Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:9]C1C2C(=NC=C(C(F)(F)F)C=2N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)NC=1)=[O:8].C(O)(C(F)(F)F)=O.C(Cl)[Cl:45]>>[ClH:45].[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[O:8]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(C(F)(F)F)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
(R)-tert-Butyl 1-(3-(pyrazine-2-carboxamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 0.237 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness to give the crude product, which was purified C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-50% CH3CN/water gradient; 25 CV). The purified product was then dissolved in DCM (with minimal MeOH to aid solubility) and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, dried and collected to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2, 3-1)]pyridin-3-yl)pyrazine-2-carboxamide hydrochloride (0.071 g, 62% yield). 1H NMR (400 MHz, D2O) δ 8.84 (s, 1H), 8.59-8.59 (m, 1H), 8.52-8.52 (m, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 3.62-3.54 (m, 1H), 3.37-3.33 (m, 1H), 3.00-2.92 (m, 3H), 2.04-2.01 (m, 1H), 1.85-1.72 (m, 1H), 1.71-1.66 (m, 1H), 1.50-1.40 (m, 1H); LCMS (APCI+) m/z 406 (M+H)+.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)[C:8]2[N:13]=[N:12][N:11]([CH2:14]C)[C:9]=2[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:8][C:9]3[N:11]([CH3:14])[N:12]=[N:13][N:10]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nnc2c(N3CC4(COC4)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as white solid. MS(m/e): 371.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[CH3:13].[Br:14]Br>C(O)(=O)C.[Cl-].[Na+].O>[Br:14][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CC(=O)O)cc1C
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C)cc(CC(=O)O)cc1Br

Procedure:
To a solution of 4-methoxy-3-methylphenylacetic acid (0.43 g) in glacial acetic acid (7 mL) was added 0.2 mL of neat bromine carefully while stirring. The mixture was stirred in dark at ambient temperature for 27 h. The resulting mixture was diluted with brine, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-bromo-5-methyl-4-methoxyphenylacetic acid. This crude product was dissolved in methanol (30 mL), treated with concentrated sulfuric acid (1 mL) carefully, stirred at reflux for 16 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with brine, extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL), treated-with boron tribromide (1 M, 2 mL) under nitrogen and stirred at ambient temperature for 1 h. The reaction mixture was poured to stirring water and extracted with ethyl acetate from 1 N HCl. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-bromo-5-methyl-4-hydroxyphenylacetic acid methyl ester (0.21 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[S:19]1[CH:23]=[CH:22][C:21]2[CH:24]=[C:25]([C:28](Cl)=[O:29])[CH:26]=[CH:27][C:20]1=2>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28]([C:25]4[CH:26]=[CH:27][C:20]5[S:19][CH:23]=[CH:22][C:21]=5[CH:24]=4)=[O:29])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1ccc2sccc2c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc2sccc2c1
Yield: 30 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and benzo[b]thiophene-5-carbonyl chloride to afford the title compound (25 mg, 30%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.91 (d, 1H, Harom, J=7.0 Hz), 7.43 (t, 1H, Harom, J=8.0 Hz), 7.60 (d, 1H, Harom, J=5.0 Hz), 7.67 (t, 1H, Harom, J=2.5 Hz), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 7.89 (d, 1H, Harom, J=6.0 Hz), 7.91 (d, 1H, Harom, J=8.0 Hz), 8.15 (d, 1H, Harom, J=8.5 Hz), 8.49 (d, 1H, Harom, J=1.5 Hz), 10.44 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C21H15N4O3: 403.0865; found: 403.0867.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([Si](OC)(OC)OC)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:22]CCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.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]>[CH3:22][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(I)cc1
Reactant: CO[Si](OC)(OC)c1ccccc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C)cc2)cc1
Temperature: 95 °C
Yield: 19.6 %

