Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[NH:9][C:10]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:11]=2[N:12]=1.S(=O)(=O)(O)O>>[CH3:17][C:14]1[CH:15]=[CH:16][C:10]2[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[C:6]3[N:12]([CH:3]=[CH:4][N:5]=3)[C:11]=2[CH:13]=1
Reactant: COC(CNC1=Nc2cc(C)ccc2Nc2ccccc21)OC
Agent: O=S(=O)(O)O
Product: Cc1ccc2c(c1)-n1ccnc1-c1ccccc1N2

Procedure:
In the manner given in Example 5, 8-methyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal is treated with concentrated sulfuric acid to give 6-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:30][CH3:31])=[CH:8][C:7]([CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[CH:6][N:5]=1)(=[O:3])[NH2:2].Cl>O1CCOCC1>[Cl:40][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([Cl:39])[C:33]=1[CH2:32][C:7]1[CH:8]=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:30][CH3:31])[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1cc(Cc2c(Cl)cccc2Cl)cnc1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N2CCNCC2)ccc1Nc1cc(Cc2c(Cl)cccc2Cl)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product of EXAMPLE 1C (76 mg, 0.13 mmol) in dioxane (1 mL) was treated with 4N HCl in dioxane (1 mL) and stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure; and the residue was neutralized with 1N aqueous NaOH and extracted with dichloromethane. The organics were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% methanol in dichloromethane) provided the title compound. 1H NMR (DMSO-d6) δ ppm 2.85 (t, 4H, J=5.2 Hz), 3.05 (t, 4H, J=5.2 Hz), 3.66 (s, 3H), 4.19 (s, 2H), 6.39-6.42 (m, 1H), 6.57 (s, 1H), 6.88-6.97 (m, 2H), 7.33 (t, 1H, J=8.4 Hz), 7.48-7.51 (m, 3H), 7.73 (s, 1H), 8.06 (s, 1H), 9.88 (s, 1H); MS (ESI) m/z 487 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:29])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:29])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Solvent: CO
Product: CCOC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Yield: 65.3 %

Procedure:
The same procedures as in Example 8 were performed except that 0.1 g (0.25 mmol) of ethyl 7-(N-benzyloxycarbonylamino)-3-oxo-2-phenylheptanoate and 1.4 mg (0.00125 mmol) of [RuI(p-cymene)(S)-BINAP]I were placed in an 100 ml autoclave, 2 ml of methanol was added, and the reaction was performed under a hydrogen pressure of 65 kg/cm2 for 18 hours, to prepare the target compound as a colorless oil. (Yield was 65.3%) The ratio of the syn-form to the anti-form was 87.5:12.5, and the optical purity of the syn-form was 93.2% ee.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33](Cl)=O>C1COCC1.CN(C=O)C.O>[CH3:16][C:15]1[C:14](=[O:17])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:33]=1[C:29]1[O:28][CH:32]=[CH:31][N:30]=1
Reactant: O=C(Cl)c1ncco1
Reactant: CCC(=O)c1cccnc1Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A solution of 1-(2-phenylamino-pyridin-3-yl)-propan-1-one (2.0 g, 8.84 mmol) in THF (17.7 mL) at 25° C. was treated with sodium bis(trimethylsilyl)amide (1.0 M in THF) (22.1 mL, 22.1 mmol). The resulting red solution was then treated with a mixture of oxazole-2-carbonyl chloride (1.51 g, 11.5 mmol) in THF (8 mL) and 10 drops of DMF. The reaction was then stirred at 25° C. overnight. The reaction was diluted with water (50 mL) and was then extracted into ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was absorbed onto silica and dried under high vacuum. Flash chromatography (25 g, 25%-75% ethyl acetate-hexanes) afforded 3-methyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one (540 mg, 20.1%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:26]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)(=[O:28])=[O:27])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC)c(OC)c3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
