Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Br:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:17])[C:10]=1[Br:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(OCc2ccccc2)c1Br
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 3-(benzyloxy)-2-bromophenol (2.55 g, 9.14 mmol) in DMF (8 mL) was added K2CO3 (1.894 g, 13.70 mmol) and MeI (0.63 mL, 10.05 mmol) at RT. The reaction mixture was stirred overnight then quenched with water and diluted with EtOAc. The organic phase was washed with water (3×), brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Heptane) to afford the title compound as a colorless oil (2.66 g, 99% yield). 1H NMR (CHLOROFORM-d) δ 7.49 (d, J=7.1 Hz, 2H), 7.36-7.43 (m, 2H), 7.30-7.35 (m, 1H), 7.20 (t, J=8.3 Hz, 1H), 6.56-6.65 (m, 2H), 5.18 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(OC(=O)C)(=O)C.C(O)(=O)C.OS(O)(=O)=O.[N+:38]([O-])([OH:40])=[O:39]>>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:38]([O-:40])=[O:39])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
3-(2-Chloro-4-trifluoromethylphenoxy)benzoic acid (275.9 g, 0.935 mole), acetic anhydride (276 g, 2.7 mole), glacial acetic acid (276 g, 4.6 mole) and conc. H2SO4 (44 g) were charged into a three-neck 5 liter flask equipped with a mechanical stirrer, thermometer and an addition funnel. Nitric acid (90%, 91.7 g, 1.3 mole) was added at 15°-25° C. over 0.5 hr. The cooling bath was substituted with a water bath and the reaction was stirred for 1.5 hrs. at 30° C. The reaction was quenched with 1250 ml of water (at 30° C.), stirred for 0.25 hr. The resultant yellow precipitate was filtered and washed with 2 liters of water. Recrystallization from toluene (750 ml) afforded 271.6 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid; m.p. 120°-121° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:15]3[C:14]([Cl:13])=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Temperature: 75 °C
Yield: 43.5 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (5.00 g, 29.0 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (7.22 g, 29.00 mmol) in anhydrous dimethyl sulfoxide (30 mL) was added cesium carbonate (18.90 g, 58.00 mmol) and the reaction mixture was heated at 70-80° C. for 4 hours. After cooling to ambient temperature, ethyl acetate was added (200 mL) and the mixture was washed with water (4×15 mL), brine (2×15 mL); dried over anhydrous sodium sulfate, and filtered. After concentration of the filtrate in vacuo, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (5.06 g, 44%): 1H NMR (300 MHz, CDCl3) 7.85 (d, J=7.7 Hz, 1H), 6.60 (d, J=12.2 Hz, 1H), 3.95-3.93 (m, 4H), 3.83 (d, J=6.3 Hz, 2H), 1.98-1.87 (m, 4H), 1.84-1.71 (m, 4H), 1.64-1.56 (m, 1H), 1.56 (s, 9H).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([N:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(N)CO
Reactant: O=C1OC(=O)c2ccccc21
Product: CCCC(CO)N1C(=O)c2ccccc2C1=O
Yield: 62 %

Procedure:
2-(1-hydroxypentan-2-yl)isoindoline-1,3-dione was prepared in a similar manner to example 9c using isobenzofuran-1,3-dione and 2-aminopentan-1-ol. Yield 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.F[B-](F)(F)F.C([O+]([CH2:32][CH3:33])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][C:9]3[C:10]=2[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15]=3[N:8]2[CH2:33][CH2:32][CH2:4][CH2:5][CH2:6]2)[CH:7]=1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN1C(N2CCCCC2)=C2N=c3cc(Cl)ccc3=C2Oc2ccccc21
Reaction time: 48 h

