Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23](=O)[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].B.Cl>O1CCCC1>[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)N(CC)CC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC

Procedure:
A solution of 0.82 g. of 5-chloro-2-[(diethylcarbamoyl)methyl]-3-phenylisoindole-1-carboxylic acid ethyl ester in 5 ml. of tetrahydrofuran is added dropwise under argon at room temperature to 3 ml. of a 1-M solution of borane in tetrahydrofuran. Subsequently, the mixture is boiled at reflux for 4 hours and then treated at 15°-20° C. with 0.8 ml. of 6-N hydrochloric acid. Then, the tetrahydrofuran is removed by distillation at atmospheric pressure. The residue is partitioned between 3 ml. of water and 5 ml. of ether. After cooling in an ice-bath, the crystallized hydrochloride is isolated and purified in a manner analogous to that described in Example 1, and there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[CH3:24][NH:25][CH3:26]>CO>[CH3:24][N:25]([CH2:22][C:5]1[C:6]([OH:20])=[C:7]2[C:8](=[C:3]([O:2][CH3:1])[C:4]=1[OH:21])[O:9][C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:12]2=[O:13])[CH3:26]
Reactant: CNC
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Reactant: C=O
Solvent: CO
Product: COc1c(O)c(CN(C)C)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.1 ml), 33% dimethylamine solution (13.6 g) was stirred under for 4 hours at 55° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as yellow solid 32.7 g of purity 99.3%. MS: (API-ES) m/z 342.5[M+H]+; 1H NMR (DMSO-d6, 400 MHz) δ 8.03˜8.04 (m, 2H, Ar-2′,6′-H), 7.59-7.60 (m, 3H, Ar-3′,4′,5′-H), 6.81 (s, 1H, 3-H), 3.97 (s, 2H, CH2), 3.82 (s, 3H, 8-OCH3), 2.56 (s, 6H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.N([O-])=[O:26].[Na+].OS(O)(=O)=O>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:26])=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of 4-amino-2-(4-tert-butyl-benzoylamino)-benzoic acid methyl ester (0.711 g, 2.18 mmol) in trifluoroacetic acid cooled to 0° C. was added NaNO2 (0.182 g, 2.64 mmol, 1.21 eq) as a solution in water (4 mL) and the reaction was stirred for 5 minutes. It was then added dropwise to a 30% solution of H2SO4 (50 mL) at 65° C. and stirred for 15 minutes. It was extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 2-(4-tert-butyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (0.508, 71%) as a white solid. mp=146.0-148.4° C.; mass spectrum (−ES, M−H) m/z 326. 1H NMR (400 MHz, DMSO-d6); δ 11.95 (bs, 1H), 10.60 (bs, 1H), 8.26 (d, 1H), 7.88 (m, 3H), 7.62 (d, 2H), 6.58 (dd, 1H), 3.85 (s, 3H), 1.32 (s, 9H). Elemental analysis: Calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28, Found: C, 69.20; H, 6.54; N, 4.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl.[N:11]([O-])=O.[Na+].[CH2:15]([O:17][C:18](=[O:24])[CH:19]([Cl:23])C(C)=O)[CH3:16].C(O[Na])(C)=O>O.CCOC(C)=O>[CH2:15]([O:17][C:18](=[O:24])[C:19]([Cl:23])=[N:11][NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:16]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(N)cc1
Agent: CC(=O)O[Na]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
p-anisidine (31.02 g, 0.252 mol) in 100 ml of H2O is suspended in a 250 ml 4-necked flask equipped with coolant, thermometer, dropping funnel and magnetic stirrer, and cooled to 0° C. in an ice bath. 60 ml of 37% HCl is added, followed by a solution of NaNO2 (20.95 g, 0.307 mol) in 50 ml of H2O, through a dropping funnel, maintaining the temperature below 5° C. After the addition the mixture is left under stirring at between 0 and 5° C. for 1 h, and the solution obtained is added at 0° C. to a solution containing ethyl-2-chloroacetoacetate (41.65 g, 0.254 mol), AcONa (47.84 g, 0.583 mol), AcOEt (200 ml) and H2O (100 ml). The biphasic system is stirred at between 0 and 5° C. for 1 h, and then at about 25° C. for 16 h. The phases are then separated and the organic phase is washed with a saturated solution of NaHCO3 (4×80 ml), anhydrified on Na2SO4, filtered and evaporated under low pressure. The compound of formula (IV) is obtained as a solid (about 57 g), which is used for the next stage without further purification.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[Cl:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][NH2:38])=O)=[CH:33][CH:32]=1>C(O)C>[Cl:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]2[NH:6][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:38][N:37]=2)=[CH:33][CH:32]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccc(Cl)cc5)[nH]4)cc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
To a sealed tube containing ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (300 mg, 0.94 mmol) dissolved in ethanol (15 mL) and triethylamine (0.3 μL, 2.82 mmol) was added 4-chlorobenzoic hydrazide (213 mg, 1.25 mmol). The tube was sealed and allowed to stir at 75° C. overnight. The solvent was removed and the material was purified by HPLC to yield the title compound (46 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.75 (s, 1H), 8.0–8.2 (m, 5H), 7.76 (d, 1H), 7.6 (m, 2H), 7.4–7.42 (t, 2H), ES-MS (m/z) 390 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27]CC)=[CH:23][CH:22]=2)[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31].Cl[CH2:37][CH2:38]Cl>>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([N:17]([CH3:18])[C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:35])=[CH:16][C:11]=3[N:10]=[C:9]2[CH:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:37][CH3:38])=[CH:25][CH:26]=2)[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCCl
Reactant: CC(C)N=C=O
Reactant: CCOc1ccc(C(C)c2nc3cc(NC)ccc3n2CC2CCCCC2)cc1
Product: CCOc1ccc(C(C)c2nc3cc(N(C)C(=O)NC(C)C)ccc3n2CC2CCCCC2)cc1
Temperature: 60 °C
Yield: 58 %

