19].[C:1]1([N:7]=[C:8]2[CH:9]=[C:10]([S:13][CH2:15][C:16]([OH:18])=[O:17])[S:11][S:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCl
Reactant: [I-]
Reactant: S=c1cc(Nc2ccccc2)ss1
Agent: [Na+]
Solvent: CC(C)=O
Product: I
Product: O=C(O)CSc1cc(=Nc2ccccc2)ss1
Temperature: 20 °C
Yield: 43.2 %

Procedure:
A solution of 5-phenylamino-1,2-dithiol-3-thione (9 g), chloroacetic acid (4.15 g) and sodium iodide (6.6 g) in acetone (135 cc) is heated under reflux for 35 minutes. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (3×15 cc), with water (3×10 cc) and then with acetone (3×10 cc). By recrystallisation of this crude product from methanol (470 cc), (3-phenylimino-1,2-dithiol-5-ylthio)-acetic acid hydroiodide (7.1 g) is obtained, melting at about 205° C. with decomposition.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([O:25][C:26](=[O:27])[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH:5]=[C:4]([Cl:11])[N:3]=2)[CH2:31][CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCn1c(Cl)nc(Cl)cc1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)cc1=O
Yield: 35.9 %

Procedure:
A solution of 2,6-dichloro-3-ethyl-3H-pyrimidin-4-one (320 mg, 1.64 mmol), DIEA (423 mg, 3.28 mmol) and (tert-butoxy)-N-(4-piperidyl)carboxamide (328 mg, 1.64 mmol) in DMF (10 mL) was heated to 120° C. for 1 h. The solvent was concentrated in vacuo and the residue was purified by silica chromatography (1:5, EA:PE) to give 210 mg (36%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.25-1.32 (m 2H), 1.35 (t, J=7.2 Hz, 3H), 1.96-2.02 (m, 2H), 2.98-3.06 (m, 2H), 3.70 (br, 1H), 4.30 (q, J=5.2 Hz, 2H), 4.44 (br, 1H), 4.57-4.61 (m, 2H), 5.95 (s, 1H). [M+H] Calc'd for C16H25ClN4O3, 357, 359. Found, 357, 359.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](C(O)=O)[N:9]=1.CNC(C)C.C(N=C=NCCCN(C)C)C.[OH:37]C1C2N=NNC=2C=CC=1.[CH:47]([N:50]([CH2:54]C)[CH:51](C)C)([CH3:49])[CH3:48]>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:54]([N:50]([CH3:51])[CH:47]([CH3:49])[CH3:48])=[O:37])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][NH:9]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: CNC(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)N(C)C(=O)C1(c2ccccc2F)NC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
1-(2-fluorophenyl)isoquinoline-3-carboxylic acid (0.910 mgs, 0.34 mmoles) was dissolved in dimethylacetamide (2 mls) to which was added methyl isopropylamine (0.039 mls, 0.37 mmoles), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 0.071 g, 0.37 mmoles), hydroxyl benzotriazole (HOBt, 0.046 g, 0.34 mmoles) and N,N-diisopropylethylamine (0.056 mls, 0.34 mmoles). The reaction was stirred at room temperature overnight and after evaporation the product was purified by automated C18 HPLC (52.6 mgs, 48% yield, 100% pure, CO-AAW0005).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>C(Cl)Cl>[CH2:15]([O:14][C:3]1[C:2]([Br:1])=[CH:9][C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:7][C:4]=1[CH:5]=[O:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(Br)c(OCc2ccccc2)c(C=O)c1

Procedure:
step 1—Benzylation of 3-bromo-5-tert-butyl-2-hydroxy benzaldehyde (36a) with benzyl bromide is accomplished treating 36a with benzyl bromide and tetrabutylammonium hydroxide in a biphasic system comprised of MeOH and DCM to afford 2-benzyloxy-3-bromo-5-tert-butyl-benzaldehyde (36b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]=[CH2:33])=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:42]=[C:43]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH:44]=[CH:45][CH:46]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:45]4[CH:46]=[CH:41][CH:42]=[C:43]([N:47]5[CH2:51][CH2:50][CH2:49][C:48]5=[O:52])[CH:44]=4)=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reactant: O=C1CCCN1c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2cccc(N4CCCC4=O)c2)nn3C2CCCCO2)CC1
Temperature: 125 °C
Yield: 67 %

