Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O)([O-:3])=[O:2].O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C1(N)CCCCC1>O.ClCCl.C(N(CC)CC)C.CN(C)C=O>[CH:21]1([NH:17][C:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][N:8]=2)=[O:15])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:20]1
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: NC1CCCCC1
Solvent: O
Product: O=C(NC1CCCCC1)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 70 h
Yield: 459.9 %

Procedure:
N-Cyclohexyl-5-nitro-1H-indazole-3-carboxamide can be obtained in the following way: a solution of 2.5 g of 5-nitro-1H-indazole-3-carboxylic acid, of 150 ml of dichloromethane, of 75 ml of dimethylformamide, 0.16 g of 1-hydroxybenzotriazole and of 2.75 g 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride is stirred for 15 minutes at a temperature of 25° C. 1.7 ml of cyclohexylamine and 1.7 ml of triethylamine are then added. The reaction medium is maintained with stirring for 70 hours and concentrated by evaporation under reduced pressure. The residue thus obtained is taken up with 50 ml of dichloromethane and 50 ml of diisopropyl ethyl. After filtration, the paste obtained is taken up with 80 ml of distilled water and the solid form is filtered through a sintered glass funnel, washed with two times 50 ml of water and then dried under reduced pressure. The resulting solid is taken up with 50 ml of ethyl acetate, filtered through a sintered glass filter, washed with two times 25 ml of ethyl acetate and dried at 50° C. under reduced pressure. 1.57 g of N-cyclohexyl-5-nitro-1H-indazole-3-carboxamide are thus obtained in the form of a beige solid (Rf=0.90, silica gel thin layer chromatography, eluent: chloroform/methanol/20% aqueous ammonia (12/3/0.5 by volume)).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([NH:19][CH3:20])[N:3]=1.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([NH:19][CH3:20])[N:3]=1
Reactant: CNc1nc(Cl)nc2c1ncn2Cc1ccccc1Cl
Reactant: CN
Product: CNc1nc(NC)c2ncn(Cc3ccccc3Cl)c2n1

Procedure:
In a manner analogous to that described in Example 2 it is possible, by reacting 2-chloro-9-(2-chlorobenzyl)-6-(N-methylamino)-9H-purine (Example 18) with N-methylamine, to obtain the 2,6-bis(N-methylamino)-9-(2-chlorobenzyl)-9H-purine, which has a melting range of from 151° to 152°, the reaction mixture being heated at 120° for 20 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].O[CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:22][C:23]2[O:27][N:26]=[C:25]([CH3:28])[CH:24]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1O
Reactant: Cc1cc(CO)on1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(Cl)cc2CN2C(=O)c3ccccc3C2=O)on1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
To a mixture of 2-[5-chloro-2-hydroxy benzyl]isoindole-1,3-dione (800 mg, 2.78 mmol), 5-hydroxymethyl-3-methyl-isoxazole (373 mg, 3.3 mmol), and triphenylphosphine (1.0 g, 4.2 mmol) in anhydrous THF (10 mL) was added diethylazodicarboxylate (0.657 mL, 4.7 mmol). The solution was stirred for 15 h at room temperature under anhydrous conditions. The solvent was then removed by rotary evaporation and the product was preadsorbed onto silica gel and purified by flash chromatography to afford the title compound (555 mg, 52%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[N:47]=[C:46]([NH:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:45]([F:53])=[CH:44][N:43]=1>C(Cl)(Cl)Cl>[C:49]([NH:48][C:46]1[C:45]([F:53])=[CH:44][N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[N:47]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)Nc1nc(N)ncc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ncc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 3 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 210 mg of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 340 mg of 2-amino-4-(t-butylamino)-5-fluoropyrimidine. The solution was concentrated under reduced pressure. To the residue were added 550 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 1 hour and 10 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel, 16 g; eluent: chloroform:methanol, 200:1), and the corresponding fractions were collected and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 98 mg of the title compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:24]=1[CH3:38]>>[CH3:38][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:27]=[CH:28][C:23]=1[NH:22][CH3:21]
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: CNc1ccc(-c2ccn3c(=O)c(C(=O)OC)cc(C4CC4)c3c2C)cc1C
Yield: 39.1 %

