Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[O:14][N:13]=[C:12](C(Cl)=O)[CH:11]=1)C.[C:18]1([C:24]2[N:25]=[C:26]3[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][N:27]3[CH:33]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH2:34].CC#N>ClCCl>[C:18]1([C:24]2[N:25]=[C:26]3[N:31]=[C:30]([NH:32][C:8]([C:10]4[O:14][N:13]=[CH:12][CH:11]=4)=[O:34])[CH:29]=[CH:28][N:27]3[CH:33]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O
Reactant: CCc1cc(C(=O)Cl)no1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
Triethylamine and 5-ethyl-isoxazole-3-carbonyl chloride were added to a solution of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1) in dichloromethane, and the mixture was stirred at RT overnight. The title compound (29 mg, 16%) was isolated from the mixture by preparative HPLC (254 nm, Agilent Zorbax XdB-C18, Run: 7 min, Flow: 30 ml/min, Gradient: 0.0 min: 95/5 H2O/CH3CN; 0.5 min: 95/5 H2O/CH3CN 4.5 min: 5/95 H2O/CH3CN; 6.9 min 5/95 H2O/CH3CN; 7 min 95/5 H2O/CH3CN).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[N:17][CH:18]=1.C(OCC)C>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[O:20])[CH:16]=[N:17][CH:18]=1
Reactant: OCc1cncc(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cncc(Br)c1
Reaction time: 1 h
Yield: 33.6 %

Procedure:
4.5 g (21 mmol) of pyridinium chlorochromate are added at room temperature to a solution of 3 g (16 mmol) of (5-bromopyrid-3-yl)methanol in 70 ml of dichloromethane. After stirring for 1 hour, 70 ml of diethyl ether are added and the reaction medium is again stirred for 1 hour. The precipitate is filtered off through sodium sulfate and the filtrate is evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1 g (35%) of 5-bromopyridine-3-carbaldehyde is obtained.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:5][CH2:4]1)=[O:2].[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:8][CH2:7]1)(=[O:27])=[O:26]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(C=O)CC1)CCCC2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C=O)CC1)CCCC3)C(=O)N2
Yield: 65.5 %

Procedure:
3-[3-(4-Formylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (61 mg, 0.2 mmol), prepared as described in Step 4 of Example 8, was condensed with 5-methylaminosulfonyloxindole (45 mg, 0.2 mmol) following the procedure used in Example 1. Brown solid precipitated out and purified by flash chromatography, eluting with (dichloromethane: methanol 50/1,35/1,30/1) to give 67 mg of the desired product.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:15][C:14]([C:16]2[N:17]=[C:18]([SH:21])[S:19][CH:20]=2)=[CH:13][CH2:12][N:11]1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])(C(C)(C)C)(C)C.C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:8][CH2:9][C@@H:10]1[CH2:15][C:14]([C:16]2[N:17]=[C:18]([SH:21])[S:19][CH:20]=2)=[CH:13][CH2:12][N:11]1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23]
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1CO
Yield: 53.7 %

