Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:28]=[CH:27][C:20]([CH2:21][CH:22]([C:24]([OH:26])=[O:25])[NH2:23])=[CH:19][CH:18]=1>>[C:24]([CH:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][C:17]([F:16])=[CH:18][CH:19]=1)([OH:26])=[O:25]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccc(F)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(F)cc1)C(=O)O
Yield: 80 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-fluoro-DL-phenylalanine to provide the title compound in 80% yield as yellow needles.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([C:14]1[C:15]([NH2:23])=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=12)([CH3:13])[CH3:12]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH2:7][C:8]([NH:23][C:15]2[C:14]([CH:11]([CH3:13])[CH3:12])=[C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCC1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1c(NC(=O)CCC2CCCC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyclopentylpropionyl chloride (0.048 mL, 0.31 mmol) in CH2Cl2 (0.2 mL) was added to a stirring solution of the product from Example 112C (35 mg, 0.20 mmol) in pyridine (1.2 mL) in a 4 mL vial. The yellow solution was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and concentrated under vacuum (repeated three times) to remove excess pyridine. The off-white solid residue was crystallized from 60% ethanol-water (8 mL) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.10-1.27 (m, 2H) 1.41 (d, J=7.1 Hz, 6H) 1.48-1.98 (m, 9H) 2.47 (t, J=7.6 Hz, 2H) 3.01-3.22 (m, 1H) 6.91 (dd, J=7.1, 4.1 Hz, 1H) 8.42 (dd, J=4.1, 2.0 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H); MS (ESI) m/z 301 (M+H)+; Anal. Calculated for C17H24N4O: C, 67.97; H, 8.05; N, 18.65. Found: C, 68.03; H, 8.03; N, 18.60.
Reaction SMILES: [C:1]1([C:6]2([CH2:11][OH:12])[CH2:10][CH:9]=[CH:8]O2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[OH:14].[Na+]>CC(C)=O.O>[OH:14][CH:10]1[CH:9]=[CH:8][C:11](=[O:12])[CH:6]1[CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: OCC1(C2=CCCC2)CC=CO1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1C=CC(O)C1C1C=CCC1
Reaction time: 24 h
Yield: 55 %

Procedure:
2-Cyclopentenyl-2-furyl methanol (131 g, 0.8 mole) was dissolved in a 2:1 mixture (1.5 liters) of acetone and water in a reactor, and polyphosphoric acid (20 g) was added thereto. Thereafter, reaction was carried out at 50° to 60° C. for about 24 hours with stirring. After completion of the reaction, the reaction solution was cooled and neutralized with addition of a saturated aqueous solution (200 ml) of sodium hydrogen carbonate, followed by extraction with a solvent. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 72 g (yield, 55%) of pure (±)-3-hydroxy-2-(2-cyclopentenyl)-4-cyclopenten-1-one having a boiling point of 115°-120° C./3 mmHg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9]2[NH:10][C@H:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C)C1C=CN=CC=1.ClCCl>[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9]2[N:13]([C:35](=[O:37])[CH3:36])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C(SCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
To a solution of 2-[(4-fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydrochloride (197) (0.50 g, 1.25 mmol), triethylamine (0.384 mL, 2.75 mmol), 4-dimethylaminopyridine (20 mg) in dichloromethane (20 mL) is added acetic anhydride (0.130 mL, 1.38 mmol), and the mixture is stirred at rt for 3 h. Additional acetic anhydride (0.100 mL, 1.06 mmol) is added, and the mixture is stirred at rt overnight. The reaction mixture is diluted with dichloromethane and washed with water, brine, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is recrystallized from heptane: dichloromethane (95:5) to give 0.37 g of the product 549. 1H NMR (CDCl3) δ 7.60-7.40 (m, 2H), 7.10-6.90 (m, 8H), 6.90-6.75 (m, 2H), 6.75-6.65 (m, 2H), 5.65 (d, 1H), 5.43 (d, 1H), 4.33 (q, 2H), 1.91 (s, 3H). MS: m/z 405 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[I-:19].[NH4+].OO>C(O)(=O)C>[NH2:1][C:2]1[C:3]([I:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:14])([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1
Reactant: [I-]
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Agent: OO
Agent: [NH4+]
Solvent: CC(=O)O
Product: C[C@]1(c2cc(N)c(I)cc2F)N=C(N)OCC1(F)F
Reaction time: 8 h