Procedure:
A solution of 5.0g of 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one in 60ml of methylene chloride was cooled to 15° and treated with 30ml of a 1N solution of triethyloxonium fluoroborate in methylene chloride. The mixture was stirred for 48 hrs. at ambient temperature. The precipitated solid was filtered, washed with methylene chloride and added to 10ml of piperidine, and the clear solution was heated for 8 hrs. on the steam bath. The mixture was diluted with water, and the precipitated solid was filtered and recrystallized from ethylacetate, mp. 244°-5°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29]C)[CH2:27]C)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])C=C[CH:3]=1.[NH:33]1C=CN=C1C=O.C(CC(NC(C1C=CC(OCCN(C)C)=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[NH:7][CH:2]=[CH:3][N:33]=1)/[C:10]([NH:12][CH:13]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:29])=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Reactant: O=Cc1ncc[nH]1
Agent: CCCC(NC(=O)CC#N)c1ccc(OCCN(C)C)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1ncc[nH]1)c1ccc(OCCN(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 1H-imidazole-2-carbaldehyde was used instead of 6-bromopicolinaldehyde, and 2-cyano-N-(1-(4-(2-(dimethylamino)ethoxy)phenyl)butyl)acetamide (30) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl) acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 8:92 methanol/dichloromethane, to give 38 (80 mg, 63%) as a light yellow oil: MS (ES+) m/z 453.2 (M+H)+.
Reaction SMILES: [C:1](/[C:3](/[CH:13]=[CH2:14])=[CH:4]\[C@@H:5]1[C@@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2].S(Cl)([Cl:17])=O>O1CCCC1.CN(C)C=O>[C:1](/[C:3](/[CH:13]=[CH2:14])=[CH:4]\[C@@H:5]1[C@@H:7]([C:8]([Cl:17])=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
(1R)-trans-3-[(1Z)-2-cyano-1,3-butadienyl]-2,2-dimethylcyclopropanecarboxylic acid (440 mg, 2.30 mmol) was dissolved in 3 mL of tetrahydrofuran and then thionyl chloride (301 mg, 2.53 mmol) and 10 mg of N,N-dimethylformamide were added and the solution was stirred at room temperature for 1 hours, and further at 60° C. of 3 hours. The reaction solution was concentrated under reduced pressure condition to obtain 460 mg of (1R)-trans-3-[(1Z)-2-cyano-1,3-butadienyl]-2,2-dimethylcyclopropanecarboxylic acid chloride represented by the following formula:
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:26][CH2:25][CH2:24][C@H:14]2[C:15]([N:17]2[CH2:23][CH2:22][CH2:21][C@H:18]2[CH2:19][OH:20])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:26][CH2:25][CH2:24][C@H:14]2[C:15]([N:17]2[CH2:23][CH2:22][CH2:21][C@H:18]2[CH:19]=[O:20])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
0.53 g of 1-[1-(2-indenylacetyl)-L-prolyl]-L-prolinol prepared in Preparation Example 41 and 0.76 g of triethylamine were dissoved in 6 ml of dimethylsulfoxide. To the solution was added 1.19 g of sulfur trioxide-pyridine complex and the mixture was stirred for one hour at room temperature. The reaction mixture to which 10 ml of ice-water was added was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, water, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to produce 0.29 g of 1-[1-(2-indenylacetyl)-L-prolyl]-L-prolinal as a colorless oil (yield: 55%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH:9]=[CH2:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][CH:9]1[O:19][CH2:10]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCCOC(=O)C(=C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCC1CO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-butenyl methacrylate (5.1 g) was added slowly to the stirred solution of m-CPBA (10.2) in methylene dichloride (70 ml). The resulting solution was stirred at room temperature for 5 hours and then was washed repeatedly with a dilute aqueous solution of potassium carbonate. The solution obtained was then dried with anhydrous magnesium sulfate and evaporated. Pure 3,4-epoxybutyl methacrylate was isolated by column chromatography on silica gel. Yield 3.9 g.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:36][CH:37]([CH3:40])[CH2:38][NH2:39]>C(Cl)Cl>[CH2:38]([NH:39][C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:8]=[CH:9][C:10]([B:13]2[O:14][C:15]([CH3:20])([CH3:21])[C:16]([CH3:18])([CH3:19])[O:17]2)=[CH:11][CH:12]=1)[CH3:1])[CH:37]([CH3:40])[CH3:36]
Reactant: CC(C)CN
Reactant: CC(C)(C(=O)O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)CNC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 0.08 h
Yield: 99.2 %

