Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][NH2:18].C(N(CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:18][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(Cl)cc(NCc2ccccc2Cl)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1 g, 6.1 mmol), [(2-chlorophenyl)methyl]amine (2.23 g, 15.8 mmol) and triethylamine (1.86 g, 18.4 mmol) in CH3OH (40 mL) was stirred for 4 hours at 50° C. The reaction mixture was evaporated to provide a yellow residue, which was purified by SiO2 chromatography (1:1 petroleum ether:EtOAc) to afford the title compound (1.2 g) as off-white solid. LC-MS (ES) m/z=328 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)CCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (1 g, 6.84 mmol, 1.0 eq) in DMF were added K2CO3 (2.3 g, 17.1 mmol, 2.5 eq.) and 4-bromo-2-methylbutan-2-ol (1.7 g, 10.27 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 60% yield (0.9 g). LC-MS (ESI): Calculated mass 233.0; Observed mass 235.0. [M+H]+ (rt: 0.64 min).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=[O:8].C([O-])(O)=O.[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]=[O:8]
Reactant: Brc1nccs1
Reactant: O=Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccccc1-c1nccs1

Procedure:
To a mixture of 2-bromothiazole (826 mg, 4.99 mmol) and tetrakis(triphenylphosphine) palladium (0) (175 mg, 0.151 mmol) in 1,2-dimethoxyethane (20 mL) was added 2-formylbenzeneboronic acid (0.9017 g, 6.01 mmol) and 1N aqueous NaHCO3 (8 mL). The resultant mixture was heated at reflux for 6 hrs. The reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The organic solution was dried over Na2SO4, filtered and concentrated. The crude product was purified by gradient flash chromatography (10% to 25% EtOAc in hexane) to yield 2-(2-thiazolyl)benzaldehyde as a white solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[C:20]3[CH2:19][O:18]C(=O)[N:16]([CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[C:15]=3[CH:14]=[N:13][C:12]=2[CH3:31])=[CH:7][CH:6]=1)#[N:4]>CO.ClCCl>[OH:18][CH2:19][C:20]1[C:11]([O:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:33][CH:32]=2)=[C:12]([CH3:31])[N:13]=[CH:14][C:15]=1[NH:16][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=1
Reactant: Cc1ncc2c(c1OCc1ccc(C#N)cc1)COC(=O)N2Cc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc(NCc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
Sodium borohydride (2.6 g, 69 mmol) was added to a solution of 4-[5-(4-cyano-benzyloxy)-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1 ylmethyl]-benzonitrile (83) (587 mg, 1.4 mmol) in a mixture of methyl alcohol and dichloromethane (1:1, 20 mL) at 0° C. The resulting solution was warmed to room temperature and stirred for 24 hours. The solvent was evaporated, residue was diluted with water and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by column chromatography on silica gel using a gradient mixture of dichloromethane:methyl alcohol (1:0 to 40:1) as eluant to give 4-{[4-hydroxymethyl-6-methyl-5-(4-cyano-benzyloxy)-pyridin-3-ylamino]-methyl}-benzonitrile (87) (175 mg, 32% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH:3]=[CH2:4].[CH:18](=[O:22])/C=C/C>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[CH:5]([CH2:1][CH2:2]/[CH:3]=[CH:4]/[CH:18]=[O:22])[CH2:14][CH2:13]2
Reactant: C=CCCC1CCc2cc(OC)ccc2C1=O
Reactant: C/C=C/C=O
Product: COc1ccc2c(c1)CCC(CC/C=C/C=O)C2=O