Procedure:
Intermediate XI-3 (R2a=F; R2b=I; R3=Me; R4 and R5=H): A solution of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) (500 mg, 1.9 mmol) and ammonium iodide (308 mg, 2.1 mmol) in acetic acid (9.6 ml) was treated at room temperature with an aqueous solution of hydrogen peroxide (35%, 0.19 ml, 2.1 mmol). After stirring overnight 50% of the starting material was left. Another equivalent of ammonium iodide and hydrogen peroxide was added and stirring continued at room temperature overnight. For the workup, the reaction mixture was filtered, the filtrate treated with sodium thiosulphate, then extracted with ethyl acetate (3×). The combined organic layers were washed with a saturated solution of sodium hydrogen carbonate, then dried over sodium sulphate and evaporated at reduced pressure. In order to eliminate residual acetic acid, the crude product was dissolved in dichloromethane and extracted again with a saturated solution of sodium hydrogen carbonate. The crude product was purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 0/100 as the eluent. The (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine was obtained as a yellow solid (415 mg, 56% of theory). MS (ISP): m/z=386.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:17]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:2]3[N:17]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: Fc1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)cc2)CC1

Procedure:
4-{4-[8-(4-Fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.190 g, 0.767 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.254 g, 0.921 mmol) in a manner analogous to Example 311a and 311b to give product. MP=88-91° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.65 (s, 1H), 8.79 (d, 1H), 8.22 (m, 2H), 7.82 (d, 1H), 7.60 (d, 2H), 7.35 (m, 2H), 7.15 (d, 2H), 7.10 (m, 1H), 4.05 (m, 2H), 2.80 (m, 2H), 2.60 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H): MS=488 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:13][CH:12]=1
Reactant: OCCC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OCCC1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-hydroxyethyl)piperidine (21.5 g), 4-fluorobenzaldehyde (17.5 ml) and p-toluene sulfonic acid (3 mg) in benzene (200 ml) was refluxed with separating water as the benzene azeotrope. After 2 hours, the mixture was evaporated in vacuo. The residue was dissolved in methanol (200 ml) and sodium borohydride (6.3 g) was added thereto at 5° C. After stirring at ambient temperature for 1 hour, the mixture was evaporated in vacuo. 4N Hydrochloric acid (200 ml) was added to the residue and washed with ethyl acetate. The aqueous layer was made basic to pH 10 with potassium carbonate and extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate, and evaporated in vacuo to give 1-(4-fluorobenzyl)-4-(2-hydroxyethyl)piperidine (32.0 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].[CH3:15][S:16]([CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:22][CH2:23]1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1F
Reactant: CS(=O)(=O)CCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Temperature: 100 °C
Yield: 68 %

