Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([C:13]1[C:21]2[O:20][CH2:19][CH2:18][C:17]=2[C:16]([CH3:22])=[C:15]([NH:23][C:24](=O)[O:25]C(C)(C)C)[C:14]=1[CH3:31])([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)[CH3:3].[C:32]([CH2:36]C(Cl)=O)([CH3:35])([CH3:34])[CH3:33]>C(OCC)(=O)C.CCCCCC>[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:2]([C:13]2[C:21]3[O:20][CH2:19][CH2:18][C:17]=3[C:16]([CH3:22])=[C:15]([NH:23][C:24](=[O:25])[CH2:33][C:32]([CH3:36])([CH3:35])[CH3:34])[C:14]=2[CH3:31])[CH3:3])=[CH:9][CH:8]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1c2c(c(C(C)(O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)OC(C)(C)C)OCC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c2c(c(C(C)c3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OCC2
Yield: 61 %

Procedure:
Using tert-butyl (7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 223 and tert-butylacetyl chloride, the title compound was synthesized in the same manner as in Example 224. Yield: 61%. Melting point: 189-190° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[C:19]3[C:18]([C:20]([O:22]C)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:25][NH2:26]>CO.Cl>[CH2:8]([C:9]1[C:11]2=[CH:12][NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]=32)[C:20](=[O:22])[NH:26][N:25]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2[nH]cc(C(=O)CCc3ccccc3)c12
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1NN=C(CCc2ccccc2)c2c[nH]c3cccc1c23

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (3 mL) was treated with 3-phenylpropionyl chloride (361 mg, 2.14 mmol) at room temperature. The orange solution was cooled to 0° C. and treated with aluminum chloride (572 mg, 4.29 mmol). The reaction mixture was stirred at room temperature for 2 h, then poured into ice-cold 1M aqueous HCl. The aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with CH2Cl2 (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-(3-phenylpropionyl)-indole-4-carboxylate as a pale-yellow solid, 395 mg (90%). A solution of the 3-(3-phenylpropionyl)-4-carboxy indole (95.5 mg, 0.31 mmol) in MeOH (3 mL) and HCl (0.1 mL) was treated with hydrazine hydrate (47 mg, 0.93 mmol) and the solution was heated at reflux for 8 h. The solution was cooled in an ice/water bath and the precipitated solid was collected by filtration to give 1,5-dihydro-3-phenethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 60.2 mg (71%). The crude product was purified by radial chromatography (2 mm SiO2, 5:1 hexanes: EtOAc) to give a yellow solid. mp 182-183.5° C.; 1H NMR (300 MHz, d6-DMSO) δ2.80 (m, 2H), 2.84 (m, 2H), 7.22 (m, 2H), 7.31 (m, 4H), 7.54 (m, 2H), 7.81 (s, 1H), 10.19 (s, 1H), 11.92 (br s, 1H); Anal. (C10H7N3O.0.1 H2O) C, H N.
Reaction SMILES: [SH2:1].[CH3:2][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17]#[N:18])[N:7]=1)([CH3:5])[CH3:4].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:5][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17](=[S:1])[NH2:18])[N:7]=1)([CH3:2])[CH3:4]
Reactant: S
Reactant: CC(C)(C)c1nc(C#N)nc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C(N)=S)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Hydrogen sulfide is bubbled through a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbonitrile (4.5 g, 19.3 mmol) and triethylamine (4.3 g, 42.4 mmol) in pyridine (20 mL) at room temperature for 6 hours. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated under vacuum and the residue is recrystallized from ether/hexane to give pure 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbothioamide (3.0 g, 58%); mp 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:21])CO)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[O:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1c2cc(C(O)CO)ccc2ccc2ncc(Cl)cc12
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (60 mg, 0.20 mmol) was dissolved in 1.8 mL of tetrahydrofuran and 0.9 mL water. Sodium periodate (51 mg, 0.24 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was then diluted with water and extracted with ethyl acetate three times. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 10-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.15 (s, 1H); 8.85 (d, 1H); 8.73 (d, 1H); 8.54 (d, 1H); 8.20 (dd, 1H); 7.75 (d, 1H); 7.47 (d, 1H); 7.31 (d, 1H).
Reaction SMILES: [CH2:1]=[C:2]([C:7]([O:10]S(F)(=O)=O)([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[C:15](O[K])([C:21]([F:24])([F:23])[F:22])([C:17]([F:20])([F:19])[F:18])[F:16].[F-].[K+].FC(F)(F)C(C(F)(F)F)=O>O.COCCOCCOC>[CH2:1]=[C:2]([C:7]([O:10][C:15]([C:21]([F:24])([F:23])[F:22])([C:17]([F:20])([F:19])[F:18])[F:16])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(O[K])C(F)(F)F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Agent: O=C(C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: C=C(C(F)(F)F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)F
Reaction time: 2 h
Yield: 75 %

