Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]2=[O:17])=[CH:6][N:5]=[C:4]([CH3:18])[N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([CH2:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[C:11]([Br:26])[C:10]2=[O:17])=[CH:6][N:5]=[C:4]([CH3:18])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(Cn2c(C)cc(O)cc2=O)c(N)n1
Solvent: CC(=O)O
Product: Cc1ncc(Cn2c(C)cc(O)c(Br)c2=O)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A mixture of 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-hydroxy-6-methylpyridin-2(1H)-one (0.5 g, 0.002 mol), and NBS (0.4 g, 0.002 mol)in glacial acetic acid (5.0 ml) was stirred at room temperature for 1 h under argon atmosphere. Acetic acid was removed in vacuo, residue was triturated with EtOAc containing 10% EtOH, and filtered. The pale yellow precipitate was washed with EtOAc containing 10% EtOH and dried in vacuo to afford the title compound (0.47 g, 725) as a pale yellow powder:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[N:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:36]([C:33]2[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: CC(C)(C)CC1CN(S(=O)(=O)c2ccc(Cl)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 998.4 %

Procedure:
In a manner similar to the method described in Example 83, a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (82 mg, 0.0195 mmol) was reacted with 6-chloropyridine-3-sulfonyl chloride (66 mg, 0.311 mmol, Enamine) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(6-chloro-pyridine-3-sulfonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (116.6 mg, 97%) as a light yellow solid.
Reaction SMILES: CC(C)[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].BrC1[CH:41]=[C:42]2[C:46](=CC=1)C(=O)N([C@@H](CC(C)C)C(OC)=O)[CH2:43]2.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:41][CH:42]([CH3:46])[CH2:43][C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](CC(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 78 %

Procedure:
The compound of example 387 was prepared analogous to compound of example 360 by reaction of the compound of example 386, compound of example 357 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9](OCCC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])C.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1.CO>[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][N:9]([CH2:32][CH2:36][O:35][C:34]3[CH:33]=[CH:8][CH:7]=[CH:6][CH:4]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(OCCc2ccccc2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared staring from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylic acid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (63%); off white powder; mp 235° C.; MS: 420.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:20])[CH:15](Cl)[C:16](=O)[CH3:17])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:16]=1[CH3:17])=[O:20])[CH3:12]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(F)cc2)nc1C
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 4-fluoro-thiobenzamide (1.25 g, 8.04 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (1.11 mL, 8.20 mmol) in ethanol (18 mL) was heated at refluxed for 16 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (1.99 g): MS: (+) m/z 266.03 (M+1).
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=1>[Pd].C1COCC1>[NH:15]1[C:16]2[C:12](=[C:11]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Nc1ccc(Br)cn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(-c2cccc3[nH]ccc23)cn1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 83.7 %

Procedure:
Palladium catalyst Pd(PPh3)4 (142 mg, 0.12 mmol) and freshly prepared aqueous sodium hydroxide (493 mg, 12.33 mmol in 6 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (1 g, 4.11 mmol) and 2-amino-5-bromopyridine (853 mg, 4.93 mmol) in THF (20 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 80° C. in an oil bath for 4.5 hours. It was then cooled to room temperature and ethyl acetate (300 mL) was added. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give 720 mg (84%) of 5-(1H-indol-4-yl)-pyridin-2-ylamine as a thick brown syrup.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[OH:24][CH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:25][OH:24])[CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OCc1cccc(B(O)O)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(CO)c4)c(C(=O)O)s3)c2cc1OC
Yield: 1.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-hydroxymethylphenylboronic acid (22.9 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-hydroxymethyl-phenyl)-thiazole-5-carboxylic acid (0.8 mg, 2.0%) as a white solid. MS 412 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].[C:41]([O:44][CH:45](Cl)[CH3:46])(=[O:43])[CH3:42].O>CN(C=O)C>[C:41]([O:44][CH:45]([O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:46])(=[O:43])[CH3:42]
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Reactant: CC(=O)OC(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol) and sodium bicarbonate (185 mg, 2.2 mmol) in DMF (2 mL) was added 1-chloroethyl acetate (270 mg, 2.2 mmol) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (30 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product, which was purified by silica gel chromatography using a Biotage (40 s) column to afford 110 mg (65% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C28H25Cl2F3N2O6 (M+Na) 635.0931. found 635.0932.
Reaction SMILES: [Cl:1]C1C=C(N2C=CC(=O)N(CCCC(O)=O)C[C@H]2C)C=CC=1C(F)(F)F.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1>>[ClH:1].[CH2:28]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:27]1
Reactant: C[C@@H]1CN(CCCC(=O)O)C(=O)C=CN1c1ccc(C(F)(F)F)c(Cl)c1
Agent: O[C@@H]1CNCCC12CC2
Product: Cl