To a solution of intermediate 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 3,4-dimethoxybenzenesulfonyl chloride (320 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12b as a solid (200 mg, 53.0%). HPLC: 99% (Rt 6.507 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:24][CH2:25][CH2:26][NH:27][C:28]2[C:29](=[O:45])[N:30]([C:41]([CH3:44])([CH3:43])[CH3:42])[S:31](=[O:40])(=[O:39])[C:32]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=O)=O)=CC=1>>[C:41]([N:30]1[C:29](=[O:45])[C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[S:31]1(=[O:39])=[O:40])([CH3:42])([CH3:43])[CH3:44]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: COC(=O)Cc1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Yield: 66 %

Procedure:
The title compound was prepared as described for Example 12 from methyl (3-hydroxyphenyl)acetate and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 20-40% EtOAc in petroleum ether 40-60° C. as eluent. The product containing fractions were evaporated and the residue was dissolved in EtOAc, washed with aqueous K2CO3 (2M) and evaporated give the title compound (0.097 g, 66%). 1H NMR (500 MHz CDCl3): δ 7.55-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.26 (t, 1H), 6.90 (dd, 1H), 6.82-6.78 (m, 2H), 5.76 (t, 1H), 3.90 (t, 2H), 3.72 (s, 3H), 3.61 (s, 2H), 3.14-3.06 (m, 2H), 1.90-1.80 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 172.1, 159.8, 158.7, 135.7, 135.3, 131.8, 129.9, 129.8, 128.8, 125.3, 122.3, 115.5, 113.4, 107.2, 65.9, 61.7, 52.3, 42.4, 41.4, 29.0, 27.8; Mass Spectrum: M+H+ 487.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C@@H:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:30])=[CH:3]1.[OH-].[Na+:32]>O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C@@H:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([O-:26])=[O:25])[C:14]2=[O:30])=[CH:3]1.[Na+:32]
Reactant: CCC[C@@H](CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC[C@@H](CC(=O)[O-])n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a mixture of (S)-3-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (1.45 g, 3.6 mmol) in H2O (25 mL) was added NaOH (1.041 M in THF) (3.1 mL, 3.2 mmol). The solution was stirred at room temperature for 2 hours. The solution was washed with EtOAc (30 mL×2) and the aqueous layer was lyophilized to give the desired sodium (S)-3-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoate (1.4 g, 91%) as a white solid. LCMS (ESMS):428.10 (M+H+).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:13]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:34][C@@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:36]([OH:41])[C:37]([O:39][CH3:40])=[O:38].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:13]([NH:15][C@H:16]([C:21]([NH:34][C@@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:36]([OH:41])[C:37]([O:39][CH3:40])=[O:38])=[O:23])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(=O)O
Reactant: COC(=O)C(O)[C@@H](N)CC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of 83 mg of N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-leucine and 40 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride in 3 ml of N,N-dimethylformamide were added 0.049 ml of diphenylphosphoryl azide and 0.058 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol = 10/1 by volume: Rf = 0.43) to obtain 43 mg of methyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-leucyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=C(NC(=O)C)C=CC=3)CC2)=CC=1OCC.Cl.Cl.[Cl:31][C:32]1[N:33]=[C:34]([NH:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2.[CH2:49]([O:51][C:52]1[CH:57]=[C:56]([CH:58]=O)[CH:55]=[C:54]([O:60][CH2:61][CH3:62])[C:53]=1[C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=1)[CH3:50]>>[Cl:31][C:32]1[N:33]=[C:34]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:58][C:56]3[CH:55]=[C:54]([O:60][CH2:61][CH3:62])[C:53]([C:63]4[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=4)=[C:52]([O:51][CH2:49][CH3:50])[CH:57]=3)[CH2:45][CH2:44]2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: Clc1cc2ccccc2c(NC2CCNCC2)n1
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)ccc1Cl
