Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[I:11]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(F)c(N)c(I)c1
Reaction time: 1 h

Procedure:
A 25 ml of two-neck round bottom flask was filled with argon gas and the solution of 4-amino-3-fluoro-benzonitrile (300 mg, 2.204 mmol, 1 equiv.) in methylenechloride was put into the flask. To the solution was added iodomonochloride (393.6 mg, 2.424 mmol, 1.1 equiv.) and stirred for 1 hour. After confirming the completion of the reaction with TLC, to resulting solution was added saturated sodium thiosulphate solution and stirred. The reaction solution was extracted with methylenechloride, washed with water(twice) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethylacetate=3/1) to yield a brown liquid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][OH:12].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CCOC(C)=O>CN(C=O)C.O>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[I:3])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cccc(CO)c1I
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(COCC(=O)OC(C)(C)C)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Sodium hydride (53 mg, 2.2 mmol) was added to a 0° C. solution of 2-iodo-3-methyl-phenyl-methanol ((Example 5: step a) 492 mg, 2 mmol) in DMF (20 mL). The solution was stirred at 0° C. for 30 min and tert-butyl bromoacetate (0.4 mL, 2.5 mmol) was added. The solution was warmed to rt over 15 min and stirred for 3 h at rt. EtOAc (80 mL) and water (40 mL) were added, the layers were separated, and the organic layer was washed with water (6×20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography (5–10% EtOAc in hexanes) yielded the title compound (0.571 g, 79%) as an oil. 1H-NMR (CDCl3): δ 7.36 (dd, 1H, J=1.4, 7.4 Hz), 7.30 (t, 1H, 7.4 Hz), 7.24 (dd, 1H, J=1.4, 7.4 Hz), 4.72 (s, 2H), 4.15 (s, 2H), 2.53 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH2:5][C:4]([C:11]([O:13]C)=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[C:18]([O:17][C:15]([N:1]1[CH2:2][CH2:3][C:4]([C:7]([O:9][CH3:10])=[O:8])([C:11]([OH:13])=[O:12])[CH2:5][CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 1-tert-butyl 4,4-dimethyl piperidine-1,4,4-tricarboxylate (6.2 g, 20.5 mmol) in THF (11 mL) and CH3OH (11 mL) was added aqueous LiOH (2 N, 11 mL, 22 mmol, 1.1 equiv.). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was neutralized with HCl (1N) and was concentrated to dryness. The residue was dissolved in ethyl acetate and dried over Na2SO4 and concentrated to give 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (4.7 g, 80%), which was used without further purification. LRMS (M+H+-Boc) m/z 188.0.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:34][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1ccc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)cc1F
Yield: 84.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (0.12 g, 0.171 mmol) prepared in Example 108a, triethylsilane (0.15 mL), trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol (1.5 mL), to yield the title compound (60 mg, 76%) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].SC1SC2C=CC(C(F)(F)F)=CC=2N=1.[Cl:27][C:28]1[S:29]C2C=CC(Cl)=CC=2N=1>>[Cl:27][C:28]1[S:29][C:2]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: FC(F)(F)c1ccc2sc(S)nc2c1
Product: FC(F)(F)c1ccc2sc(Cl)nc2c1
Temperature: 95 °C

Procedure:
The title compound was prepared from 2-fluoro-5-trifluoromethylaniline via 2-mercapto-5-trifluoromethyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 95° C. for 4 h.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:31]C(=O)OC(C)(C)C)[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][OH:29])=[CH:23][CH:22]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:31][CH:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][N:13]=1)[C:17]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:28][OH:29])=[O:30])=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)NCc1ccc(C(=O)NO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)NCc1ccc(C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
t-Butyl 3-(5-(benzyloxy)pyridin-2-yl)-1-(4-(hydroxyl-carbamoyl)benzylamino)-1-oxopropan-2-ylcarbamate (0.26 g, 0.5 mmol) was dissolved in TFA/DCM (v/v=1:1) (30 mL) and stirred for 4 h at room temperature (monitored by TLC). The solution was evaporated with DCM three times to give 0.021 g HPW101x048 (81%): mp 151-154° C.; NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 3.12 (m, 2H, CH2), 4.25 (m, 2H, CH2), 4.40 (m, 1H, CH), 5.15 (s, 1H, OBn), 7.21 (m, 3H, Ar—H), 7.40 (m, 7H, Ar—H), 7.67 (d, 1H, Ar—H, J=8.21 Hz), 7.84 (d, 1H, Ar—H, J=7.96 Hz), 8.26 (br, 2H, NH2), 8.27 (s, 1H, NH), 8.92 (br, 1H, NH), 11.19 (br, 1H, OH).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[C:17]=1N)=[O:12])[CH3:9].[Cl:29]N1C(=O)CCC1=O>ClCCl>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[C:17]=1[Cl:29])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1N
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
tert-Butyl nitrite (154 mg) was added slowly dropwise to a solution of 5-amino-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (300 mg) and N-chlorosuccinimide (200 mg) in dichloromethane (10 ml) and stirred at room temperature for three hours. The reaction solution was concentrated while keeping not dried up, and the residue was purified with silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (140 mg) as a white solid.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([I:18])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]2[C:17]([Cl:19])=[C:16]([I:18])[N:15]=[CH:14][N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@@H](Nc2cc(I)ncn2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2ncnc(I)c2Cl)CC1
Temperature: 25 °C

