Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[C:25]#[N:26])[CH3:5].O.[NH3:29]>C1C=CC=CC=1>[C:25]([C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:12][C:7]=1[O:6][CH:4]([CH3:5])[C:3]([NH2:29])=[O:2])#[N:26]
Reactant: N
Reactant: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Solvent: c1ccccc1
Solvent: O
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N)C(N)=O
Temperature: 0 °C
Yield: 57.1 %

Procedure:
A 10 g of methyl-α-[2-cyano-5-(2-chloro-4-trifluoromethyl phenoxy) phenoxy]propionate was dissolved in 20 ml of benzene. The solution was cooled at 0° C and 10 g of 28% ammonia water was added dropwise to react them at room temperature for 2 hours. After the reaction, the benzene phase was separated and was washed with water. The benzene was distilled off and the product was recrystallized from methanol to obtain 5.5 g of the object compound having a melting point of 134° to 137° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: CNC(C)C
Product: CC(C)N(C)Cc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with N-Isopropylmethylamine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide afford 10-bromo-9-fluoro-3-((isopropyl(methyl)amino)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 31 mg (35%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[[isopropyl(methyl)amino]methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][C:34](C1C=CC(C(F)(F)F)=CC=1)=O.C(O[BH3-])(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:33][CH3:34])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(CC)C2)c1
Temperature: 25 °C

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (47 mg, 0.11 mmol), and 4-Trifluoromethylacetophenone (20 mg, 0.11 mmol), in 1,2 dichloroethane (0.7 ml) was added sodium acetoxyborohydride (29 mg, 0.14 mmol) and acetic acid (6.6 μl, 0.12 mmol). The reaction stirred at room temperature with little product. The reaction was heated at 50° C., then reflux over 48 hours. The solution was concentrated in vacuo, and purified by silica gel chromatography to give the above pictured by product. Calcd for C28H36F3NO2 (M+H) 475.59, Found 476.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCCC4)CC3)cc1F)C2=O
Temperature: 80 °C

Procedure:
2-[2-Fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) and pyrrolidine (84.3 mg, 1.19 mmol) were dissolved in anhydrous CH3CN (2 mL). To this colorless solution was added powder K2CO3 at r.t. The suspension was heated in an oil bath maintained at 80° C. for 24 h. The suspension was concentrated to dryness. The residue was taken in water (2 mL) and DCM (2 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 mL×2). The combined DCM extracts were washed with sodium bicarbonate (2 mL), brine (2 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% of MeOH in DCM and 5% 7N NH3 of MeOH solution in DCM to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](Br)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(N)cc1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(Nc2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Reaction time: 6 h
Yield: 82 %

Procedure:
In a reactor were charged p-toluidine (80 parts), 1-methylamino-4-bromoanthraquinone (15.8 parts), sodium acetate (7.5 parts) and copper acetate (0.5 part) and the mixture was kept at 115° to 120° C. for 6 hours under a nitrogen atmosphere. Thereafter, the reaction mixture was diluted with methanol (100 parts) and cooled. The precipitate produced was filtrated, washed with methanol (500 parts) and then water (200 parts), and dried at 80° to 90° C. to obtain 1-methylamino-4-(4'-methylanilino)-anthraquinone (yield 82%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1)[NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23](=[O:24])[O:25][CH3:26]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 68 h
Yield: 69.7 %

Procedure:
To a solution containing the product from Example 150E (0.22 mmol) in tetrahydrofuran (2.5 mL) were added the product from Example 1F (0.046 g, 0.243 mmol), DEPBT (0.099 g, 0.331 mmol), and N,N-diisopropylethylamine (0.19 mL, 1.09 mmol) and the mixture was stirred at room temperature for 68 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on reverse phase HPLC on a C18 column, eluting with a gradient starting with water and ending with methanol to give the title compound (0.108 g, 70% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.79 (s, 9 H), 0.82 (s, 9 H), 1.42-1.59 (m, 2 H), 2.71-2.79 (m, 3 H), 3.48 (s, 3 H), 3.55 (s, 3 H), 3.61-3.67 (m, 1 H), 3.81 (d, J=9.9 Hz, 1 H), 3.91 (d, J=9.6 Hz, 1 H), 4.03-4.20 (m, 2 H), 4.87 (d, J=5.2 Hz, 1 H), 6.64 (d, J=9.6 Hz, 1 H), 6.80 (d, J=9.6 Hz, 1 H), 7.12-7.23 (m, 8 H), 7.50-7.60 (m, 4 H), 7.65 (d, J=5.9 Hz, 2 H), 7.80 (d, J=8.5 Hz, 1 H), 8.61 (d, J=5.9 Hz, 2 H).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[C:16]1[CH2:15][CH:14]([C:22]([NH2:24])=O)[CH2:13][CH2:12][C:11]=1[O:10]2.S(Cl)(Cl)=O>O>[CH3:6][C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[C:16]1[CH2:15][CH:14]([C:22]#[N:24])[CH2:13][CH2:12][C:11]=1[O:10]2
Reactant: Cc1ccc2c(=O)c3c(oc2c1)CCC(C(N)=O)C3
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(=O)c3c(oc2c1)CCC(C#N)C3
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To 15 ml of a dimethyl formamide suspension solution containing 1.0 g of 6-methyl-1,2,3,4-tetrahydro-9-oxo-xanthene-2-carboxylic acid amide was amide was added dropwise 1.19 g of thionyl chloride at 0° C., and the mixture was stirred for 30 minutes. The resulting mixture was then poured into iced water and decomposed. The separated powder was recrystallized from acetone to obtain 0.40 g (yield: 41%) of 6-methyl-1,2,3,4-tetrahydro-9-oxo-xanthene-2-carbonitrile as a white powder having a melting point of 176° to 178° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]>CN(C=O)C>[C:1]([O:8][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCC(=O)O
Solvent: CN(C)C=O
Product: CCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 5 h
Yield: 74.3 %