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)cc4ccccc34)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile (example 38/step 3) from (3-chloro-isoquinolin-1-yl)-piperidin-4-yl-amine dihydrochloride (intermediate B13) and 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (intermediate E22) in a yield of 8.9 mg (11%). MS (ISP): 534.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:28]Br)[CH:6]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:4]2[S:3]1.C(OCC)(=O)C.P(=O)(O)(O)O>CN(C)C=O>[CH3:1][C:2]12[CH2:28][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:4]1[S:3]2
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Temperature: -10 °C
Yield: 39.1 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2-bromomethyl-6-(2-phenylacetamido)penam-3-carboxylate(1.08 g.) in dimethylformamide (10 ml.) was added 1,8-diazabicyclo[5,4,0]undecene-7(360 mg.) under cooling at -50° to -60°C and stirred at the same temperature for an hour The inner temperature of the reaction mixture was raised to -10°C. The mixture was poured into a solution of ethyl acetate and dilute phosphoric acid and then extracted. The extract was washed with dilute phosphoric acid, water, a saturated aqueous solution of sodium bicarbonate and water in turn, treated with activated charcoal and dried over magnesium sulfate. After removing the solvent, the residue was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate(360 mg.), mp. 140° to 143°C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][N:4]1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[NH2:16])[CH3:2].C(OC([NH:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38](O)=[O:39])=O)(C)(C)C>>[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38]([NH:16][C:11]1[CH:12]=[N:13][N:14]([CH3:15])[C:10]=1[N:4]1[CH2:5][CH2:6][N:7]([CH3:9])[CH2:8][C@@H:3]1[CH2:1][CH3:2])=[O:39]
Reactant: CC[C@H]1CN(C)CCN1c1c(N)cnn1C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC[C@H]1CN(C)CCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C

Procedure:
Following the procedure for Example 110 starting from (S)-5-(2-ethyl-4-methylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-amine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave 176 as a lilac solid (53 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.88 (s, 1H), 7.37-7.27 (m, 1H), 7.01 (t, J=8.8 Hz, 2H), 6.16 (s, 2H), 3.76 (s, 3H), 3.32 (t, J=11.3 Hz, 1H), 3.22 (t, J=9.3 Hz, 1H), 2.96 (t, J=12.9 Hz, 2H), 2.79 (d, J=11.0 Hz, 1H), 2.42-2.22 (m, 4H), 1.96 (t, J=10.2 Hz, 1H), 1.41-1.33 (m, 1H), 1.29-1.15 (m, 1H), 0.80 (t, J=7.5 Hz, 3H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]3([CH3:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]3([CH3:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC2(C)CCOCC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: COc1cn(C(CC2(C)CCOCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
69.0 mg (119 μmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoate (racemate) in 4.3 ml of ethanol/water (3/1) were reacted with 198 mg (609 μmol) of caesium carbonate according to General Method 4, giving the title compound after preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 38 mg (57% of theory)
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[NH:15][NH:16][C:17](=O)[C:18]3[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([O:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]=3[O:31][CH2:32][O:33][CH3:34])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[OH-].[K+].Cl.C(=O)([O-])O.[Na+]>>[CH:24]([C:22]1[C:21]([O:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]([O:31][CH2:32][O:33][CH3:34])=[C:18]([C:17]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[C:14]([OH:36])=[N:15][N:16]=2)[CH:23]=1)([CH3:26])[CH3:25]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NNC(=O)Nc1ccc(N2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(O)n1-c1ccc(N2CCOCC2)cc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
