Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH3:4].Br[CH2:13][C:14]1[N:15]([CH3:30])[C:16]2[C:21]([N:22]=1)=[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[N:19]=[C:18]([Cl:29])[N:17]=2>>[Cl:29][C:18]1[N:17]=[C:16]2[C:21]([N:22]=[C:14]([CH2:13][N:9]3[CH2:10][CH2:11][CH:6]([C:3]([O:2][CH3:1])([CH3:5])[CH3:4])[CH2:7][CH2:8]3)[N:15]2[CH3:30])=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: COC(C)(C)C1CCNCC1
Product: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Yield: 98.3 %

Procedure:
4-(2-methoxypropan-2-yl)piperidine (0.12 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.25 g) via General Procedure E to give 300 mg of crude 4-(2-chloro-8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine, of which 0.78 g was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine via General Procedure A to yield 12 mg of 155 as a white solid following reverse phase purification. MS (Q1) 531.3 (M)+
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10](Cl)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:27]([NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([NH2:43])=[CH:38][C:37]=1[OH:44])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:27]([NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([NH:43][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:25]=[CH:26][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:38][C:37]=1[OH:44])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reactant: Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Temperature: 5 °C

Procedure:
An amount of 843 g (2.1 mol) of 2-(p-nitrophenoxy]-myristoyl chloride is added dropwise in 60 min to a cooled (0°-5° C.) solution of 525 g (2 mol) of 2-benzamido-4-chloro-5-aminophenol in 6 l of tetrahydrofuran and 220 ml of quninoline. The temperature of the reaction mixture is kept below 10° C. The precipitate of quinoline hydrochloride is filtered off. The filtrate is concentrated by evaporation. The residual oil is poured out in 5 l of hot (50° C.) acetonitrile. Upon cooling to 5° C. a precipitate forms, whch is filtered, dried, and recrystallized from boiling isopropyl ether.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>C(O)CO.O>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[N:24]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=C1N=c2c(OC(F)(F)F)cccc2=C2OCCC12
Reactant: COc1ccccc1N
Solvent: OCCO
Solvent: O
Product: COc1ccccc1N1CCc2c1c1cccc(OC(F)(F)F)c1[nH]c2=O
Temperature: 210 °C
Yield: 76 %

Procedure:
4-Oxo-6-trifluormethoxy-2,3-dihydrofuro[3,2-c] quinoline (272 mg, 1.0 mmol) was dissolved in 10 ml of ethylene glycol in a pressure tube and 2-methoxyaniline (282 μl, 1.0 mmol) was added under nitrogen. The reaction mixture was heated at 210° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 286 mg of desired compound as solid in 76% of yield.
Reaction SMILES: COC1C=CC=CC=1C([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=O.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=O)=[N:26][CH:27]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[C@H:8]([NH:7][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:31])=[CH:27][N:26]=1)=[O:30])[CH2:9]2
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)cn1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 5-(trifluoromethyl)picolinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.06 (s, 1H), 8.30 (dd, J=8 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 6.42 (s, 1H), 4.19 (m, 1H), 3.47 (dd, J=16 Hz, 1H), 2.92-2.85 (m, 4H), 2.64 (ddd, J=16 Hz, 1H), 2.08 (m, 1H), 1.74 (m, 3H), 1.58 (m, 1H). C14H16F3N3O=299.12 LCMS (M+H): m/z 300
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:25])[CH:11]=1
Reactant: Fc1ccc(NCc2cccnc2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)N(Cc1cccnc1)c1ccc(F)cc1