Procedure:
3.6 g (10 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-iodopyrimidine and 2.0 g of N-chlorosuccinimide were heated at reflux for 8 hours in 15 ml of chloroform. After cooling to room temperature, the mixture was extracted by stirring with dilute sodium hydroxide solution and water and the organic phase was dried and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 4:1) to give first of all 2.3 g (58.4% of theory) of product (a colorless oil which gradually crystallized, m.p. 89° to 90° C.) and, finally, 1.0 g of unreacted starting material.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][C:15]=1[CH3:32].C(N=C=NC(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:7][O:8][C:29]([C:23]2[C:24](=[O:28])[NH:25][C:26](=[O:27])[N:21]([C:17]3[CH:18]=[C:19]([CH3:20])[C:14]([O:13][C:12]4[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:10]([Br:9])[CH:11]=4)=[C:15]([CH3:32])[CH:16]=3)[N:22]=2)=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)OCC4CCCCC4)c(=O)[nH]c3=O)cc2C)cc1Br
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of cyclohexylmethanol (9 μmol) in DMF were added sequentially solutions of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (5 μmol), diisopropylcarbodiimide (10 mmol) and 4-dimethylaminopyridine (10 μmol). The resulting soution was shaken at 50° C. for 18 h. HPLC and LCMS shows the starting material to be consumed and the desired product present. MS Calc.: 557.1; Found: 556.1 (M−1).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=O)C>[OH-].[K+]>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
3.36 g (0.0185 mol) of 4-acetamido-2-nitrobenzoic acid were dissolved in 34 ml of 10% KOH and stirred at 90° for 1 hr. After cooling to 0° C. the mixture was acidified with 37% HCI, stirred for a further 1 hr., the precipitate was filtered under suction, washed with water and dried in a high vacuum at 45° C. 2.32 g (69%) of 4-amino-2-nitrobenzoic acid were obtained as yellow crystals. MS: me/e=205 (C7H6NaN2O4 +).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[OH:24].CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.Cl.ClC1C=CN=CC=1>CN(C)C=O>[OH:24][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:2]=1[N:1]1[CH:27]=[CH:31][CH:30]=[CH:29]1)[CH2:6][NH:7]/[CH:8]=[C:9]1\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]2[C:18]\1=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Agent: Cl
Agent: Clc1ccncc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(-n2cccc2)c(O)c1
Reaction time: 2 h
Yield: 26.1 %

Procedure:
A mixture of (4Z)-4-{[(4-amino-3-hydroxybenzyl)amino]methylene}-6-iodoisoquinoline-1,3(2H,4H)-dion (300 mg, 0.67 mmol), 2,5-dimethoxytetrahydrofuran (182.2 mg 1.4 mmol), and 4-chloropyridine hydrochloride (101 mg, 0.67 mmol) were placed in a flask and N,N-dimethylformamide (5 mL) is added. The mixture is then placed in a pre-heated oil bath at 80° C. for 2 hours. After cooling, all the solvent is evaporated. The brown solid is stirred in water and washed with ether to give the product as a brown solid 85 mg (25% yield).; mp 230-231° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][C:10]([O:12]CC)=O)=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33]Br>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]2[C:9]3([CH2:33][CH2:32]3)[C:10](=[O:12])[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:4]=2[N:3]=1
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NCc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN2C(=O)C3(CC3)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 80 °C
Yield: 82.7 %