Procedure:
The title compound 76 is prepared according to the procedure reported in step C of Example 8 with tetralone 75 (130 mg, 0.56 mmol) and crotonaldehyde (0.19 mL, 2.24 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum/diethyl ether=1:1) afford the title compound 76 as an off-white solid. (Yield 121 mg, 83%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[N:40][NH:41]3)=[CH:37][CH:36]=2)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH:41]1[C:42]2[C:38](=[CH:37][CH:36]=[C:35]([C:2]3[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]4[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[O:18])[CH2:11]4)[CH:3]=3)[CH:43]=2)[CH:39]=[N:40]1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3cn[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (600 mg, 1.61 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (509 mg, 2.09 mmol, 1.3 equiv), Pd2(dba)3 (110 mg, 0.12 mmol, 0.075 equiv), tricyclohexylphosphine (68 mg, 0.24 mmol, 0.15 equiv), and K3PO4 (579 mg, 2.73 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (12 mL) and water (4 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. Purification was performed by silica gel column chromatography using gradient elution of 1% A to 70% A in CHCl3 (A was a mixture of 200/80/800 CH3OH/NH4OH/CHCl3). Trituration of the residue collected from the chromatography in a mixture of CHCl3 (2 mL), MTBE (3 mL) hexane (6 mL), followed by drying under vacuum at 65° C. for 20 hours gave the title compound (526 mg) as a pale yellowish solid. LC-MS (ES) m/z=456 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.31 (d, J=7.1 Hz, 3H), 1.75-1.90 (m, 3H), 1.99-2.10 (m, 1H), 2.45-2.55 (m, 1H), 2.97 (s, 3H), 3.10-3.19 (m, 1H), 4.42 (s, 2H), 4.50-4.60 (bs, 1H), 4.75-4.85 (bs, 1H), 6.50 (s, 1H), 7.24-7.38 (m, 5H), 7.69 (dd, J=8.5, 1.1 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5].[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH2:4][NH:5][C:11]([CH3:12])=[N:1]2
Reactant: NCc1c(N)cccc1F
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CCO
Product: CC1=Nc2cccc(F)c2CN1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A solution of 2-amino-6-fluorobenzylamine (1.1 g, 7.86 mmol) and triethylorthoacetate (1.58 mL, 8.64 mmol) in ethanol (30 mL) was heated at 80° C. for 14 h. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo. The yellow oil was triturated with diethyl ether to give the title compound as white solid (0.74 g, 57%).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17]C=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>>[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:3]=1[CH2:2][C:1]([OH:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Yield: 87.2 %

Procedure:
The title compound was prepared using the method of example 110, starting with diethyl malonate (Aldrich, 30.5 mL, 200 mmol), 3,4-dichloronitrobenzene (Aldrich, 19.2 g, 100 mmol), cesium carbonate (Aldrich, 81.5 g, 250 mmol) and 150 mL of aqueous 6N HCl solution. 18.8 g (87%) of compound 111 was obtained as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([C:17]([O:19][CH3:20])=[O:18])[C:4]=2[CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:17]([O:19][CH3:20])=[O:18])([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1c2ccccc2N(C)c2ccc(Cl)cc21
Reactant: CN(C)CCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2ccc(Cl)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
3.9 gm of 2-chloro-9-methoxycarbonyl-10-methyl-acridane were dissolved in 10 cc of tetrahydrofuran and 5 cc of hexamethyl phosphortriamide and the solution was heated to 45°C and 3.4 gm of potassium tert.-butylate were added thereto. After stirring the mixture for 1 hour at 45°-47°C, 4.5 gm of β-dimethylaminoethyl chloride were added thereto and the mixture was stirred for 16 hours at 46°-48°C. After cooling the mixture, 150 cc of water were added and the mixture was extracted with ether. The organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness to obtain 4.2 gm of raw 2-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-cyclopentyl]-methanol (319) (12 g, 56.95 mmol) in dichloromethane (110 mL) was added triethyl amine (16 mL, 113.90 mmol) followed by mesyl chloride (5.3 mL, 68.34 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, diluted with dichloromethane (50 mL) and washed with water (100 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic part was dried, concentrated and purified by CombiFlash column (eluted at 10-20% ethyl acetate in hexane) to get methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 85%) as a light yellow crystalline solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[N:2]=1.Cl>C1COCC1>[OH:17][C:7]1([C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: OC1(c2cccnn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2cccnn2)CC1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To the product from step A (7.79 mmol, 1.84 g) in THF (15 mL) was added HCl (45 mmol, 15 mL). The reaction was stirred overnight and subsequently quenched using Na2CO3. The reaction was then extracted using EtOAc (3×100 mL). The organic layers were combined, dried and concentrated in vacuo to afford the desired ketone (780 mg, 52%). MS [M+H]+ 193.1.
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([CH:28]3[CH2:30][CH:29]3[C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[O:34][CH:35]([CH3:38])[C:36]#[N:37])=[N:25]2)=[CH:20][CH:19]=1>CCOC(C)=O.C1(C)C=CC=CC=1.CC(O)=O>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([CH:28]3[CH2:30][CH:29]3[C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[O:34][CH:35]([C:36]3[NH:16][N:15]=[N:14][N:37]=3)[CH3:38])=[N:25]2)=[CH:20][CH:19]=1
Reactant: CC(C#N)Oc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(Oc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1)c1nnn[nH]1