Procedure:
In analogy to the procedure described in Example 15, 4-[(R)-4-(3-chloro-4-trifluoromethyl-phenyl)-3-methyl-7-oxo-2,3,4,7-tetrahydro-[1,4]diazepin-1-yl]-butyric acid (22% ee) (intermediate 34) and 1.1 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave after purification by flash chromatography (50 g amine-silica, ethyl acetate/n-heptane 1:1, 4:1, 9:1, 100%, ethyl acetate/ethanol 99:1 to 95:5) 69% of the title compound as off-white foam. MS: 500.19 (MH+, Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][C:21]([F:36])([CH:33]([F:35])[F:34])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:30]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]([F:36])([F:20])[CH:33]([F:35])[F:34])=[CH:29][N:28]=4)=[O:31])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)F)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid (prepared as described in Banner, D. et al., WO 2011/069934) following procedure G yielded the title compound as a white solid. MS: m/z=501.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:5])C.O[Li].O>C1COCC1.O>[CH2:19]([N:9]1[CH2:10][C:11]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 0.555 g (1.26 mmol) 1-benzyl-5-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester and 261 mg (6.2 mmol) LiOH.H2O in 15 mL THF and 5 mL water was stirred at room temperature over night. The mixture was evaporated to dryness, taken up in ethyl acetate, acidified with HCl to pH=1 and extracted with ethyl acetate. The combined organic layers were washed with water, evaporated to dryness and the residue was subjected to preparative HPLC chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 0.254 g (50%) of the title compound as white solid. MS (m/e): 328.2 [(M+H)+].
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:9][CH2:8][CH2:7]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][CH2:5][C@@H:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:9][CH2:8][CH2:7]1
Reactant: CC(=O)OC[C@@H]1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A mixture of (5R)-5-acetyloxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.49 g), potassium carbonate (1.11 g) and methanol (15 ml) is stirred at room temperature for 20 minutes. The reaction solution is poured into water, and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, and concentrated under reduced pressure to give (5S)-5-hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.33 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:13]=2)[N:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][CH3:9].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[Cl:10][C:6]1[C:7]([CH2:8][CH3:9])=[C:2]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]2[N:4]([CH:11]=[CH:12][N:13]=2)[N:5]=1
Reactant: Nc1ccccc1
Reactant: CCc1c(Cl)nn2ccnc2c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(Cl)nn2ccnc2c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A mixture of 8-bromo-6-chloro-7-ethylimidazo[1,2-b]pyridazine (60 mg, 0.2 mmol, 1 eq) from 1d, aniline (20.3 μL, 0.22 mmol, 1.1 eq) and potassium tert-butoxide (0.51 mL, 0.51 mmol, 2.5 eq) were suspended in DMF (3 mL) and stirred at RT for 1 h. The mixture was quenched with ethyl acetate and washed with lithium chloride saturated solution, dried with sodium sulfate and concentrated in vacuo. The residue was purified using an ISCO chromatography system (4 g silica cartridge, 5% ethyl acetate in heptane) to provide 6-chloro-N-phenyl-7-ethylimidazo[1,2-b]pyridazin-8-amine (22 mg). LC/MS, m/e 273.14 (M+1). HPLC Rt, 2.24 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[O:14][CH2:13][CH2:12][O:11]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2sccc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2cc(C3OCCO3)ccc2s1
Reaction time: 7 h

Procedure:
16.5 g of 1-benzothiophene-5-carbaldehyde and 49.5 mL of ethylene glycol were dissolved in 165 mL of toluene, to which 0.30 g of para-toluenesulfonic acid monohydrate was added, and this solution was stirred for 7 hours while heating it under reflux. The reaction mixture was cooled to room temperature, to which an aqueous solution of sodium hydroxide was added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 15.8 g of 2-(1-benzothiophen-5-yl)-1,3-dioxolane as yellow oil.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.O.[NH2:28][NH2:29]>CO>[C:16]1([CH:4]2[NH:5][C:6]3[C:11]4[C:2](=[N:28][NH:29][C:12](=[O:14])[C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH:3]2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cncs1)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1cncs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
Methyl 4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (110 mg, 0.29 mmol) and hydrazine monohydrate (2 mL) were added to methanol (10 mL) and the mixture was stirred room temperature for 4 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered; the filtrate was concentrated to give 8-phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (13 mg, yield 13%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 4.67 (d, 1H), 4.78 (d, 1H), 7.10-7.19 (m, 4H), 7.24 (t, 2H), 7.45-7.56 (m, 2H), 8.76 (s, 1H); LC-MS (ESI) m/z: 347 (M+1)+.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([OH:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[OH:59].[OH-].[Na+:61]>O.CO>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([O-:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[OH:59].[Na+:61]
Reactant: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)N[C@H](C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](O)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc([O-])c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)N[C@H](C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](O)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O

