Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.[I:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH2:27])[NH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([CH:6]3[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]3)[N:19]=[C:18]([I:17])[C:26]=12
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1

Procedure:
A suspension of tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (1.32 g) obtained in Step 1 above, 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.37 g), and cesium carbonate (3.47 g) in DMF (10 ml) was stirred at 90° C. for 10 hours. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow amorphous substance (482 mg). Physical properties: m/z [M+H]+ 417.0
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:2]=2[CH3:1])=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cc2C)c(O)n1
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 2-methyl-4-phenoxybenzoic acid (100 mg, 0.44 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol), and triethylamine (77 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 4 hours. The mixture was washed with water (50 mL) and the organic phase was separated, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-phenoxybenzamide (40 mg, 25%) as a white solid. LRMS (M+H+) m/z: calcd 362.16. found 362. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 7.40-7.31 (m, 3H), 7.18-7.13 (m, 1H), 7.02-6.99 (m, 2H), 6.83-6.76 (m, 2H), 6.12 (s, 2H), 4.47 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])#[N:3].C(N(C(C)C)C(C)C)C.[C:25](ON=C(C1C=CC=CC=1)C#N)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>O.O1CCOCC1>[C:25]([NH:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]1[CH:13]=[CH:14][CH:15]=[C:4]([C:2]#[N:3])[CH:5]=1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N#Cc1cccc(C[C@H](N)C(=O)O)c1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)O
Reaction time: 16 h

Procedure:
6 g (26.5 mmol) of 3-cyano-(L)-phenylalanine hydrochloride and 9.1 ml (53.2 mmol) of N-ethyldiisopropylamine was suspended in 17 ml of water. To this suspension was added a solution of 7.2 g (29.2 mmol) of 2-(Boc-oxyimino)-2-phenylacetonitrile in 20 ml of dioxane and stirring continued for 16 hours at room temperature. After subsequent addition of 50 ml of water, the solution was extracted with 50 ml of ethyl acetate, the organic phase separated and the pH of the aqueous phase adjusted to 3 with dilute hydrochloric acid. After 3 extractions with 100 ml each of ethyl acetate, the collected organic solutions were washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.CO.[BH4-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCC(O)c1ccc(-c2ccccc2F)cc1

Procedure:
To a solution of 15 gm (0.05 mol) of ethyl 4-(2'-fluoro-4-biphenylyl)-4-oxo-butyrate in 100 ml of methanol 1.9 gm (0.05 mol) of sodium borohydride were added at a temperature between 0° and 5° C., while stirring. The precipitate was vacuum-filtered off and dissolved in ether. The ethereal solution was washed with an aqueous sodium bicarbonate solution and then with water, dried and evaporated. The residual oil was recrystallized from cyclohexane. Yield: 12 gm (79.5% of theory), m.p. 61°-62° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:36]1[C:45]2[C:44](=[O:46])[NH:43][CH:42]=[CH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:43]4[C:44](=[O:46])[C:45]5[N:36]=[CH:37][CH:38]=[CH:39][C:40]=5[CH:41]=[CH:42]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: O=c1[nH]ccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ccc5cccnc5c4=O)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A suspension of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (27.0 mg, 0.051 mmol), 1,7-naphthyridin-8(7H)-one (22.4 mg, 0.153 mmol) and Cs2CO3 (66.5 mg, 0.204 mmol) in anhydrous DMF (1.0 mL) was heated in a microwave at 150° C. for 50 min. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 90% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H32ClN4O4S: 639.2; found: 639.3.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:5]=1[NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]=1[C:19]([F:22])([F:21])[F:20].Cl[S:32][N:33]([CH3:44])[S:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>C1COCC1>[Cl:3][C:4]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:5]=1[N:6]([C:7]1[C:8]([C:19]([F:22])([F:21])[F:20])=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[S:32][N:33]([CH3:44])[S:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)N(C)SCl)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)SN(c2cc(C(F)(F)F)ccc2Cl)c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a suspension of 0.25 g sodium hydride in 20 ml anhydrous THF was added 3.2 g of 2-[2'-chloro-5'-(trifluoromethyl)anilino]-3,5-dinitrobenzotrifluoride, in portions, at 10° to 20° C. After stirring for 30 minutes, a solution of 2 g of N-chlorothio-N-methyl-p-toluenesulfonamide in 20 ml dry THF was added rapidly at a temperature below -20° C. The mixture was stirred in an ice bath for 30 minutes, then quenched by careful addition of ether and water. The organic phase was washed once with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The resultant oil was crystallized from a mixture of hexane and chlorobutane to give 3.2 g of N-[N-[2-chloro-5-(trifluoromethyl)-phenyl]-N-[2,4-dinitro-6-(trifluoromethyl)phenyl]-aminothio]-N,4-dimethylbenzenesulfonamide, mp 142.5°-144° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(C(N)CC)C.[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5N(CC)[C:44]6[CH:48]=C[C:50](C(O)=O)=[CH:51][C:43]=6[N:42]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5[N:42]([CH:43]([CH2:51][CH3:50])[CH2:44][CH3:48])[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CCC(N)CC
Product: CCC(CC)n1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21

Procedure:
The title compound was prepared from Resin 534a and 1-ethylpropylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:28][CH2:29][CH2:30][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[CH3:31][NH:32][CH3:33]>O>[CH3:31][N:32]([CH3:33])[CH:16]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH2:15][N:11]1[C:10]2[CH2:9][CH2:8][N:7]3[CH2:28][CH2:29][CH2:30][CH:6]3[C:5]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]1=2
Reactant: CNC
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2cnccn2)CCN2CCCC12
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(c2cnccn2)N(C)C)CCN2CCCC12
Temperature: 25 °C

Procedure:
Methanesulfonic acid 2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl ester (300 mg, 0.70 mmol) in 40% dimethylamine in water (20 mL) was heated at 90° C. for 1 h. The reaction mixture was cooled to RT and extracted with DCM (12×50 mL) The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of dimethyl-[2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl]-amine. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.1 (s, 1H), 7.4 (s, 1H), 7.1 (d, 1H), 5.1 (t, 1H), 4.42 (m, 2H), 3.6 (m, 3H), 3.2 (m, 1H), 3.17 (m, 1H), 3.15 (s, 6H), 2.85 (m, 2H), 2.63 (m, 1H), 2.42 (s, 3H), 2.3 (m, 2H), 2.15 (m, 1H). Chiral HPLC separates the racemate into diastereomers II-7a-d.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:23](=[O:40])[CH2:24][CH2:25][C:26]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)=[O:27])[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].CS(C1C=C([C@@H](O)CCC(C2C=C(OC)C(OC)=C(OC)C=2)O)C=C(OCC2C=CC=CC=2)C=1OCCC)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:23]([OH:40])[CH2:24][CH2:25][CH:26]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[OH:27])[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:3])=[O:4]
Reactant: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O
Agent: CCCOc1c(OCc2ccccc2)cc([C@@H](O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O
Product: CCCOc1c(OCc2ccccc2)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O

Procedure:
This compound was prepared from 1-(3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl)-4-(3,4,5-trimethoxyphenyl) butan-1,4-dione (STEP D) as shown for (-)-(1S)-1-(3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl)-4-(3,4,5-trimethoxyphenyl butan-1-ol-4-one (STEP F) and used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][N:5]2[C:4]=1[CH3:15])[CH3:2]>[OH-].[Na+]>[CH2:1]([C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][N:5]2[C:4]=1[CH3:15])[CH3:2]
Reactant: CCc1sc2nc(C(=O)OC)cn2c1C
Agent: [Na+]
Agent: [OH-]
Product: CCc1sc2nc(C(=O)O)cn2c1C
Yield: 85.3 %

Procedure:
1.5 g of 2-ethyl-3-methyl-6-carbomethoxy-imidazo-(2,1-b)thiazole (obtained as described in Example 45) are refluxed for 2 hours in 5 ml of 10% NaOH. The solution obtained is treated in the same manner as described in Example 49 to yield 1.2 g of 2-ethyl-3-methyl-imidazo-(2,1-b)thiazole-6-carboxylic acid m.p. 243°-245° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:16]([O:18]C)=O)[C:7]2[CH:8]=[N:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[CH:12]=1.[NH2:20][CH2:21][C:22]1[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:16]([NH:20][CH2:21][C:22]2[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=2[CH3:28])=[O:18])[C:7]2[CH:8]=[N:9][N:10]([CH:13]([CH3:14])[CH3:15])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
Aqueous NaOH (1.5 equiv in 1 mL water) was added to a solution of methyl 6-bromo-1-isopropyl-1H-indazole-4-carboxylate (1.5 g, 4.8 mmol) in EtOH (20 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and acidified using 1N HCl solution. Extraction was carried out using ethyl acetate and the combined organic layers washed with water, brine and dried over anhydrous Na2SO4 before filtration and concentrated under reduced pressure. The crude acid (1.26 g, 4.45 mmol) was then dissolved in DMSO (5 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (1.35 g, 8.90 mmol) was added. The reaction mixture was stirred at room temperature for 15 min before PYBOP (3.47 g, 6.67 mmol) was added to it and stirring continued overnight. After completion of the reaction, the mixture was poured into ice and the resulting precipitate filtered and washed with acetonitrile followed by ether to provide 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (0.8 g, 43.2%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([CH2:28][CH2:29][NH:30][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCCN1CCOCC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc2c1=O
Yield: 54 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (29 mg, 0.0912 mmol) is reacted with 2-morpholin-4-yl-ethylamine according to the GPA affording 21 mg (54%) of a red powder. Rt=2.33 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-:11].[K+]>C(O)C>[NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:11]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(C(N)=O)c(N)c1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
2-amino-4-methylbenzonitrile (10 g, 75.7 mmol) was dissolved in ethanol, added with potassium hydroxide (21.2 g, 378 mmol), followed by refluxing for 8 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate. The organic layer formed was washed with a saturated aqueous solution of sodium bicarbonate and brine. The obtained organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain the title compound (4.9 g, 43%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH2:17])[CH:9]=[CH:8]1.C(N(CC)CC)C>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH:17][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[CH:9]=[CH:8]1
Reactant: NCc1cccc2cc[nH]c12
Reactant: CC(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Br)C(=O)NCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Add 2-bromopropionyl chloride to a solution of (indol-7-yl)methylamine and triethylamine (0.49 g, 47.6 mmol) in tetrahydrofuran (20 ml) at 0° C. Stir for 1 hour at room temperature and quench with saturated aqueous sodium bicarbonate. Extract with ethyl acetate, concentrate under reduced pressure and subject the residue to silica gel chromatography to provide the desired compound (0.62 g, 46%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl.Cl.NC1C2C(=CC=CC=2O)C(S(O)(=O)=O)=CC=1N.S(=O)(O)[O-].[Na+]>CCO.O>[OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccccc1-c1ccc(C=O)c(O)c1
Agent: Cl
Agent: Nc1cc(S(=O)(=O)O)c2cccc(O)c2c1N
Agent: O=S([O-])O
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)cc1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 104.5 %

Procedure:
To an agitated solution of 2-hydroxy-4-(2′-methylphenyl)benzaldehyde (0.030 g, 0.14 mmol) in EtOH (0.80 mL) was added 1,2-diamino-8-hydroxy-naphthalene-4-sulfonic acid dihydrochloride (0.033 g, 0.10 mmol) and sodium bisulfite (0.03 g) in water (0.20 mL). The solution was heated to 60° C. and agitated over 18 hours. The solution was cooled to room temperature, the tan precipitate was isolated by filtration and washed with water and ethyl acetate to provide the title compound (0.029 g, 60%) MS(ES) m/z 445 [M−H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CC2)cc1
Yield: 57.9 %

Procedure:
4-hydroxy-benzoic acid methyl ester (2.0 g, 13.1 mmol, 1.2 eq) was dissolved in acetone (20 mL), NaI (0.97 g, 6.5 mmol, 0.5 eq) and K2CO3 (3.0 g, 21.8 mmol, 2.0 eq) were added and the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (1.1 mL, 10.3 mmol, 1.0 eq) was added, and the reaction was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and the product was extracted with DCM. The organic phase was dried over Na2SO4 and the solvent evaporated under reduced pressure. The title product (1.23 g, yield 79%) was recovered and used without further purification.
Reaction SMILES: Br.[CH2:2]([N:4]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[N:7]([CH3:16])[C:6]2[CH:17]=[CH:18][C:19]([O:21]C)=[N:20][C:5]1=2)[CH3:3]>C(O)(=O)C>[CH2:2]([N:4]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[N:7]([CH3:16])[C:6]2[CH:17]=[CH:18][C:19]([OH:21])=[N:20][C:5]1=2)[CH3:3]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OC)nc21
Agent: Br
Solvent: CC(=O)O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(O)nc21
Yield: 28.1 %

Procedure:
Hydrobromic acid (48%, 2 ml) was added to a solution of 5,11-dihydro-11-ethyl-2-methoxy-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.3 g) in acetic acid (2 ml), and the resulting mixture was rapidly heated to reflux for 5 min. The reaction mixture was quenched with 10% sodium hydroxide (10 ml) and the product was extracted with ethyl acetate, dried (anhydrous magnesium sulfate) and concentrated to give a solid which was recrystallized from ethyl acetate to give 0.08 g of product, m.p. 215°-218° C.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)[N:16]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2ccc(C(F)(F)F)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: OC1CCC(n2ccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
The intermediate (0.56 g, 1.6 mmol) from step C was dissolved in CH2Cl2 (10 mL) and to it was added a 1 M solution of TBAF in CH2Cl2 (5 mL). After being stirred at room temperature for 2 hours, the solution was diluted with CH2Cl2. The resulting solution was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 2:1 EtOAc/hexanes provided the title compound (0.27 g, 71%) as an oil. MS calculated (M+H)+ 235, found 235.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([N:19]=1)=[N:8][C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:10]([OH:12])[N:11]=2)[NH2:2].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(Cl)CCl.O>CN1C(=O)CCC1>[OH:12][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([NH:1][NH:2][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)=[N:19][C:7]2=[N:8][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccnc1
Reactant: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Solvent: ClCCCl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NNc1ccc2nc(O)c(-c3ccccc3)nc2n1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-hydrazino-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-3) (3.7 g, 14.5 mmol) and nicotinic acid (2.1 g, 17.4 mmol) in NMP (50 mL) was added EDC (3.1 g, 16.0 mmol), and stirred at room temperature for overnight. To the mixture was added water, and the resulting solid was collected by filtration to yield N-(2-hydroxy-3-phenylpyrido[2,3-b]pyrazin-6-yl)nicotinohydrazide (3-4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[CH:34]=[CH2:35].C1(C=CC(O)=CC=1)O>C(O)(C)C>[Cl:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[CH2:34][CH2:35][NH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CN)cc2)CC1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: Oc1ccc(O)cc1
Solvent: CC(C)O
Product: COc1cc(CCNCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A stirred solution of 4-(4-aminomethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.531 g, 1.82 mmol), 1-chloro-4-methoxy-5-nitro-2-vinylbenzene (Example 50C) (0.3 g, 1.40 mmol) and quinol (61.8 mg, 0.562 mmol) in isopropyl alcohol (16 mL) was heated to 100° C. for 30 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 2% methanol in DCM to give the title compound (0.460 g, 65%)