Procedure:
CH2═C(CF3)CF2OSO2F (10 g, 0.041 mole) is added at 20° C. to (CF3)2CFOK, prepared from freshly dried potassium fluoride (KF) (2.4 g, 0.041 mole), hexafluoroacetone (HFA) (9.3 g, 0.056 mole) and dry diglyme (10 ml). The reaction mixture is agitated for 2 hours and then poured into water, the organic layer separating. The organic layer is washed with dilute hydrochloric acid, then sodium bicarbonate solution, then water, after which it is dried over magnesium sulfate (MgSO4). Distillation of the reaction mixture gives CH2═C(CF3)CF2OCF(CF3)2 (10.2 g, 75% yield, b.pt. 87-88° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)cc2F)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4ccc(F)cc4F)C3)CC2)cc1
Yield: 44.6 %

Procedure:
The title compound (D154) (55 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-(2,4-difluorophenoxy)azetidin-1-yl)nicotinic acid (D108) (82 mg, 0.240 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (54.79 mg, 0.240 mmol).
Reaction SMILES: Cl.[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:11][CH2:10]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(#N)C.[Cu](I)I>[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[C:19]([C:31]#[C:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:11][CH2:10]1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc(Br)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Agent: I[Cu]I
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1

Procedure:
1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(5-bromo-2-methoxyphenyl) piperidine hydrochloride (compound no. 187) (60 mg, 0.15 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (11 mg, 0.015 mmol) and copper iodide (6 mg, 0.030 mmol) were suspended in anhydrous acetonitrile (500 μL) in a microwave vial and treated with phenylacetylene (77 mg, 0.75 mmol), followed by triethylamine (250 μL). The vial was flushed with nitrogen, capped and microwaved at 140° C. for 20 min. The reaction was diluted with methanol (750 μL), filtered (Whatman 0.20 μm PTFE) and subjected to reverse-phase HPLC purification (5-50% CH3CN/0.08% TFA) to yield 1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(2-methoxy-5-(phenyl-ethynyl)phenyl)piperidine (compound no. 64) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 386.2 [M+H]+, retention time 2.86 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36](Cl)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([C:23]#[C:22][C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (example B.14) according to general procedure II. Obtained as a yellow solid (44 mg, 30%). MS (ISP) 590.0 (M+H)+]; mp 220–223° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.O.Cl.[CH2:14](OCC)C>>[CH3:14][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: CCOCC
Reactant: CC1Cc2ccccc2C1=O
Agent: Cl
Solvent: O
Product: CC1=Cc2ccccc2C1C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 15.02 g (103 mmoles) of (+/-)-2-methyl-1-indanone in 200 mL of anhydrous diethyl ether at -78° C. under an argon atmosphere was injected 50 mL of a 3.0 M methylMgl solution in ether (150 mmoles MeMgl). The reaction was allowed to slowly warm to room temperature over three hours and then it was heated at 35° C. for 1 hour. The reaction was poured into 1L of water, and concentrated HCl was slowly added until a pH of 1 was achieved. The mixture was transferred to a separatory funnel and shaken vigorously. The layers were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with water (1×500 mL), with aqueous NaHCO3 (1×500 mL), and with saturated aqueous NaCl (1×500 mL). The organic layer was dried over anhydrous MgSO4 and filtered. GC showed that some alcohol was still present so the mixture was stirred with approximately 100 ml of 10 weight percent aqueous HCl for 1 hour. The mixture was transferred to a separatory funnel, and the layers were separated. The organic phase was washed with water (1×200 mL), with aqueous NaHCO3 (1×300 mL), and with saturated aqueous NaCl (1×250 mL). Drying over MgSO4 followed by filtration and solvent removal yielded 14.7 g (99 percent) of 1,2-Dimethylindene.
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 870.1 %

