Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]1[C:48](=[O:49])[NH:47][C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[CH2:44][CH2:43]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[NH:41][C@@H:42]1[C:48](=[O:49])[NH:47][C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[CH2:44][CH2:43]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@H]1CCc2ccccc2NC1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCc4ccccc4NC3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (5.0 mg, 0.0088 mmol) and (S)-3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (1.6 mg, 0.0088 mmol) to give a white solid (5.1 mg, 80% yield). Anal. Calcd. for C41H48N4O6S m/z 724.9. found: 725.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.24-6.90 (m, 14H), 6.28-6.20 (m, 1H), 5.29-5.20 (m, 1H), 5.04-4.97 (m, 2H), 4.93-4.84 (m, 2H), 4.30-4.20 (m, 1H), 3.60-3.53 (m, 3H), 3.20-3.04 (m, 1H), 2.82-2.50 (m, 8H), 2.37-2.19 (m, 4H), 1.96-1.88 (m, 2H), 1.85-1.68 (m, 2H), 1.67-1.31 (m, 6H), 1.27-1.14 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.[C:19]1([CH2:25][C:26]2[N:30]=[C:29]([CH2:31][CH2:32][CH2:33]O)[O:28][N:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:33][CH2:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:30]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Reactant: OCCCc1nc(Cc2ccccc2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.3 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.74 mmol) in THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (195 mg, 0.89 mmol) and PPh3 (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol) was added in one portion and the mixture was left to stir at rt under nitrogen for 18 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified by a silica SPE column using a 0-70% cyclohexane/EtOAc gradient. The product fractions were combined, concentrated and further purified by a silica SPE column using a 0-60% cyclohexane/EtOAc gradient. The product fractions were combined and concentrated then dissolved in anhydrous THF (4 ml). The solution was degassed by high vacuum then Pd(PPh3)4 (86 mg, 0.074 mmol) and morpholine (644 μl, 7.4 mmol) were added and the mixture left to stir at rt under nitrogen for 1 day. The mixture was partitioned between EtOAc and HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 2-4% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (74 mg, 23%).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C=CC1C=CC=CC=1.O[C@@H:34]([C@H:37]1[O:42][C:41]([CH3:44])([CH3:43])[O:40][C@H:39]2[C@@H:45]([O:49][CH2:50][CH3:51])[C:46](=[O:48])[O:47][C@@H:38]12)[CH2:35]O.II>C1(C)C=CC=CC=1>[CH2:50]([O:49][C@@H:45]1[C@@H:39]2[O:40][C:41]([CH3:44])([CH3:43])[O:42][C@H:37]([CH:34]=[CH2:35])[C@@H:38]2[O:47][C:46]1=[O:48])[CH3:51]
Reactant: CCO[C@H]1C(=O)O[C@@H]2[C@H]1OC(C)(C)O[C@@H]2[C@H](O)CO
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C=Cc1ccccc1
Product: C=C[C@H]1OC(C)(C)O[C@@H]2[C@H]1OC(=O)[C@@H]2OCC
Reaction time: 2 h

Procedure:
2.12 g of imidazole (31.13 mmol) and 10.37 g of triphenylphosphine supported by a styrene copolymer (Fluka, cas: 39319-11-4, 31.13 mmol) are added to a 250 mL three-necked flask containing 2.15 g of 49 (7.78 mmol) and 100 mL of toluene, with stirring and under an argon atmosphere. The medium is heated to the reflux temperature, and 5.93 g of iodine (23.35 mmol) are added in small portions. The heating is continued for 2 h, and then the mixture is cooled, the resin is filtered and washed with 20 mL of toluene and 50 mL of AcOEt. The filtrate is washed twice with 150 mL of a solution of water saturated with NaHCO3. The organic phase is dried over anhydrous magnesium sulphate, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (250 g, eluent CH2Cl2/MeOH— in a 0 to 10% MeOH gradient). 800 mg of expected product 50 are recovered.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH:37]=[C:36]1[C:44](O)=[O:45].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH:37]=[C:36]1[C:44]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:45]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (100 mg, 0.22 mmol), 2-benzofurancarboxylic acid (36 mg, 0.22 mmol) and triethylamine (66 mg, 0.66 mmol) in dimethylformamide (0.75 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and the resulting precipitate was collected, washed with water and dried. The precipitate was purified by chromatography on silica gel eluting with 1:20 methanol:dichloromethane to give 1-((1R,5S)-8-{2-[1-(1-benzofuran-2-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a clear oil (0.075 g, 60%). 1H NMR (400 MHz, CDCl3) δ 7.66 (m, 2H), 7.52 (m, 1H), 7.26-7.44 (m, 9H), 7.16 (m, 2H), 4.61 (m, 1H), 4.16 (m, 2H), 3.40-3.57 (m, 2H), 3.26 (m, 1H), 2.57 (m, 3H), 2.34 (m, 4H), 1.94 (m, 9H), 1.62 (m, 4H). HRMS C37H40N4O2 m/z 573.3229 (M+H)Cal., 573.3238 (M+H)Obs..