Procedure:
To a solution of 1-(cyclohexylmethyl)-2-[1-(4-ethoxyphenyl)ethyl]-N-methyl-1H-benzimidazol-5-amine (2.1 g, 5.4 mmol) in 1,2-dichloroethane (270 mL) was added isopropyl isocyanate (1.1 mL, 10.8 mmol) at room temperature and the reaction mixture was heated at 60° C. overnight. The solution was cooled to room temperature, the solvent was evaporated and the brown residue was purified by MPLC (EtOAc on silica gel) to afford the title compound as a beige foam (1.5 g, 58%). 1H NMR (400 MHz, CD3OD) δ 0.95–1.18 (m, 11H), 1.36 (t, J =7.0 Hz, 3H), 1.41–1.68 (m, 6H), 1.82 (d, J=7.0 Hz, 2H), 3.31 (s, 3H), 3.89–3.95 (m, 1H), 4.01 (apq, J=7.0 Hz, 2H), 4.13–4.18 (m, 1H), 4.68 (q, J=7.2 Hz, 1H), 7.17–7.20 (m, 2H), 7.35 (dd, J=2.0, 8.8 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H). MS (ESI) (M+H)+=477.48 (M+1)+. Anal. Calcd for C29H40N4O2+0.5HCl+0.8 CH3OH: C, 68.76; H, 8.46; N, 10.26. Found: C, 68.75; H, 8.61; N, 10.98.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH:19][CH:20]([C:25]([CH3:27])=[CH2:26])[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.O>C1C=CC=CC=1>[F:1][C:2]1[C:15]([NH:16][C:17]([O:19][CH:20]([C:21]([O:23][CH3:24])=[O:22])[C:25]([CH3:27])=[CH2:26])=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OC
Reactant: C#CCN1C(=O)COc2cc(F)c(N=C=O)cc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC(C(=C)C)C(=O)OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 7-fluoro-6-isocyanato-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (2.5 g) and methyl 2-hydroxy-3-methyl-3-butenoate (1.3 g) in benzene (50 ml), triethylamine (0.5 g) was added at room temperature. The resulting mixture was refluxed for 1 hour, cooled to room temperature, combined with water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using a mixture of toluene and ethyl acetate as the eluent to give Compound No. 72 (2.9 g). nD25.0 1.4868
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH3:24])[CH:10]=2)[N:5]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:42]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][NH:39][C:40]=4[CH:41]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1>>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:39]4[C:40]5[CH:41]=[C:42]6[C:29]7([CH2:32][O:33][C:34]6=[CH:35][C:36]=5[CH2:37][CH2:38]4)[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]7)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH3:24])[CH:10]=2)[N:5]=1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COCc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COCc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)no1
Yield: 62 %