Procedure:
To a solution of ethyl 2-(2,4-dichloro-6-(4-methoxybenzylamino)pyrimidin-5-yl)acetate (27.1 g, 73.2 mmol) and powder potassium carbonate (101.1 g, 732.4 mmol) in N,N-dimethyllformamide (800 mL) was added 1,2-dibromoethane (27.5 g, 146.4 mmol) dropwise under nitrogen atmosphere at 40° C. After the addition was over, the reaction mixture was heated to 80° C. for 1 h. Quenched with water, extracted with ethyl acetate, and the organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product as a snow-white solid (21.2 g, yield 82.7%). 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.38 (m, 2H), 6.86 (dd, J=8.4, 1.3 Hz, 2H), 4.94 (d, J=0.8 Hz, 2H), 3.79 (d, J=1.6 Hz, 3H), 2.14 (qd, J=4.3, 1.6 Hz, 2H), 1.79 (qd, J=4.3, 1.6 Hz, 2H).
Reaction SMILES: CO[C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[N:11]1([C:3]([C@H:4]2[NH:5][C:6](=[O:9])[CH2:7][CH2:8]2)=[O:10])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1

Procedure:
L-pyroglutamic acid methyl ester (23.91 g, 177 mmol), morpholine (21.8 g, 250 mmol) and 4-dimethylaminopyridine (0.2 g, 1.64 mmol) are heated under reflux in toluene (130 ml) for 12 hours. The product precipitates as an oil. The oil is separated from the toluene, diluted with dichloromethane (100 ml) and washed successively with 0.1 M HCl, 0.1 M NaOH and water (50 ml each). The dichloromethane phase is concentrated to obtain a suspension, which is filtered yielding the crude product. The crude product is dissolved in THF (200 ml) at 45° C. and, upon cooling in an ice bath, (S)-5-morpholine-4-carbonyl)pyrrolidin-2-one precipitates as white crystals. Enantiopurity (GC) 88.7% (S)-Enantiomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13]([CH2:16][C:17](O)=O)(=[O:15])=[O:14])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:23]=1C=O.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[N:7][C:6]([CH2:12][S:13](/[CH:16]=[CH:17]/[C:23]2[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:14])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)nc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c([N+](=O)[O-])n2)c(OC)c1
Yield: 35.3 %

Procedure:
A mixture of 2-((5-methoxy-6-nitropyridin-2-yl)methylsulfonyl)acetic acid (0.29 g, 1.0 mmol) in dry toluene (2 mL) was added 2,4,6-trimethoxybenz-aldehyde (0.196 g, 1.0 mmol) and acetic anhydride (0.38 mL). After refluxing for 5 hrs, the reaction mixture was evaporated to dryness. The residue was precipitated by adding methanol (15 mL). The precipitate was filtered to give 150 mg (35%) the titled compound as grey coloured powder. 1H-NMR (Acetone-D6): δ 3.92 (s, 9H, 3×OCH3), 4.07 (s, 3H, OCH3), 4.52 (s, 2H, CH2), 6.32 (s, 2H, Ph-H), 7.20 (d, J=15.6 Hz, 1H, CH), 7.74 (d, 1H, J=15.6 Hz, CH), 7.87 (d, 1H, J=8.4 Hz, Py-H), 7.95 (d, 1H, J=8.8 Hz, Py-H); HR-MS (ESI+) m/z 425.1053 [M+1]+ C18H20N2O8S requires 424.0940.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=1.C1C=C[C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.C(Cl)CCl.C1(N)CC1>ClCCl>[CH:20]1([NH:22][C:13]([C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[O:12][N:11]=2)=[O:15])[CH2:21][CH2:19]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(-c2ccccc2O)on1
Agent: NC1CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a 20 mL flask was added the crude acid from step 3 (20 mg, 0.1 mmol), HOBt (16 mg, 0.12 mmol), and EDC (23 mg, 0.12 mmol). To this was added dichloromethane (3 mL) and the resulting heterogeneous mixture was stirred for 30 minutes at room temperature. To the resulting solution was added cyclopropylamine (9.0 mg, 0.15 mmol) and the reaction was monitored by HPLC for product formation. After 2 hours, the reaction was complete and concentrated to a thick oil. This oil was partitioned between EtOAc (3 mL) and water (2 mL) with stirring for 10 minutes. The layers were then allowed to separate and the aqueous layer was discarded. The organic layer was then washed with water (2 mL), brine (2 ml) and dried over Na2SO4. Concentration gave an oil that was purified by column chromatography (30% EtOAc in hexanes) to give 6.1 mg (25% yield) of the desired isoxazole 6; 1H NMR (400 MHz, d6-DMSO)S 8.85 (d, 1H), 7.78 (d, 1H), 7.32 (t, 1H), 7.08 (s, 1H), 7.01 (d, 1H), 6.94 (t, 1H), 2.82 (m, 1H), 0.67 (m, 2H), 0.59 (m, 2H). LC/MS (electrospray ionization, positive mode) M+H=245.0.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][C:20](=[O:32])[N:21]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:17]([C:33]([O:35]CC)=O)[N:16]=1)=O)(C)(C)C.[NH2:38]C1C(C(OCC)=O)=NC(NC[C@@H]2CCCN2C(OC(C)(C)C)=O)=NC=1NC1C=CC=CC=1OC>ClCCl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:21]1[C:20](=[O:32])[NH:19][C:18]2[C:22]1=[N:23][C:15]([NH:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:16][C:17]=2[C:33]([NH2:38])=[O:35]
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@@H]3CCCN3)nc21
Yield: 98 %