Procedure:
N-[(3-pyridyl)methyl]-N-(4-fluorophenyl)-(4-chlorophenylamino)carboxamide was prepared by the method of Example 21 by reacting 5.0 g. of N-(4-fluorophenyl)-[(3-pyridyl)methyl]amine with 3.76 g. of 4-chlorophenylisocyanate in 200 ml. of ethyl acetate. Weight 1.8 g. M.P. 95°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:24][C:25]([CH:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:32]1[CH2:31][CH2:30][N:29]([CH:27]([C:25]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])[CH3:28])[CH2:34][CH2:33]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CCCCCCNC(=O)C(C)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.39 g of 3,4,5-trimethoxycinnamoyl chloride is added with stirring at room temperature to a solution of 5.00 g of 1-[1-(hexylaminocarbonyl)ethyl]piperazine in 80 ml of chloroform, and the resulting solution is stirred at room temperature for 15 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[O:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:16][CH:14]2[CH2:15][O:12][CH2:13]2)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: OC1COC1
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(OC2COC2)c(Cl)cn1
Temperature: 120 °C
Reaction time: 25 h
Yield: 110.8 %

Procedure:
To a solution of 5-chloro-4-iodo-pyridine-2-carboxylic acid (CAN 120643-06-3, 360 mg, 1.27 mmol) in DMF (10 mL) was added with stirring Oxetan-3-ol (CAN 7748-36-9, 104 mg, 1.4 mmol) and sodium hydride 60% (107 mg, 2.67 mmol). The resulting mixture was stirred at room temperature for 30 min and at 120° C. for 25 h, cooled and the reaction mixture was concentrated in vacuo. The residue was suspended with ethylacetate, transferred into a separatory funnel and extracted with 4.0 mL of 0.5M aqueous solution hydrochloric acid. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness to give the title compound (323 mg, 111%) as a solid which was used crude without any further purification. MS (ESI, m/z): 228.4 (M−H+)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[C:20]([CH3:21])=[C:19]([Cl:22])[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:22][C:19]1[C:20]([CH3:21])=[C:15]([S:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=[CH:17][N:18]=1
Reactant: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Cl)ncnc1SC1CCNCC1
Temperature: 25 °C
Yield: 114.2 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (2.3469 g, 6.82 mmol) and 40 mL of 4M HCl in dioxane was stirred at room temperature over night. Mixture was concentrated to give 4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine as a yellowish solid (1.8985 g, 99%). Exact mass calculated for C10H14ClN3S 243.06, found 244.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:8]3/[C:9](=[O:11])[NH:10][C:5]4[C:6]/3=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2nc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)nc2/C1=C\c1ccc2cn[nH]c2c1
Yield: 67.4 %

Procedure:
The title compound (40 mg, 67%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 30 min) using 5-chloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (33.7 mg, 0.2 mmol) and 1H-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 10.90 (s, 1H), 8.93 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H); MS ESI 297.0 [M+H]+, calcd for [C15H9ClN4O+H]+ 297.1.
Reaction SMILES: [NH2:1][C:2]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]2[C:19]=1[CH:20]=[CH:21][N:22]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=2[N:8]=1)[C:3]([F:6])([F:5])[F:4].[C:37](OCC)(=O)[CH:38]=[O:39].CO.[BH4-].[Na+]>ClCCCl>[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:2]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([NH:1][CH2:37][CH2:38][OH:39])[C:3]([F:6])([F:5])[F:4])=[N:8][C:9]=2[CH:15]=1)#[N:17]
Reactant: CCOC(=O)C=O
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NCCO)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F