Procedure:
Methyl 8-(3-methyl-4-(methylamino)phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (101.5 mg, 0.41 mmol). The residue was rinsed with DCM and dried in a vacuum stove to afford the title compound as a yellow solid (50 mg, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:30]1([CH2:35][B-](F)(F)F)[CH2:34][CH2:33][CH2:32][CH2:31]1.[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)CN1CCCC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and potassium pyrrolidin-1-ylmethyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COCOc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Oven-dried potassium carbonate (0.272 g, 2 mmol) was added to a solution of 2-hydroxy-4-methoxymethyloxy-benzaldehyde (0.182 g, 1 mmol) in 10 mL of acetonitrile and the mixture was stirred for one hour at RT. Benzylbromide (0.24 mL, 2 mmol) was added and the mixture was refluxed for 10 hours. After disappearance of 2-hydroxy-4-methoxymethy-benzaldehyde (TLC), the solvent was evaporated. The residue was chromatographed over silica using hexanes:EtOAC (5:1). The organic fractions were evaporated to obtain 0.218 g (80%) of yellow oil; TLC Rf0.27 hexanes:EtOAc (5:1), 1H NMR (400 MHz, CDCl3) δ 10.4 (s, 1H, CHO); 7.81-7.83 (d, 1H, J=8.4 Hz, Ar—H6); 7.46-7.39 (m, 5H, C6H5); 6.7-6.69 (m, 2H, Ar—H3/Ar—H5); 5.21 (s, 2H, O—CH2—O); 5.16 (s, 2H, PhCH2); 3.48 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ 188.6, 163.9, 162.9, 136.1, 130.5, 128.9, 128.5, 127.6, 120.2, 108.8, 101, 94.4, 70.7; analysis calc'd. for C16H16O4: C, 70.57; H, 5.92; O, 23.5. found: C, 70.35; H, 5.95; O, 23.72.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[N:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]=[O:22]>>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][NH:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]([S:14](=[O:15])(=[O:16])[N:17]([CH3:18])[CH3:19])=[CH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1)=[O:22])[CH3:29]
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)N(C)C)cc1
Reactant: CCOC(=O)CCN=C=O
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)s1

Procedure:
Using 4-(2-amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and replacing ethyl isocyanatoacetate with ethyl 3-isocyanatopropion-ate (0.05 ml, 0.34 mmol) in the above reaction affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17](O)=[O:18])=[O:6].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17]([N:32]1[CH2:33][C:30]([F:34])([F:29])[CH2:31]1)=[O:18])=[O:6]
Reactant: FC1(F)CNC1
Reactant: CC1OCc2sc(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)c(C(=O)O)c21
Agent: Cl
Product: CC1OCc2sc(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)c(C(=O)N3CC(F)(F)C3)c21

Procedure:
The title compound was prepared from the product of Example 50A and commercially available 3,3-difluoroazetidine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (d, J=6.4 Hz, 3H), 4.30-4.51 (m, 4H), 4.89-5.02 (m, 2H), 5.17-5.26 (m, 1H), 7.80 (d, J=8.5 Hz, 1H), 8.03 (dd, J=8.0, 8.0 Hz, 1H), 11.85 (br s, 1H). MS (ESI+) m/z 499 (M+H)+. Anal. calcd. for C19H13ClF6N2O3S: C, 45.75; H, 2.63; N, 5.62. Found: C, 46.17; H, 2.51; N, 5.33.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][O:37][CH2:36]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]2[CH2:39][CH2:38][O:37][CH2:36]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (150 mg, 0.428 mmol) was heated in dry DMF (2.5 ml) at 60° C. for 1 hour with potassium carbonate (237 mg, 1.713 mmol). The reaction mixture was cooled to room temperature and 3-(3-bromopropyl)tetrahydrofuran (99 mg, 0.514 mmol) was added. The mixture was then heated at 50° C. overnight. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were separated and then dried by passage through a hydrophobic frit and evaporated to dryness. The residue was dissolved in 1:1 MeOH:DMSO (2.8 ml) and purified by mass directed autopreparation. Product containing fractions were evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a clear gum (84 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[C:12]1(S(OC)(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH3:12][O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][Br:1])=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)c1ccccc1
Reactant: OCc1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCc1ccc(CCBr)cc1