Procedure:
To a solution of allyl (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (539 mg, 1.30 mmol) in ethanol(40 ml)/THF(3 ml) was added p-toluenesulfonic acid monohydrate (50 ml). Four hours later the solvent was removed in vacuo. The residue was made alkaline by adding an aqueous 1N NaOH solution. To the mixture were added ethyl acetate and hexane, and the mixture was separated with a separating funnel. To the aqueous layer was added 6N hydrochloric acid, and the mixture was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution, was dried over magnesium sulfate and the organic solvent was removed under reduced pressure to give allyl (2S)-2-(hydroxymethyl)-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (218 mg, 55%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([NH:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[I:26]>CC(C)=O>[I-:26].[CH3:11][SH2+:12].[C:1]([NH:8][C@H:9]([C:14]([NH:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CI
Agent: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: C[SH2+]
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the resultant tert-butyl 2-(Boc-L-methionyl)-1-hydrazine carboxylate in acetone (20 ml) was combined with methyl iodide (17 ml, 240 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated, and the resultant residue was triturated from ether, collected by filtration, washed with ether and dried to obtain tert-butyl 2-(Boc-L-methionyl)-1-hydrazine carboxylate methylsulfonium iodide (19.14 g) as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=[O:29])=[CH:18][CH:19]=3)[O:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:34]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH3:35].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=[O:45].N1CCOCC1.CN(C1C=CC=CN=1)C>C1COCC1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([O:30][CH2:35][CH2:34][N:36]4[CH2:39][CH2:40][O:45][CH2:38][CH2:37]4)=[O:29])=[CH:18][CH:19]=3)[O:14][CH:13]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(OCc4cccc(C(=O)O)c4)ccc3c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CCN(CC)CC
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCN1
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(OCc4cccc(C(=O)OCCN5CCOCC5)c4)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 100 mL round bottomed flask 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid (315.0 mg, 0.677 mmol) was treated with triethylamine (137.0 mg, 1.354 mmol, 2.0 equiv) and 2,4,6-trichlorobenzoyl chloride (198.2 mg, 0.812 mmol, 1.2 equiv) in THF (6 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. To the mixture were added a solution of 4-hydroxyethyl)morpholine (133.2 mg, 1.016 mmol, 1.5 equiv) in THF (3 mL) and dimethylaminopyridine (82.7 mg, 0.677 mmol, 1.0 equiv). Again, the mixture was stirred at room temperature for 1 hour. To the mixture were added H2O (50 mL) and the whole was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and dried with Na2SO4. The solvent was removed under a reduced pressure to give a crude mixture. The crude mixture was purified by a column-chromatography (SiO2=80 g, 2.5% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) to give 2-morpholinoethyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[OH-].[K+]>CCOC(C)=O.O>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Chloroacetyl chloride (1.05 mL, 13.1 mmol) is added in one portion to a biphasic mixture of N-methyl-4-nitroaniline (1.0 g, 6.57 mmol), KOH (1.11 g, 19.7 mmol) in 12 mL EtOAc and 12 mL H2O, cooled to 0° C. The resulting mixture is stirred at this temperature for 5 min, then the ice bath was removed and it was allowed to warm to RT. The reaction was stirred for an additional one hour at RT.
Reaction SMILES: [Br-:1].C([N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][C:26](=[O:29])[N:25]([CH3:30])[C:24]=2[CH:31]=1>C(Cl)Cl.CO>[NH2:19][C:20]1[C:21]([Br:1])=[CH:22][C:23]2[O:28][CH2:27][C:26](=[O:29])[N:25]([CH3:30])[C:24]=2[CH:31]=1
Reactant: CN1C(=O)COc2ccc(N)cc21
Reactant: [Br-]
Agent: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CN1C(=O)COc2cc(Br)c(N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Tetra-tert-butyl ammonium bromide (6.77 g, 14.04 mmol) was added to a solution of 6-amino-4-methyl-4H-benzo[1,4]oxazin-3-one (2.5 g, 14.04 mmol) in methylene chloride (100 ml) and MeOH (50 ml). The mixture was stirred at room temperature for 20 minutes, then quenched with aqueous sodium bisulfite solution. The mixture was extracted with methylene chloride, and the combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure and purified via column chromatography to give 1.30 g of 6-amino-7-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one as a light yellow solid, 40%.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[C:25]([NH2:35])=[C:24]([CH:36]([CH3:38])[CH3:37])[CH:23]=1)([CH3:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[C:25]([N:35]2[CH2:2][CH2:3][N:4]=[C:5]2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:24]([CH:36]([CH3:38])[CH3:37])[CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc(C(C)C)c2c(oc3ccccc32)c1N
Reactant: O=C(NCCCl)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(C(C)C)c2c(oc3ccccc32)c1N1CCN=C1c1ccccc1
Yield: 55.9 %

Procedure:
N-(2-chloroethyl)benzamide (6.3 g, 34 mmol) and PCl5 (7.9 g, 38 mmol) were suspended in xylene (75 mL) and refluxed for two hours. Then 1,3-diisopropyldibenzo[b,d]furan-4-amine (10 g, 38 mmol) was added. The mixture was refluxed overnight. After cooling by ice-bath, no precipitation was observed. The mixture was concentrated and the residue was washed with small amount of toluene and hexane. The crude 1-(1,3-diisopropyldibenzo[b,d]furan-4-yl)-2-phenyl-4,5-dihydro-1H-imidazole (7.5 g, 19 mmol, 54.8% yield) was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2[O:12][C:11](C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33]>>[CH:11]([OH:12])=[O:33].[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(Cc1ccccc1Br)NCCO
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3CS(=O)(=O)NCCO)cc2F)cn1
Product: O=CO