Procedure:
A solution of (±)-tert-butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (50 mg, 0.100 mmol) and ethyl glyoxylate (50% in toluene) (39.7 μL, 0.200 mmol) in DCE (1.00 mL) was stirred at room temperature. After 50 minutes MeOH (1 mL) was added followed by NaBH4 (11.36 mg, 0.300 mmol). After 30 minutes additional NaBH4 (4 mg, 0.106 mmol) was added. After 25 more minutes additional NaBH4 (40 mg, 1.06 mmol) was added. After 15 more minutes the reaction was quenched with water, extracted twice with EtOAc, dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 544.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from N-methylpiperazine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by the procedure analogous to example 17.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:40])=[C:36]([CH:39]=1)[CH2:37]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[C:32]([F:31])[CH:33]=[CH:34][C:35]=3[CH3:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1ccc(F)cc1Cn1ccc2c(-c3ccc4c(c3)CCCO4)c(C(OC(C)(C)C)C(=O)O)c(C)nc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 5-fluoro-2-methylbenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.42 (m, 1 H), 7.26-7.21 (m, 1 H), 7.18-7.12 (m, 1 H), 6.98-6.85 (m, 3 H), 6.66 (dt, J=3.3, 9.5 Hz, 1 H), 6.25 (dd, J=3.5, 12.3 Hz, 1 H), 5.62-5.56 (m, 1 H), 5.47-5.34 (m, 2 H), 4.27 (t, J=5.0 Hz, 2 H), 2.94-2.77 (m, 2 H), 2.73-2.66 (m, 3 H), 2.31 (d, J=3.3 Hz, 3 H), 2.14-2.06 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=517.31 (M+1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:18]1[C:19]([CH3:38])=[N:20][C:21]2[C:26]([N:27]=1)=[C:25]([C:28]1[NH:36][C:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=3[CH:29]=1)[CH:24]=[CH:23][CH:22]=2>>[Cl:7][C:8]1[C:13]([C:18]2[C:19]([CH3:38])=[N:20][C:21]3[C:26]([N:27]=2)=[C:25]([C:28]2[NH:36][C:35]4[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=4[CH:29]=2)[CH:24]=[CH:23][CH:22]=3)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1cccnc1Cl
Temperature: 100 °C
Yield: 4 %

Procedure:
A mixture of Na2CO3 (102 mg, 0.959 mmol), Pd(Ph3)4 (18.47 mg, 0.016 mmol; Strem Chemicals), (2-chloropyridin-3-yl)boronic acid (75 mg, 0.480 mmol; Alfa Aesar, Ward Hil, Mass.), and 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (100 mg, 0.320 mmol, 254c) was added to a conical vessel, sealed, and evacuated and backfilled with nitrogen three times. 1,4-dioxane (2.4 mL) and water (0.8 mL) were added via syringe, and the reaction was heated to 100° C. overnight. The reaction was cooled to RT and concentrated under reduced pressure to a residue. The residue was taken up in 2 mL DMSO, filtered through a syringe filter, and purified by reverse-phase preparative HPLC using a Xbridge C18 column (150 mm×30 mm, 10 mm), 40 mL min with 0.1% TFA in CH3CN/H2O, gradient 25% to 75% over 12 min. The product fractions were concentrated in a Genevac EZ-2 evaporator. The resulting solids were taken up in MeOH and eluted through a Si-carbonate cartridge (Silicycle, pre-washed with MeOH). The eluent was concentrated under reduced pressure to give 2-(3-(2-chloro-3-pyridinyl)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (5 mg, 4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (1H, s) 8.84-8.98 (1H, m) 8.79 (1H, d, J=4.89 Hz) 8.08 (1H, dd, J=5.97, 2.64 Hz) 7.89-7.95 (2H, m) 7.82 (1H, d, J=4.89 Hz) 7.16-7.23 (1H, m) 7.01 (1H, br. s.) 3.33-3.43 (2H, m) 2.83 (2H, t, J=6.94 Hz) 2.54 (3H, s) m/z (ESI, +ve) 390.8 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.O>CN(C)C=O>[Br:21][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 0 °C
Yield: 99.5 %