Procedure:
The title compound was prepared from 4'-(5-methoxymethyl-1,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (D112) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) using a similar procedure as described in Example 1. This afforded the title compound as a pale yellow solid (62%), which was converted to its hydrochloride salt to give an off white solid m.p. 247-251° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:37])[CH2:34][NH:35][CH3:36])[CH:30]=[CH:31][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:37])[CH2:34][N:35]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:36])[CH:30]=[CH:31][CH:32]=1
Reactant: CNCC(O)c1cccc(N)c1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2cccc(N)c2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (90 mg, 0.23 mmol), 1-(3-aminophenyl)-2-(methylamino)ethanol (Khim.-Farm. Zh 1983, 17, 1093)(69 mg, 0.42 mmol) and diisopropylethylamine (60 μL, 0.34 mmol) in dry DMF (4.6 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with ice (6 g). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the tide compound (79 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[F:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].FC1C=CC=CC=1C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:15]([N:16]([CH3:18])[CH3:17])[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[F:12]
Reactant: C[N+](C)=Cc1ccccc1F
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CNC
Agent: O=Cc1ccccc1F
Agent: [Cl-]
Product: CN(C)C(c1ccccc1F)c1c[nH]c2ccc(Cl)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (2-fluoro-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CN(C=O)C>[CH3:4][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][CH2:22][N:23]([CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:28]([F:30])([F:31])[F:29])[CH3:2]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C(F)(F)F
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
7-{5-[4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 19) (160 mg, 0.353 mmol), DIPEA (0.234 ml, 1.342 mmol) and ethyl 4-bromobutanoate (0.110 ml, 0.767 mmol) were stirred at room temperature in DMF (10 ml) for 5 hours. The reaction mixture was then heated to 60° C. for 5 h, and allowed to stand overnight at room temperature. Further ethyl 4-bromobutanoate (0.055 ml, 0.383 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (183 mg, 0.310 mmol) as an orange solid. MS (ES): C28H32F3N3O4 requires 531; found 532 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:21][O:20][C:5]1[C:6]2[N:7]=[C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])[S:9][C:10]=2[C:2]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: OB(O)c1ccncc1
Product: COc1ccc(-c2ccncc2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 6 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid (4-methoxy-7-pyridin-4-yl-benzothiazol-2-yl)-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-bromo-4-methoxy-benzothiazol-2-yl)-amide (192 mg, 0.50 mmol) and 4-pyridylboronic acid (92 mg, 0.75 mmol) using the general procedure A as a white solid in 6% yield. MS: m/e=381 (M+).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[C:31]1(C)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH2:38]OB(C1C=CC=CC=1)O.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[NH2:38][C:31]1[CH:36]=[CH:35][C:34]([C:13]2[N:12]=[C:11]3[N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]4)[N:17]=[CH:18][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:33][CH:32]=1
Reactant: NOB(O)c1ccccc1
Reactant: CC(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1

Procedure:
isopropyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (680 mg, 1.56 mmol) was dissolved in ethanol (8 mL) and toluene (8 mL) and divided over two microwave vials. To each vial was added 1.3 eq of aminophenylboronic acid, pinacol ester (220 mg, 1 mmol to each vial) and a 2M aqueous solution of Na2CO3 (1.57 mL, 3.14 mmol, 4 eq. to each vial). The vials were purged with nitrogen gas and 10 mol % tetrakis(triphenylphosphine)palladium was added (91 mg to each vial). Each vial was heated under microwave irradiation for 60 minutes. The contents of both vials were combined, diluted with dichloromethane and water and filtered over Celite. The organic phase was washed with brine (2×), dried over MgSO4 and concentrated to give the product as an orange foam, which was used without further purification. MS: 492.3 [M+H], RT 2.31
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.[CH3:32][NH:33][C:34]([C:36]1[CH:46]=[CH:45][C:39]([CH:40]=[CH:41][C:42](O)=[O:43])=[CH:38][CH:37]=1)=[O:35].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:42](=[O:43])[CH:41]=[CH:40][C:39]3[CH:45]=[CH:46][C:36]([C:34](=[O:35])[NH:33][CH3:32])=[CH:37][CH:38]=3)[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCNCC4)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)N2CCN(C(=O)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)CC2)cc1
Reaction time: 3 h
Yield: 116.1 %

Procedure:
To a solution of 8-[2,6-dichloro-3-(piperazine-1-carbonyl)benzyloxy]-2-methylquinoline dihydrochloride (60 mg), 4-(methylcarbamoyl)cinnamic acid (20.9 mg) and 1-hydroxybenzotriazole (22.6 mg) in N,N-dimethylformamide (0.6 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (27.4 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[4-[4-(methylcarbamoyl)cinnamoyl]piperazine-1-carbonyl]benzyloxy]-2-methylquinoline (73 mg) as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[CH2:31][N:6]1[C:7](=[O:28])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:29]=[C:5]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)C(C)(C)C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (3 g), 1-bromo-3,3-dimethylbutan-2-one (1.1 mL), potassium carbonate (2.1 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.53 g, 15%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:14]([CH3:13])(=[O:16])=[O:15])[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.06 mmol) in dry THF (30 mL) was added NaH (246 mg, 6.12 mmol) at room temperature. The suspension was stirred for 30 min before addition of methanesulfonyl chloride (540 mg, 4.80 mmol). The solution was stirred at room temperature for another 30 min and poured into water (50 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over MgSO4 and filtered, the filtrate was evaporated under vacuum to afford white solid (780 mg, 93%). The crude product was used directly for the next reaction. LC/MS: Rt 3.26 mis.; (m/e=275.0, 276.9 (M+H, M+2+H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].C(Cl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N:30]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:8]([C:18]([NH:40][C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:30]=[CH:31][CH:32]=[CH:33]3)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2ncccc2c1
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 6-quinolinamine the title compound was obtained in 83% purity by LC/MS. MS(ESI+): m/z=415.2.