Procedure:
2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (10 g, 34.46 mmol), EDC (7.26 g, 37.91 mmol) and HOBt (5.12 g, 37.91 mmol) were mixed in DCM (350 mL) and stirred for 5 minutes then 2-methylpropan-1-amine (3.6 mL, 36.19 mmol) was added. The reaction mixture was stirred at room temperature overnight then diluted with dichloromethane and washed successively with aq. HCl (0.5N), water, aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was crystallized from EtOAc/hexane to give 11.8 g of product as a white solid in 99% yield. 1H NMR (400 MHz, CDCl3): δ 0.76-0.78 (d, 6H), 1.35(s, 12H), 1.57 (s, 6H), 1.62 (m, 1H), 2.97 (t, 2H), 5.15 (br-s, 1H), 7.38-7.40 (d, 2H), 7.79-7.81 (d, 2H). MS (M+H, 346).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([OH:31])[CH:25]=2.[C:32]([C@@H:36]1[CH2:41][CH2:40][C@H:39](O)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33].C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:32]([C@H:36]1[CH2:41][CH2:40][C@H:39]([O:31][C:26]2[CH:25]=[C:24]3[C:29]([CH:30]=[C:21]([CH3:20])[N:22]=[CH:23]3)=[CH:28][CH:27]=2)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1cc2ccc(O)cc2cn1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2cn1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (5.14 g, 19.6 mmol) was added to a solution of 3-Methylisoquinolin-7-ol (2.08 g, 13.1 mmol) and cis-4-tert-butylcyclohexanol (3.06 g, 19.6 mmol) in Toluene (60 mL, 600 mmol). The mixture was stirred for 15 minutes then Diisopropyl azodicarboxylate (3.86 mL, 19.6 mmol) was added. The mixture was then stirred at room temperature overnight. The solvent was removed under vacuum. The crude product was dissolved in methylene chloride, adsorbed onto silica gel and purified by flash chromatography to give the title compound in 2.01 g (52%) yield. ESI-MS (M+H+): 298.46.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH3:25])=[N:23][N:24]=[C:20]3[C@H:19]([CH3:26])[CH2:18][NH:17][C:16]=2[CH:27]=1.C([O-])(C)(C)C.[K+]>CS(C)=O.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH3:25])=[N:23][N:24]=[C:20]3[C@H:19]([CH3:26])[CH2:18][N:17]([C:2]3[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[C:16]=2[CH:27]=1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NC[C@H]2C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc([N+](=O)[O-])nc1)C[C@H]2C
Temperature: 120 °C
Yield: 77.1 %

Procedure:
To a solution of 5-fluoro-2-nitropyridine (284 mg, 2 mmol) and (R)-8-bromo-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (292 mg, 1 mmol) in dimethyl sulfoxide (5 mL) was added potassium tert-butanolate (223 mg, 2 mmol). The reaction mixture was heated at 120° C. for 1 hour under microwave (pressure: 3.2 bar, equipment power: 150 W). The mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give (R)-8-bromo-1,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (320 mg, 77%) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]([NH2:17])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[N:7]=1)[CH3:2].Cl.[C:19](=O)([O-])[O-:20].[K+].[K+]>CO.C(Cl)(Cl)Cl>[CH2:1]([N:3]=[C:4]([NH2:17])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[NH:16])[O:20][CH3:19])[N:7]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN=C(N)Nc1cnn(CCCCC#N)n1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN=C(N)Nc1cnn(CCCCC(=N)OC)n1
Reaction time: 60 h

Procedure:
A solution of 5-[4-[2-ethylguanidino)-1,2,3-triazol-2-yl]valeronitrile (1.35 g.) in MeOH (5 ml.) and chloroform (20 ml.) was saturated with gaseous HCl at 0° and the solution kept at 0° for 2.5 days. Evaporation of the solvent gave an oil which was basified with cold potassium carbonate solution and then extracted with chloroform to give methyl 5-[4-(2-ethylguanidino)1,2,3-triazol-2-yl]valerimidate (1.57 g.) which was used without further purification.
Reaction SMILES: C#C.[C:3](O[K])(C)(C)[CH3:4].[CH2:9]1[CH2:19][CH:18]2[CH:12]([CH2:13][C:14]([CH2:16][CH2:17]2)=[O:15])[CH2:11][CH2:10]1>C1COCC1>[C:3]([C:14]1([OH:15])[CH2:16][CH2:17][CH:18]2[CH:12]([CH2:11][CH2:10][CH2:9][CH2:19]2)[CH2:13]1)#[CH:4]
Reactant: O=C1CCC2CCCCC2C1
Reactant: CC(C)(C)O[K]
Agent: C#C
Solvent: C1CCOC1
Product: C#CC1(O)CCC2CCCCC2C1
Reaction time: 3.5 h
Yield: 85.5 %

