Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[C:10]2[S:11][C:12]([C:14]3[N:19]=[C:18]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[CH:16][CH:15]=3)=[CH:13][C:9]=2C=[CH:7][CH:6]=1.[NH4+:40].[Cl-].CCO>[Fe].O>[NH2:37][C:35]1[CH:34]=[CH:33][C:3]([O:4][C:5]2[CH:6]=[CH:7][N:40]=[C:9]3[CH:13]=[C:12]([C:14]4[N:19]=[C:18]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH:17]=[CH:16][CH:15]=4)[S:11][C:10]=23)=[C:2]([F:1])[CH:36]=1
Reactant: COCCN(Cc1cccc(-c2cc3cccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1)C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1)C(=O)OC(C)(C)C
Yield: 103.8 %

Procedure:
A solution of 58 (1 g, 1.81 mmol) and NH4Cl (97 mg, 1.8 mmol) in a 2:1 mixture of EtOH and water (30 mL) was treated with iron powder (605 mg, 10.8 mmol) and stirred at reflux for 1 hour. The reaction mixture was then filtered through a celite pad and concentrated yielding title compound 59 (980 mg, 100% yield) that was used in the next step (scheme 18) without further purification. MS (m/z): 525.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:10][C@H:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methoxymethylpyrrolidine (2.8 g) and methanesulfonyl chloride (1.12 ml) in dichloromethane (30 ml) was added dropwise triethylamine (2.38 ml) at 0° C. After 30 minutes, the reaction mixture was washed in turn with 1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and evaporated to give an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give (2S,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methoxymethylpyrrolidine (3.61 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[O:5][C:6]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:7]=2[C:8]=1[OH:9].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:18])[O:5][C:6]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:7]=2[C:8]=1[O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1c(O)c2ccc(OC(C)=O)cc2oc1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(OCc2ccccc2)c2ccc(OC(C)=O)cc2oc1=O
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 8.11 g of 3-methoxy-4-hydroxy-7-acetoxy-2H-l-benzopyran-2-one (27.8 mmol) and 5.71 g of benzyl bromide (33.4mmol) in 50 ml of DMF was added 4.61 g of sodium carbonate (33.4 mmol) under argon atmosphere, then the mixture was stirred at 50° for 2 hours. The solid in the reaction mixture was filtered off, the filtrate was poured into 200 ml of water and extracted with 500 ml of benzene. The organic layler was concentrated in vacuo after drying over magnesium sulfate to give oily residue. The residue was purified on silica gel column chromatography (eluent: benzene/ethyl acetate=7/3) to give 3.50 g of the title compound. (yield=33%)
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:8][C:7]=2[C:19]([O-:21])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:33][NH2:34])=[N:29][C:30]=1[O:31][CH3:32].CCCP(O)(O)=O.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[CH:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:8][C:7]=2[C:19]([NH:34][CH2:33][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[C:30]([O:31][CH3:32])[N:29]=2)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CN)nc1OC
Reactant: Cc1cncc(-c2cnc(C3CCCC3)c(C(=O)[O-])c2)c1
Agent: CCCP(=O)(O)O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(C)c3)cnc2C2CCCC2)nc1OC
Temperature: 40 °C

Procedure:
To a suspension of sodium 6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxylate (6-3, 0.022 g, 0.078 mmol, 1.0 equiv) in acetonitrile (0.8 mL) was added 1-(5,6-dimethoxypyridin-2-yl)methanamine (11-6, 0.039 g, 0.234 mmol, 3.0 equiv), 1-propylphosphonic acid cyclic anhydride (0.149 g, 0.234 mmol, 3.0 equiv, 50 weight percent in EtOAc), and diisopropylethylamine (0.060 g, 0.47 mmol, 6.0 equiv) and the system was heated to 40° C. for 24 h. The reaction mixture was cooled and diluted with ethyl acetate (30 mL). The reaction mixture was washed with saturated sodium bicarbonate (2×10 mL), water (2×10 mL) and brine (1×10 mL), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (0 to 40% methanol in EtOAc, silica) followed by reverse phase chromatography (5 to 65% acetonitrile in water, 0.1% TFA buffer) to afford the desired product (6-4) as a white solid after free-basing and concentration. 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J=2.5 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.65 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.72 (bs, 1H), 4.64 (d, J=5.0 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.52-3.48 (m, 1H), 2.42 (s, 3H), 2.04-1.80 (m, 6H), 1.70-1.60 (m, 2H). HRMS [M+H] C25H28N4O3 calc'd 433.2234, found 433.2226.
Reaction SMILES: Cl.[C:2]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)#[N:3].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][C:2]#[N:3])[CH2:12][CH2:11]1
Reactant: N#CCCCC1CCNCC1
Reactant: Clc1ccccc1C(Br)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
20 g (106 mmol) 4-(3-cyanoprop-1-yl)-piperidin hydrochloride, 40.2 g (127 mmol) bis(2-chlorophenyl)-bromomethane and 35.2 g (254 mmol) potassium carbonate are heated to boiling in 90 ml acetone for six hours. After cooling, the mixture is freed from solution under vacuum. The residue is dispersed between 90 ml tolueneand 90 ml water. The aqueous phase is extracted with 10 ml tolueneand the combined organic phases are washed with 10 ml water. The organic phase is concentrated and the residue is chromatographically purified over silica gel with CHCL3. Yield: 11.2 g (27%).
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[C:17]([CH3:19])[C:15]([NH2:16])=[C:14]([CH3:20])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([N:16]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:17]([CH3:19])[CH:18]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Cc1cc(OC23CC4CC(CC(C4)C2)C3)cc(C)c1N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(OC23CC4CC(CC(C4)C2)C3)cc(C)c1N1CCCC1
Yield: 111.2 %