Procedure:
To a solution of 0.014 g (0.477 mmol) of 4-iodotoluene and 0.159 g (1.058 mmol) of phenyl trimethoxysilane in 10 mL of DMF was added 25 mg (0.043 mmol) of Pd(dba)2. Then 1.10 mL (1.10 mmol) of TBAF was added to the reaction mixture via syringe. The reaction mixture was degassed to remove oxygen via one freeze-pump-thaw cycle. The brown reaction was heated at 95° C. for 2 h. The resulting brown mixture was quenched by the addition of 50 mL of water; the aqueous layer was then extracted with 4×50 mL Et2O, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (30 mm, 16 cm, pentane) gave 17 mg (40%) of 4,4′-dimethylbiphenyl. This matched an authentic sample (purchased from Aldrich) by GC and TLC.
Reaction SMILES: [C:1](=[O:8])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])N.[C:9]1([OH:15])C=C[CH:12]=[CH:11][CH:10]=1>>[C:1](=[O:8])([O:15][CH2:9][CH2:10][CH2:11][CH3:12])[O:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Oc1ccccc1
Reactant: CCCCOC(N)=O
Product: CCCCOC(=O)OCCCC

Procedure:
A liquid containing 42.6% by weight (hereinafter, “wt %”) of dibutyl carbonate, 11.4 wt % of butyl carbamate and 46.0 wt % of phenol was fed at the rate of 300 g/hr at 100° C. to a center portion of a distillation column made from glass provided with a vacuum jacket (filled Sulzer Labopacking, inner diameter 50 mmφ, height of filling portion: concentration portion 550 mm, recovery portion 550 mm) and the continuous distillation was performed under a top section pressure of 20 mmHg in the distillation column. The distillation column was operated in a reflux ratio of 3 and adjusted to distill out 265 g/hr of a distillate from the top section and thus steady state was maintained. In the distillation, a liquid containing 48.2 wt % of dibutyl carbonate and 51.8 wt % of phenol was obtained as a distillate of the top section. Butyl carbamate content in the liquid thus obtained was below 0.05 wt %. A liquid containing 98.0 wt % of butyl carbamate and 2.0 wt % of phenol was obtained at the rate of 35 g/hr from the bottom section. Dibutyl carbonate content in the liquid thus obtained was below 0.05 wt %. In this distillation, the top section temperature was 94° C. and the bottom section temperature was 118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][S:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:17][C:16]2[CH:18]=[CH:19][C:13]([S:12][CH3:11])=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CSc1ccc(N)cc1
Product: COc1ccc(C=Nc2ccc(SC)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methoxybenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as a slightly yellow powder (yield 100%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>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>[CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH:20]=[CH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OCC2CCCCC2)c(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc(C(=O)OC)ccc1OCC1CCCCC1
Temperature: 100 °C