Procedure:
In analogy to example 1 were reacted 6,36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 1,81 g (2 mmol) of acryloyl chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 6,5 g (87%) acrylic acid 2,6-di-ethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid. Elemental analysis calculated for C23H35NO3: C 73,95%; H 9,44%; N 3,75%. Found: C 74,43%; H 9,44%; N 3,91%.
Reaction SMILES: [C:1]([C:3](=[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)SC)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:20]1([CH2:25][C:26]([NH2:28])=[NH:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:20]1([CH2:25][C:26]2[NH:28][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)C(C#N)=C(Nc1cccc(F)c1)SC
Reactant: N=C(N)CC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(Nc2cccc(F)c2)nc(CC2CCCC2)[nH]c1=O

Procedure:
0.1 g (0.37 mmol) of methyl 2-cyano-3-[(3-fluorophenyl)amino]-3-(methylsulfanyl)-2-propenoate and 0.06 g (0.41 mmol) of 2-cyclopentylethanamidine hydrochloride are dissolved in 1 ml of DMF and heated with 0.11 g (0.82 mmol) of potassium carbonate at 90° C. overnight. After filtration, the solvent is removed in vacuo and the residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) purified. 70 mg (59% of theory) of the product are obtained as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[CH2:25][CH3:26])C1C=CC=CC=1.[H][H].C>CN(C)C=O.[Pd].C(OCC)(=O)C>[CH2:25]([C:10]1[N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])[CH3:26]
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(O)c(=O)ccn1CCOC(=O)C(C)(C)C
Yield: 534.9 %

Procedure:
To a solution of 3-benzyloxy-2-ethyl-1-(2-pivaloyloxyethyl)pyridin-4-one (0.5 g) in dimethylformamide (25 ml) was added 5% palladium on charcoal catalyst (0.1 g) and the reaction mixture was stirred at room temperature under a constant stream of hydrogen for 24 hours. The dimethylformamide was then removed under high vacuum by rotary evaporation to give an oil. The solid obtained on cooling the oil was dissolved in hot ethyl acetate and the solution treated with activated charcoal, refluxed for 5 minutes, filtered and rotary evaporated. The resultant residue was recrystalized from petroleum ether (boiling point 40°-60° C.) to give the title compound (2 g, 53%) as colourless crystals, m.p. 113°-115° C., νmax (nujol) 1580, 1630, 1725, 3130 cm-1 ; δ(90 MHz, CDCl3), 7.25 (1H, d), 6.43 (1H, d), 5.25 (1H, s, br), 4.29 (2H, t), 4.21 (2H, t), 2.85 (2H, q), 1.27 (3H, t), 1.28 (9H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccc(Cn3ncc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of indazole (0.244 g, 2.07 mmol) in DMF at 0° C. was treated with sodium hydride (0.076 g, 1.98 mmol), stirred for 10 minutes at room temperature, treated with ethyl 2-[4-(chloromethyl)phenyl]-1,3-oxazole-4-carboxylate (0.5 g, 1.88 mmol) and stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo to give a solid residue. The resultant residue was purified by column chromatography (silica, EtOAc:hexanes, 50%) to give ethyl 2-[4-(1H-indazol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylate as white solid. The resulting solid (0.45 g, 1.29 mmol) was dissolved in 1:1 MeOH:THF treated with 1.0 M LiOH for 3 hours at 60° C. and concentrated in in vacuo. The resulting residue was diluted with water, treated with 1.0 M HCl and filtered to afford the title product 92% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 320 (MH+).
Reaction SMILES: [CH3:1][S+:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[CH3:1][S+:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([CH2:18][C:17]([OH:19])=[O:12])=[CH:5][CH:4]=1
Reactant: C[S+](C)c1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: COS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[S+](C)c1ccc(CC(=O)O)cc1

