Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S([N:12]2[C:28]3[C:15]4=[C:16]([CH:25]=[CH:26][CH:27]=3)[C@H:17]3[O:22][CH2:21][C:20](=O)[NH:19][C@@H:18]3[CH2:24][C:14]4=[CH:13]2)(=O)=O)=CC=1.[CH3:30]I.O>CN(C=O)C>[CH3:30][N:19]1[C@@H:18]2[CH2:24][C:14]3[C:15]4[C:28]([NH:12][CH:13]=3)=[CH:27][CH:26]=[CH:25][C:16]=4[C@H:17]2[O:22][CH2:21][CH2:20]1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(cccc42)[C@H]2OCC(=O)N[C@@H]2C3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Sodium hydride (50% in mineral oil, 1.1 gms, 0.045 m) is added in portions to a stirred solution of trans 4-(p-tolylsulphonyl)-4,6,6a,8,9,10a hexahydro-7H-indolo-[3,4 gh]-[1,4] benzoxazin-8-one (7.0 gm, 0.018 m) in DMF (14 ml). The resulting mixture is stirred at room temperature for 1/2 hour. Methyl iodide (5.0 gm, 0.035 m) is added dropwise to the reaction mixture. After stirring an additional 1/2 hour, the reaction solution is poured into water, and the solid is removed by filtration. The tan solid is chromatographed (silica, chloroform) to give 3 gms of trans-4,6,6a,8,9,10a-Hexahydro-7-methyl-7H-indolo-[3,4 gh]-[1.4]-benzoxazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25](Cl)=[O:26].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][NH:13][C:25]([C:17]2[O:16][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=2)=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)CN)cc1OC
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C(C)(C)CNC(=O)c2cc3ccccc3o2)cc1OC
Reaction time: 15 h
Yield: 86.3 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-2-methyl-propylamine (106 mg, 0.506 mmol) and benzofuran-2-carbonyl chloride (90.7 mg, 0.502 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (139 μL, 1.00 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, redissolved in dichloromethane, and extracted with 1M hydrochloric acid, 1M sodium hydroxide, and a saturated aqueous solution of sodium chloride. The organic layer dried over sodium sulfate and evaporated to dryness. The crude product was then purified by column chromatography on silica gel using a gradient of 1-30% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (153 mg, 0.433 mmol, 86.3%). ESI-MS m/z calc. 353.2, found 354.2 (M+1)+. Retention time of 2.99 minutes. 1H NMR (400 MHz, CD3CN) δ 1.38 (s, 6H), 3.60 (s, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.85-7.06 (m, 4H), 7.31-7.39 (m, 2H), 7.46 (t, J=8.4 Hz, 1H), 7.52-7.56 (m, 1H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[S:16]1[CH:20]=[CH:19][C:18]([Mg]I)=[CH:17]1.[NH4+].[Cl-]>C1COCC1>[O:14]=[C:4]([C:18]1[CH:19]=[CH:20][S:16][CH:17]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: I[Mg]c1ccsc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of the Weinreb amide 45 (1.53 g, 7 mmol) in anhydrous THF (10 mL) was added dropwise (over a 10-min period) a solution of thiophen-3-ylmagnesium iodide (0.3 M in THF, 50 mL) under nitrogen atmosphere at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was poured into a saturated NH4Cl solution and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled compound (776 mg, 46%). MNa+264.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[O:22]1CCOCC1>O.CCOC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=[O:22]
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(C(Br)Br)cc2n1
Reactant: C1COCCO1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(-c2ccccc2)c2ccc(C=O)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(dibromomethyl)-4-phenylquinoline-2-carbonitrile (2.02 g, 4.81 mmol) in 1,4-dioxane (75 mL) was added a solution of silver nitrate (3.27 g, 19.24 mmol) in 30 mL of water, and the reaction mixture stirred 1 h at reflux. After cooling to rt, the mixture was diluted with EtOAc and filtered. The solid was washed with EtOAc and the organic phases combined. The filtrate was washed twice with water and the combined aqueous layers were back-extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (eluting with acetone-CH2Cl2-toluene, 10:40:50) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 10.39 (s, 1H), 8.80 (s, 1H), 8.21 (s, 2H), 8.07 (s, 1H), 7.66 (m, 5H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19](CC)CC)[CH3:18].C(Cl)(=O)OCC.C(N)C>O.O1CCCC1>[CH2:17]([NH:19][C:14](=[O:16])/[CH:13]=[CH:12]/[C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.76 g), triethylamine (0.8 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.4 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ethylamine solution (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give (E)-N-ethyl-3-(5-phenyl-4-isoxazolyl)propenamide (0.78 g, yield 91%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 156–157° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=1.