Procedure:
A mixture of 1.8 g (6.63 mmoles) of 4-(1-adamantyloxy)-2,6-dimethylaniline, 1.43 g (6.63 mmoles) of 1,4-dibromobutane, and 2.01 g (14.6 mmoles) of K2CO3 in 25 ml deaerated absolute ethanol is refluxed for forty-five hours, cooled, and evaporated. The residue is taken up in CH2Cl2 (125 ml) and water (125 ml). The CH2Cl2 layer is washed with water, and the combined aqueous layers are extracted with CH2Cl2 (50 ml.). The combined organic layers are dried and concentrated to give 2.4 g of a brown oil, which is chromatographed by HPLC on a 2.54 cm×109 cm column at 40 psi eluting with 0.5% acetone in CH2Cl2 and then 0.75% acetone in CH2Cl2 to give 0.45 g in the first liter eluted from the column. This solid in 1 ml of CH2Cl 2 and 5 ml of ether is treated with 3.5 N HCl in ether. The hydrochloride is filtered, washed with ether, and dried to give 0.38 g of white solid, m.p. 184.4-185.6 (dec.).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.OC1(C2C=CC(C#N)=CC=2)CCC(=O)CC1>>[OH:1][C:2]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=2)[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Agent: N#Cc1ccc(C2(O)CCC(=O)CC2)cc1
Product: N#Cc1ccc(C2(O)CCC(=O)CC2)cn1

Procedure:
The title compound was synthesized from 5-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)pyridine-2-carbonitrile using the same typical deprotection procedure as for 4-(1-hydroxy-4-oxocyclohexyl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Cl[CH2:19][CH2:20][CH:21]1[O:25][C:24](=[O:26])[N:23]([CH3:27])[CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(O)CCC>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH:21]3[O:25][C:24](=[O:26])[N:23]([CH3:27])[CH2:22]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CN1CC(CCN2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)OC1=O
Yield: 78 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 4.0 g (0.15 mol) of 1-(4-chloro-3-trifluoromethylphenyl)piperazine (Emka-Chemie), 2.5 g (0.015 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 5.3 g (0.05 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue. The gum was converted to the fumaric acid salt and the solid was recrystallized from 95% ethanol to yield 5.7 g (78%) of white solid, mp 198°-201° C. (dec.).
Reaction SMILES: [CH2:1]([S:6]([OH:9])(=O)=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].P(Cl)(Cl)(Cl)(Cl)[Cl:11]>C1C=CC=CC=1>[CH2:1]([S:6]([Cl:11])(=[O:9])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCS(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCS(=O)(=O)Cl
Yield: 91 %

Procedure:
To a solution of (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]amino]pentylsulfonic acid (2.34 g, 4.80 mmol) in benzene (10 mL) was added phosphorus pentachloride (1.48 g, 7.21 mmol) at 22° C. The mixture was heated to reflux for 2 hours. This mixture was concentrated under reduced pressure and rediluted with CH2Cl2 (120 mL). This solution was washed with water (100 mL), dried over Na2SO4 and filtered. The organic solution was concentrated to afford 2.21 g of (4R)-4-[2, 5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride as pale yellow oil in 91% yield. LC/MS 504.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:34])[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1.[BH4-].[Na+]>CCO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:34])[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)COc1cccc(CC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1cccc(CC(O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Reaction time: 0.5 h