Procedure:
In 30 ml of acetonitrile was dissolved 2.6 g of p-dimethylsulfoniophenol methylsulfate, and 0.8 ml of acetyl chloride and 1.4 ml of triethylamine were dropwise added thereto. The reaction mixture was filtered to remove the deposited triethylamine hydrochloride. The filtrate was concentrated under reduced pressure and the residue was crystallized by adding ether.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[C:17]([CH2:19][C:20]([OH:22])=O)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[C:20](=[O:22])[CH2:19][C:17]#[N:18])[CH2:4]2)=[N:13][CH:12]=1
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CC#N)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.9 %

Procedure:
To a solution of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (75 mg, 0.345 mmol) and 2-cyanoacetic acid (35 mg, 0.414 mmol) in THF (5 mL) were added HATU (157 mg, 0.414 mmol) and DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 20 hours. The precipitate was filtered, washed with EtOAc, and dried under reduced pressure to give the title compound (45 mg, 46%). MS (m/z): 285 (M+H)+.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1.CC#N.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(-n2cccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(-n3cccn3)cc2)cc1
Temperature: 130 °C
Yield: 56 %

Procedure:
Prepared using General Procedure 16. A stirring mixture of p-tolylboronic acid (391 mg, 2.88 mmol) and 1-(4-bromophenyl)-1H-pyrazole (535 mg, 2.40 mmol) INT-84 in THF (4 mL), MeCN (4 mL) and sodium carbonate (1 M aqueous) (4.8 mL, 4.80 mmol) was de-gassed by bubbling through N2 gas. PdCl2dppf (88 mg, 0.120 mmol) was added and the reaction mixture further de-gassed. The reaction was heated at 130° C. for 30 min in a microwave. The mixture was cooled to room temperature, poured onto water (100 mL) and extracted with EA/THF (2×50/10 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (EA/hexanes) to afford 315 mg (56%) of 1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole INT-85. LCMS-ESI (m/z) calculated for C16H14N2: 234; found 235 [M+H]+, tR=2.60 min (Method 10).
Reaction SMILES: [O:1]=[C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:7]=[CH:8]1.[CH:16](=[N:23]/[OH:24])\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>CC#N>[CH:16](=[N:23][O:24][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2](=[O:1])[CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O/N=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(ON=Cc2ccccc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
(Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (330 mg, 1.56 mmol), (E)-benzaldehyde oxime (286 mg, 2.36 mmol) and DBU (0.007 mL, 0.05 mmol) were combined in MeCN (0.5 mL) and the mixture was stirred at room temperature for 48 hr. The solvent was removed under reduced pressure and the residue purified via preparative HPLC to give tert-butyl 5-(benzylideneaminooxy)-3-oxoazepane-1-carboxylate as a brown oil (127 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:20]([CH2:19][CH3:18])[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(CC)Oc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mixture of 30 g of p-hydroxyacetophenone and 30 g of potassium carbonate was stirred in 500 ml of ethanol at 60° C. for 30 minutes. After cooling to room temperature, 52 g of ethyl 5-bromo-2,2-dimethylpentanoate was added to the reaction mixture. The resulting mixture was heated under reflux overnight while stirring. The solvent was removed from the reaction mixture by distillation and, 500 ml of chloroform and 300 ml of a 5% aqueous hydrogen sodium carbonate solution were added to the residue. After stirring the mixture, the chloroform layer was fractionated and washed successively with water and then with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of chloroform by distillation gave a residual oily substance. The oily substance was subjected to silica gel column chromatography and eluted using chloroform as an eluant to give 42 g of ethyl p-acetylphenoxy-2,2-dimethylpentanoate as an oily substance. The thus obtained oily substance was dissolved in 1.6 l. of anhydrous methylene chloride and 24 g of bromine was dropwise added to the solution under ice cooling while stirring to allow to react for 3 hours. To the reaction mixture was added 1 liter of ice water. After thoroughly stirring, the organic layer was successively washed with water and with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of methylene chloride by distillation gave the aimed product, ethyl 5-[p-(bromoacetyl)phenoxy]-2,2-dimethylpentanoate, as an oily substance.