4-[4-(morpholin-4-yl)-phenyl]-1-[5-isopropyl-2,4-bis(methoxymethoxy)-benzoyl]semicarbazide (IM5-O-a01: 104.9 mg, 0.209 mmol) was mixed with 5% aqueous sodium hydroxide solution (2 mL) and stirred 105° C. (bath temperature) for 2 hours. Further, potassium hydroxide (100 mg) was added to the reaction mixture and the resulting mixture was stirred at 130° C. (bath temperature) for 3 hours. After cooling to room temperature, the reaction mixture was neutralized with 2 N hydrochloric acid and aqueous sodium hydrogencarbonate, extracted with dichloromethane (50 mL) and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol=20:1) to obtain the title compound (IM6-O-a01: colorless syrup, 16.3 mg, 16%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH:12]1[C:17]([CH:18]=O)=[CH:16][C:15]2[O:20][CH2:21][O:22][C:14]=2[CH:13]=1.[OH-].[Na+].C(O)C>O>[O:22]1[C:14]2[CH:13]=[CH:12][C:17]([CH:18]=[CH:1][C:2]([C:4]3[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=3[OH:11])=[O:3])=[CH:16][C:15]=2[O:20][CH2:21]1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
1 g (5.86 mmol) of 5-chloro-2-hydroxyacetophenone, 3 molar equivalents of piperonal, and 3 molar equivalents of sodium hydroxide was mixed in 15 ml of aqueous 80% ethanol solution, and then the mixture was stirred at room temperature for 15 hours. After the reaction was completed, 50 ml of water was added thereto, and the mixture was stirred for about 10 minutes. The obtained pale yellow solid was filtered, washed with water and diethylether, and dried to give 1.42 g (Yield 80%) of the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)([CH2:21][CH3:22])[C:17](OC)=[O:18])=[CH:12][CH:11]=1>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)([CH2:21][CH3:22])[C:17](=[O:18])[CH2:2][C:1]#[N:3])=[CH:12][CH:11]=1
Reactant: CC#N
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C(=O)CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of acetonitrile (180 mg, 4.4 mmol) in tetrahydrofuran (3 mL) was added BuLi (1.9 mL, 4.8 mmol, 2.5 M in hexane) at −78° C. After stirring for 30 min, a solution of methyl 2-(4-chlorophenyl)-2-(4-(methylsulfonamido)-1H-indol-1-yl)butanoate (840 mg, 2.0 mmol, Enantiomer A), as described in Example 3 step D, in tetrahydrofuran (3 mL) was added to the mixture at −78° C. The resulting mixture was stirred at −78° C. for another 1 h, and then quenched with water (15 mL), extracted with ethyl acetate. The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (5/1 to 3/1, v/v) to get the title compound as a colorless amorphous solid (Enantiomer A). LC/MS m/z=429.8[M+H]+.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=[O:8].[C-:17]#[N:18].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:7]([OH:8])[C:17]#[N:18])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14]
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)c1ccc(OC(F)F)c(OC(F)F)c1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To 132A (470 mg, 2.0 mmol) in ethyl acetate (5 mL) was added a solution of KCN (676 mg) and NaHSO3 (1.08 g) dissolved in H2O (5 mL). It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 132B (383 mg, 72% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.56 (d, J=5.27 Hz, 1H) 6.32-6.77 (m, 2H) 7.32-7.36 (m, 1H) 7.40-7.44 (m, 1H) 7.45 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:30][NH:31][CH:32]([CH3:34])[CH3:33]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:32]([N:31]([CH3:30])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1)([CH3:34])[CH3:33]
Reactant: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(OCCCl)cc3c2=O)c1
Reactant: CNC(C)C
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(OCCN(C)C(C)C)cc3c2=O)c1
Temperature: 150 °C
Yield: 63.3 %

Procedure:
3-[7-(2-Chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide (150 mg), potassium iodide (129 mg) and methylisopropylamine (244 μL, 2.34 mmol) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave 3-[7-[2-(Isopropylmethylamino)ethoxy]-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide as a foam (104 mg); NMR Spectrum: (DMSO d6) 0.97 (d, 6H), 1.12 (t, 3H), 2.11 (s, 3H), 2.23 (s, 3H), 2.75 (t, 2H), 2.83 (m, 1H), 3.29 (m, 2H), 4.13 (m, 2H), 6.73 (d, 1H), 7.23 (d, 1H), 7.41 (m, 1H), 7.51 (d, 1H), 7.67 (d, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 7.89 (m, 1H), 8.51 (t, 1H); Mass Spectrum: M+H+ 422.