Procedure:
Acetylene was bubbled for 4 hours through a mixture of tBuOK (95.8 g, 0.85 mol) in THF (11) at 0° C. 2-Decalone (100 g, 0,66 mol) was added slowly at RT to the slightly yellow suspension and the resulting mixture was stirred for additional 3.5 hours, quenched with saturated NH4Cl (500 ml) solution, and extracted with MTBE (2×700 ml). The combined organic phases were washed with NH4Cl (500 ml), H2O (2×500 ml), saturated NaCl (500 ml) solution until neutral pH was achieved, dried (MgSO4), and concentrated in vacuo. The crude orange oil was flash distilled (0.01 Torr, 88-90° C.) yielding 100.6 g (86%) of 2-ethynyldecahydro-naphthalen-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][NH:49][CH:50]([CH3:52])[CH3:51]>CN(C=O)C>[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][N:49]([C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH:50]([CH3:52])[CH3:51]
Reactant: COC(=O)CCNC(C)C
Reactant: COc1cc(Cl)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.1 %

Procedure:
To a stirred solution of 3-chloro-5-methoxy-benzoic acid (0.932 g), TBTU (3.21 g) and in DMF (10 ml) was added DIPEA (1.73 ml) followed by 3-isopropylamino propionic acid methyl ester (0.871 g) after 10 min. The reaction mixture was stirred at room temperature for 48 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 2M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (1.6 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[C-:34]#[N:35].[Na+].[I-].[K+]>CC(N(C)C)=O.O>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([C:34]#[N:35])=[N:3][C:4]=3[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN1CCN(CCCOc2ccccc2Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCN(CCCOc2ccccc2Nc2nc(C#N)nc3c2ncn3C2CCCC2)CC1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine (0.1 mmol), sodium cyanide (50 mg), potassium iodide (5 mg) are suspended in DMA (2 ml) and heated up to 160° C. and the mixture is stirred at this temperature for 24 hours. The mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is dissolved in diethylether, filtered over powdered charcoal and cooled to 4° C. The solid material formed is filtered of and dried (vacuum). A white powder with mp. 136-138° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:21]=1)[C:6]1[CH:7]=[C:8]([OH:20])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A 350-mL pressure vessel was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (4.00 g, 11.52 mmol), 3-pyridylboronic acid (3.54 g, 28.8 mmol), tetrakis(triphenylphosphine)palladium(0) (1.331 g, 1.152 mmol), THF (57.6 mL), and potassium carbonate (2.0M aq. solution) (28.8 mL, 57.6 mmol). The vessel was sealed and heated to 100° C. and stirred for 2 hours. The layers were partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (emulsion!), dried over sodium sulfate and filtered with the aid of 10% MeOH/DCM. The filtrate was evaporated to give a yellow solid. This solid was taken up in minimal DCM and sonicated for 5 min. The solid was filtered and washed with DCM (30 mL). Filtering and washing with DCM afforded (S)-2-amino-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a pale-yellow solid
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[N:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:16]([CH3:26])[N:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:26][C:16]1[N:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[N:18][C:17]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: Cc1nc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1nc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (130 mg, pale brown solid) from 4-chloro-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.39 mmol, Intermediate-72, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[CH2:15][CH2:16]2)=[O:9])[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Product: O=C(c1cc(Cl)ccn1)N1CCN(CCO)CC1

Procedure:
Using 4-chloropicolinic acid chloride and 4-(2-hydroxyethyl)piperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (282 mg, 0.52 mmol), and (4-chloro-pyridin-2-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (175 mg, 0.65 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a colorless solid (210 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-202) as a colorless powder (114 mg, 80%).