Reaction SMILES: [N:1]1([CH2:14][CH2:15][O:16][CH2:17][C:18]#[CH:19])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.I[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C)C=O>[S:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:19]#[C:18][CH2:17][O:16][CH2:15][CH2:14][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: C#CCOCCn1cnc2cnc3ccccc3c21
Reactant: Ic1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1cccs1)COCCn1cnc2cnc3ccccc3c21
Reaction time: 0.83 h
Yield: 60.8 %

Procedure:
A dried round bottom flask was charged with a stir bar, 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl)ether (11.78 g, 46.88 mmol), anhydrous triethylamine (14 mL, 121.9 mmol), 2-iodothiophene (5.7 mL, 51.57 mmol) and anhydrous dimethyl formamide(130 mL) under a nitrogen atmosphere and heated to 80° C. After 5 minutes dichlorobis(triphenylphosphine)palladium(II) (0.658 g, 0.937 mol) and copper(I) iodide (0.357 g, 1.875 mmol) were added neat to the solution. The reaction was judged complete after 50 minutes. The volatiles were removed under reduced pressure and the resulting solid partitioned between dichloromethane and 0.5N aqueous potassium hydroxide. The aqueous fraction was extracted with dichloromethane (3×); the combined organic fractions were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide a brown solid. The glassy solid obtained from purification by chromatography over silica gel (98/2 dichloromethane/methanol) was triturated with ether to provide 9.5 g of 1-{2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin as a tan solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].Cl[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]2[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:23]=[N:24][C:13]=12>C1COCC1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[C:14]3=[N:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([CH2:11][N:7]4[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]4=[O:9])=[C:13]3[N:24]=[CH:23]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(Cn2cnc3c(CCl)cc(C(F)(F)F)nc32)cc1
Reactant: CCCC1CNC(=O)C1
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cc2cc(C(F)(F)F)nc3c2ncn3Cc2ccc(OC)cc2)C1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
4-propylpyrrolidin-2-one x1 (0.22 g, 1.1 eq with respect to x199, 1.7 mmol) is dissolved in absolute THF (10 ml). A 1.06 M solution of Li-HMDS in THF (1.76 ml, 1.1 eq, 1.87 mmol) is added at −78° C. in a flow of argon. The reaction mixture is stirred for 15 min at −30° C. and cooled again to −78° C. A solution of 7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine x202 in absolute THF (10 ml) is added dropwise at this temperature. The reaction mixture is allowed to heat up slowly to room temperature. In order to complete the reaction, the reaction mixture is refluxed the next morning for 1 h, and then partitioned between saturated aqueous NH4Cl and ethyl acetate. The organic layer is dried with anhydrous sodium sulfate and evaporated. The product is purified by HPLC (water/acetonitrile) to afford 0.14 g of 1-{[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x205 (0.14 g).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.[CH2:13]([N:16]=[C:17]=[O:18])[CH:14]=[CH2:15]>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:13]([NH:16][C:17]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:18])[CH:14]=[CH2:15]
Reactant: ON=C1CCOc2ccccc21
Reactant: C=CCN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCNC(=O)ON=C1CCOc2ccccc21
Yield: 72.6 %

Procedure:
A solution containing 6.52 g (0.04 mole) of 4-chromanone oxime and 75 ml benzene was stirred and refluxed for 0.50 hrs. using a Dean-Stark apparatus. The solution was cooled to 60° and 6 drops triethylamine and 3.32 g (0.04 mole) allyl isocyanate in 10 ml benzene was added. The solution was stirred and refluxed for 4 hrs., concentrated to dryness, and the residue was recrystallized from 20 ml toluene to give 7.15 g (73%) of the product, m.p. 83°-86°.