Procedure:
A mixture of tributyltin azide (1.603 g, 1.5 eg.) and the nitrile (Step 4) (1.115 g, 3.20 mmoles) was heated at 120° C. for 4 hours. Flash chromatography of this reaction mixture using EtOAc: toluene AcOH 20:80:1 and 40:60:1 yielded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C@H:21]2[CH2:25][CH2:24][C@:23]3([CH2:29][CH2:28][N:27]([CH3:30])[C:26]3=[O:31])[N:22]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:16]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C@H:21]3[CH2:25][CH2:24][C@:23]4([CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[N:22]3[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:16]=2[CH3:39])[CH:9]=1)[CH3:2]
Reactant: Cc1c(Br)ccnc1[C@H]1CC[C@]2(CCN(C)C2=O)N1C(=O)OC(C)(C)C
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2ccnc([C@H]3CC[C@]4(CCN(C)C4=O)N3C(=O)OC(C)(C)C)c2C)c1
Temperature: 140 °C
Yield: 28.9 %

Procedure:
To a microwave vial containing a solution of (5-ethoxy-2-fluoro-phenyl)boronic acid (121.99 mg, 0.6600 mmol) in MeCN (3 mL) and water (0.6000 mL) was added tert-butyl (2R,5R)-2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (which may be prepared as described in Description 98) (225.1 mg, 0.5300 mmol), sodium carbonate (112.41 mg, 1.06 mmol) and bis(triphenyl-phosphine)palladium (II) dichloride (18.39 mg, 0.0300 mmol). The microwave vial was sealed and heated at 140° C. for 20 minutes. The reaction was concentrated in vacuo, and the residue was purified on silica (25 g, SNAP cartridge), eluting with EtOAc in isohexane from 0% to 100%. Fractions containing desired product were combined and concentrated in vacuo to give tert-butyl (2R,5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3-methyl-2-pyridyl]-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D100) (74.2 mg, 0.1534 mmol, 28.9% yield) as a colourless oil;
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:22]1[CH2:26][CH:23]1[CH2:24]O.C(N(CC)CC)C.O>C1C=CC=CC=1>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([O:15][CH2:24][CH:23]3[O:22][CH2:26]3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CO1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCC3CO3)cccc2c1=O
Reaction time: 20 h
Yield: 75.2 %