Procedure:
To a solution of 4.64 g (0.04 mol) of hexanoic acid and 5.75 g (0.05 mol) of N-hydroxy succinimide in 100 mL distilled DMF, 10.3 g (0.05 mol) of DCCl was added. The mixture was cooled with an ice-water bath and stirred for 5 h. The dicyclohexyl urea (DCU) precipitate was removed by filtration, and the DMF solvent was removed by vacuum rotary evaporation. The yellow oil residue was washed with water and hexane to yield a white solid, which was vacuum dried at 78° C. to give 6.34 g (74%) of N-hexanoyloxy succinimide. IR (KBr): 1816 cm−1 (ν(C═O) of ester), 1745-1786 cm−1 (ν(C═O) of imide). 1H-NMR (DMSO-d6, ppm): 0.86 (3H, —CH3), 1.31 (4H, —(CH2)2CH3), 1.62 (2H, CH2CH2COO—), 2.64 (2H, —CH2COO—), 2.80 (4H, —COCH2CH2CO—).
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][C:9](=[O:18])[C:10]([CH3:17])([CH3:16])[CH2:11][C:12](=[O:15])[CH2:13]Br)[CH3:7].[CH3:19][C:20]([SH:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CCCCCC>[CH2:6]([O:8][C:9](=[O:18])[C:10]([CH3:17])([CH3:16])[CH2:11][C:12](=[O:15])[CH2:13][S:23][C:20]([CH3:22])([CH3:21])[CH3:19])[CH3:7]
Reactant: CCOC(=O)C(C)(C)CC(=O)CBr
Reactant: CC(C)(C)S
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Temperature: -2.5 °C
Reaction time: 25 h

Procedure:
To a reaction flask containing tetrahydrofuran (5.0-fold, V/W of starting material) was added 5-bromo-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester (1.0 eq) under nitrogen. The mixture was cooled to a temperature of −5-0° C., and a solution of 2-methyl-2-propanethiol (1.2 eq) and triethylamine (1.25 eq) was added while maintaining the temperature below 0° C. The reaction was stirred at room temperature for 25 hours, and then hexane (3.0-fold, V/W of starting material) was slowly added. After agitating for 30 minutes, the solid material was removed by filtration and washed with 50% ethyl acetate/hexane solution. The filtrate was concentrated under reduced pressure to give the desired product, which was taken on to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.NN.[C:18]([O-])(=O)[CH3:19].[Na+].C(I)C>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:18][CH3:19])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Solvent: O
Product: CCS(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To 2-bromo-5-(chlorosulfonyl)benzoic acid (Preparation 72, 10.1 g, 33.8 mmol) dissolved in THF (100 mL) was added hydrazine monohydrate (3.32 mL, 67.6 mmol) cautiously at 0° C. under nitrogen. A fine precipitate formed, the reaction was allowed to warm to room temperature over 126 hours before filtering. The solid was washed with heptanes, dried under reduced pressure and dissolved in industrial methylated spirit (100 mL). To this solution was added sodium acetate (16.6 g, 203 mmol) and ethyl iodide (13.5 mL, 169 mmol) and the reaction heated to reflux for 20 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue partitioned between EtOAc (500 mL) and sodium hydroxide solution (1M, 500 mL). The layers were separated and the organic layer discarded. The aqueous layer was acidified to pH=1 with HCl (1M, 500 mL) and extracted with EtOAc (5×500 mL). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to give the title compound as a tan solid in 48% yield, 4.82 g.
Reaction SMILES: [F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[CH:22]([NH:24][C:25](=[O:27])[CH3:26])=[CH2:23].C(N(CC)CC)C.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9]([C:22]([NH:24][C:25](=[O:27])[CH3:26])=[CH2:23])[CH:10]=[CH:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=S(=O)(Oc1cccc(C(F)(F)C(F)(F)F)c1)C(F)(F)F
Reactant: C=CNC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(NC(C)=O)c1cccc(C(F)(F)C(F)(F)F)c1
Temperature: 130 °C

