Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:4]4[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]4)=[O:8])[CH2:10]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 75 mg (0.75 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 127 mg (55% of theory).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH:20]=O)=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:20]([CH2:19][O:18][C:17]3[CH:22]=[CH:23][C:14]([C:13]([F:12])([F:24])[F:25])=[CH:15][CH:16]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCOc1ccc(C(F)(F)F)cc1
Product: CCc1nc(I)c2n1CCNC2COc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (3.880 mmol) and (4-trifluoromethyl-phenoxy)-acetaldehyde (0.792 g; 3.880 mmol) afforded 3-ethyl-1-iodo-8-(4-trifluoromethyl-phenoxymethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.73 min.; [M+H]+=452.12 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH2:28][N:29]1[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]1[CH3:35]>O1CCOCC1>[CH3:35][C:30]1[N:29]([CH2:28][CH2:27][NH:26][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:33]([CH3:34])=[CH:32][CH:31]=1
Reactant: Cc1ccc(C)n1CCN
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NCCn2c(C)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
9.1 g (0.05 mol) of 3,4-dimethoxybenzoic acid and 8.2 g (0.05 mol) of carbonyldiimidazole in 50 ml of dioxane are stirred at 60° C. for 15 min. After addition of 6.2 g (0.045 mol) of 1-(2-aminoethyl)2,5-dimethylpyrrole in 20 ml of dioxane to the mixture it is stirred at room temperature for 20 h, concentrated, and aqueous sodium bicarbonate solution is added and the mixture is extracted with methylene chloride. The extract is chromatographed over an alumina column, and the product is crystallized using ethyl acetate/ether/ligroin. Yield: 6.9 g (46% of theory), Melting point: 82°-84° C. Elemental analysis: C17H22N2O3 (302.37) calculated: C 67.5 H 7.3 N 9.3 O 15.9 found: C 67.3 H 7.2 N 8.8 O 16.6
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28][N:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8])[CH2:10][CH3:11]
Reactant: O=C1CCCC(=O)N1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)CCCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-piperidin-2,6-dione was prepared as for Example 10 from piperidin-2,6-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl[C:28]1[C:37]([CH3:38])=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:25][C:28]3[C:37]([CH3:38])=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Reactant: Cc1cc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4cc3C)cc2)cc1)C(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 12.2 %

Procedure:
Step 1C [Intermediate 3: 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (1.2 g, 3.2 mmol, 1.0 equiv.), 2-chloro-3-methyl quinoline (2.26 g, 12.7 mmol, 4 equiv.) were dissolved in DMF (30 mL) followed by the addition of NaH (382 mg, 60% in oil, 9.54 mmol, 3 equiv.). The mixture was stirred at 100° C. for 5 hrs, then at room temperature overnight. The reaction mixture was then poured into cold water, solid precipitated from the mixture was collected by filtration and washed with water. Regular column chromatography (Silica gel, 1% MeOH/CH2Cl2) to yield 203 mg of 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester in 12% yield.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:16]1[C:11]([NH:10][CH3:9])=[N:12][CH:13]=[C:14]([C:17]([F:23])([F:22])[C:18]([F:19])([F:20])[F:21])[CH:15]=1
Reactant: CNc1ccc(C(F)(F)C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CNc1ncc(C(F)(F)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
5.0 g of N-bromosuccinimide was added to a mixture of 4.6 g of methyl-(5-pentafluoroethyl-pyridin-2-yl)-amine and 70 ml of acetonitrile, and the mixture was stirred at room temperature for 8 hours. A saturated aqueous sodium thiosulfate solution and an aqueous sodium bicarbonate solution were added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 6.3 g of (3-bromo-5-pentafluoroethyl-pyridin-2-yl)-methyl-amine.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:19][O-:20].[Na+]>>[CH2:15]([N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([O:20][CH3:19])[C:11]=2[N:12]=[CH:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: C[O-]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [Na+]
Product: COc1nc2ccccc2c2c1ncn2CC(C)C

Procedure:
Using the method of Example 157, 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (from Example 96) was reacted with sodium methoxide to provide 1-isobutyl-4-methoxy-1H-imidazo[4,5-c]quinoline, melting point 111°-114° C. after sequential recrystallizations from aqueous ethanol and diethyl ether. Analysis: Calculated for C15H17N3O: %C, 70.6; %H, 6.7; %N, 16.5; Found: %C, 70.6; %H, 6.7; %N, 16.5.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42]>>[OH:42][CH2:41][C@H:40]([NH:39][C:33](=[O:35])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1)[CH2:43][CH3:44]
Reactant: CC[C@@H](N)CO
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CC[C@H](CO)NC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 64.8 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 39 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=[O:25])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]1([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccccc1)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccccc1)C1CCCNC1
Yield: 0.1 %