[CH2:16]([O:23][C:24]1[C:25]([F:33])=[C:26]([C:29]([F:32])=[CH:30][CH:31]=1)[CH:27]=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].Cl>CO.O>[CH2:16]([O:23][C:24]1[C:25]([F:33])=[C:26]([CH:27]([C:15]2[C:9]3[C:10](=[N:11][CH:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[NH:13][CH:14]=2)[OH:28])[C:29]([F:32])=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=Cc1c(F)ccc(OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(F)ccc(OCc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (20, 750.0 mg, 0.003842 mol, prepared as in Example 9) in methanol (20.0 mL) were added 3-benzyloxy-2,6-difluoro-benzaldehyde (27, 1.12 g, 4.5 mmol) and potassium hydroxide (1.50 g, 0.0267 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight and then poured into water, acidified with 1N HCl to pH around 2 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound (28, 700 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9]I>>[Cl:1][C:2]1[N:3]([CH3:9])[C:4](=[O:8])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cccc(Cl)[nH]1
Reactant: CI
Product: Cn1c(Cl)cccc1=O
Reaction time: 5 h

Procedure:
51.82 g of 2-chloro-pyrid-6-one (400 mmol) and 12.7. g of 83% sodium-hydride dispersion in mineral oil (440 mmol) are reacted in 400 ml absolute dimnethylfomamide at room temperature under argon for 15 minutes. 32.4 ml methyl-iodide (520 mmol) are added dropwise and stirring is continued at 50° for 5 hours. The reaction mixture is evaporated on a rotary evaporator until the solvent starts to distill from a bath of 60°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:3]1.C1COCC1.[H][H]>C(O)C.[Pd]>[OH:1][C@@H:2]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH2:3]1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)C=Cc3ccncc3)CC[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CCc3ccncc3)CC[C@@H]12
Reaction time: 5 h
Yield: 37.9 %

Procedure:
A solution of 3α-hydroxy-21-(4-pyridylmethylene)-5β-pregnan-20-one (100 mg, 0.245 mmol) in 4 mL each of ethanol and THF containing 20 mg of 5% Pd/C was subjected to hydrogen atmosphere via a balloon, and stirred for 5hours. The catalyst was then filtered off and the solution concentrated in vacuo. The residue was subjected to flash column chromatography eluting with hexane:acetone to give the title compound (38 mg) as a solid; TLC Rf (hexane:acetone 2:1)=0.28.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[O:19][CH2:18][N:17]([C:20]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:16](=[O:29])[C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>ClCCl>[CH:13]([C:14]1[O:19][CH2:18][N:17]([C:20]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:16](=[O:29])[C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:12]
Reactant: CC(C)(c1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(c1ccccc1)N1COC(C=O)=C(c2ccccc2)C1=O
Reaction time: 9 h
Yield: 95.7 %

Procedure:
Pyridinium chlorochromate (4.70 g) was suspended in dichloromethane (20 ml), and a dichloromethane solution (27 ml) of 6-hydroxymethyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 53, 4.70 g) was added thereto at room temperature. After stirring for about 9 hours, a large amount of ether was added and separated by decantation. The organic layer was dried with magnesium sulfate and the solvent was evaporated. The crude product was purified by silica gel chromatography to afford the captioned compound (4.47 g, yield 96%).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH2:16][CH2:17][C:18](=[O:22])[CH2:19]2)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C@@H:9]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=1)C=C)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[Si:25]([O:24][C@H:9]1[CH2:8][CH2:7][C@H:6]2[C@H:5]3[C@H:14]([CH2:13][CH2:12][C@:10]12[CH3:11])[C@:15]1([CH3:23])[C@H:20]([CH2:19][C:18](=[O:22])[CH2:17][CH2:16]1)[CH2:21][C@H:4]3[CH2:1][CH:2]=[CH:3][C:42]1[CH:45]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[C:40]([O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:41]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: C=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: C=CC[C@@H]1C[C@H]2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CC=Cc4cc(OCc5ccccc5)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 30 °C