Procedure:
To 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, Step C) (0.20 g, 1.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.23 g, 1.2 mmol), and K2CO3 (0.49 g, 3.5 mmol) was added DMSO (10 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (0.25 g, 0.68 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.22 (d, J=11.5 Hz, 2H), 3.00-3.14 (m, 2H), 2.92 (s, 3H), 2.69 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.76-1.97 (m, 4H), 1.35-1.70 (m, 3H), 1.24 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:17]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[CH:17]=2)[CH2:31][CH2:30]1
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Reactant: O=C1NCCCc2cc(OCCCCl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C1NCCCc2cc(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)ccc21
Temperature: 150 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
A mixture consisting of 7-(chloropropoxy)-2,3,4,5-tetrahydro-1H-2-benzoazepin-1-one (0.507 g, 2 mmol) and 1-(2-quinolylmethyl)piperazine (1.81 g, 8 mmol) was stirred for 4 hours at a bath temperature of 150° C. under an argon gas stream. After the reaction mixture was allowed to cool down, chloroform was added to the reaction mixture to dissolve the same. The resulting solution was rendered basic with a dilute aqueous solution of sodium hydroxide. The thus-obtained solution was washed with water and then dried over anhydrous magnesium sulfate. After the resulting solution was purified by subjecting it to chromatography on a silica gel column (developer: chloroform/methanol=40/1), recrystallization was conducted from acetone. The title compound (0.613 g) was obtained as yellow leaflets (yield: 68.9%).
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1)[C:3]([OH:5])=O.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH3:37])[C:21]1=[O:38])=[O:18])[CH3:16]>>[F:13][C:8]1[CH:7]=[C:6]([CH:2]([F:1])[C:3]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH3:37])[C:21]2=[O:38])=[O:18])[CH3:16])=[O:5])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: O=C(O)C(F)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)C(F)c1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenyl-α-fluoroacetic acid (Example S) and 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Y), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (35:65).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][C@@H:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])(=O)=O.O>CS(C)=O>[CH3:29][C@@H:22]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][CH2:19][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)=CCC[C@H](C)CCCS(C)(=O)=O
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCC[C@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a suspension of sodium theobromine (4.05 g, 20.0 mmol) in dimethylsulfoxide (50 mL) was added 1-methanesulfonyl-4-(S)-methyl-8-methylnon-7-ene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL, 2×50 mL). The organic portions were combined, dried using magnesium sulfate, and evaporated to give a residue which was purified by column chromatography (ethyl acetate/hexane) to yield 1.83 g (30% yield) 1-(4-(S)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (inventive compound no. 2536S) as a white solid.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][N:5]1[N:9]=[N:8][C:7]([CH2:10][CH2:11][NH2:12])=[N:6]1.C(N(CC)CC)C.[F:20][C:21]1[CH:22]=[C:23]([C:31]2[S:35][C:34]([NH:36][C:37](N3C=CN=C3)=[O:38])=[N:33][C:32]=2[CH3:44])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>CN(C=O)C>[F:2][CH2:3][CH2:4][N:5]1[N:9]=[N:8][C:7]([CH2:10][CH2:11][NH:12][C:37]([NH:36][C:34]2[S:35][C:31]([C:23]3[CH:24]=[CH:25][C:26]([S:27]([CH3:30])(=[O:28])=[O:29])=[C:21]([F:20])[CH:22]=3)=[C:32]([CH3:44])[N:33]=2)=[O:38])=[N:6]1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: NCCc1nnn(CCF)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)NCCc2nnn(CCF)n2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 2-[2-(2-Fluoro-ethyl)-2H-tetrazol-5-yl]-ethylamine hydrochloride (0.150 g, 0.0.77 mmol) in DMF (5 ml) was added triethylamine 0.243 ml, 0.1.74 mmol) followed by imidazole-1-carboxylic acid [5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (0.265 g, 0.7 mmol). After stirring at room temperature for 3.5 hours, the reaction mixture was filtered and water (3 ml) is added to the filtrate with vigorous stirring. The resulting solid was filtered and dried under high vacuum to yield the titled product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][CH2:20][C:21]#[N:22]>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: COc1cccc(Cl)c1CCC#N
Reactant: Nc1ccncc1C=O
Product: COc1cccc(Cl)c1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-aminonicotinaldehyde and 3-(2-chloro-6-methoxyphenyl)propionitrile.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([OH:14])=O)=[CH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C:43](=[NH:48])[O:44]C(C)C)=[CH:34]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]2[C:43](=[O:44])[NH:48][C:12](=[O:14])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:34]1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A stirred solution of 406 mg (2 mmol) of 1-methyl-3-indolylglyoxylic acid in 20ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and 273 mg (2 mmol) of isobutyl chloroformate. After 0.5 hour, the solution was added dropwise to a stirred solution of 533 mg (2 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 808 mg (8 mmol) of triethylamine in 50 ml of dichloromethane. The solution obtained was heated to reflux under nitrogen for 18 hours, cooled and treated with 1.9 g (10 mmol) of p-toluenesulfonic acid. After 1 hour, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (8:1) for the elution to give 107 mg(30% ) of 3,4-bis-(1 -methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of an orange colored solid of melting point >310° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 82 %