Procedure:
A solution of 3-(S)-Phenylcarbamoyl-piperidine-1-carboxylic acid benzyl ester (1.80 mol, 608 mg) and Pd—C 30% (100 mg) in CH3OH (10 mL) at 25° C. were added to a Paar hydrogenator low pressure reaction vessel. The mixture was reacted at 55 psi with vigorous shaking until hydrogen uptake subsided (2 h). The catalyst was filtered through a pad of celite. The filtrate was concentrated in vacuo which provided piperidine-3-carboxylic acid phenylamide (367 mg, 367 mg theoretical, 99%) as a white foam: LRMS m/z 205 (M++1, C12H16N2O requires 205).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Product: CCCc1c(OC)cc(C=Cc2cc(OC)cc(OC)c2)cc1OC
Yield: 25 %

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 3,5-dimethoxybenzaldehyde in 25% yield as the same procedure as described in Example 5(b)
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]4[CH2:20][CH2:19][CH2:18][CH:12]4[C:13](=S)[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:21]>>[NH2:21][C:13]1[CH:12]2[CH2:18][CH2:19][CH2:20][CH:11]2[C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:16][C:15]=2[N:14]=1
Reactant: S=C1Nc2cc(N3CCOCC3)ccc2C2CCCC12
Reactant: N
Product: NC1=Nc2cc(N3CCOCC3)ccc2C2CCCC12
Yield: 53 %

Procedure:
Analogously to Example 4, 7-(4-morpholinyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (80 mg, 0.28 mmol) in 7N methanolic ammonia solution (15 ml) is reacted to form 40 mg (53%) of product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([Cl:19])[CH:25]=[C:24]([Cl:26])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(Cl)cc(Cl)c3)cccc2c1N
Yield: 52.5 %

Procedure:
Using method B, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,5-dichlorophenyl boronic acid (252 mg, 1.32 mmol) were reacted to afford the title compound (65 mg, 52.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.26 (br, 1H), 8.48 (d, J=8.2 Hz, 1H), 7.95 (d, J=7.2 Hz, 2H), 7.74-7.85 (m, 3H), 7.67 (t, J=2.0 Hz, 1H), 3.31 (m, overlapped with H2O), 1.60 (m, J=7.3 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H). MS APCI, m/z=375/377 (M+H). HPLC 2.52 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([NH2:25])[CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:23]1[CH:24]=[C:19]([CH3:18])[CH:20]=[CH:21][C:22]=1[S:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Nc1cc(C)ccc1Sc1ccccc1

Procedure:
The product from Example 10a (438 mg, 2.03 mmol) was reacted with the product from Example 1f (510 mg, 2.03 mmol) for 10 min following the procedure from Example 1g giving the title compound which was purified by silica gel column chromatography eluting with 4% MeOH/CH2Cl2 as a solid (114 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (t, J=6.99 Hz, 3H) 2.16 (s, 3H) 2.62 (s, 3H) 4.29 (q, J=7.11 Hz, 2H) 6.86 (s, 1H) 7.04 (d, J=8.09 Hz, 1H) 7.15-7.34 (m, 6H) 7.39 (d, J=7.72 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 9.17 (s, 1H) 10.13 (s, 1H); MS (ESI+) m/z 430 (M+H)+, (ESI−) m/z 428 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH3:16])[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:8]=2[CH:24]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27]>N1C=CC=CC=1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:9]1[C:8]2[CH:24]=[C:4]([C:1](=[N:26][OH:27])[CH3:2])[CH:5]=[CH:6][C:7]=2[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH3:16])[N:10]=1
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C

Procedure:
A solution of 4.41 g (13.60 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one and 4.41 g (63.46 mmol) of hydroxylamine hydrochloride in 250 ml of pyridine is stirred at room temperature for 19 hours, subsequently poured on to ice and extracted with chloroform. The organic extracts are washed successively with 2 N hydrochloric acid and water, dried and evaporated. After chromatography of the residue on 250 g of silica gel using chloroform/ethanol (98:2) as the elution agent, there is obtained 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 101°-103°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](Cl)=[O:36]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:35]([C:31]3[S:30][CH:34]=[CH:33][N:32]=3)=[O:36])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1nccs1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4nccs4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.57 g, 1.75 mmol) in CH3CN (10 ml), were added triethyl amine (0.61 mL, 4.4 mmol) and 1,3-thiazole-2-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford thiazole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.52 g, 74%): mp, 189-191° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.9 min (97%); 1H NMR (DMSO-d6): δ 2.05-2.12 (m, 1H), 2.53-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.94 (d, J=6.2 Hz, 2H), 5.18 (dd, J=5, 11 Hz, 1H), 7.68-8.10 (m, 5H), 9.50 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.32, 48.88, 121.98, 125.99, 127.17, 131.56, 132.92, 134.85, 138.43, 143.98, 159.59, 163.18, 166.93, 167.51, 169.81, 172.73. Anal Calcd for C18H14N4O5S: C, 54.27; H, 3.54; N, 14.06; S, 8.05. Found: C, 53.98; H, 3.49; N, 13.75; S, 8.22.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:30])=[O:29])=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 41 %