Procedure:
To a solution of 23-3 (810 mg, 2.5 mmol) in 11.5 mL of dioxane was added 820 mg (2.6 mmol) of vinyltributyl tin followed by 58 mg (0.05 mmol) of Pd(PPh3)4. The resulting solution was then heated at 100° C. for 20 h. The solvent was distilled under reduced pressure and the residue was chromatographed to afford product 23-4.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
24.3 g (100 mmol) of 9-phenylcarbazole was put into a 2-L Erlenmeyer flask and dissolved by addition of 600 mL of glacial acetic acid. 17.8 g (100 mmol) of N-bromosuccinimide was slowly added into this solution and stirred for about 12 hours at room temperature. By dripping this reaction solution into 1 L of ice water while being stirred, a white solid was separated out. This separated white solid was recovered by suction filtration and washed three times with water. This solid was dissolved in 150 mL of diethyl ether and washed with a saturated sodium acid carbonate solution and water. This organic layer was dried with magnesium sulfate. Suction filtration of the mixture was performed, and the resulting filtrate was enriched. Recrystallization thereof was performed by addition of about 50 mL of methanol into this enriched solution and being left standing, whereby 28.4 g of a white powder solid of 3-bromo-9-phenylcarbazole was obtained at a yield of 88%.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([NH2:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>CN(C)C(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([NH:13][CH2:2][C:3](=[O:5])[CH3:4])([CH3:12])[CH3:11]
Reactant: CC(=O)CCl
Reactant: CC(C)(N)c1cccc(Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)CNC(C)(C)c1cccc(Cl)c1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
27.8 g (0.3 mol) of chloroacetone, 16.0 g (0.1 mol) of 3-chloro-α,α-dimethylbenzylamine and 11.2 g (0.11 mol) of triethylamine were dissolved in 200 ml of N,N-dimethylacetamide, and the mixture was heated at 80° C. for 3 hours under stirring. The reaction solution was cooled, then poured into a large amount of water and extracted with toluene. The toluene layer was washed with water and then dried over anhydrous magensium sulfate. Then, the toluene layer was distilled off under reduced pressure to obtain 6.9 g (yield: 30.6%) of the desired compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH2:14])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc([C@H](N)C(C)C)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](c3cccc(C(C)C)c3)C(C)C)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-isopropylphenyl)-2-methylpropan-1-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 573 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[C:9](I)=[CH:10][C:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:12][C:5]=2[CH2:4][CH2:3]1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:10][C:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:12][C:5]=2[CH2:4][CH2:3]1
Reactant: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(I)c2CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(-c3ccccc3)c2CC1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
A mixture of 3-methyl-7-(4fluorophenylsulfonyl)-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (0.9 g, 2 mmol), phenylboronic acid (0.4 g, 3 mmol), potassium carbonate (1.6 g, 12 mmol), ethanol (6 ml), water (6 ml), and toluene (25 ml) was degassed, then tetrakis(triphenylphosphine)palladium (0) (100 mg) was added and the mixture heated at 60° C. for 18 h. After cooling the mixture was poured into water (50 ml) and extracted with more ethyl acetate (50 ml). The resulting organic layer washed with brine (100 ml), dried (MgSO4), and evaporated. Isolation using an SCX column and subsequent chromatography on silica eluting with 0 to 10% methanol in dichloromethane containing 0.1M ammonia, gave the title compound as a white foam (0.6 g). 1H NMR δ (d6-DMSO) 2.2 (3H, s), 2.5 (4H, m), 2.8 (2H, m), 3.1 (2H, m), 7.2 (2H, m), 7.4 (5H, m), 7.6 (1H, s), 7.8 (1H, s), and 8.1 (2H, m).
Reaction SMILES: [Cl-].[Li+].[CH3:3][O:4][C:5](=[O:29])[C:6]1[CH:11]=[C:10]([Sn](CCC)(CCC)CCC)[CH:9]=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)[CH:7]=1.[CH:30]([C:33]1[C:34](OS(C(F)(F)F)(=O)=O)=[N:35][S:36][N:37]=1)([CH3:32])[CH3:31]>C1COCC1.[Pd]>[CH3:3][O:4][C:5](=[O:29])[C:6]1[CH:7]=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)[CH:9]=[C:10]([C:34]2[C:33]([CH:30]([CH3:32])[CH3:31])=[N:37][S:36][N:35]=2)[CH:11]=1
Reactant: CCC[Sn](CCC)(CCC)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Reactant: CC(C)c1nsnc1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2nsnc2C(C)C)c1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
Lithium chloride (0.094 g) and palladium II tetrakis(triphenylphosphine) (0.048 g) were suspended in dry THF under nitrogen atmosphere. To this suspension was added a solution of 3-(5-Methyl-pyridin-2-yl)-5-tripropylstannanyl-benzoic acid methyl ester (0.656 g, 1.27 mmol) and trifluoro-methanesulfonic acid 4-isopropyl-[1,2,5] thiadiazol-3-yl ester (0.26 g, 0.942 mmol) in 6 mL of dry THF. The reaction mixture was heated to reflux for 70 hours. The reaction mixture was cooled to room temperature and ice water was added. After one hour the mixture was extracted wtih EtOAc and the combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (17:1 EtOAc/hexanes) to give 0.118 g of 3-(4-isopropyl-[1,2,5] thiadiazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=354.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#N.S(=O)(=O)(O)[OH:13].[OH2:17]>C(OCC)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]([OH:13])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: Cc1cccc(CC#N)c1Br
Solvent: CCOCC
Product: Cc1cccc(CC(=O)O)c1Br