Procedure:
A solution of benanomicin A (82.7 mg) in a mixture of 10 ml of water and 1.1 ml of 0.1M NaOH was lyophilized. The residue was dissolved in 3 ml of methanol and chromatographed on a Sephadex LH-20 column (300 ml) developed with methanol to obtain benanomicin A sodium salt (75.8 mg).
Reaction SMILES: [CH3:1][C:2]12O[C:8]([CH3:12])([CH:9]=[CH:10]1)[CH:7]1[CH:3]2[C:4](=[O:14])[O:5][C:6]1=[O:13]>S(=O)(=O)(O)O>[CH3:12][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[C:6](=[O:13])[O:5][C:4]2=[O:14]
Reactant: CC12C=CC(C)(O1)C1C(=O)OC(=O)C12
Agent: O=S(=O)(O)O
Product: Cc1ccc(C)c2c1C(=O)OC2=O
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
1,7-Dimethyl-4,10-dioxa-tricyclo[5.2.1.0]dec-8-ene-3,5-dione 1 (30.0 g, 0.150 mol) is added slowly in portions to stirred 98% sulfuric acid (300 mL) in a 1 L flange flask cooled to −5° C. using a salt-ice bath—note that the temperature is kept below 0° C. during the addition. The mixture is stirred for 30 mins at −5° C. and then allowed to warm up to 22° C. The mixture is carefully poured onto crushed ice (1.5 L). The cream precipitate that formed is filtered off and washed with ice water. The precipitate is dissolved in a 5% aq. sodium hydroxide solution (225 mL) with stirring. Glacial acetic acid (20 mL) is added slowly to the stirred solution. A cream precipitate forms and this is filtered off and discarded. 37% Hydrochloric acid (50 mL) is added to the stirred filtrate and the mixture is stirred for 2 h during which time a precipitate is formed. The precipitate is filtered off and dried in the vacuum oven overnight to yield the product as a cream solid (11.13 g, 41%). The filtrate is allowed to stand overnight during which time further product precipitated out. The second crop of precipitate is filtered off and dried under vacuum to yield the product 2 as a cream solid (5.79 g, 21%): 1H-NMR (300 MHz, CDCl3) δ 7.18 (s, 2H), 2.40 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([NH:14][CH:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][NH:35][C:16](=[O:18])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:31]=[CH:32][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=2)=[CH:9][CH:10]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=1
Reactant: COc1ccc(Oc2ccc(C(=O)NC(Cc3ccc(OC(F)(F)F)cc3)C(=O)O)cc2)cc1
Reactant: NCCO
Product: COc1ccc(Oc2ccc(C(=O)NC(Cc3ccc(OC(F)(F)F)cc3)C(=O)NCCO)cc2)cc1
Yield: 89.3 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4-methoxyphenoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (490 mg, 1.03 mmol) prepared in Example 49 (49a) and 2-aminoethanol (112 μL, 1.86 mmol) to give 477 mg of the title compound (white powder, yield: 89%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: [H][H]
Reactant: CCOC(=O)c1cncc(-c2ccc(C(C)C)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCC(c2ccc(C(C)C)cc2)C1

Procedure:
2.4 g (8.9 mmol) of ethyl 5-[4-(1-methylethyl)phenyl]pyridine-3-carboxylate were dissolved in 60 ml of ethanol, 1.33 g Pd/C (10%) were added and the mixture was hydrogenated in an autoclave at 60° C. at a hydrogen pressure of 50 bar overnight. The reaction mixture was filtered through silica gel. The resulting solution was concentrated under reduced pressure. Water was added to the residue and the solution was adjusted to pH 8 using aqueous 1 N sodium hydroxide solution. The mixture was then extracted with dichloromethane. The organic phase was dried over sodium sulphate and concentrated. Yield: 2.1 g (81% of theory)