Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][C:37]1[C:38]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([F:36])[C:38]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCN2CCCCC2)c(F)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 42.2 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (92 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and diluted with 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography, followed by MeOH re-crystallization to give the title compound (54 mg, 0.076 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.42 (d, J=6.96 Hz, 1H), 8.50 (s, 1H), 8.30-8.34 (m, 1H), 8.11 (s, 1H), 7.80-7.86 (m, 1H), 7.77 (d, J=8.06 Hz, 1H), 7.71 (d, J=9.16 Hz, 1H), 7.43-7.48 (m, 1H), 7.32-7.40 (m, 1H), 7.26 (d, J=8.61 Hz, 1H), 7.16 (t, J=8.06 Hz, 2H), 7.00 (t, J=6.23 Hz, 2H), 6.67 (d, J=4.94 Hz, 1H), 3.97 (s, 3H), 3.82 (s, 3H), 3.26-3.27 (m, 2H), 2.70 (t, J=7.33 Hz, 2H), 2.34-2.42 (m, 4H), 1.43-1.50 (m, J=4.76 Hz, 4H), 1.32-1.39 (m, 2H). MS (ESI): 708 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)=[CH:3][CH:2]=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: CC1(C)CN(Cc2ccncc2)c2ccc(O)cc21
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2ccncc2)cc1

Procedure:
The title compound was synthesized from 1-(4-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-dimethylaminophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (2.1 mg, 6%) having the following characteristics.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30]C)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([OH:30])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 24 h

Procedure:
To a solution of methyl (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoate (0.3 g) in a mixture of ethanol (8 ml) and tetrahydrofuran (5 ml) was added 1N-NaOH solution (3.5 ml). After being stirred for 24 hours at the same temperature, the solvent was removed. The residue was partitioned between ethyl acetate and lN-HCl and the organic layer was washed with brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with a mixture hexane and ether to afford (S)-3-{[2-(4,5-diphenyl-oxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid(O.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:28][CH2:29][CH2:30][CH3:31])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23](OCC)=O)=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:32].[Na+].[CH3:34][OH:35]>>[C:34]([CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=1)([OH:35])=[O:32]
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (2.717 g) was dissolved in methanol (50 ml), 2N NaOH (8.72 ml) was added and the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure to remove methanol. The concentrate was poured in 6N HCl while cooling with ice. The precipitated crystals were filtered and recrystallized from acetonitrile to obtain (S)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide (1.629 g).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([OH:15])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([NH:37][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:15]
Reactant: O=C(O)CC1Nc2ccccc2NC1=O
Reactant: NCCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1Nc2ccccc2NC1=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the solution of (3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetic acid (510 mg, 2.48 mmol) in THF (18 mL) was added triethylamine (0.38 ml, 2.74 mmol) and ethyl chloroformate (0.24 ml, 2.74 mmol). The mixture was stirred at rt for 1.5 hours and then phenethylamine (0.34 ml, 2.74 mmol) was added. The resulting mixture was again stirred at rt for 4.5 hours. The precipitate was filtered off and washed with small amount of THF a few times. The solvent was removed under the reduced pressure to give the title compound as a yellow solid: 1H NMR (DMSO-d6) δ=10.24 (bs, 1H), 8.03 (t, 1H, J=5.4 Hz), 7.30–7.15 (m, 5H), 6.75–6.70 (m, 3H), 6.61–6.56 (m, 1H), 5.79 (bs, 1H), 4.08–4.04 (m, 1H), 3.30–3.24 (m, 2H), 2.71 (t, 2H, J=7.8 Hz), 2.60 (dd, 1H, J=3.9, 15.3 Hz), 2.31 (dd, 1H, J=8.7, 15.3 Hz).
Reaction SMILES: O=C1N(CC(OC(C)(C)C)=O)C2C=CC=CC=2N1.C([O:23][C:24](=[O:43])[CH2:25][N:26]1[C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[C:34]([CH3:35])[C:29]=2[N:28]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:27]1=[O:42])(C)(C)C>>[CH3:41][O:40][C:38](=[O:39])[CH2:37][N:28]1[C:29]2[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=2[N:26]([CH2:25][C:24]([OH:43])=[O:23])[C:27]1=[O:42]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC(C)(C)C)c2cc(C)cc(C)c21
Agent: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: COC(=O)Cn1c(=O)n(CC(=O)O)c2cc(C)cc(C)c21