Procedure:
(S)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. (S)-Ethyl 5-amino-2-((1-(tert-butoxy-carbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.340 g, 0.740 mmol) and carbonyldiimidiazole (1.13 g, 7.40 mmol) in dichloromethane (20 mL) were reacted according to general procedure F and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title product (0.352 g, 98%). MS (ESI) m/z 513.5 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:6][C:5]2[C:7]([CH3:28])=[CH:8][C:9]([CH3:27])=[C:10]([NH:11][C:12](=[O:26])[C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[O:3]1.[N+:30]([O-])([OH:32])=[O:31]>C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>[CH3:29][C:2]1([CH3:1])[CH2:6][C:5]2[C:7]([CH3:28])=[C:8]([N+:30]([O-:32])=[O:31])[C:9]([CH3:27])=[C:10]([NH:11][C:12](=[O:26])[C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[O:3]1
Reactant: CCCCCCCCCCC(C)(C)C(=O)Nc1c(C)cc(C)c2c1OC(C)(C)C2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCC(C)(C)C(=O)Nc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C)C2
Temperature: 0 °C
Yield: 78 %

Procedure:
A 64 mg amount of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide (434) was dissolved in 0.5 ml of acetic anhydride, and 24 mg of nitric acid was slowly added to the solution while cooling the solution to 0° C. The mixture, as such, was allowed to react at 0° C. for one hour with stirring. The reaction solution was diluted with 5 ml of ice-cold water, 10 ml of a saturated aqueous sodium hydrogencarbonate solution was added thereto to effect neutralization, and the mixture was extracted with ethyl acetate (20 ml×twice). The organic layer was washed with water and brine in that order and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and 72 mg of the resultant crude product was purified by silica gel column chromatography (hexane/ethyl acetate) to provide 56 mg of the intended tittle compound. The yield was 78%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1)(=[O:27])=[O:26]
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1CCCNC1
Reactant: O=S(=O)(Cl)c1cccs1
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1C1CCCN(S(=O)(=O)c2cccs2)C1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in pyridine, 1.00 mL), thiophene-2-sulfonyl chloride (7.3 mg) was heated at 90° C. for 16 hours. The reaction mixture was concentrated and redissolved in N,N-dimethylformamide. PS-Trisamine (50 mg), PS-Isocyanate (50 mg) was added and the mixture agitated at ambient temperature for 6 hours then filtered. The filtrate was concentrated in vacuo and purification by preparative high performance liquid chromatography gave 1-[1-(2-thienylsulfonyl)piperidin-3-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.3 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CN(Cc1ccccn1)Cc1ccccn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Cl)cc1CN(Cc1ccccn1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Pd on carbon (10% wt, 1.01 g) was placed in a 100 mL flask purged with Ar and 40 mL of MeOH was added. 2-Nitro-5-chloro-1-[bis(2-pyridylmethyl)aminomethyl]-benzene (569 mg, 1.55 mmol) was dissolved in 10 mL of MeOH and added to the reaction flask with a syringe. A balloon with H2 was attached and the reaction was left to stir vigorously under H2 for 1 h at rt. The reaction was purged with Ar, filtered through Celite and dried to yield a brown solid (380 mg, 72%) that was used without further purification. The product can be purified by flash chromatography on basic Al2O3 (20:4:2.5 CH2Cl2:EtOAc:isopropylamine) to give a brown solid (65%). 1H NMR (CDCl3, 300 MHz) δ 3.59 (2H, s), 3.80 (4H, s), 6.52 (1H, d), 7.00 (2H, m), 7.11 (2H, m), 7.38 (2H, t), 7.60 (2H, 5), 8.55 (2H, d). 13C NMR (CDCl3, 300 MHz) δ 57.18, 58.71, 116.62, 121.28, 121.98, 123.20, 123.67, 127.91, 130.29, 136.39, 144.94, 148.64, 158.22. HRMS (ESI) calcd MH+, 339.1371; found, 339.1383.