Procedure:
2-bromo-3-methylbenzylcyanid (8.8 g, 42 mmol) was added to a mixture of conc sulfuric acid (50 ml) and water (60 ml) and was refluxed overnight. Water (150 ml) and diethyl ether were added and the organic layer was separated. To the organic layer was added a saturated sodium bicarbonate solution and the aqueous layer was separated. The aqueous layer was made acidic by additon of conc sulfuric acid. The acidic water solution was extracted with diethyl ether and the organic layer was washed with water, dried (Na2SO4) and evaporated under reduced pressure to give 6.5 g of the title compound.
Reaction SMILES: Cl[CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].Cl.N[CH2:36][C:37]([NH2:39])=[O:38].C([N:42](CC)CC)C.CN1CCCN(C)C1=O>CO>[C:37]([NH:39][NH:42][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4])(=[O:38])[CH3:36]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: NCC(N)=O
Agent: Cl
Solvent: CO
Solvent: CN1CCCN(C)C1=O
Product: CC(=O)NNC(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Temperature: 75 °C
Yield: 85.8 %

Procedure:
A mixture of 0.14 g of α-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide, 0.17 g of glycinamide HCl, 0.15 g of triethylamine, 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1 ml of methyl alcohol is heated at 75° C. for 2 days. The methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The solid is dissolved in ethyl acetate and washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with ether-hexanes to give 0.13 g of tan solid. MS(CI): 494(M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[C:27]([C:36](O)=[O:37])=[C:26]2[CH3:39])=[CH:21][CH:20]=1)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[C:27]([C:36]([N:1]3[CH2:6][CH2:5][C:4]4([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[C:8](=[O:15])[O:7]4)[CH2:3][CH2:2]3)=[O:37])=[C:26]2[CH3:39])=[CH:21][CH:20]=1)[CH3:17]
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: CCOc1ccc(-n2c(C)c(C(=O)O)c3cc(OC)ccc32)cc1
Product: CCOc1ccc(-n2c(C)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)c3cc(OC)ccc32)cc1

Procedure:
Following the general procedure I as described above, the acylation of 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one prepared as described in example 16, with commercially available 1-(4-ethoxyphenyl)-5-methoxy-2-methyl-1H-indole-3-carboxylic acid, gave the title compound. ES-MS m/e (%): 511.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]#N)[C:6](=[O:12])[NH:7]2.S(=O)(=O)(O)O.[OH2:20].[OH-:21].[NH4+]>CCOCC.C(O)(=O)C.CO>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([OH:21])=[O:20])[C:6](=[O:12])[NH:7]2
Reactant: O
Reactant: [OH-]
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1nccc2[nH]c(=O)c(C(=O)O)cc12
Temperature: 25 °C

Procedure:
A mixture containing 63 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile, 100 ml of concentrated sulphuric acid and 100 ml of water was heated on a steam bath for 16 hours, after which time tlc analyses (20% methanol in ether) indicated the presence of a considerable amount of starting material. Therefore, the reaction mixture was heated in a oil bath at 135°-140° C. for 8 hours, cooled to room temperature and poured on ice (1 1. beaker, 1/3 filled). The resulting aqueous mixture was neutralized by adding aqueous ammonium hydroxide until slightly basic and was then reacidified by adding acetic acid. The resulting solid was collected, washed successively with water and methanol, and dried at 100° C. to yield 54.8 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid, m.p. 255°-257° C. with decomposition. Another 7.2 g of the product, m.p. 252°-255° C. was obtained from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]I)[CH:12]=3)=[CH:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.ClCCl.CO>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: CN1CCNCC1
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCN(C)CC3)c2cc1OC
Yield: 55.5 %

Procedure:
But using 0.98 g of 4-chloro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.21 g of potassium carbonate and 0.31 g of 1-methylpiperazine in 100 ml of acetonitrile. After flash chromatography on a silica column [eluent: dichloromethane/methanol (90/10 by volume)], 0.52 g of 4-chloro-2-{5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl}-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of an oil, the characteristics of which are as follows: