Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[O:27][CH3:28].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([O:27][CH3:28])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(OC)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(-c2ccc(C(=O)O)c(OC)c2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 7.5 g (19.3 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-methoxy-benzoic acid methyl ester using 4.05 g (96.5 mmoL) LiOH in 100 mL water and 200 mL THF. The reaction mixture is stirred over night at room temperature. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and Acetonitrile. After drying 6.5 g (89%) of the desired product is obtained as solid material.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.O>CN(C)C=O>[N:13]1([C:4]2[N:3]=[C:2]([O:1][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (7.1 g, 27.6 mmol) in N,N-dimethylformamide (100 ml) were added potassium carbonate (7.8 g, 60 mmol) and 4-fluorobenzylbromide (3.74 ml, 30 mmol) and the mixture was stirred at 80° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added. The precipitated crystals were collected by filtration, washed several times with cold water and cold ether and dried to give the title compound (8.6 g, 79%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(Cl)(=O)[C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1.N1C=CC=CC=1.[O:27]1CCCC1>C(OCC)(=O)C>[C:3]([O:4][CH:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)(=[O:27])[C:2]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1CCC(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-ol (4.44 g), benzoyl chloride (3.9 mL), pyridine (2.7 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (50 mL), and 6 M hydrochloric acid (4.7 mL) was added thereto, and then the mixture was stirred at 60° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow oil (2.64 g, 43%).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](Cl)=[O:23])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>O1CCCC1>[OH:3][NH:2][C:22](=[O:23])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:15][CH:16]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) in tetrahydrofuran (5 ml) saturated NaHCO3 solution (3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (83a) (0.27 g, 0.68 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from acetonitrile and washed with diethyl ether affording the title compound as a white solid (0.1 g, 37%). M.p. 190–191.5° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.29 (1H, d, J=16.0 Hz); 7.16 (2H, d, J=8.0 Hz); 7.24–7.78 (8H, m); 7.86 (4H, m); 8.94 (1H, br s); 10.57 (1H, s); 10.66 (1H, br s). HPLC analysis on Zorbax SB—C18 column: impurities 4% (column size 4.6×150 mm; mobile phase acetonitrile—0.1% H3PO4, gradient from 30 to 100%; sample concentration 0.2 mg/ml; flow rate 1.0 ml/min; detector UV 254 nm). Anal. Calcd for C21H18N2O4S, %: C, 63.94; H, 4.60; N, 7.10. Found, %: C C, 63.64; H, 4.45; N, 7.00.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11](C#N)=[CH:10][CH:9]=1.[CH3:20][O:21]C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:20][O:21][C:11]1[CH:14]=[CH:15][C:8]([C:7]2[C:6](=[O:16])[N:5]3[CH:17]=[CH:18][S:19][C:4]3=[N:3][C:2]=2[CH3:1])=[CH:9][CH:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Yield: 78.9 %

Procedure:
The title compound was prepared by coupling reaction of Step 2 intermediate from Intermediate 4 (6.8 g, 23.271 mmol) with 4-methoxyphenylboronic acid (4.95 g, 32.490 mmol) in the presence of Pd[(C6H5)3P]4 (1.076 g, 0.931 mmol) and sodium carbonate (14.812 g, 139.071 mmol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 yielded 5.0 g of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.83 (s, 3H), 6.92-6.96 (m, 3H), 7.20-7.23 (m, 2H), 7.94 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 273.51 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.COC1C=C[C:15]([S:18]([C@@H:21]([C@@H:32]2[CH2:35][O:34][C:33]2=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(O)(=O)C.[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1>>[CH3:43][O:44][C:45]1[CH:41]=[CH:42][C:15]([S:18]([C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:32]([CH2:35][S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:33]([OH:36])=[O:34])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@@H]2COC2=O)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)[C@@H](CCCCc2ccccc2)[C@@H](CSc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82 %

Procedure:
A 60% suspension of NaH in mineral oil (84 mg, 2.2 mmol) is carefully added to a solution of thiophenol (0.30 g, 2.7 mmol) in THF (10 mL) at 0° C. The mixture is allowed to warm to ambient temperature and is transferred to a solution of (±)-3-(R*)-[1-(R*)-(4-methoxybenzenesulfonyl)-5-phenylpentyl]-oxetan-2-one (0.63 g, 1.6 mmol) in THF (10 mL). The reaction is stirred 14 hours and then acidified with acetic acid. The crude mixture is azeotroped with methanol (2×50 mL) and purified by column chromatography using gradient elution (silica, 1 to 3% MeOH in CH2Cl2) to yield pure (±)-(2R*,3S*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid (0.64 g, 82%): m.p. 133-135; 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.6 Hz, 2H), 7.30-7.17 (m, 8H), 7.06 (d, J=7.3 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H), 3.84 (s, 3H), 3.63 (bs, 1H), 3.52 (dd, J=14.2, 7.7 Hz, 1H), 3.14 (dd, J=14.2, 5.2 Hz, 1H), 2.98 (bs, 1H), 2.43 (t, J=7.4 Hz, 2H), 1.95-1.83 (m, 1H), 1.78-1.62 (m, 1H), 1.50-1.34 (m, 2H), 1.28-1.07 (m, 2H); MS (FAB) m/e 489 (M+); Anal. (C27H30O5S2) C, H, N.
Reaction SMILES: C(OCC)(=O)C.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]=[N+]=[N-])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[O:52]=[C:53]1[CH2:57][CH2:56][CH2:55][N:54]1[CH2:58][CH2:59][CH2:60][NH:61][C:62]([C@@H:64]1[CH2:68][CH2:67][CH2:66]N1)=[O:63]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]1[CH2:66][CH2:67][CH2:68][C@H:64]1[C:62]([NH:61][CH2:60][CH2:59][CH2:58][N:54]1[CH2:55][CH2:56][CH2:57][C:53]1=[O:52])=[O:63])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: O=C(NCCCN1CCCC1=O)[C@@H]1CCCN1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCCN1CCCC1=O)OCc1ccccc1

Procedure:
To 30 ml of a ethyl acetate solution of compound (4) prepared from 2.12 g of compound (3) by a known method was added 5 ml of a DMF solution of 1.17 g of compound (100) under ice-cooling and the reaction was maintained overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (90:10:1), 2.00 g of Nα -benzyloxycarbonyl-L-histidyl-N-[3-(2-oxo-1-pyrrolidinyl)-propyl]-L-prolinamide (101) was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:11])=[S:10])=[CH:5][CH:4]=1.Br[CH2:15][CH:16]=O.Cl>C(O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:15]=[CH:16][N:11]=2)=[CH:5][CH:4]=1
Reactant: O=CCBr
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2nccs2)cc1
Yield: 49.3 %

Procedure:
In a manner similar to Step B of Example 1, the reaction of 10.0 grams (0.0487 mole) of (4-trifluoromethylphenyl)thiocarboxamide, 125 ml of ethanol, 8.35 grams (0.0490 mole) of bromoacetaldehyde, and 2 ml of concentrated hydrochloric acid produced 5.5 grams of 2-(4-trifluoromethylphenyl)thiazole as a solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7]1([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]4)[CH:17]=3)[CH:12]=2)[CH2:10][O:9][CH2:8]1.[OH-].[Li+].O1CCCC1.O>>[C:28]([C@H:25]1[CH2:24][CH2:23][C@H:22]([O:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([C:7]2([NH:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH2:8][O:9][CH2:10]2)[CH:20]=[CH:19]3)[CH2:27][CH2:26]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)CCNC1(c2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)COC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C4(NCCC(=O)O)COC4)ccc3c2)CC1

Procedure:
A solution of 3-{3-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-oxetan-3-ylamino}-propionic acid methyl ester (18.0 mg, 0.0409 mmol) and Lithium hydroxide (6.41 mg, 0.268 mmol) in Tetrahydrofuran (0.6 mL, 8 mmol) and Water (0.2 mL, 9 mmol) was stirred at r.t. overnight. LCMS showed a single desired product peak M+Na at m/z 448.20, RT 1.56 min. The solvent was concentrated and neutralized with citric acid and concentrated and purified on HPLC to give product (5.8 mg, 33%). 1H NMR (400 MHz, MeOD) d=7.91 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.31 (s, 1H), 7.20 (d, J=6.8 Hz, 1H), 5.26 (d, J=7.9 Hz, 2H), 5.13 (d, J=7.7 Hz, 2H), 4.43-4.32 (m, 1H), 3.05 (t, J=5.1 Hz, 2H), 2.70-2.62 (m, 2H), 2.27 (d, J=11.2 Hz, 2H), 1.96-1.85 (m, 2H), 1.50-1.35 (m, 2H), 1.34-1.18 (m, 2H), 1.17-1.04 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:26]CC)[CH2:5][N:6]([CH2:23][CH2:24][CH3:25])[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21])[CH3:2].[CH2:29](O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:44]([O:47][CH2:48][CH3:49])(=[O:46])C>C(O)C>[CH2:23]([N:6]([CH:44]1[O:47][CH2:48][CH2:49][O:46]1)[C:7]1[C:8]([N+:20]([O-:22])=[O:21])=[CH:9][C:10]([C:16]([F:17])([F:18])[F:19])=[C:11]([CH3:29])[C:12]=1[N+:13]([O-:15])=[O:14])[CH2:24][CH3:25].[CH2:23]([N:6]([CH2:5][CH:4]1[O:3][CH2:1][CH2:2][O:26]1)[C:7]1[C:8]([N+:20]([O-:22])=[O:21])=[CH:9][C:10]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:24][CH3:25]
Reactant: CCOC(C)=O
Reactant: CCCN(CC(OCC)OCC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Product: CCCN(c1c([N+](=O)[O-])cc(C(F)(F)F)c(C)c1[N+](=O)[O-])C1OCCO1
Temperature: 120 °C

Procedure:
N-(2,2-Diethoxyethyl)-N-propyl-2,6-dinitro-4-trifluoromethylaniline (5.5 grams; 0.0132 mol), ethylene glycol (0.84 grams; 0.0132 mole), p-toluenesulfonic acid (200 mg) and ethanol solvent were placed in a glass reaction flask equipped with stirrer, heating mantle and thermometer. The mixture was heated to 120° C. After the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate was added and the mixture was washed with water and sodium bicarbonate solution. The solution was then dried over anhydrous magnesium sulfate and evaporated to yield the desired product N-propyl-N-1,3-dioxolan-2-ylmethyl-2,6-dinitro-4-trifluoromethylaniline as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+:19]([O-:21])=O)[CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22]NO.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:22][N:19]([OH:21])[C:12]1[CH:11]=[C:10]([O:9][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)[CH:15]=[CH:14][C:13]=1[N+:16]([O-:18])=[O:17]
Reactant: CNO
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(Cl)cc2Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(O)c1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(3,5-dichloro-2-pyridyloxy)-1,2-dinitrobenzene (800 mg, 2.42 mmol), N-methylhydroxyamine (472 mg, 4.84 mmol), K2CO3 (400 mg, 2.90 mmol) and THF (10 ml) is stirred at RT for 48 hours. The reaction mixture is filtered, and the filtrate is concentrated and then taken up in methylene chloride, washed, dried and evaporated to give N-methyl-N-[2-nitro-5-(3,5-dichloro-2-pyridyloxy)phenyl]-hydroxyamine, a crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:22][S:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)(=[O:25])=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]([C:19](=[O:21])[NH:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:29]4[CH2:28][CH2:27][N:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:31][CH2:30]4)=[CH:34][CH:35]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1ccc(-c2cc(C(=O)O)ccc2Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 6-chloro-biphenyl-3,4′-dicarboxylic acid 4′-ethyl ester (152 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (175 mg), EDAC (125 mg), HOBT (88 mg) and N-methylmorpholine (143 μl) in DMF (3 ml) was stirred at room temperature. After 1 h, water (30 ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Gradient elution with 30-100% ethyl acetate in petrol gave a beige solid (240 mg).
Reaction SMILES: CNC([C:5]1[NH:6][C:7]2[C:12]([N:13]=1)=[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:10]=[C:9]([Cl:20])[N:8]=2)=O.[C:21](=O)([O-])[O-].[Cs+].[Cs+].[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>O>[Cl:20][C:9]1[N:10]=[C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:12]2[N:13]=[C:5]3[N:6]([C:7]=2[N:8]=1)[CH2:21][CH2:27][N:28]([CH3:29])[C:30]3=[O:31]
Reactant: CNC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [Cs+]
Solvent: O
Product: CN1CCn2c(nc3c(N4CCOCC4)nc(Cl)nc32)C1=O
Temperature: 100 °C
Yield: 77 %

Procedure:
A mixture of 2-chloro-6-morpholin-4-yl-9H-purine-8-carboxylic acid methylamide (56 mg, 0.19 mmol) 1,2-dibromoethane (0.058 mL, 0.68 mmol) and cesium carbonate (0.25 g, 0.76 mmol) in DMF (2 mL) was heated at 100° C. for 2 h, then cooled, diluted with water and extracted five times with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated twice with diethyl ether and the solid was dried under vacuum to give 3-Chloro-7-methyl-1-morpholin-4-yl-6,7-dihydro-5H-2,4,4b,7,9-pentaaza-fluoren-8-one (47 mg, 77%). LCMS RT=2.36, [M+H]+=323/32
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.200 ml 2-(4-chloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 437 mg light yellow oil (96%). MS (ISP) 302.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[NH2:35])=[O:15])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A benzene (20 ml) solution containing 1.40 (5.1 mmol) of 3-(4-nitrobenzyloxy)benzoic acid and 2 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (20 ml), this solution was added dropwise under ice-cooling to a pyridine (30 ml) solution containing 0.97 g (5.6 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 1.9 g (yield: 87.0%) of the title compound.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[C:31](Cl)(=[O:35])[C:32](Cl)=[O:33].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][OH:41]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][O:41][C:31](=[O:35])[C:32]([N:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2Nc2ccccc2)CC1
Reactant: CN(C)CCO
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)CCOC(=O)C(=O)N(c1ccccc1)c1ccccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound prepared in Example 303 (100 mg) in toluene (20 mL) was treated with oxalyl chloride (0.09 mL) for 2 hours at room temperature. 2-(dimethylamino)ethanol (873 mg) was added and the reaction was stirred for 1 hour at room temperature. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title material (120 mg), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14]2[N:22](S(C3C=CC=CC=3)(=O)=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)C.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
A solution of 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.87 g, 4.3 mmol) in ethanol (38.7 mL) and tetrahydrofuran (77.4 mL) was treated with an aqueous sodium hydroxide solution (10%, 14.6 mL). The reaction was stirred at 70° C. for 18 h. After cooling to 25° C., the reaction mixture was diluted with water (70 mL) and extracted with ethyl acetate (3×60 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 10:1) afforded 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.05 g, 90%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 9.91 (s, 1H), 7.95 (dd, 1H, J1=3.6 Hz, J2=1.2 Hz), 7.89 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.23 (t, 1H, J=7.8 Hz), 7.02 (s, 1H), 6.92-6.82 (m, 3H), 6.50 (s, 1H), 5.99 (d, 1H, J=9.9 Hz), 3.76 (s, 3H), 2.94-2.91 (m, 1H), 1.11 (s, 3H), 1.09 (s, 3H).