Procedure:
The 1-(2-bromoethyl)-4-hydroxymethylbenzene (0.5 g) is then added to a solution of 0.44 g methyl benzenesulfonate and 0.32 g K2CO3 in 10 ml of methanol and allowed to react for 4 h. The solution is neutralized with methanolic HCl and extracted with ether. The ether extract is dried over Na2SO4, filtered, and the solvent removed under vacuum to yield 1-(methoxymethyl)-4-(2-bromoethyl)benzene (13).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C:25]([O:31]C(=O)C)([CH3:30])[C:26]([F:29])([F:28])[F:27]>O.CC(C)=O>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:22])[CH2:20][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: CC(=O)OC(C)(C(=O)Nc1ccc(Sc2ccc(NC(=O)CCl)cc2)cc1Cl)C(F)(F)F
Reactant: CNC
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CC(=O)Nc1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1

Procedure:
Dimethylamine (0.17 ml of a 40% solution in water) was added to a solution of (R)-N-{2-chloro-4-[4-(2-chloroacetylamino)phenylsulphanyl}phenyl -2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (Method 19) (0.25 g) in acetone (1.5 ml). After 24 hours volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water, and the organic layer was poured onto a Varian Chem Elut column. Elution with ethyl acetate gave the title compound (0.25 g) as a foam. NMR: 1.6 (s, 3H), 3.1 (s, 2H), 3.3 (s, 6H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 (d, 2H), 7.7 (m, 3H), 7.9 (d, 1H), 9.7 (s, 1H), 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH:16]1([CH2:19][O:20][C:21]2[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=2[CH3:30])[CH2:18][CH2:17]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCC1CC1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC1CC1
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (1.39 g, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1.14 g, 4.09 mmol, Step-1 of Intermediate-1) and 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (994 mg, 4.09 mmol, Amine-70, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)[OH:12])=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:10][CH:9]([C:1]1[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=1)[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: C1=COCCC1
Solvent: c1ccccc1
Product: COc1ccc(C(=O)C(OC2CCCCO2)c2ccc(OC)cc2)cc1
Yield: 71.6 %

Procedure:
82 parts of p-anisoin are reacted with 34 parts of 3,4-dihydro-2H-pyran (approx. 35% molar excess) in 500 parts by volume of benzene, analogeously to Example 1. p-anisoin tetrahydropyranyl ether is obtained in a yield of 71.6% and melts over the range of 96° to 102° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:20])[CH2:9]2)(=[O:4])=[O:3].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:20])[CH2:9]3)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:26][CH2:27]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)CN1C(=O)Cc2cc(NS(C)(=O)=O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)Cc2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Temperature: 65 °C
Yield: 15.1 %

Procedure:
A mixture of methyl 2-(5-(methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.500 g, 1.607 mmol) (prepared in an analogous manner as described in Example 20, Scheme 20, Steps 1, 2, 3, 4), 4-(2-chloroethyl)morpholine hydrochloride (0.393 g, 2.112 mmol), and K2CO3 (0.524 g, 3.788 mmol) in DMF (25 ml) was heated at 65° C. for 2 hours. The mixture was partitioned between ethyl acetate and aqueous 5% NaHCO3; the organic phase was washed several times with brine and dried over sodium sulfate. The solvent was removed under vacuum and the dark crude was purified by flash chromatography on silica gel column (DCM:MeOH=99:1 to 97:3) affording methyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.100 g, 0.243 mmol, 14.5% yield, MS/ESI+ 412.0 [MH]+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12].[Cl:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[NH:20][CH:21]=[N:22]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NC(=O)c1cccc(OCCCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(OCCCCCn2cnc3c(Cl)ncnc32)c1
Yield: 19.4 %

Procedure:
A solution of 3-(bromopentyloxy)benzamide (500 mg, 1.7 mmols), 6-chloropurine (270 mg, 1.7 mmols) and potassium carbonate (240 mg, 1.7 mmols) in DMF (7.5 ml) was stirred for two days at room temperature. The solvent was then removed under vacuum (0.001 mmHg) and the white solid (mixture of N7 and N9 isomers) was chromatographed (silica, 10% MeOH/CH2CI2) to give a single product (N9 isomer) as a glass. This was triturated with ether (=5 ml) to give a white solid which was recrystallised from ethyl acetate to give the product (120 mg, 0.33 mmols, 20% yield)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]=1)=[O:4].CC([O-])=O.[Na+]>CO>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)c1coc2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1COc2ncccc21
Reaction time: 20 h