Procedure:
Essentially following the procedures described for Intermediate 7, but using tert-butyl [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step C in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=293 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2c(c(C(=O)O)c1)CCCC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(c(C(=O)Cl)c1)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.97 mmol) in DCM (5 mL) was added oxalyl chloride (0.11 mL, 1.21 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and 3-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39]OS(C)(=O)=O)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C)C=O.O>[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][O:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COS(C)(=O)=O)cc1Cl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
To a solution of phenol (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.5 ml) was added sodium hydride (60% in mineral oil, 5.2 mg) under ice-cooling. Thirty minutes later, a solution of 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (68 mg, 0.12 mmol) in N,N-dimethylformamide (1 ml) was dropwise added, which was followed by stirring at room temperature for 3 hr. The reaction mixture was cooled with ice and water was added. Its pH was adjusted to 4 by dropwise addition of 1N hydrochloric acid. The resulting product was extracted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel thin layer chromatography (eluent: chloroform/methanol=20/1) and crystallized from ethyl acetate to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((phenyloxy)methyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (30 mg) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:17]([C:21]1[NH:25][C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=1)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[C:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=[C:21]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
Intermediate (2a) (13.6 g, 45 mmol, 1.0 eq), 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (8.4 g, 45 mmol, 1.0 eq) and potassium carbonate (12.4 g, 90 mmol, 2.0 eq) were added to 90 mL of DMF. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with 300 mL EtOAc and extracted with 100 mL 10% aq. LiCl, 2×200 mL water, 100 mL saturated aqueous NaCl, dried over MgSO4, and filtered. The filtrate was evaporated and purified by flash chromatography (40% EtOAc:hexanes) to yield intermediate (2b) (13.0 g). MS m/z: [M+H+] calcd for C19H26ClN3O3S, 412.1; found 412.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O.[NH2:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[ClH:18].[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:20][C:21]3[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=3[C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[O:24])=[O:13])=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(-c3ccncc3)cc2)cc1
Product: Cl
Reaction time: 48 h
Yield: 30.7 %

Procedure:
To a stirring suspension of 4-(4-pyridyl)benzoic acid (0.2 g, 1 mmol) in toluene (35 mL) was added thionyl chloride (0.55 mL, 7.5 mmol) and the mixture was heated to reflux. After 1 h the solution was cooled and added to a solution of 2-amino-N-(4-methoxyphenyl)benzamide (0.176 g, 0.73 mmol) in pyridine (2 mL) and toluene (5 mL). After stirring for 48 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed with sat. NaHCO3, brine and dried (MgSO4), filtered and concentrated to give 103 mg of brown solid which was chromatographed by RPHPLC Method B. Upon standing, a sample of the title compound (14 mg, 4%) crystalized from one of the product containing fractions.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3].[Br:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:14][C:11]1([CH3:13])[CH2:10][C:9]2[CH:15]=[C:5]([S:2]([NH:1][C:18](=[O:19])[CH:17]([Br:16])[CH3:21])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[O:12]1
Reactant: CC(Br)C(=O)Cl
Reactant: CC1(C)Cc2cc(S(N)(=O)=O)ccc2O1
Product: CC(Br)C(=O)NS(=O)(=O)c1ccc2c(c1)CC(C)(C)O2
Yield: 87.7 %

Procedure:
In a manner similar to Step C of Example 9, the reaction of 4.0 g (0.017 mole) of 5-aminosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran with 7.0 mL (0.069 mole) of 2-bromopropionyl chloride produced 5.4 g of N-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)sulfonyl-2-bromopropionamide as a solid (mp 125°-128° C.).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]=[CH2:3].[N:15]1[CH:20]=CC=C[CH:16]=1.[C:21]([OH:27])(=O)[CH2:22]C(O)=O.C(=O)=O.C(N(CC)CC)C.CN(C)C(Cl)=O>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:22][C:21]([N:15]([CH3:20])[CH3:16])=[O:27])([OH:13])[C:5]1=[O:14])[CH:2]=[CH2:3]
Reactant: c1ccncc1
Reactant: C=CCN1C(=O)C(=O)c2ccccc21
Reactant: O=C(O)CC(=O)O
Agent: CN(C)C(=O)Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2ccccc21
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
A 1 L flask is charged with 1-allyl-1H-indole-2,3-dione (Example 25) (63.6 g, 339 mmol), and pyridine (107.5 g, 1.36 mol). To this, malonic acid (42.4 g, 407 mmol) is added, which leads to a slight exothermic reaction. The obtained slurry is heated at 80° C. until the formation of carbon dioxide ceases and TLC indicates no starting material to be present. To the reddish solution, triethyl amine (51.6 g, 441 mmol) is added, and the mixture is stirred for another 10 minutes when a dark red solution forms. To this solution, dimethyl carbamoyl chloride (47.5 g, 441 mmol) is added during 15 minutes which gives an exothermic reaction with vigorous formation of carbon dioxide. The mixture is stirred for another 15 minutes, and then the solvent is removed on the rotavapor. To the residue, water (about 300 mL) and chloroform (about 300 mL) are added. The pH is adjusted to slightly acidic (6.0) by adding 2 N HCl. The organic layer is separated off, and the aqueous layer extracted once more with chloroform (100 mL). The combined organic layers are dried (sodium sulfate), filtered and, after removal of the solvent, a light brown solid is obtained (107 g). This is triturated with cold water (500 mL, 4° C.), and filtered. After washing and drying the title product is obtained as beige crystals (76.6 g, 82%). 1HNMR (DMSO, 300 MHz) δ 2.63, 2.94 (2 s, 3H each, N(CH3)2); 3.04, 3.30 (AB, 2H, 2J=16.4 Hz, CH2CONMe2); 4.28, 4.35 (ABdtr, 2H, 2J=16.3 Hz, NCH2CH═CH2); 5.15 (ddtr, 1H, 2J=1.5 Hz, 3J=10.3 Hz, 4J=1.5 Hz, CH2CH═CHcis); 5.38 (ddtr, 1H, 3J=17.3 Hz, 4J=1.8 Hz, CH2CH═CHtrans); 5.84 (ddtr, 1H, 3J=4.7 Hz, CH2CH═CH2); 6.82 (d, 1H, J=7.6 Hz, H-7); 6.95 (dtr, 1H, 3J=7.6 Hz, 4J=1.2 Hz, H-5); 7.21 (dtr, 1H, 3J=7.6 Hz, 4J=1.5 Hz, H-6); 7.32 (dd, 1H, 3J=7.3 Hz, 4J=1.2 Hz, H-4). 13C-NMR (DMSO, 75 MHz) δ 35.22, 37.67 (N(CH3)2); 41.23 (CH2CONMe2); 42.27 (NCH2CH═CH2); 73.69 (C-3); 109.36 (C-7); 117.34 (NCH2CH═CH2); 122.22 (C-5); 123.66 (C-4); 129.29 (C-6); 132.39 (C-9); 132.75 (NCH2CH═CH2); 144.30 (C-8); 168.79 (CONMe2); 177.13 (C-2).
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[C:31]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH3:26][N:25]1[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:28])[N:17]=[C:16]1[CH:15]=[CH:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([N:40]3[CH2:41][CH2:42][N:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:38][CH2:39]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)nc4)cc3)n(C)c(=O)c12
Solvent: c1ccncc1
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(N5CCN(c6ccccc6)CC5)nc4)cc3)n(C)c(=O)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[2-[4-(6-chloronicotinoyl)-phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (333 mg) in pyridine (5 ml) was added 1-phenylpiperazine (156 ml) and the mixture was stirred at 90° C. for 4 hours. This reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed serially with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate (1:1)) to provide 162 mg of yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(F)ccc1OCc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(F)ccc1OCc1ccccc1Cl

Procedure:
10.0 g (34 mmol) of methyl 2-(2-chlorobenzyloxy)-5-fluorobenzoate are dissolved in 80 ml of methanol and 40 ml of 40% strength sodium hydroxide solution and stirred at RT for 12 h. The solvent is distilled out in vacuo, water is added to the residue until it has all dissolved, and the solution is then extracted with ethyl acetate. The aqueous phase is acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, washed with ethyl acetate and concentrated. The residue is mixed with petroleum ether, and the crystals which have separated out are filtered off with suction and dried on a clay dish. 6.00 g (21.3 mmol, 63% of theory) of the title compound are isolated.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:13][N:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:35]=[C:34]([CH:36]=O)[O:33][N:32]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:35]=[C:34]([CH2:36][N:21]2[CH2:22][CH2:23][CH:18]([CH2:17][O:16][C:12]3[C:11]4[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8][O:9][C:10]=4[CH:15]=[N:14][N:13]=3)[CH2:19][CH2:20]2)[O:33][N:32]=1
Reactant: c1ccc(-c2noc3cnnc(OCC4CCNCC4)c23)cc1
Reactant: O=Cc1cc(-c2ccccc2Cl)no1
Product: Clc1ccccc1-c1cc(CN2CCC(COc3nncc4onc(-c5ccccc5)c34)CC2)on1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 89 instead of the compound obtained in Example 11 and 3-(2-chlorophenyl)isoxazole-5-carbaldehyde instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:10]1[S:12][CH2:11]1>CCOCC.O>[Cl-:1].[CH3:2][S:3][C:4]1[CH:5]=[N+:6]([CH2:10][CH2:11][SH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: C1CS1
Reactant: CSc1cccnc1
Reactant: Cl
Solvent: O
Solvent: CCOCC
Product: CSc1ccc[n+](CCS)c1
Product: [Cl-]

Procedure:
To a solution of 3-methylthiopyridine1 (2.00 g, 0.016 mol) in 10 mL of ether was added 15 mL of 1N HCl and the mixture was well shaken. The aqueous phase was separated, washed with 10 mL of ether and then evaporated. The residual hydrochloride was then dried in vacuo (P2O5) to give a white solid. To this solid hydrochloride was added 3-methylthiopyridine (1.88 g, 0.015 mol) and ethylene sulfide (0.89 mL, 0.015 mol) and the resulting mixture was heated (oil bath) at 55°-65° C. under N2 for 15 h. This gave a slightly turbid oil which was taken up in 125 mL of H2O and washed with CH2Cl2. The aqueous solution was concentrated to about 25 mL and then a few drops of acetonitrile were added to make the mixture homogeneous. The resulting aqueous solution was applied to a C18 reverse-phase column. Elution with H2O and subsequent evaporation of the relevant fractions afforded the product (2.66 g 80%) as a pale yellow, viscous oil. ir (film) νmax : 2410 (br, --SH) cm-1 ; 1Hnmr (d6 -DMSO+D2O) δ: 8.88-7.88 (m, 4H, aromatic), 4.70 (t, J=6.5 Hz, 2H, N-CH2), 3.08 (skewed t, J=6.5 Hz, 2H, S-CH2), 2.64 (s, 3H, S-Me). 1Prepared by the method of J. A. Zoltewiez and C. Nisi, J. Org. Chem. 34, 765 (1969).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:29][CH3:30])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][NH:21]2)=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[C:31]1([O:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:30][O:29][CH:13]([O:12][CH3:11])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[C:38]([O:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2C(=O)Oc1ccccc1
Temperature: -25 °C
Reaction time: 1.42 h

Procedure:
A solution of LHMDS in THF (1M, 500 μL, 0.500 mmol) was added drop wise to a solution of 7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 321, 130 mg, 0.474 mmol) and diphenylcarbonate (105 mg, 0.490 mmol) in THF (2.2 ml) at −25° C. The reaction mixture was stirred for 85 minutes at −25° C., then warmed to room temperature and stirred for 45 min, placed in a fridge and stored over the weekend at 4° C. The reaction mixture was then cooled to −65° C. and further LHMDS (500 μl, 0.500 mmol) was added and it was allowed to warm to −45° C. to −35° C. and stirred for 80 min. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and water. Phases were separated and the water phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-5%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.78 min; ESI-MS 395.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.44-7.34 (m, 3H), 7.25-7.15 (m, 5H), 5.11 (s, 1H), 4.04-3.96 (m, 2H), 3.34 (s, 6H), 2.90 (t, 2H), 2.15-2.04 (m, 2H).