Procedure:
The product obtained from Step B (5 mmol) in 50 mL of EtOH is treated with (2 mmol) of NaBH4 at room temperature. After 30 min, the reaction mixture is diluted with water and extracted with EtOAc. The organic solution is dried and evaporated and purified by dry column chromatography to give ethyl 2-(3-(2-(3-(2-quinolinylmethyloxy)phenyl)-2-hydroxyethyl)phenoxy)acetate.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[O:8]1[C:10]2[CH2:11][CH2:12][CH2:13][C:9]1=2>[Pd].O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:8][CH:9]1[CH2:13][CH:12]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])[CH:11]=[CH:10]1
Reactant: C1CC2=C(C1)O2
Reactant: O=c1cccc[nH]1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: O=c1ccccn1C1C=CC(O)C1
Yield: 18.5 %

Procedure:
21 g (0.22 mol) of 2-pyridone are added at 0° C. to a solution of the palladium(0) catalyst prepared as above (2 mol % of palladium(II) acetate) in 200 ml of dry tetrahydrofuran, and 20.1 g (0.245 mol) of epoxycyclopentene, dissolved in 80 ml of tetrahydrofuran, are then added dropwise over a period of 2 hours, while stirring. The solution which forms is stirred at room temperature for 2 days and then concentrated, the residue is dissolved in methylene chloride, the solution is extracted by shaking with 1 A sodium carbonate solution and the organic phase is concentrated. The residue is chromatographed over silica gel using ethyl acetate/methanol 9/1. 7.2 g (18.49% of theory) of 1-[(1RS,4SR)-4-hydroxycyclopent-2-en-1-yl]pyridin-2(1H)-one are obtained as a viscous oil. 1H NMR (60 MHz, d6 -DMSO), δ[ppm]: 7.65-7.25 (m, 2H), 6.55-6.08 (m, 3H), 5.95-5.63 (m, 2H), 5.26 (d, 1H), 4.73 (m, 1H), 2.85 (m, 1H), 1.32 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH:21]([CH3:23])[CH3:22])[C:12]2=[O:31])[CH:5]=1.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:20](=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:32])=[O:2])[C:12]2=[O:31])[CH:21]([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(CN2C(=O)C(=C(c3ccc(Cl)cc3)C(C)C)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=C1C(=O)N(Cc2cccc(C(=O)O)c2)c2ccccc21)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 51.5 %