Reaction time: 14 h

Procedure:
Under argon atmosphere, 7α-allyl-17β-(tert-butyldimethylsilyloxy)-5α-androstan-3-one (200 mg), 3,5-dibenzyloxystyrene (285 mg) and benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (37 mg) were dissolved in methylene chloride (2.5 ml) and stirred at 30° C. for 14 hours. After evaporation under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3,5-dibenzyloxyphenyl)-2-propenyl)-5α-androstan-3-one.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:26]=1[NH2:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:27][C:26]4[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=4[CH3:24])=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1cc(C)c(N)c(C)c1
Product: Cc1cc(C)c(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c(C)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (75.0 mg) and 2,4,6-trimethylaniline (71.6 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2,4,6-trimethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (29.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH:23]4OCC[O:24]4)[CH:17]=3)=[C:13]([CH:28]([CH3:30])[CH3:29])[C:12](=[O:31])[NH:11][C:10]2=[O:32])[CH:5]=[C:4]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O.CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[C:20]([CH3:22])[CH:21]=3)[CH:23]=[O:24])=[C:13]([CH:28]([CH3:29])[CH3:30])[C:12](=[O:31])[NH:11][C:10]2=[O:32])[CH:5]=[C:4]([NH:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C5OCCO5)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
A mixture of (15) (908 mg, 1.53 mmol), PPTS (77 mg, 0.31 mmol), and water (7 drops) in acetone (10 ml) was heated under reflux for 3 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 350 mg (50%) of a white foam; 1H NMR (200 MHz, CDCl3) δ 1.11 (6H, d, J=6.8 Hz), 2.40 (3H, s), 2.68 (1H, m), 3.80 (3H, s), 4.29 (2H, d, J=5.4 Hz), 4.72 (2H, s), 5.02 (1H, t, J=5.4 Hz), 6.01 (1H, s), 6.26 (1H, s), 6.85-6.89 (3H, m), 7.09 (1H, s), 7.21-7.27 (2H, m), 7.40 (1H, s), 8.98 (1H, s), 9.89 (1H, s).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[C:39]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48](O)=[O:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(N(CC)CC)C>C(#N)C>[C:39]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([NH:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1cc2ncnc(N3CCC(CCN)CC3)c2cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCC(CCNC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
N,N'-dicyclohexylcarbodiimide (0.53 g) was added to a mixture of 4-(2-aminoethyl)-1-(6,7-dimethoxyquinazolin-4-yl)piperidine.2HCl (1.2 g), Boc-L-proline (1.1 g), triethylamine (0.72 ml) and acetonitrile (20 ml). The mixture was stirred at room temperature for 12 hours and filtered. The filtrate was dried and concentrated under reduced pressure. The residue was partitioned between an aqueous solution of 10% NaHCO3 and chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by using a 40 g silica gel column to give 4-{2-(Boc-L-prolylamino)ethyl}-1-(6,7-dimethoxyquinazolin-4-yl)piperidine (1.23 g; 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:12]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:13](=[O:16])[CH2:14]Cl.[C:23]([O-:26])(=[O:25])[CH3:24].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:12]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:13](=[O:16])[CH2:14][O:26][C:23](=[O:25])[CH3:24]
Reactant: Cc1ccc2ccccc2c1N(C(=O)CCl)C1CCOC1=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(=O)N(c1c(C)ccc2ccccc12)C1CCOC1=O
Temperature: 25 °C

Procedure:
A mixture of 18.2 g of N-(2-methylnaphthyl)-N-(2-oxo-tetrahydrofuran-3-yl)-N-chloroacetyl-amine, 11.5 g of anhydrous sodium acetate and 0.1 g of KJ in 70 ml of dimethylformamide (DMF) is heated at 110° for 16 hours. The reaction mixture is afterwards cooled to room temperature, poured into 200 ml of water and extracted three times with 50 ml of ethyl acetate each time. The combined extracts are washed with 50 ml of water, dried over sodium sulfate, filtered and then concentrated by evaporation. The dark-brown oil remaining is purified through silica gel 60 (particle size 0.06-0.2 mm) using chloroform/diethyl ether (1:1) as the eluant. The last 10 of 12 fractions are combined and the eluant is evaporated off. The diastereoisomeric mixture of the compound No. 19 which remains solidifies on cooling, m.p. 50°-70°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:18]([O:22][C:23](=[O:24])[NH:25][CH2:26][C:27](=[O:28])[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2c1cnn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(2-Pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine (1.00 g, 4.34 mmol), tert-butoxycarbonylamino-acetic acid (0.836 g, 4.77 mmol), ethyldimethylpropylcarbodiimide hydrochloride (1.00 g, 5.24 mmol), N-hydroxybenzotriazole (0.707 g, 5.24 mmol) and N-methyl morpholine (1.10 g, 10.9 mmol) were dissolved in 30 mL of DMF, and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 1.62 (m, 4H), 2.44 (m, 4H), 2.86 (t, 2H, J=6.78), 3.86 (d, 2H, J=6.11), 4.47 (t, 2H, J=6.78), 7.08–7.65 (m, 4H), 8.24 (s, 1H), 9.97 (s, 1H); MS (DCI/NH3) m/z 388 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[C:4]([F:10])[C:3]=1[CH3:11].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC#N>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([CH3:11])=[C:4]([F:10])[C:5]=1[O:9][CH3:12]
Reactant: Cc1c(Br)cc(Br)c(O)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1c(Br)cc(Br)c(C)c1F
Temperature: 30 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a homogeneous CH3CN (200 mL) solution of 4,6-dibromo-2-fluoro-3-methylphenol (2, 28.4 g, 100 mmol) at rt, K2CO3 (16.59 g, 120 mmol) was added, followed by MeI (9.3 mL, 150 mmol). The cloudy solution was stirred at 30° C. overnight. The reaction went to completion monitored by LC and TLC. The mixture was cooled to rt, quenched by addition of H2O (100 mL) and sat. aq. NH4Cl (100 mL), two layers were mixed well and then separated, aqueous layer was extracted with EtOAc (50 mL), organic layers were combined, dried (MgSO4), filtered, solvent was removed in vacuo. The crude product, an oil, was dissolved in CH2Cl2 (˜80 mL) and the solution was passed through a silica gel pad (˜50 g of silica gel), washing with CH2Cl2 (˜100 mL). The filtrate was collected, and the solvent was removed in vacuo. 1,5-Dibromo-3-fluoro-2-methoxy-4-methylbenzene was obtained as a solid: 31.62 g (>99% yield); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=2.1, 1H), 3.92 (s, 3H), 2.29 (d, J=2.8, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]=1[NH2:9]
Reactant: NC1CCOCC1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(Cl)c(N)c(NC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
2,5-diamino-4,6-dichloropyrimidine (6 g, 33.5 mmol), 4-aminotetrahydropyran (3.39 g, 33.5 mmol, 1 equiv.), sodium bicarbonate (9.85 g, 117.2 mmol, 3.5 equiv.) and 1-butanol (120 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 95/5 methylene chloride/methanol to 90/10 methylene chloride/methanol) to give 7.1 g (87% yield) of the desired product as a pink solid. In an alternative procedure, water (300 mL) was added to the residue (before chromatographic purification) and the mixture stirred for 30 min at room temperature. Filtration under vacuum, thorough washing of the precipitate with water, followed by thorough drying of the pink solid in vacuum oven at 60° C., provided high purity desired product in 78% yield. 1H NMR (300 MHz, CD3OD) δ, ppm: 4.21-4.12 (m, 1H), 4.01-3.96 (m, 2H), 3.53 (td, J=11.7, 2.2 Hz, 2H), 2.01-1.96 (m, 2H), 1.60 (tdd, J=12.1, 11.7, 4.6 Hz, 2H); MS (EI) m/z 244.3 (MH)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[N:16]=1>CN(C)C=O.[Cu]I>[CH3:22][S:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:18]=1
Reactant: CSc1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (1.60 g, 0.0024×4.1 mol), sodium hydride (0.29 g, (ca.60% in mineral oil), 0.0024×3.0 mol) and CuI (0.22 g, 0.0024×0.5 mol) in dimethylformamide, 2-chloro-4-methylmercapto-6-(3-thienylmethyloxy)pyridine (0.64 g, 0. 0024 mol) was added and the resultant solution was refluxed for about 6 hours.