Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2N2C=C(C3(N)NC=NC4SC=CC3=4)N(C)C2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC([C:44]2[N:45]=[CH:46][N:47]([CH3:59])[C:48]=2[C:49]2[S:58][C:52]3[N:53]=[CH:54][N:55]=[C:56]([NH2:57])[C:51]=3[CH:50]=2)=CC=1>>[C:1]1([C:7](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:44]3[N:45]=[CH:46][N:47]([CH3:59])[C:48]=3[C:49]3[S:58][C:52]4[N:53]=[CH:54][N:55]=[C:56]([NH2:57])[C:51]=4[CH:50]=3)=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(N)ncnc2s1
Reactant: CN1CN(c2ccccc2N=C(c2ccccc2)c2ccccc2)C=C1C1(N)NC=Nc2sccc21
Product: Cn1cnc(-c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 109 but using 6-[4-(4-iodophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 64) in place of 6-[4-(3-iodophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Example 49). Colourless solid (31 mg, 64%);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(O)C>[CH2:10]([N:9]([C:20]([NH:19][CH2:17][CH3:18])=[O:21])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NNCc1ccccc1
Reactant: CCN=C=O
Solvent: CCO
Product: CCNC(=O)N(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of N'-benzylhydrazinecarboxylic acid tert-butyl ester (2.5 g, 11.8 mmol) in 99% ethanol (40 ml) was added ethyl isocyanate (1.1 g, 15.2 mmol) and the mixture was stirred for 2 h. Then the mixture was concentrated in vacuo and chromatographed on silica (20 g) with petrol ether/ethyl acetate 3:2 to give 3.0 g of 2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[CH:4]([CH2:20][C:21]([O:23]CC)=[O:22])[O:3]1.[OH-].[Li+].Cl>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[CH:4]([CH2:20][C:21]([OH:23])=[O:22])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-methoxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (150 mg, 0.44 mmol) in THF (2 mL) was added an aqueous solution of lithium hydroxide (90 mg, 2.2 mmol) in 3 mL of water at 0° C., The reaction mixture was stirred at room temperature for 1.5 hr and acidified to pH=2 using diluted hydrochloride acid. The resulting mixture was extracted with ethyl acetate (15 mL×2) and combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (71 mg, Y: 51.0%). 1H NMR (400 MHz, DMSO-d) δ 9.28 (s, 1H), 8.56 (s, 1H), 8.39-8.40 (d, J=2.4 Hz, 1H), 8.24 (s, 1H), 7.00-7.02 (d, J=10.8 Hz, 2H), 5.44-5.46 (m, 1H), 3.81 (s, 3H), 3.13-3.16 (m, 1H), 2.14-2.20 (m, 1H). MS (ESI) m/z=317 [M+H]+.
Reaction SMILES: CS([C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1)(=O)=O.[CH3:30][O-:31].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:31][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reaction time: 2 h
Yield: 26.9 %

Procedure:
To a solution of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole (150 mg, 0.35 mmol) in N,N-dimethylformamide (3 mL) was added sodium methoxide (23 mg, 0.42 mmol) at room temperature, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (35.4 mg, yield 27%) as colorless crystals.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15]C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:28]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:17](=[O:19])[NH:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH2:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
19.7 g of N-carbobenzoxy-DL-norleucine are dissolved in 200 ml of absolute tetrahydrofuran, the solution is treated dropwise while cooling with ice with 10 g of thionyl chloride and then stirred for 1 hour. To this solution there is rapidly added dropwise a solution of 17 g (0.065 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 130 ml of absolute tetrahydrofuran and the mixture is then stirred at room temperature for 60 hours. The solution is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 450 g silica gel column using methylene chloride as the eluting agent and crystallised from ethanol. There is obtained benzyl-rac-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]butyl}carbamate which melts at 148°-150° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.C(O)(C)C.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[C:25]([C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1)[N:26]2[CH3:31]>C(N(CC)CC)C>[CH2:37]([N:35]1[CH:36]=[C:32]([C:25]2[N:26]([CH3:31])[C:27]3[C:23]([N:24]=2)=[C:22]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]2)[N:30]=[CH:29][N:28]=3)[CH:33]=[N:34]1)[CH3:38]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCn1cc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
To a solution of 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.1 g, 0.33 mmol) in an anhydrous isopropanol (8 mL) and triethylamine (0.2 mL) was added 6-chloro-8-(1-ethyl-1H-pyrazol-4-yl)-9-methyl-9H-purine (65 mg, 0.25 mmol). The reaction mixture was heated to 80° C. for 16 hours, and cooled to room temperature. The resulting precipitates were collected by vacuum filtration, and triturated with 15 mL of ethanol at 75° C. for 30 min. The solids were collected by vacuum filtration to give 107 mg (97% yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 8.03 (d, 1H), 7.13 (dd, 1H), 6.93 (m, 3H), 5.61 (s, 2H), 4.53 (dd, 1H), 4.22 (q, 2H), 3.84 (s, 3H), 3.18 (s, 2H), 2.33 (m, 2H), 1.82 (d, 2H), 1.40 (t, 3H); MS (EI) for C23H25N9O: 444.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[O:6])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: COc1ccc(NC(=O)c2ccc(OC)c(N)c2)cc1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccc(OC)c(NC(=S)Nc3cc(Cl)cc(Cl)c3)c2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 79.6 %

Procedure:
A mixture of 3-amino-4-methoxy-N-(4-methoxyphenyl)-benzamide from Example 3 (0.681 g, 2.50 mmol) in ethyl acetate (80 mL) was heated briefly to 60° C. then filtered to clarity and mixed with 3,5-dichlorophenyl isothiocyanate (0.511 g, 2.50 mmol). The reaction was allowed to stand for 3 days at room temperature then concentrated to two-thirds volume and allowed to stand overnight. Filtration afforded the product (0.948 g); m.p 175-182° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Reactant: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C)CC2)c1=O
Yield: 94 %

Procedure:
Following the procedure of Example 1(10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 94.0%).
Reaction SMILES: FC(F)(F)CN.[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25](NCC1C=CC(F)=CC=1)[N:24]=[C:23]2[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42]>>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1)[N:24]=[C:23]2[NH:39][CH2:40][C:41]([F:42])([F:44])[F:43]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1ccc(CNc2nc(NCC(F)(F)F)c3cc(Br)ccc3n2)cc1
Agent: NCC(F)(F)F
Product: NS(=O)(=O)c1ccc(CNc2nc(NCC(F)(F)F)c3cc(Br)ccc3n2)cc1

Procedure:
6-Bromo-2-methanesulfonyl-quinazolin-4-yl)-(2,2,2-trifluoro-ethyl)-amine was reacted with 4-Aminomethyl-benzenesulfonamide in a manner analogous to 6-Bromo-N2-(4-fluoro-benzyl)-N4-(2,2,2-trifluoro-ethyl)-quinazoline-2,4-diamine as described in Example 49. The product was characterized as follows: MS (m/z) 490 [M+H]+; HPLC Rt=1.90 minutes (Method B).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([OH:10])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:16](OC(OC)=O)(OC)=O>CO>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([O:10][CH3:16])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)OC(=O)OC
Reactant: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)O
Solvent: CO
Product: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)OC
Yield: 90 %

Procedure:
104 Mg (0.49 mmole) of (+)-cis-3-oxo-2-pentyl-1-cyclopentaneacetic acid (97:3 cis/trans ratio) in 0.5 ml of methanol were treated with 76 μl of dimethyl dicarbonate [CH3O(CO)O(CO)OCH3, origin: Bayer; 96 mg, 0.72 mmole, 1.5 eq.]. The resulting solution was heated to 45° during 16 h and then evaporated under vacuum. After distillation of the residue in a bulb-to-bulb apparatus (oven t. 150°/10 Pa), there were obtained 100 mg (0.44 mmole, yield 90%) of pure methyl (±)cis-3-oxo-2-pentyl-1-cyclopentaneacetate (97:3 cis/trans ratio).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:31](=[O:33])[CH3:32])[CH:9]=1)[C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:17]([CH3:19])[CH3:18])[CH3:2]
Reactant: CCOC(=O)CN(Cc1cccc(N)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CN(Cc1cccc(NC(C)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 735 (435.0 mg, 1.06 mmol) in pyridine (3.0 ml) was added acetic anhydride (50 μL, 1.59 mmol) and the reaction allowed to stir overnight. The reaction was diluted with EtOAc and 1N HCl. The layers were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated to dryness to provide 480 mg of 742. ##STR121##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:21])[CH2:10][CH:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4].C(O)(=O)C.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21][CH2:33][C:32]3[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=[C:30]([C:29]([F:28])([F:42])[F:43])[CH:31]=3)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2C(N)CC1C
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (208 mg, 0.64 mmol) in anhydrous 1,2-dichloroethane (5 mL) was added acetic acid (0.041 mL, 0.71 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (172 mg, 0.71 mmol) and sodium triacetoxyborohydride (0.205 g, 0.97 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane (45 ml) and water (100 ml) and the aqueous phase was adjusted to pH 9. The aqueous phase was extracted with dichloromethane (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 20% acetone/hexanes as eluent afforded the title product (337 mg, 95%). MS m/z 567 (M+ +NH4); 1H NMR (CDCl3) δ 1.40 (d, 3H), 7.14 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>CS(C)=O.CCOC(C)=O>[N+:32]([C:29]1[CH:30]=[CH:31][C:22]([NH:14][CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25])([O-:34])=[O:33]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: NCC1CCN(c2ccncc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 17 h
Yield: 42 %