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)-N-(2-hydroxyethyl)methanesulfonamide. MS (ESI): mass calcd. for C19H19FN4O3S, 402.12; m/z found, 403.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (d, J=1.2, 1H), 8.31 (s, 1H), 8.02 (m, 1H), 7.70-7.63 (m, 1H), 7.49-7.40 (m, 2H), 7.40-7.30 (m, 3H), 4.40 (s, 2H), 3.51 (t, J=5.9, 2H), 2.95 (t, J=5.9, 2H), 2.66 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[CH3:26]N1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C[CH:57](C)[CH2:58][C:59]([NH:61][CH2:62][C:63]([OH:65])=O)=[O:60]>>[C:59]([NH:61][CH2:62][C:63]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:65])(=[O:60])[CH:58]([CH3:57])[CH3:26]
Reactant: CC(C)CC(=O)NCC(=O)O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CC(C)C(=O)NCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 38 %

Procedure:
The crude product (174 mg) obtained using Compound 18 (200 mg, 0.602 mmol), N-methylmorpholine (0.132 mL, 1.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.842 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.783 mmol) and (3-methylbutyrylamino)acetic acid (115 mg, 0.722 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (chloroform/methanol=80/20), followed by triturating in mixed solvent of ethyl acetate/ethanol to obtain Compound 126 (105 mg, 37%).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][CH:9]([CH3:25])[C:10]([O:12][CH2:13][O:14][C:15](ON1C(=O)CCC1=O)=[O:16])=[O:11]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:15]([O:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([CH3:25])[CH3:8])=[O:16])[C:5]([OH:7])=[O:6]
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)C(=O)OCOC(=O)N[C@H](CO)C(=O)O
Yield: 34 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (161 mg, 1.5 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (330 mg, 1.3 mmol) were reacted to provide 110 mg (35% yield) of the title compound (32) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.61 (br s, 1H), 6.51 (d, 1H), 5.65 (m, 2H), 4.41 (m, 1H), 4.02 (m, 1H), 3.84 (m, 1H), 2.59 (m, 1H), 1.09 (d, 6H). MS (ESI) m/z 250.15 (M+H)+; 267.17 (M+NH4)+; 272.13 (M+Na)+; 248.12 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>CC(O)(C)C.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCOCCCl
Reactant: Nc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cc2ccc(N3CCOCC3)cc2[nH]1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A mixture of 1H-indol-6-amine (3.14 g, 23.76 mmol), 1-chloro-2-(2-chloroethoxy)ethane (4.18 mL, 35.6 mmol), and sodium carbonate (10.07 g, 95 mmol) in t-BuOH (90 mL) was heated at 100° C. in a pressure tube for 3.5 days. On cooling to room temperature, the mixture was diluted with ethyl acetate and filtered through CELITE®. The filtrate was concentrated under vacuum to dryness. To the residue was added water (50 mL). The mixture was adjusted to pH 11 with saturated NaHCO3 solution and extracted with CH2Cl2 (4×80 mL). The combined extract was washed with brine (50 mL) and dried over anhydrous MgSO4. The desired product (3.96 g, 19.58 mmol, 82% yield) was isolated as a beige solid with ISCO (300 g silica gel, solid loading, 20-50% ethyl acetate/hexane).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[O:16][CH3:17].C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.N1CCNCC1>CC#N>[CH3:17][O:16][C:6]1[C:7]([O:14][CH3:15])=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])cc(OCCCl)c1OC
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(OCCN2CCN(C)CC2)c1OC