Procedure:
To a suspension of furo[2,3-b]pyridine-3-carboxylic acid methyl ester (48 mmol) in 180 mL MeOH was added NaOAc (97 mmol). The flask was evacuated and filled three times with argon, 20% wet Pd(OH)2 on carbon (1000 mg) was added and the reaction was stirred for 20 h under a hydrogen atmosphere. It was then filtered over a 2 cm pad of celite and was washed with EtOH (50 mL) and EtOAc (50 mL). The filtrate was concentrated in vacuo to afford the desired compound as colorless oil.
Reaction SMILES: [C:1]([O:12]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[O-]CC.[Na+].S(=O)(=O)(O)O>>[CH3:10][CH2:9][O:8][C:6]([CH:5]1[C:1](=[O:12])[CH2:2][CH2:3][CH2:4]1)=[O:7]
Reactant: CCOC(=O)CCCCC(=O)OCC
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1CCCC1=O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
The process was carried out in a high-viscosity reactor model CRP 2,5 Batch from List AG. The high-viscosity reactor is a machine having two horizontal corotating mixing shafts. Kneading devices which intermesh and thus ensure rapid and homogeneous mixing are located on the shafts. In addition, the machine has a discharge screw by means of which the product can be conveyed out of the reaction chamber. It can be operated continuously or batchwise. The reactor has a free volume of about 2.5 l. The reaction chamber of the machine can be heated. Volatile constituents can be taken off via a vent. 1336 g of diethyl adipate and 472 g of sodium ethoxide were placed in the high-viscosity reactor. After start-up of the kneader and commencement of mixing of the starting materials a viscous mass was immediately formed. While kneading slowly, the temperature was slowly increased to 120° C. A vacuum of 10 mbar was slowly built up. The temperature of 120° C. was reached after about 15 minutes. Slow kneading was then continued at a temperature of 120° C. for 30 minutes until a pulverized white solid had been obtained. The powder formed was discharged by means of a transport screw and subsequently hydrolysed using half-strength sulphuric acid. Phase separation and distillation at 120° C./10 mbar gave 1021 g of ethyl cyclopentanone-2-carboxylate, viz. about 99% of theory. Diethyl adipate could no longer be detected.
Reaction SMILES: S[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10].N1C(=O)NC(=O)NC1=O.C([O-])([O-])=O.[K+].[K+].[Br:32]C(Br)CCCCC>CS(C)=O>[Br:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]
Reactant: CCCCCC(Br)Br
Reactant: O=c1[nH]c(=O)n(CCCCCCS)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(CCCCCCBr)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A scheme for the synthesis of Mercaptohexyl Isocyanuric Acid (MH-ICA) is shown in FIG. 10A. 6-Bromohexyl isocyanuric acid was synthesized using methods and materials known in the art (see, e.g. Berl et al., Chem. Eur. J. 2000, 6, 1938-1946; and Hoeben et al., Org. Biomol. Chem. 2006, 4, 4460-4462). Briefly, 1-2 Cyanuric acid (6.2 g, 48 mmol) and ground K2CO3 (1.66 g, 12.0 mmol) were dissolved in DMSO (200 mL). After the mixture was stirred for 30 min, dibromohexane (2.98 g, 12.0 mmol, 0.25 equiv.) was added and was heated to 60° C. for 16 h. Upon cooling down the reaction to room temperature, the mixture solution was partitioned between diethyl ether and saturated KHSO4. The organic fraction was collected and the solvent was removed by rotary evaporator. Recrystallization of the residue from hexane yielded 6-bromohexyl isocyanuric acid which was extensively rinsed with hexane. The product (450 mg) was obtained in high purity. 1H NMR (500 MHz, DMSO-d6) δ: 11.38 (s, 2H), 3.62 (t, 2H), 3.52 (t, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.38 (m, 2H), 1.27 (m, 2H) ppm; 13C NMR (125 MHz, DMSO-d6) δ: 149.85, 148.64, 40.28, 35.09, 32.12, 27.21, 27.15, 25.22 ppm. ESI-MS (M+): 293.98 (calculated 293.13).