Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:18]([CH:21]=[O:22])=[CH:19][N:20]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN1C(=O)N(C)CCC1.O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:18]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])=[CH:19][N:20]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: [Li]c1ccccc1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCCN(C)C1=O
Product: COc1cc(Nc2ncc(C(O)c3ccccc3)s2)ccc1-n1cnc(C)c1
Temperature: 0 °C

Procedure:
To a solution of 100 mg (0.32 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde in DMPU (1 ml) and tetrahydrofurane (2 ml) was added slowly 0.67 ml (1.27 mmol) 1.9 M phenyl lithium solution in diethyl ether at −72° C. under nitrogen. The reaction was warmed to 0° C. over 40 minutes. The solvent was evaporated under reduced pressure. The residue was partitioned between in ethyl acetate and 1N aqueous NaOH solution. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed twice with water, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The residue was purified on silica gel with methylene chloride/methanol 9/1 yielding 39 mg (22%) {2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-5-yl}-phenyl-methanol as a yellow oil. MS ISP (m/e): 393.0 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.56 (s, 1H), 7.47-6.84 (m, 11H), 5.99 (s, 1H), 3.79 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][C:22]2[C:21]([O:24][CH3:25])=[C:20]3[C:11]([CH:12]=[C:13]4[C:18](=[C:19]3[OH:26])[CH:17]=[CH:16][CH:15]=[C:14]4[O:27][CH3:28])=[C:10]([O:29][CH3:30])[C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cr](O)(O)(=O)=[O:37].S(=O)(=O)(O)O.O>C(Cl)Cl.C(OC(=O)C)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:34]([O:33][C:31]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:23][C:22]2[C:21]([O:24][CH3:25])=[C:20]3[C:11]([C:12](=[O:37])[C:13]4[C:14]([O:27][CH3:28])=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]3=[O:26])=[C:10]([O:29][CH3:30])[C:9]=2[CH2:8][CH2:7]1)=[O:32])[CH3:35]
Reactant: O=[Cr](=O)(O)O
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2c(c(OC)c3c(O)c4cccc(OC)c4cc3c2OC)C1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCc2c(c(OC)c3c(c2OC)C(=O)c2c(OC)cccc2C3=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
The product of the principal reaction of example VII (compound VI) has added thereto ice (3 g) and there is added thereto a chromic acid solution of (4 ml.) from a previously prepared solution comprising chromium trioxide (24 g.), concentrated sulfuric acid 30 g, and water to 100 ml. The chromic acid solution is added dropwise with agitation while holding the mixture at 0° C. Thirty minutes after reaction is complete the reaction mixture is removed from the cooling bath and permitted to warm to ambient temperature at which it remains for 2 hours. The reaction mixture is then diluted with distilled water (20 ml.) and extracted with ethyl acetate (20 ml.). The aqueous phase is further extracted with ethyl acetate (20 ml.) and the organic phases iare combined. To the organic phase is added zinc dust (1 g) and the mixture shaken briefly, the zinc dust is removed by filtration and the organic filtrate washed successively with dilute aqueous hydrochloric acid (3 N. 20 ml.) saturated aqueous sodium bicarbonate (20 ml.) and distilled water (20 ml.) The organic extract is dried over anhydrous magnesium sulfate, filtered, and the solvent removed from the filtrate by evaporation under reduced pressure to yield an orange residue which was taken up in methylene-chloride/ethylacetate (17:3, 20 ml.) and passed through a silica gel column: (20 g). The solvent is removed from the eluate under reduced pressure and the residue recrystallized (from aqueous methanol) to give 9,9-Bis(ethoxycarbonyl)-4,6,11-trimethoxy-7,8,9,10-tetrahydronaphthacene-5,12-quinone (VII) (860 mg., 0.017 moles 62%) as yellow needle crystals m.p. 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[N:6][CH:7]=1.CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[ClH:45]>O.C1COCC1>[ClH:1].[ClH:45].[ClH:1].[C:16]([C:14]1[CH:13]=[CH:12][C:11]([NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:31])([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(NCC2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCC(CNc2ccc(C(=O)O)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 72 h
Yield: 52 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-5-methoxycarbonylbenzamide (0.50 g, 1.1 mmol) in 1:1:1 methanol:THF:water was treated with barium hydroxide octahydrate (3.6 g, 11 mmol). After 3 days, the mixture was treated with 5 N HCl and concentrated under reduced pressure until precipitation resulted. The mixture was filtered affording 250 mg (52%) of the title compound as a hydrochloride salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:5]=[C:4]2[N:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[C:20](=[O:23])[NH:21][CH2:22][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:64])[C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)=[CH:42][CH:41]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[N:19]1[C:4]2[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[CH2:12][CH2:13]3)[N:7]=[C:2]([C:50]3[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=3[CH3:54])[C:47]([NH:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[O:64])[C:3]=2[CH2:22][NH:21][C:20]1=[O:23]
Reactant: O=C1NCc2c(Cl)nc(N3CCC(N4CCCC4)CC3)nc2N1c1c(F)cccc1F
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 54.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-[4-(1-pyrrolidinyl)-1-piperidinyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were added potassium carbonate (34 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) and N-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22 mg, 0.062 mmol). The reaction mixture was bubbled with N2 for 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (14 mg, 54%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:20][CH3:21])[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:11]([NH:10][C:7]1[O:8][CH2:9][C:4]3[CH:3]=[C:2]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=4)[CH:23]=[CH:22][C:5]=3[N:6]=1)[CH2:12][CH2:13]2
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4nccc(C(F)(F)F)n4)cc3CO1)CC2
Yield: 61.9 %