Procedure:
A solution of 1-(4-pyridyl)piperidine-4-methylamine (1.13 g, 5.92 mmol) and potassium carbonate (816 mg, 5.92 mmol) in dimethyl sulfoxide (12 mL) was treated with methyl 2-fluoro-5-nitrobenzoate (1.18 g, 5.92 mmol). After 17 h, the mixture was cooled, diluted with EtOAc, and filtered. The filtrate was concentrated and partitioned between EtOAc and 10% HCl. The aqueous layer was washed with EtOAc (1×), pH adjusted (>10) by addition of NaOH, and washed with EtOAC (3×). The combined extracts were washed with H2O (5×), brine, dried (sodium sulfate), and concentrated. The residue was purified by column chromatography (SiO2, 1 to 3% [2 N NH3 in MeOH]:chloroform) yielding 920 mg (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[CH:5]2.CCN=C=[N:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].C1C=NC2N(O)N=NC=2C=1.CN(CCCN)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[O:16])=[CH:5]2
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: CN(C)CCCN
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1ccccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 50 °C
Yield: 30 %

Procedure:
A mixture of crude 2-(5,6-dichloro-1H-indol-2-yl)benzoic acid (0.19 g, 0.62 mmol), WSC (0.13 g, 0.68 mmol), HOAT (0.093 g, 0.68 mmol), dimethylamino propylamine (0.13 g, 1.3 mmol) in DMF (2 ml) was heated at 50° C. for 16 h. The mixture was then poured on water and extracted with ethyl acetate. The organic phase was washed twice with water, dried over MgSO4, concentrated in vacuo and the residue was purified by column chromatography (SiO2, CH2Cl2/CH3OH/NH4OH; 9/1/0.1) to afford the title compound as an oil, which crystallised by trituration in diisopropyl ether obtaining, after filtration, 0.072 g (0.18 mmol yield 30%) of the title compound as white crystals, mp=169° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:20]([NH:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2NCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
To a solution of 0.090 g (0.35 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in 3.5 ml of dichloromethane was added 0.040 mL (0.36 mmol) of benzaldehyde, 0.184 g (0.87 mmol) of sodium triacetoxyborohydride and few drops of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in dichloromethane and a saturated aqueous solution of sodium carbonate, extracted with dichloromethane and washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 95/5/0.5 to give 0.022 g (13%) of pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:29])[C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH:13]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:29])[C:12]2[CH:13]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH:15]=[C:16]([O:18][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[Cl:30])[CH:17]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccccc1COc1cc(O)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Reactant: Clc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1COc1cc(OCc2ccccc2Cl)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Temperature: 85 °C
Reaction time: 17 h

Procedure:
A solution of N-(5-nitropyridin-2-yl)-3-[(2-cyanobenzyl)oxy]-5-hydroxybenzamide (195 mg) in DMF (3 ml) was treated with Ag2CO3 (165 mg) and 2-Chlorobenzyl bromide (0.073 ml). Heated to 85° C. and stirred for 17 hours under Nitrogen. Allowed to cool to ambient temperature. Water (25 ml) added. Extracted with ethyl acetate (50 ml), washed with brine (25 ml), dried over MgSO4. Volatile material was removed by evaporation to give a solid, which was purified by flash chromatography on silica eluted with 0-5% ethyl acetate in dichloromethane to give the title compound (43 mg) as a solid, 1H NMR δ (d6-DMSO): 5.20 (s,2H), 5.33 (s, 2H), 6.96 (s, 1H), 7.40 (m, 5H), 7.57 (m,2H), 7.72 (m, 2H), 7.90 (d, 1H), 8.40 (d, 1H), 8.64 (dd, 1H), 9.22 (s, 1H), 11.50 (s,1H). LCMS rt=3.27 min (97.4%), ES+515.50 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](Br)[C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:15]([Sn](CC)(CC)CC)[CH3:16]>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([CH2:15][CH3:16])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CC[Sn](CC)(CC)CC
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Yield: 52.5 %

Procedure:
A solution of 2,4-dinitro-6-bromoaniline (1.6 g, 6.1 mmol), tetraethyltin (2.4 ml, 12.2 mmol) and Cl2Pd(PPh3)2 (100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reaction mixture was concentrated in vacuc, yielding an oil which was purified on silica gel column chromatography (CH2Cl2, neat) to provide 0.68 g (3.2 mmol, 33%) of 2,4-dinitro-6-ethylaniline, which was converted to the diamine (0.45 g, 95%) on hydrogenation (H2/Pd—C).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[O:19]>C1(C)C=CC=CC=1.O>[CH2:21]([O:20][C:18](=[O:19])[NH:10][C:8](=[NH:9])[S:7][CH3:6])[CH2:22][CH:23]=[CH2:24]
Reactant: C=CCCOC(=O)Cl
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCCOC(=O)NC(=N)SC
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
To a solution of 2-methyl-2-thiopseudourea sulfate (12 g, 278 mmol) and potassium carbonate (12 g, 138 mmol) in toluene (50 ml) and water (50 ml) at 25° C. was added but-3-en-1-yl chloroformate (3.0 g, 134 mmol) then stirred for 2.5 h. The biphasic reaction mixture was separated, and the organic phase was washed with water (2×80 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to afford but-3-en-1-yl[imino(methylthio)methyl]carbamate (4.0 g, 96%). MS (EI) for C7H12N2O2S: 287 (MH+).