Procedure:
To a solution of 4-[6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.56 mmol) in DMF (2.55 mL) were added 1-(3-iodo-phenyl)-pyrrolidin-2-one (0.19 g, 0.67 mmol), tri(o-tolyl)phosphine (34 mg, 0.11 mmol) and triethylamine (2.55 mL). The resulting solution was degassed using argon, palladium acetate (6 mg, 0.03 mmol) was then added and the reaction mixture was heated at 125° C. overnight. The reaction mixture was concentrated under vacuum and the residue taken up in water and then acidified to pH=1. The precipitate was filtered, washed with water and then dried under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc (0-100%) in cyclohexane to yield the title compound as a beige solid (0.26 g, 66%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br.Cl>CN(C)C=O.O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: COC(CBr)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1cccc(Br)c1)OC
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a suspension of 60% sodium hydride (60 g) in N,N-dimethylformamide (1.4 1) was added dropwise 3-bromophenol (260 g) under ice - cooling. After stirring for 10 minutes, to the solution was added dropwise bromoacetaldehyde dimethyl acetal (318 g) and the mixture was heated with stirring for 3 hours at 90° C. After cooling, water was added to the resulting solution and acidified with 1M hydrochloric acid and then extracted with ether (3 l). The organic layer was washed with successive water, saturated aqueous sodium bicarbonate solution and saturated aqueous NaCl solution. After drying over anhydrous sodium sulfate, ether was removed in vacuo and the residue was purified by silica gel column chromatography to give 363.3 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH2:21][CH2:22][CH3:23])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:33]>C(#N)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH2:21][CH2:22][CH3:23])=[C:18]([NH2:33])[N:19]=2)=[N:6]1
Reactant: CCCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.730 g (4.748 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-propyl-1,2,4-triazin-5-ol were admixed with 23 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 100 ml of dry acetonitrile and, with ice-cooling, stirred into 330 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the mixture was concentrated on a rotary evaporator, the residue was stirred with 200 ml of water and filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 1.360 g (60% of theory) of the target compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH:17]2Br>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH:18]=[CH:17]2
Reactant: COc1ccc2c(c1)C(Br)CC2=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(c1)C=CC2=O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
DBU (9.2 mL, 61.7 mmol) was added to a solution of 5-methoxy-3-bromo-1-indanone (14.8 g, 61.7 mmol) in THF (100 mL) at −10° C. dropwise over 10 minutes. The resulting solution was stirred at −10° C. for 20 minutes, quenched via addition of saturated aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 5.4 g (55%−two steps) of the subtitle compound. 1H NMR (CDCl3 300 MHz) δ 7.42 (d, 1H), 7.38 (d, 1H), 6.62 (s, 1H), 6.60 (d, 1H), 5.89 (d, 1H), 3.85 (s, 3H) ppm. MS calculated for C10H8O2+H: 161, observed: 161.
Reaction SMILES: CSC.B.[F:5][C:6]1([F:25])[C:11](=O)[NH:10][CH2:9][C:8]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:7]1>C1COCC1>[F:25][C:6]1([F:5])[CH2:11][NH:10][CH2:9][C:8]2([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]2)[O:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)O2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Temperature: 55 °C

Procedure:
Borane methyl sulfide complex (2M in THF, 2.69 mL) was added dropwise to a solution of tert-butyl 2,2-difluoro-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step b) (0.55 g) in THF (15 mL). The reaction mixture was heated at 55° C. under nitrogen for 25 minutes and then cooled to room temperature. The mixture was quenched by careful dropwise addition of methanol (5 mL). N1,N2-dimethylethane-1,2-diamine (0.633 g) was then added and the mixture heated at 70° C. for minutes. The solvents were removed under reduced pressure and the residue was purified by flash silica chromatography using 4% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.32 g. Used directly.
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][C:19]1[S:20][CH:21]=[C:22]([CH:24]=O)[N:23]=1>COCCOC.C(OCC)(=O)C>[CH3:18][C:19]1[S:20][CH:21]=[C:22](/[CH:24]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:23]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: Cc1nc(C=O)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1nc(/C=C/c2ccccc2)cs1
Temperature: 0 °C
Yield: 65.6 %

Procedure:
Sodium hydride (120 mg of a 60% suspension in mineral oil, 3.0 mmol) was slurried in DME (6 mL) and cooled to 0° C. Diethyl benzylphosphonate (1.1 g, 5.0 mmol) was added dropwise and after 15 minutes, 2-methyl-1,3-thiazole-4-carbaldehyde (320 mg, 2.5 mmol) in DME (5 mL) was added dropwise to the reaction mixture. After 3 h at 0° C. the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous NH4Cl (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 90:10 hexane:ethyl acetate to afford 2-methyl-4-[(E)-2-phenylethenyl]-1,3-thiazole (330 mg, 65% yield) as an oil. 1H NMR (CDCl3, 300 MHz) δ 7–7.5 (m, 8H), 2.7 (s, 3H). MS (ESI) 202.1 (M++H).
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([C:9]#[C:10][CH2:11][CH2:12][CH3:13])[CH2:5][CH2:4]2)[O:2]1.N.[Na].S(=O)(=O)(O)O>O1CCCC1.O.CC(C)=O>[CH:9](/[CH:6]1[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]1)=[CH:10]\[CH2:11][CH2:12][CH3:13]
Reactant: CCCC#CC1CCC2(CC1)OCCO2
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCC/C=C/C1CCC(=O)CC1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A solution of 4.5 g of 1,1-ethylenedioxy-4-(1-pentynyl)cyclohexane in 54 ml of tetrahydrofuran was treated dropwise with about 50 ml of pre-condensed ammonia in a sulphonation flask equipped with magnetic stirrer. The mixture was subsequently treated portionwise at -78° C. within 7 hours with 1.3 g of sodium. 1.5 hours after the last addition the ammonia was evaporated off and the reaction mixture was neutralized with 25% hydrochloric acid and left to stand overnight. Thereafter, the reaction mixture was partitioned three times in water/diethyl ether. The aqueous phases were back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate and freed from solvent on a rotary evaporator. The pale yellow liquid obtained (3.8 g) was treated with 200 ml of acetone and 0.1 ml of concentrated sulphuric acid. The mixture was heated to reflux for 10 minutes, then treated with water and freed from acetone on a rotary evaporator. The residue was partitioned three times in methylene chloride/water. The aqueous phases were back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. Chromatographic separation of the residual, yellow liquid (3.5 g) on silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 3.0 g (83.5%) of 4-(1E-pentenyl)cyclohexanone as a pale yellow liquid.