Procedure:
The title compound (141 mg, 62%), yellow foam, MS (ISP): m/e=456.3 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(7-methoxy-indan-1-yl)-amine (Example 74) (187 mg, 0.5 mmol) and commercially available 2-amino-4-trifluoromethyl-pyrimidine (163 mg, 1.0 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:47]([O:49][C:50](=[O:60])[C@H:51]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[NH2:52])[CH3:48].CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:52][C@H:51]([C:50]([O:49][CH2:47][CH3:48])=[O:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:19])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A mixture of 4-[(5-nitro-1H-indol-1-yl)methyl]benzoic acid (1.78 g, 6.0 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol), 1-hydroxybenzotriazole hydrate (0.81 g, 6.0 mmol), and L-phenylalanine ethyl ester hydrochloride (1.38 g, 6.0 mmol) was stirred in CH2Cl2 (150 mL). N-methylmorpholine (3.03 g, 30 mmol) was added and the mixture was stirred at room temperature for 15 h. The mixture was then washed with 0.05 N HCl and water. The resulting solution was dried with MgSO4 and concentrated to give ethyl N-{4-[(5-nitro-1H-indol-1-yl)methyl]benzoyl}-L-phenylalaninate as an off-white solid (2.55 g, 90%): MS (ESI) m/z 472; MS (ESI) m/z 470.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH:17]=5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38]([O:40]CC)[CH3:39]>C(OC(C)=C)(=O)C>[C:38]([O:26][C:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH:12]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:17]=1)(=[O:40])[CH3:39]
Reactant: CCOCC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(c5cccnc5)=CC[C@@H]34)[C@@]2(C)CC1
Temperature: 80 °C
Yield: 44 %

Procedure:
17-(3-pyridyl)androsta-4,16-dien-3-one (174 mg, 0.50 mmol) was dissolved in isopropenyl acetate (2 ml). p-Toluenesulfonic acid (130 mg, 0.68 mmol) was then added and the mixture heated at 80° C. for 12 h. After allowing to cool the mixture was poured into diethyl ether, washed with saturated aqueous sodium bicarbonate, dried (Na2CO3) and concentrated. Chromatography on elution with light petroleum-diethyl ether (1:1), afforded the title Compound (86 mg, 44%), IR νmax 1755 cm-1, 1H-NMR (CDCl3) inter alia δ1.05 (6H,s,18-CH3 and 19-CH3), 2.15 (3H,s,COCH3) 5.44 (1H,m,6-H), 5.72(1H,m,4-H), 6.00 (1H,m,16-H), 7.25 (1H,m,Py 5-H), 7.66 (1H,m,Py 4-H), 8.47 (1H,M,Py 6-H), 8.63 (1H,m,Py 2-H). MS m/z 389 (M+).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)C1CCC1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CCC3)no2)C1

Procedure:
150 mg (0.373 mmol) of the compound from Example 44A and 85 mg (0.746 mmol) of N′-hydroxycyclobutanecarboximidamide were reacted according to the General Method 2. Yield: 58 mg (48% of theory)
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:15]([CH:19]=[O:20])=[C:14]([O:21][CH3:22])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:8])=[CH:5][N:6]=1.CN(C)C=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][O:21][C:14]1[CH:13]=[CH:12][C:11]2[CH2:10][N:9]([C:7]([C:4]3[S:3][C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:6][CH:5]=3)=[O:8])[CH2:18][CH2:17][C:16]=2[C:15]=1[CH:19]=[O:20]
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)c1cnc(Br)s1)C2
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1C=O)CCN(C(=O)c1cnc(N3CCN(C)CC3)s1)C2
Yield: 38.3 %