Procedure:
The title compound is prepared in analogy to Example 3a) from 4-fluoro-nitro-benzene and 4-trifluoromethyl-benzyl alcohol. Yield 82% of a slightly brown solid. Mp.=80.5–81.5° C.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[OH:13][C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]1[C@@H:28]2[C@@H:23]([NH:24][C:25]([NH:27]2)=[O:26])[CH2:22][S:21]1)=O>CC(C)=O>[O:26]=[C:25]1[NH:27][C@@H:28]2[C@H:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:14]([O:12][CH2:11][C@H:9]([C@@H:7]3[C:5]([OH:6])=[C:3]([OH:4])[C:2](=[O:1])[O:8]3)[OH:10])=[O:13])[S:21][CH2:22][C@@H:23]2[NH:24]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CC(C)=O
Product: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)OC[C@@H](O)[C@H]2OC(=O)C(O)=C2O)N1
Temperature: 40 °C
Reaction time: 32 h

Procedure:
54.1 g of ascorbic acid (306.9 mmol; 5 eq.) and 15 g of biotin (61.4 mmol; 1 eq.) are dissolved in 180 ml of anhydrous acetone under a protective gas, 1 g of lipase (Candida antarctica) is added, and the mixture is shaken at 40° C. for 32 h. The enzyme is filtered off, 50 ml of water are added to the solution, and the product is precipitated by pouring into toluene.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:15]([N:19]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: CC(C)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2ncnn2c2c1CCN2CC(C)C

Procedure:
A mixture of 2.3g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 1g of isobutylamine, 1.8g of sodium carbonate and 20 ml of ethanol was treated by the same manner as described in Example 3. The crystals thus obtained were recrystallized from aqueous methanol to give 1.4g of pale yellow prisms of m.p. 143° - 145° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17]Cl>>[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Product: Cc1cc(C)c(Cn2ccc3ccc(C(=O)O)cc32)c(C)c1
Yield: 47.2 %

Procedure:
The titled compound (790 mg) as a pale yellow solid was prepared from methyl indole-6-carboxylate (1.0 g) and 2,4,6-trimethylbenzyl chloride (1.2 g) according to the method of Example 1.
Reaction SMILES: N[C:2]1[CH:7]=CC(OC)=[CH:4][C:3]=1S(N)(=O)=O.[NH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([O:22]C)=[CH:17][C:16]=1[S:24]([NH2:27])(=[O:26])=[O:25]>>[O:25]=[S:24]1(=[O:26])[C:16]2[CH:17]=[C:18]([OH:22])[C:19]([F:21])=[CH:20][C:15]=2[N:14]2[CH2:7][CH2:2][CH2:3][CH:4]2[NH:27]1
Reactant: COc1cc(S(N)(=O)=O)c(N)cc1F
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Product: O=S1(=O)NC2CCCN2c2cc(F)c(O)cc21

Procedure:
In Step A, 2-amino-5-methoxybenzenesulphonamide is replaced by 2-amino-4-fluoro-5-methoxybenzenesulphonamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH:15]C(OCC1C=CC=CC=1)=O)[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH2:15])[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](N)CCO[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
In a Parr shaker bottle was placed (S)-2-benzyloxycarbonylamino-4-(t-butyl-dimethyl-silanyloxy)-butyric acid methyl ester (478 mg, 1.25 mmol), methanol (10 mL) and 10% palladium on activated carbon (100 mg). The bottle was placed on the Parr Shaker and charged with hydrogen to 40 psi and shaken for 1.5 h. After this time, the mixture was filtered through celite and the filterate concentrated in vacuo to afford (S)-2-amino-4-(t-butyl-dimethyl-silanyloxy)-butyric acid methyl ester (291 mg, 94%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CC1CCCCN1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC1CCCCN1c1ccc(C#N)c2ccccc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 18.9 %

Procedure:
1-Cyano-4-fluoronaphthalene (100 mg, 0.58 mmol), 2-methylpiperidine (0.28 mL, 2.3 mmol) and DBU (0.01 mL, 59 μmol) were dissolved in pyridine (2 mL) and stirred at 60° C. for 3 days. The temperature was raised to 110° C. and the stirring was continued for 10 days. The reaction was worked up in the same way as for 198RL60. The crude compound was purified by preparative TLC followed by preparative HPLC to give the title compound (27.4 mg, 19%) as a colourless oil, which was stored under argon atmosphere.