Procedure:
A solution of 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (0.40 g, 0.90 mmol) was dissolved in THF 15 ml. Then a solution of lithium hydroxide (0.38 g, 9.0 mmol) in water (3.0 ml) was added. After stirring for 12 hours, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid as a yellow powder (200 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J=6.82 Hz, 6H) 4.90-4.99 (m, 1H) 5.05 (s, 2H) 5.59 (d, J=7.83 Hz, 1H) 6.64 (t, J=7.71 Hz, 1H) 6.91 (d, J=7.83 Hz, 1H) 7.10 (t, J=7.71 Hz, 1H) 7.27 (d, J=8.34 Hz, 2H) 7.49 (t, J=7.58 Hz, 1H) 7.63 (d, J=8.34 Hz, 2H) 7.59 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.58 Hz, 1H) 7.92 (s, 1H) 13.05 (s, 1H). MS calcd. for C26H22ClNO3 431.5, obsd. (ESI+) [(M+H)+] 432.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C(Cl)Cl>[C:25]([O:18][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OCCOCC(O)c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(COCCOC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
37.0 g of 1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol was dissolved in 70 ml of methylene chloride. To the solution were added 12.9 g of pyridine and 16.6 g of acetic anhydride. The resulting mixture was stirred for 24 hours at room temperature. The reaction mixture was added to a mixture of 150 ml of ice water and 100 ml of methylene chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with a saturatred aqueous sodium hydrogencarbonate solution and water in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 40.0 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethane.
Reaction SMILES: [C:1]([C:9]1[C:14]([C:15]([O:17]CC)=O)=[CH:13][N:12]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][NH:35][NH2:36]>C(O)CCC>[CH3:34][N:35]1[C:15](=[O:17])[C:14]2[CH:13]=[N:12][C:11]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:25][CH:26]=3)=[N:10][C:9]=2[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:36]1
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1ccccc1
Reactant: CNN
Solvent: CCCCO
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)n(C)nc(-c5ccccc5)c4n3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of Example 3B (50 mg, 0.112 mmol) and methylhydrazine (6.50 μl, 0.123 mmol) in n-butanol (12.5 mL) was heated to 170° C. by microwave irradiation (Biotage Initiator) for 3 hour. The reaction mixture was cooled to room temperature, and the solid was filtered and air-dried to provide the title compound. MS ESI(+) m/z 428.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ ppm 10.34 (s, 1H), 9.29 (s, 1H), 7.94-7.91 (m, 2H), 7.59-7.48 (m, 5H), 6.84 (d, J=8.7 Hz, 2H), 3.75 (s, 3H), 3.13-3.05 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH2:11].[H-].[Na+].Cl[C:15]1[N:24]=[CH:23][C:22]2[N:21]=[C:20]([C:25]3[C:30]([Cl:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[Cl:36])[C:19](=[O:37])[N:18]([CH3:38])[C:17]=2[N:16]=1>CN(C)C=O>[Cl:31][C:30]1[C:29]([O:32][CH3:33])=[CH:28][C:27]([O:34][CH3:35])=[C:26]([Cl:36])[C:25]=1[C:20]1[C:19](=[O:37])[N:18]([CH3:38])[C:17]2[N:16]=[C:15]([NH:11][C:3]3[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[N:24]=[CH:23][C:22]=2[N:21]=1
Reactant: COc1cc(OC)c(Cl)c(-c2nc3cnc(Cl)nc3n(C)c2=O)c1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(-c2nc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
To a solution of 2-methyl-6-nitrobenzenamine (100 mg, 1 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (53 mg, 1.3 mmol), and the mixture was stirred at RT (10° C.) for 10 mins, followed by the addition of 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpteridin-7(8H)-one (322 mg, 1 mmol). The mixture was stirred at RT (10° C.) for another 30 min and then quenched by water. The precipitate was collected via filtration, washed with cold water and dried to give the title compound (180 mg, 75%) as a yellow powder. MS (ES+) C22H18Cl2N6O5 requires: 516, 518. Found: 517, 519 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:42]=[N:43][CH:44]=[N:45][CH:46]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1cncnc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cncnc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-5-carboxamide.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([OH:13])(=O)[CH:10]=[CH2:11].C(N(CC)CC)C.[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][N:26]=[C:25]2[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1>C1COCC1.CN(C=O)C.CCOCC>[CH3:39][C:35]1[CH:34]=[C:33]([NH:32][C:25]2[C:24]3[C:29](=[CH:30][CH:31]=[C:22]([NH:21][C:9](=[O:13])[CH:10]=[CH2:11])[CH:23]=3)[N:28]=[CH:27][N:26]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: C=CC(=O)O
Reactant: Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(C)c3)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 34.9 %

Procedure:
Isobutyl chloroformate (20.35 g, 0.15 mol) was added dropwise over 20 minutes to a solution of acrylic acid (10.82 g), 0.15 mol) and triethylamine (30.19 g, 0.30 mol) in THF (400 mL), stirred under nitrogen at 0° C. The slurry was stirred at that temperature for 30 minutes, and then 6-amino-4[(3-methylphenyl)amino]quinazoline (27.71 g, 107 mmol) in DMF (80 mL) was added dropwise over 45 minutes. After a further 4 hours, further mixed anhydride (from acrylic acid (3.61 g, 50 mmol), isobutyl chloroformate (6.80 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) in THF (100 mL) at 0° C.) was added in one portion. After a further 15 minutes, the reaction mixture was stirred at 25° C. for 30 minutes, and then poured onto ice-water (1 L). Ether (200 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (500 mL), and the combined organic phases were washed with water (500 mL), and saturated brine (250 mL). The solution was stirred with anhydrous MgSO4 for 2 minutes, filtered, and silica gel (150 g) was added. The mixture was stripped to dryness, and used as the origin of a flash silica chromatography column (700 g), eluting with acetone/dichloromethane (25% 4 L, 35% 8 L, 40% 4 L). The solvent was stripped from the appropriate fractions and the residue was suspended in EtOAc (200 mL) refluxed for 5 minutes and sonicated at 60° C. for 20 minutes, then collected by Buchner filtration, rinsed with EtOAc (3×25 mL), and dried in a vacuum oven at 75° C. for 16 hours, to give N-[4-[(3-methyl-phenyl)amino]quinazolin-6-yl]acrylamide (11.38 g, 35%) as a light yellow solid, mp 247-8° C.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][NH:15][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc(CCN)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)C2CCC2)cc1OC
Yield: 104.3 %

Procedure:
Cyclobutanecarbonyl chloride (19 g) was added dropwise at ambient temperature to a stirred solution of 3,4-dimethoxyphenethylamine (30.5 g) and triethylamine (23.5 ml) in tetrahydrofuran (11). After 1.5 hours the mixture was poured onto dilute hydrochloric acid (1 l) and the product was extracted into ethyl acetate. The extracts yielded N-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (44 g) which was used without further purification.