Procedure:
21.3 g of 3-methylflavone-8-carboxylic acid were slowly added, over a period of 4 hours at 20° C., to a stirred solution of 5.55 g of 2,3-epoxy-1-propanol and 8.34 g of triethylamine in 165 ml of anhydrous benzene. The mixture was permitted to stand at 20°-25° C. for 20 hours, and then 60 ml of water were added. The entire reaction mass was stirred for 15 minutes and the layers were separated. The organic layer was washed and dried, the solvent was evaporated off and 18.95 g of 2,3-epoxypropyl 3-methylflavone-8-carboxylate, m.p. 103°-105° C., were obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[CH:37][C:38]=1[Cl:39].O[CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>O1CCCC1>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[Cl:39])[O:40][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
Diethyl azodicarboxylate (41 ml) was added to a solution of triphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After 15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15 minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) in tetrahydrofuran (400 ml) was added dropwise over 30 minutes. The solution was stirred at room temperature for 16 hours and concentrated to a small volume. Purification by flash chromatography (silica) eluting with ethyl acetate: iso-hexane (95:5) gave the sub-title compound as an oil (61.3 g).
Reaction SMILES: C(ON=O)CC(C)C.[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1N.NC1C=CC=CC=1.CCCCCC.CCOCC.[S:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1>>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[C:36]1[S:35][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1Br
Reactant: c1ccsc1
Agent: CC(C)CCON=O
Solvent: Nc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: Brc1ccccc1-c1cccs1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
A solution of 8.8 mL of isoamylnitrite (65.5 mmol) in 85 mL of thiophene under a nitrogen atmosphere was heated to 50° C. and treated dropwise with a solution of 7.5 g of 2-bromoaniline (43.5 mmol) dissolved in 20 mL of thiophene. After addition was complete, the temperature was raised to 90° C. After 90 minutes, no starting aniline was observed by thin layer chromatography (hexane/ether;100:5). The reaction mixture volume was reduced by atmospheric distillation. The residue was dissolved in ether and the organic layer was washed twice with water, dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in n-hexane/ether (100:5) and passed over silica gel, eluting with n-hexane/ether (100:5) to give 3.5 g (14.6 mmol, 34%) of the product, 1H NMR (200 MHz, CDCl3): 7.11 (m, 1H), 7.16 (dd, 1H), 7.27 (m, 2H), 7.37 (dd, 1H), 7.42 (dd, 1H), 7.66 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5](C2C=CC=CC=2)=[N:6][CH:7]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(=O)C1C(=CC=CC=1)O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[CH:7]=[N:6][CH:5]=[N:4][CH:3]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Brc1cnc(-c2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Cu]I
Agent: CCN(CC)C(=O)c1ccccc1O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2)CC1
Temperature: 90 °C
Yield: 47.8 %

Procedure:
A mixture of 5-bromo-2-phenyl-pyrimidine (3.50 g, 14.89 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.48 g, 22.33 mmol, 1.5 equiv), copper(I) iodide (0.28 g, 1.49 mmol, 0.1 equiv), N,N-diethylsalicylamide (0.58 g, 2.98 mmol, 0.2 equiv) and K3PO4 (3.16 g, 14.89 mmol, 1.0 equiv) in degassed DMF (30 mL) was heated under Ar to 90° C. for 24 h. The solvent was removed under reduced pressure and the crude reaction product extracted from water (300 mL) and 25% NH4OH (30 mL) with ethyl acetate (3×300 mL). The combined organic phases were dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a gradient of heptane/ethyl acetate (4:1→1:1) to provide 1.98 g (38%) of the title compound. MS (ESI): 377.1 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:28]([C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:40][CH2:39]2)[CH:35]=[C:34]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:33]=1)([CH3:31])([CH3:30])[CH3:29].[ClH:53].C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:53].[C:28]([C:32]1[N:37]=[C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:42][CH2:43]2)[CH:35]=[C:34]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccc(F)cc3)CC2)n1
Reaction time: 68 h
Yield: 74.2 %

Procedure:
0.45 g of 4-fluorobenzoic acid (3.21 mmol) and 0.98 g of triethylamine (9.7 mmol) were dissolved in 30 ml of dimethylformamide. At room temperature, 0.5 g of hydroxybenzotriazole (HOBt, 3.7 mmol), 1.2 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.47 mmol), and 0.7 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.65 mmol) were added and the mixture was stirred for 68 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). The oily residue was re-dissolved in isopropanol and 1 N hydrochloric acid in diisopropyl ether was added. The resulting precipitate was filtered and dried to yield 1.2 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[Se](=O)=[O:14]>C(OCC)(=O)C>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH:1]=[O:14])[CH:11]=[N:10]2
Reactant: O=[Se]=O
Reactant: Cc1cnc2cc(F)ccc2n1
Solvent: CCOC(C)=O
Product: O=Cc1cnc2cc(F)ccc2n1
Yield: 29 %

Procedure:
Using the method of Kepez (Monatahefte fur Chemie, 1989, 120, 127-130), a solution of 2-methyl-6-fluoroquinoxaline (225 mg 1.39 mmol) in ethyl acetate (30 mL) was treated with selenium dioxide (2.5 g) and the reaction mixture heated at reflux for 36 hours. The reaction was filtered hot and concentrated. Chromatography through a Biotage silica cartridge (8×4 cm i.d.) using a gradient of hexane to 10% ethyl acetate (in hexane) afforded 71 mg (29%) of 6-fluoroquinoxaline-2-carboxaldehyde.