Procedure:
To a solution of 2-(2-Bromo-thiazole-5-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (229 mg, 0.60 mg) in abs. N,N-dimethylformamide (4 mL), N-methyl piperazine (133 μL, 120 mg, 1.20 mmol) and dry potassium carbonate (248 mg, 1.80 mmol) was added. The resultant mixture was stirred under nitrogen at 100° C. for 2 h in a closed vial. The reaction was cooled, water (10 mL) was added, and the resultant solution was extracted with ethyl acetate (3×15 mL) The combined organic layers were dried (MgSO4) and evaporated to afford title compound (92 mg, 0.23 mmol, 38%) as a pale yellow crystalline solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[C:35]([F:42])[CH:34]=1>>[C:37]([C:36]1[CH:40]=[CH:41][C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:30]=2)=[CH:34][C:35]=1[F:42])(=[O:38])[NH2:39]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: NC(=O)c1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Yield: 16.3 %

Procedure:
Following the General Procedure-3, the titled compound (25 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2-fluorobenzamide (77 mg, 0.35 mmol) as a white solid. M.P.: 202-206° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.22 (t, J 8.3, 1H), 7.89 (s, 1H), 7.59-7.49 (m, 3H), 7.37 (dd, J 1.6, 13.24, 1H), 6.71 (d, J 9.5, 1H), 5.85 (s, 1H), 4.15 (d, J 10.7, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.8, 2H), 2.20-2.12 (m, 2H), 1.99-1.85 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:19])[CH:13]=[C:14]([C:16](O)=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.O.[NH2:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:19])[CH:13]=[C:14]([C:16]([NH:39][C:40]4[NH:44][N:43]=[N:42][N:41]=4)=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: Cn1c2ccc(Cl)cc2c2oc(C(=O)O)cc(=O)c21
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: O
Solvent: c1ccccc1
Product: Cn1c2ccc(Cl)cc2c2oc(C(=O)Nc3nnn[nH]3)cc(=O)c21
Reaction time: 0.75 h

Procedure:
A mixture of 2.5 g (9.1 mmole) 8-chloro-4, 5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylic acid and 4.8 g (19.7 mmole) N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in 300 ml benzene was stirred for 45 min under nitrogen. To the reaction mixture was added 1.1 g (10.7 mmole) of 5-aminotetrazole monohydrate, and stirring was continued for a total of 88 hrs. The precipitate that had formed was filtered, stirred overnight in 50 ml of methanol, and refiltered. Two recrystallizations from DMF yielded a yellow solid of mp 300° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[NH:9][C:10]([CH3:18])=[C:11]3[C:16]=2[CH:15]=[N:14][NH:13][C:12]3=[O:17])[CH:7]=1.C(N(CC)CC)C.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>ClCCl.O1CCCC1>[CH3:18][C:10]1[NH:9][C:8]([C:6]2[CH:7]=[C:2]([NH:1][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:3]=[CH:4][C:5]=2[O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:16]2[CH:15]=[N:14][NH:13][C:12](=[O:17])[C:11]=12
Reactant: Cc1[nH]c(-c2cc(N)ccc2Oc2ccccc2)c2cn[nH]c(=O)c12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(Oc2ccccc2)c(-c2[nH]c(C)c3c(=O)[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
To a solution of Example 74f (0.05 g, 0.150 mmol) and triethylamine (0.084 mL, 0.602 mmol) in dichloromethane (1.504 mL) and tetrahydrofuran (1.504 mL) was added drop-wise ethanesulfonyl chloride (0.046 mL, 0.481 mmol). The reaction mixture was stirred for three hours at ambient temperature and concentrated. The residue was diluted with dioxane (3 mL) and 1 M sodium hydroxide (1 mL) and heated at 60° C. for 1 hour. The mixture was cooled and diluted with water and ethyl acetate adjusting the pH to 6 with 1 M HCl. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. Purification by chromatography (silica gel, 1-5% methanol in dichloromethane) afforded the title compound (0.03 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 11.41 (s, 1H), 9.83 (s, 1H), 8.04 (s, 1H), 7.43 (d, J=2.71 Hz, 1H), 7.26-7.33 (m, 2H), 7.22 (dd, J=8.82, 2.71 Hz, 1H), 7.00-7.08 (m, 2H), 6.90 (d, J=7.46 Hz, 2H), 3.15 (q, J=7.23 Hz, 2H), 2.59 (s, 3H), 1.24 (t, J=7.46 Hz, 3H). MS (ESI+) m/z 425 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-:17].[K+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:17])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1Br
Reactant: [OH-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 2.37 g (8.49 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-bromo-4,6-dimethylpyridine (14) in 30 mL of dioxane-degassed water 1:1 were added 311 mg (0.34 mmol) of Pd2dba3 followed by 288 mg (0.68 mmol) of 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbyphenyl (L1) and 1.42 g (25.46 mmol) of potassium hydroxide. The reaction mixture was stirred at 100° C. under argon atmosphere during 3 h. The reaction mixture was poured into 150 mL of water and extracted with two portions of 150 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and the concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 3:1 gave the expected product as a white solid: yield 1.19 g (65%). 1H-NMR (CDCl3) δ 6.89 (s, 1H), 5.75 (s, 2H), 2.45 (s, 3H), 2.22 (s, 3H), 2.05 (s, 6H); 13C-NMR (CDCl3) δ 148.80, 145.03, 143.12, 135.51, 128.43, 122.32, 106.01, 18.48, 15.95, 12.80.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2]([CH3:1])=[N:3][C:4]=3[CH:10]=2)=[O:13])=[CH:17][CH:16]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: NCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A suspension of 2-methyl-1H-benzo[d]imidazole-5carboxylic acid (0.750 g, 4.26 mmol), 2-(4-chlorophenyl)ethanamine (0.596 g, 3.83 mmol), HBTU (1.78 g, 4.68 mmol) and DIEA (1.11 mL, 6.39 mmol) in 10 mL of DCM was stirred at ambient temperature overnight. To the reaction was added DMF (10 mL) which caused a clear solution to form. The reaction was loaded onto a silica gel samplet and the product eluted using a gradient of 0.5% MeOH/DCM to 10% MeOH/DCM. Isolated N-(4-chlorophenethyl)-2-methyl-1H-benzo[d]imidazole-5carboxamide (0.65 g, 48.7% yield) as a yellow oil. MS(ESI)=314.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH2:23])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH:23][C:35]([NH:34][C:32]4[N:31]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=4)=[O:36])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4nc(N)c(=O)[nH]c34)c3ccccc23)n(-c2ccccc2)n1
Yield: 44 %