Procedure:
A mixture of 1-(2-chloroethoxy)-2,3-dimethoxy-5-nitrobenzene (1.382 g, 5.28 mmol), K2CO3 (1.83 g, 13.2 mmol), and N-methylpiperazine (1.76 mL, 15.85 mmol) was stirred and heated under N2 in CH3CN (20 mL) under reflux overnight. The next day 0.80 g K2CO3 and 0.66 mL piperazine were added (1.1 eq.) and heated for 3 h more when HPLC showed that the reaction was complete. The solids were filtered and washed well with CH3CN and the filtrate was evaporated at 80° C. to remove excess amine. The resulting red oil was dissolved in CH2Cl2 and washed with water. The aqueous layer was washed with CH2Cl2. The combined organic layers were dried and evaporated giving 2,3-dimethoxy-1-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrobenzene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:11][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[CH3:38])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:33]([C:32]3[CH:36]=[CH:37][C:29]([O:28][CH:25]([CH3:26])[CH3:27])=[C:30]([CH3:38])[CH:31]=3)=[O:34])[CH2:15][CH2:14]2)[O:11][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC(c3ccccc3)OC3(CCNCC3)C2)cc1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccccc2)O3)ccc1OC(C)C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 4-benzyl-2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane (222 mg, 0.69 mmol), 4-isopropoxy-3-methyl-benzoic acid (140 mg, 0.72 mmol) and HATU (262 mg, 0.69 mmol) was stirred in a mixture of DCM (1 mL) and DMF (1 mL) for 5 minutes. Triethylamine (192 μL, 1.38 mmol) was added and the reaction mixture was stirred for 16 hours, then concentrated in vacuo, diluted with sat. aq. NaHCO3, extracted with ethyl acetate (3×2 mL), dried over MgSO4, filtered and concentrated in vacuo and purified by silica gel column chromatography using 0-60% EtOAc/DCM as eluent to give (10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (343 mg, 100%) as a yellow oil. ESI-MS m/z calc. 406.5. found 407.7 (M+1)+; Retention time: 1.13 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:29])C=1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:11]1[C:10]2[C:9](=[O:19])[C:8]3[CH:7]=[CH:6][C:5]4[O:20][CH:2]([CH2:3][OH:29])[CH2:1][C:4]=4[C:17]=3[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: C=CCc1c(O)ccc2c(=O)c3c(F)cccc3oc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1c2ccc3c(c2oc2cccc(F)c12)CC(CO)O3
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
A mixture of 4-allyl-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (1.4 g), m-chloroperbenzoic acid (1.2 g) and chloroform (250 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. After addition of potassium carbonate (2 g) and water (50 ml), the mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 1.2 g of 7-fluoro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene. m.p. 220°-221° C. This compound gave a mass spectrum having a molecular ion peak at m/e 286.
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.CC1CCOC1.C([C:24]1C(C)=CC=C(C(C)(C)C)[C:25]=1[OH:35])(C)(C)C.SCCC[Si](OC)(OC)OC.[C:47]([O:51]CCO)(=[O:50])[CH:48]=[CH2:49]>O1CCCC1>[C:47]([OH:51])(=[O:50])[CH:48]=[CH2:49].[NH2:8][C:9]([O:35][CH2:25][CH3:24])=[O:10]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C(C)(C)C
Reactant: C=CC(=O)OCCO
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CC1CCOC1
Agent: CO[Si](CCCS)(OC)OC
Solvent: C1CCOC1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In a reaction vessel equipped with a stirrer were charged 228.1 g of 2,4-tolylene diisocyanate, 1699.8 g of a ring-opening copolymer of tetrahydrofuran and 3-methyltetrahydrofuran, having a number average molecular weight of 2,000, and 0.5 g of 2,6-di-t-butyl-methylphenol, as a polymerization inhibitor. After cooling the mixture to a temperature of below 10° C. in an ice water bath, 1.6 g of dibutyltindilaurate was added to initiate the reaction. The reaction was carried out for 2 hours while controlling the temperature at 20-35° C. Then, after the addition of 20.4 g of γ-mercaptopropyltrimethoxysilane, the mixture was stirred for a further one hour at 35-40° C., whereupon 89.3 of hydroxyethyl acrylate was added, followed by stirring for 5 hours at 40-60° C., to obtain liquid urethane acrylate (A-1) having a number average molecular weight of 4,750.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C-:13]#[N:14].[K+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:16]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]1[C:13]#[N:14])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [C-]#N
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2ncccc2c1
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(c1)C=CC(C#N)N2C(=O)c1ccccc1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
A solution of 10 g (63 mmol) of 6-methoxyquinoline in 80 ml of dichloromethane is mixed with a solution of 12.4 g (188 mmol) of potassium cyanide, and 14.5 ml (125 mmol) of benzoyl chloride are then added slowly. The mixture is stirred for 18 h, the organic phase is then separated off and the aqueous phase is extracted with dichloromethane. The organic phases are washed with aqueous 5% hydrochloric acid solution and then with water, with aqueous sodium hydroxide solution and again with water, they are dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The oil obtained is crystallized from 95% ethanol. 13.4 g of product are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH2:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][N:13]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CCN(C(C)C)C(C)C>C(O)(C)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][C:16]3([CH2:12][N:13]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:15]3)[CH2:17][CH2:18]2)[CH:7]=[CH:6][N:5]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc(C(F)(F)F)n3)CC2)C1
Yield: 47 %

Procedure:
4-Chloro-2-(trifluoromethyl)pyrimidine (2.72 mmol, 1 eq.) and isopropanol (4 ml) were introduced into a microwave vessel. tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.72 mmol, 1 eq.) and DIPEA (0.6 ml, 6.8 mmol), 2.5 eq.) were added in succession and the reaction mixture was introduced into a microwave oven at 75° C. for 45 min. After TLC control, the reaction mixture was concentrated on a rotary evaporator. A reddish liquid remained and was diluted with methylene chloride (200 ml). The organic phase was washed with water (2×100 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated. The brown liquid residue was purified by column chromatography (silica gel, ethyl acetate). Yield: 47%