Procedure:
To a solution of the crude product of step 1 (0.75 g, 2.2 mmol) in DMF (10 ml) was added N-vinylacetamide (0.37 g, 4.36 mmol), triethylamine (243 mg, 0.33 ml, 2.40 mmol), palladium acetate (20 mg, 4 mol %) and bis(diphenylphosphino)propane (40 mg, 0.1 mmol). The reaction mixture was heated for 30 min at 130° C. using microwaves. The red solution was diluted and washed with hydrochloric acid (1M, 2×15 ml) and sodium hydrogen carbonate (saturated, 20 ml). The organic phase was dried over sodium sulphate and evaporated. Purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane (2:1) gave the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C:11]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(C(C)(C)C)cc2C1=O
Yield: 53 %

Procedure:
A solution of 11.0 g of 6-tert-butyl-1-indanone, 12.5 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 41 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). 7.35 g (53%) of (RS)-2-(2-buten-1-yl)-6-tert-butyl-1-indanone was obtained as a yellow oil.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[H-].[Na+].C[O:12][C:13](=[O:27])[C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C1COCC1.O>[C:20]([N:15]1[CH2:16][C@H:17]([O:19][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([Br:28])=[CH:30][CH:31]=2)[CH2:18][C@H:14]1[C:13]([OH:12])=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(O)[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.6 %

Procedure:
The compound of formula (P5), wherein R′ is 4-Bromo and the bonds linking the benzyloxy and methyl ester groups (depicted in P5 as wavy bonds) define the trans, L-proline configuration (2S,4R) was prepared as follows. To a suspension of sodium hydride (60% in oil) (0.12 g) (1.5 eq.) in 5 mL of dry THF was added trans-N-Boc-4-hydroxy-L-proline methyl ester (0.5 g) in 5 mL of dry THF. The reaction mixture was stirred for 45 minutes and a solution of 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5 mL of dry THF was added. The reaction mixture was refluxed for 3 hours. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and evaporated under reduced pressure to afford trans-N-Boc-4-(4-bromo-benzyloxy)-L-proline (0.25 g). NMR (CDCl3, 200 MHz): 7.47 (2H, d), 7.2 (2H, d), 4.50-4.30 (3H, m), 4.25-4.1 (1H, m), 3.75 (3H, s), 3.8-3.5 (2H, m), 2.5-2.3 (1H, m), 2.15-1.95 (1H, m), 1.5-1.35 (9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][C:4]=2[N:3]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[ClH:1].[O:25]([C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][C:4]=2[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CC(c2ccccc2)Cc2nc(Cl)ccc21
Reactant: Oc1ccccc1
Product: Cl
Product: O=C1CC(c2ccccc2)Cc2nc(Oc3ccccc3)ccc21

Procedure:
In analogy to the procedure described in Example 9, 2-chloro-7-phenyl-7,8-dihydro-6H-quinolin-5-one was treated with phenol to give the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)[C:35](=[O:36])[CH2:34][C:29]2[NH:28][C:27]3[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=3[S:31](=[O:32])(=[O:33])[N:30]=2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(2-cyclopropyl-ethylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (338.2 mg, 1.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) under a nitrogen atmosphere, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 493 mg, 1.48 mmol), N-methylmorpholine (0.33 mL, 2.96 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg, 1.48 mmol) were added sequentially. After shaking at 25° C. for 21 h, additional (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 150 mg, 0.45 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.44 mmol) were added. After another 26 h, a 1.0 M aqueous hydrochloric acid solution (12 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated aqueous brine solution (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a red oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H34N4O7S2 566.19, found 567.4 [M+H+].
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[N:18](COCC[Si](C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[N:21]=2)=[O:16])[CH2:4][CH2:3]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl.CCO>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=2)=[O:16])[CH2:4][CH2:3]1
Reactant: CC1CCN(c2ccccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CC1CCN(c2ccccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 40 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
A solution of 153 mg (0.348 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with EtOH (1 drop) and TFA (1 mL), and the mixture was warmed to 40° C. for 2 h and left at RT for 2 days. The mixture was concentrated to dryness, taken up in CH2Cl2 (5 mL), and treated with EtOH (1 drop) and TFA (1.00 mL) at RT for 7 h. The mixture was concentrated in vacuo. The residue was taken up in MeOH (2.5 mL) and a 10% solution of acetonitrile in water (7.5 mL) to form a suspension. The solid was filtered and triturated with a minimum amount of acetone to afford 50.7 mg (34%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.35-8.32 (m, 1H), 8.03 (s, 1H), 7.29-7.26 (m, 1H), 7.15-7.12 (m, 2H), 3.09-2.99 (m, 2H), 2.81-2.74 (m, 2H), 1.85-1.80 (m, 2H), 1.72-1.56 (m, 3H), 1.09 (d, 3H, J=6.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C17H19N5O, 310.2 (M+H), found 310.0.