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4- carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98° C.; MS: 559.6 (M+H)+
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH:22]1([Mg]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=3)=[CH:9][CH:10]=2)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CON(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cc(C(F)(F)F)on2)cc1)C1CCCCC1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A solution of N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide (Preparative Example 15, 300 mg, 1.0 mmol) in THF (10 mL) was treated with a 1 N THF solution of cyclohexylmagnesium bromide (4 mL, 4 mmol) and stirred for 2 hr then quenched with a saturated ammonium chloride solution (2 mL) and diluted with EtOAc (10 mL). The organic layer was then washed with brine (2×10 mL), dried over MgSO4, filtered, evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (81 mg, 25%). 1H NMR (CDCl3) 1.26-1.58 (m, 5 H), 1.74-1.94 (m, 5 H), 3.23-3.32 (m, 1 H), 7.09 (s, 1 H), 7.79 (d, J=8.3, 2 H), 7.87 (d, J=8.3, 2 H). 19F NMR −64.6. LC/MS 7.79 min, [M+1]+ 324.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Br:10]N1C(=O)CCC1=O>O1CCCC1.N1C=CC=CC=1>[Br:10][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c(Br)c1
Reaction time: 72 h
Yield: 49.7 %

Procedure:
A solution (70 mL) of methyl 1H-pyrrole-3-carboxylate (4.48 g) in tetrahydrofuran was cooled to −78° C., N-bromosuccinimide (6.30 g) was added, pyridine (5 drops) was added, and the mixture was left standing in a freezer (−20° C.) for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a pale-yellow solid (yield 3.59 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.I.CS[C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[NH:31]>C(O)C>[CH2:25]([N:17]([CH:14]1[CH2:13][CH2:12][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:30]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[NH:31])[CH:3]=3)[NH:7][CH:6]=2)[CH2:16][CH2:15]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:26]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 76.6 %

Procedure:
A solution of compound 119 (0.4 g, 1.119 mmol) in dry ethanol (20 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.63 g, 2.239 mmol) at room temperature and stirred for 24 h. The solvent was evaporated, diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×25 mL). The CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 120 (0.4 g, 60%) as a yellow solid in 2:3 ratio of cis-trans diastereomers. 1H NMR (DMSO-d6) δ 0.98-1.08 (m, 3H), 1.38-1.56 (m, 11H), 1.68-1.85 (m, 4H), 2.05-2.18 (m, 2H), 3.02-3.17 (m, 3H), 3.70-3.76 (m, 1H), 6.31 (brs, 2H), 6.62-6.67 (m, 1H), 6.96-7.01 (m, 1H), 7.09-7.11 (m, 1H), 7.22-7.30 (m, 2H), 7.60 (d, 1H, J=5.1 Hz), 7.70-7.72 (m, 1H), 10.59, 10.62 (2s, 1H); ESI-MS m/z (%): 467 (MH+, 100).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:16]2[C:11](=[C:12](C(C)C)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[C:9](C(C)C)[C:8]=1[Si](C)(C)C)=[O:6])([CH3:3])[CH3:2].[Br:33]N1C(=O)CCC1=O>C(#N)C>[CH:1]([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:9][C:8]=1[Br:33])=[O:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OC(=O)c1c([Si](C)(C)C)c(C(C)C)c(C(=O)OC(C)C)c2c(C(C)C)cccc12
Solvent: CC#N
Product: CC(C)OC(=O)c1cc(Br)c(C(=O)OC(C)C)c2ccccc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Under a nitrogen stream, a mixture of diisopropyl 2-trimethylsilanyl-naphthalene-1,4-dicarboxylic acid diisopropyl ester (0.25 g, 0.671 mmol), N-bromosuccinimide (179 mg, 1.006 mmol) and acetonitrile (12.5 mL) was stirred for 30 minutes at 150° C. under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (1:9)), to thereby obtain the titled compound (209 mg, 82%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:9]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]2)=[CH:9]1
Reactant: Fc1ccc2c(C3CCNCC3)cn(CCC3OCCO3)c2c1
Reactant: COC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCC3OCCO3)c3cc(F)ccc23)CC1
Yield: 22 %

Procedure:
This compound was prepared following the procedure described in Example 13 (part D) starting with 0.04 g (0.11 mmol) of 1-(2-[1,3]dioxolan-2-yl-ethyl)-6-fluoro-3-piperidin-4-yl-1H-indole and 0.03 g (0.15 mmol) of of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After purification over a Varian C18 column, 0.012 g (22% yield) were obtained.