Reaction SMILES: Br.[NH2:2][C:3]1[N:12](CC2C=CC(OC)=CC=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:22])[N:4]=1.I[CH2:24][C:25](OCC)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:22][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][NH:12][C:3]1[N:4]2[CH2:24][C:25](=[O:26])[N:2]=1
Reactant: CCOC(=O)CI
Reactant: COc1ccc(CN2Cc3c(Cl)cccc3N=C2N)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN2C(=N1)NCc1c(Cl)cccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.15 mol of 2-amino-5-chloro-3,4-dihydro-3-(p-methoxybenzyl)-quinazoline hydrobromide in 800 ml of dimethylformamide is treated with 0.18 mol of ethyl iodoacetate and 0.2 mol of potassium carbonate and stirred at room temperature for 18 hours. Then, the mixture is stirred at 90° for an additional 5 hours, cooled and poured into 5 l of ice/water. The precipitated product, 6-chloro-4-(p-methoxybenzyl)-5H-imidazo[1,2-a]quinazolin-2(1H)-one, is removed by filtration and washed well with water. In order to prepare the hydrochloride, the product is recrystallized from ethanol/hydrochloric acid; m.p. 230° (decomposition).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([N:13]([CH3:43])[C:14]([N:16]([CH3:42])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:46]C(C)([O-])C.[K+].CI>CN(C=O)C>[F:45][C:2]([F:44])([F:1])[C:3]1[CH:4]=[C:5]([N:13]([CH3:43])[C:14]([N:16]([CH3:42])[C@H:17]2[C@H:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:32][CH2:33][C@H:34]([N:37]([CH3:46])[S:38]([CH3:41])(=[O:39])=[O:40])[CH2:35][CH2:36]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](NS(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N(C)S(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the compound (0.23 g) obtained in Example 242 in DMF (7.0 mL) were added potassium tert-butoxide (0.079 g) and methyl iodide (0.055 mL) at 0° C. The mixture was stirred at room temperature for 12 hr, diluted with ice water, and extracted with ethyl acetate. The extract was washed with water, 1N aqueous potassium hydrogen sulfate solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (0.17 g, 70%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][O-:26].[Na+]>CO>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([O:26][CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 18 h

Procedure:
To 25 ml of methanol was added 1.0 g (0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine and 0.18 g (0.00335 mol) of sodium methoxide. The reaction was stirred for 18 hr, and evaporated to dryness. The solid was dissolved in 50 ml of dichloromethane and washed with 40 ml of water, dried and evaporated to dryness. The oil was crystallized and recrystallized from ether/petrol and then from ether to give the end product as white prisms, mp 137°-141°.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].C(N(CC)CC)C.O>ClCCl>[Br:2][CH2:3][CH2:4][NH:5][C:7](=[O:8])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCBr
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCBr)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To an ice-cooled suspension of 5.0 g of 2-bromoethylamine hydrobromide and 3.91 g of phenyl chloroformate in 50 ml of dichloromethane, 5.1 g of triethylamine was added. The mixture was stirred for 2 hours, and water was added thereto. The organic phase separated was concentrated to dryness under reduced pressure. The residue was crystallized with hexane to give 5.33 g of the entitled compound as colorless crystals.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[O:20])[CH2:11]1)=[O:7])(C)(C)C.[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35](C(O)=O)=[C:34]([O:42][CH3:43])[CH:33]=1>>[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)=[O:20])[CH2:11]2)=[O:7])=[C:34]([O:42][CH3:43])[CH:33]=1
Reactant: Cn1cc(C(=O)NCCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-1-methyl-1 H-indole-3-carboxamide (0.44 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.26 g) to give N-(3-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)propyl)-1-methyl-1H-indole-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](O)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:35])=O>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([Cl:35])=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)O)s5)nn34)ccnc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)Cl)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carboxylic acid (prepared by General Method A)(0.150 g, 0.335 mmol) in dichloromethane (2 mL) was added thionyl chloride (0.734 ml, 10.1 mmol and DMF (1 drop). The solution was stirred at room temp for three hours then concentrated and taken forward without further purification.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([O:30][C:31]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride salt (0.17 mmol, 70 mg), ethylchloroformate (0.25 mmol, 25 μL) and triethylamine (0.51 mmol, 72 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water. The product was extracted with ethyl acetate. Removal of organic solvents in vacuo and purification by HPLC provided compound A123 as a white solid (14 mg, 15%). Exact mass calculated for C20H23N5O5S 445.49, found 446.10 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]=[C:12]1[CH2:18][CH:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32](=[O:34])[CH3:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl>O1CCCC1.ClCCl.O>[CH2:35]([C:17]1([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32](=[O:34])[CH3:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13][C:12](=[CH2:11])[CH2:18]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=C1COc2ccc(C(C)=O)cc2C(S(=O)(=O)c2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1COc2ccc(C(C)=O)cc2C(Cc2ccccc2)(S(=O)(=O)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
0.152 ml (2.2 equivalents) of 1,3-dimethylpropyleneurea and then 1.286 ml (2.2 equivalents) of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added at ambient temperature to 200 mg (0.58 mmol) of 1-[3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-yl]ethanone, prepared according to example 13, in solution in 5.8 ml of tetrahydrofuran. The reaction medium then assumes a dark yellow color. After 15 minutes, 0.0698 ml (1 equivalent) of benzyl bromide is added. Water is immediately added, and 1N hydrochloric acid and dichloromethane. After separating the organic and aqueous phases, the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are washed with brine, are dried and are finally concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 30/70) to provide 245 mg (97%) of 1-[5-benzyl-3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-yl]ethanone in the form of a white solid; M.p.=131–132° C.