Procedure:
To a stirred solution of 2,6-diisopropylaniline (14 g, 78.97 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL) at 0° C. was added a solution of NBS (14 g, 78.65 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) dropwise in 60 min. The reaction was stirred for another hour at 0° C. then water (900 mL) was added. The resulting mixture was extracted with 300 mL of ethyl acetate. The combined organic layers was washed with 3×100 mL of saturated NH4Cl solution and 1×100 mL of water then dried over anhydrous sodium sulfate and concentrated under vacuum to give 20.05 g (99%) of 4-bromo-2,6-diisopropylaniline as a red oil. 1H NMR (400 MHz, DMSO-d6): δ 6.95 (s, 2H), 4.77 (s, 2H), 5.47-5.39 (m, 1H), 3.04-2.98 (m, 1H), 1.13 (d, J=6.8 Hz, 12H) ppm.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:36])=[C:10]([CH:35]=1)[C:11]([C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([CH3:34])=[CH:15][N:14]=1)=[O:12]>C1COCC1.CC(O)=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:18]2[C:13]([C:11](=[O:12])[C:10]3[CH:35]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=[CH:8][C:9]=3[Cl:36])=[N:14][CH:15]=[C:16]([CH3:34])[CH:17]=2)(=[O:22])=[O:21])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CN=C=O
Reactant: Cc1cnc(C(=O)c2cc(N)ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Cl)c(C(=O)c2ncc(C)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
Methylisocyanate (17 μL, 0.235 mmol) was added to N-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzene sulfonamide (59 mg, 0.117 mmol) in THF (2 mL) and AcOH (0.5 mL) and stirred at room temperature for 4 h. The reaction mixture was directly purified by preparative HPLC (20-80% acetonitrile in water) to afford 4-chloro-N-{2-[2-chloro-5-(3-methyl-ureido)-benzoyl]-5-methyl-pyridin-3-yl}-3-trifluoromethyl-benzene sulfonamide (25 mg) in 38% yield. 1H NMR (400 MHz, CDCl3+CD3OD) δ 8.14 (m, 2H), 7.95 (m, 2H), 7.63 (d, 1H), 7.58 (dd, 1H), 7.41 (dd, 1H), 7.19 (d, 1H), 2.76 (s, 3H), 2.42 (s, 3H); ESMS m/z (relative intensity): 561 (M+H)+ (100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[N:10].Cl.[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)[C:16]=2[O:15][CH2:14][CH2:13]1>CC(C)=O>[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH2:23][CH2:24][N:25]([CH2:8][C:9]#[N:10])[CH2:26][CH:27]=3)[C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: C1=C(c2cccc3c2OCCO3)CCNC1
Reactant: N#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCN1CC=C(c2cccc3c2OCCO3)CC1

Procedure:
2.5 g of potassium carbonate and, dropwise, a solution of 1.08 g of bromoacetonitrile in 10 ml of acetone are added to a solution of 1.9 g of the amine hydrochloride obtained in Stage B in 40 ml of acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:5]([C:6]([OH:8])=O)[CH:4]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:5]([C:6]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:8])[CH:4]=1
Reactant: COc1cc(C(=O)O)nc2ccc([N+](=O)[O-])cc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccc([N+](=O)[O-])cc12

Procedure:
4-Methoxy-6-nitroquinaldic acid (1 g) and N,N'-carbonyldiimidazole (0.7 g) in dimethylformamide (25 ml) were heated on a steam bath for 1 hour. 5-Aminotetrazole (0.7 g) was added and the mixture was heated for 30 minutes on a steam bath. 4-Methoxy-6-nitro-N(1H-tetrazol- 5-yl) quinaldamide, m.p. 308° was filtered off.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](O)=[O:29]>>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)=[O:29]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-chloro-6-methylbenzoic acid using the general procedures described in example 7 and was obtained as a white solid: mp 238-240° C. FAB-HRMS m/e calcd for C24H24ClN3O5 (M+H) 470.1483, found 470.1489.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Reactant: O=C(O)C1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 86b) and cyclohexanecarboxylic acid as brown solid (31%). MS 414 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C1(C)C=CC=CC=1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (75 g), triethylamine (37.5 cc) and 4-(4-nitrophenyl)piperazine (55.3 cc) in toluene (600 cc). The mixture is heated for 10 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate as eluant (80-20 vol), and recrystallization from boiling methyl ethyl ketone (1100 cc), 2-{3-[4-(4-nitrophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide(41.8 g) is obtained, m.p. 186° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:22])[C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:22][CH:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1
Reactant: CSc1ccc(C(C)Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: CSc1ccc(C(C)Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(α-methyl-4-methylthiobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 146°-149° C.) and piperazine.