Procedure:
Method F2 was used with 3-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a yellow/orange solid (46 mg, 44%). 1H-NMR (DMSO-d6), δ (ppm), J (Hz): 1.30 (s, 9H, tert-Bu), 6.28 (d, 1H, Harom, J=5.5 Hz), 6.42 (s, 1H, Harom), 7.31 (d, 1H, Harom, J=8.3 Hz), 7.44 (t, 1H, J=7.1 Hz), 7.55-7.66 (m, 6H, Harom), 7.89-7.96 (m, 2H, Harom), 7.99 (d, 1H, Harom, J=5.5 Hz), 8.08 (d, 1H, Harom, J=8.6 Hz), 8.82 (s, 1H, NHurea), 9.11 (s, 1H, NHurea), 12.38 (s, 1H, NHlactame). 13C-NMR (DMSO-d6), δ (ppm), J (Hz): 30.08 (tert-Bu), 31.93 (tert-Bu), 95.78, 104.61, 113.91, 116.44, 118.37, 121.92, 122.14, 124.09 (2*C), 126.45, 126.47, 126.54, 127.09, 127.73, 129.15 (2*C), 131.63, 137.13, 138.59, 144.28, 145.43, 146.74, 151.01, 151.12, 152.33, 154.75, 160.69. HRMS (EI): m/z [M+H] calcd for C31H28N8O3: 561.2357. found: 561.2350.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[CH:7][C:6]=2[CH:12]=1.[BH4-].[Na+].P(Br)(Br)[Br:16]>CCO>[Br:16][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][C:6]=2[CH:7]=1
Reactant: BrP(Br)Br
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Compound 34 (160 mg, 0.89 mmol) was dissolved in EtOH (5 mL). NaBH4 (36 mg, 0.98 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvent was evaporated off in-vacuo. The resulting crude alcohol residue was dissolved in toluene (5 mL) and the solution was cooled to 0° C. PBr3 (92 μL, 0.98 mmol) was added dropwise over 10 min. The mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 35 (128 mg, 57%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.48 (1H, d, J=2.05 Hz, ArH), 7.37 (1H, d, J=8.70, ArH), 7.25 (1H, dd, J=8.80 & 2.05 Hz ArH), 6.68 (1H, s, ArH), 4.55 (2H, s, 2-CH2).