Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20][C:12]=4[C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[Li+].[OH-:32].Cl>O1CCOCC1>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20][C:12]=4[C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:29])([F:30])[F:28])(=[O:32])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (9.0 mg, 0.022 mmol) in dioxane (1 mL) was added 1M LiOH (aq) (3.0 mL). The reaction was stirred at 50° C. for 48 h. 1M HCl (aq) was added to adjust pH to 3. The mixture was extracted with EtOAc. The EtOAc extract was dried over MgSO4 and the residue was purified by preparative HPLC/MS to give the title compound as a solid (2.1 mg). LCMS m/z=433.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.14 (m, 1H), 2.32-2.42 (m, 1H), 2.57-2.78 (m, 4H), 5.20 (s, 2H), 6.72 (d, J=11.37 Hz, 1H), 6.93 (d, J=2.40 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H), 7.50-7.59 (m, 2H), 7.76 (d, J=7.58 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 10.47 (s, 1H), 12.17 (bs, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1.C(N(CC)CC)C.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29].[Cl-].[NH4+]>C(Cl)Cl>[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1)(=[O:39])=[O:38])([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H](N)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
tert-Butyl (3R,4R)-3-amino-4-phenylpiperidine-1-carboxylate (124 mg) was dissolved in methylene chloride (2 ml), and thereto were added triethylamine (125 μl) and 2-nitrobenzene sulfonyl chloride (109 mg) at 0° C., and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=1/1) to give the title compound (202 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C@H:26]1([NH2:33])[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][C@H:29]3[CH2:30][CH2:31][C@@H:26]([NH2:33])[CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: N[C@H]1CC[C@@H](N)CC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@H]3CC[C@@H](N)CC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and cis-cyclohexane-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91-7.85 (m, 2 H), 7.79 (s, 1 H), 7.58 (td, J=7.45, 1.26 Hz, 1 H), 7.51-7.44 (m, 1 H), 7.29 (d, J=8.59 Hz, 1 H), 7.21 (dd, J=8.59, 1.52 Hz, 1 H), 6.17 (d, J=7.58 Hz, 1 H), 6.03 (s, 1 H), 5.06 (brs, 2 H), 4.50 (brs, 1 H), 4.11 (d, J=4.55 Hz, 1 H), 3.67 (d, J=4.80 Hz, 1 H), 3.64-3.56 (m, 2 H), 3.16 (m, 2 H), 3.06 (brs, 1 H), 2.35 (s, 3 H), 1.83-1.44 (m, 8 H).
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([O:29]CC)=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CCO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([OH:29])=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCn1ccc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCn1ccc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure, and the residue was dissolved in water (20 ml), and washed with AcOEt (10 ml). The aqueous layer was neutralized with 2N HCl and extracted with AcOEt (50 ml). The AcOEt layer was washed successively with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4](=[O:21])[CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([C:3]1[C:2](=[O:1])[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4]=1[OH:21])(=[O:24])[CH3:23]
Reactant: COc1cccc(-c2ccsc2C2CC(=O)C=C(O)C2)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(-c2ccsc2C2CC(=O)C(C(C)=O)=C(O)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a 200 mL recovery flask was added 3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone (30F, 4.9 g, 16.3 mmol, 1.0 eq.), CH2Cl2 (100 mL), acetic anhydride (2.15 g, 21.1 mmol, 1.3 eq.), Et3N (6.8 mL, 48.8 mmol, 3.0 eq.), and DMAP (catalytic). The reaction mixture was stirred overnight at room temperature whereupon LC/MS showed two signals corresponding to M+H=344. Additional acetic anhydride (0.5 mL, 5.3 mmol, 0.32 eq.) was added and the reaction mixture was heated for 6 h at 40° C. LC/MS analysis showed the reaction to be complete whereupon the mixture was concentrated to a solid and purified via flash chromatography (70% CH2Cl2/Hex to 100% CH2Cl2) to yield a dark orange solid 30G (1.72 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.57 (m, 3H) 2.83 (m, 2H) 3.09 (m, 2H) 3.78 (s, 3H) 4.68 (m, 1H) 6.74 (d, J=8.34 Hz, 1H) 7.32 (d, J=7.33 Hz, 1H) 7.41-7.47 (m, 1H) 7.51 (d, J=5.31 Hz, 1H) 7.76 (t, J=7.96 Hz, 1H). ESI-MS: m/z 344.3 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[CH2:12][O:11][CH2:10][CH:9]1[CH3:25])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH:13]2[CH2:12][O:11][CH2:10][CH:9]([CH3:25])[NH:8][CH2:14]2)=[CH:18][C:19]=1[CH3:24]
Reactant: Cc1cc(OCC2COCC(C)N(Cc3ccccc3)C2)ccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC2CNC(C)COC2)ccc1F
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A suspension of 4-benzyl-6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-6, 36 mg, 0.11 mmol) and Pearlman's catalyst (wet 20% Pd(OH)2/C, 100 mg) in methanol (20 mL) was stirred under a hydrogen balloon at 23° C. for 2 h. The mixture was filtered and the filtrate concentrated to give 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-7) as a ˜1:1 mixture of diastereomers (colorless oil). LRMS m/z (M+H) 254.3 found, 254.2 required.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 90 °C
Yield: 90.1 %

Procedure:
To a suspension of 4-carboxybenzeneboronic acid (2.0 g, 12.1 mmol) and 1-(2-bromo-phenyl)-ethanone (1.63 mL, 12.1 mmol) in dry acetonitrile (60 mL) was added a 0.4 M aqueous sodium carbonate solution (60 mL) and the reaction mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.433 mmol) was then added and the reaction mixture heated to 90° C. for 22 hours. The hot reaction mixture was filtered through celite and then concentrated in vacuo to remove acetonitrile. The resulting aqueous suspension was diluted with water to 75 mL then washed with diethyl ether (75 mL). The aqueous phase was acidified to pH 1 by the addition of concentrated hydrochloric acid and the resulting white suspension cooled to 4° C. for 1 hour. The solid product was filtered, washed with water and then dried in vacuo at 50° C. overnight to afford the title compound (2.62 g, 91%) as a white solid, m.p. 199-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[C@H:58]([O:60][CH3:61])[CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:62][C@H:57]([C:55]1[NH:54][C:53]2[CH:63]=[CH:64][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[C@H:58]([O:60][CH3:61])[CH3:59])=[O:7]
Reactant: CO[C@H](C)[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H](C)[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 72 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (1R,2R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxypropylamine in tetrahydrofuran. Yield: 72%; Rf value: 0.56 (silica gel: dichloromethane/ethanol=9:1); C23H22Cl2N4O3 (473.358); mass spectrum: (M+H)+=473/475/479 (chlorine isotope) and (M−H)−=471/473/475 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccccc1F
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 10 g (64.9 mmol) of 2-fluorophenylacetic acid in 100 ml of THF was slowly added to a suspension of 2.46 g (64.0 mmol) of lithium aluminum hydride in 50 ml of THF at room temperature. After stirring for 1 hr, sodium sulfate 10-hydrate was slowly added until no effervescence was observed. The reaction mixture was filtered and the filtrate was distilled off to obtain 8.83 g of the title compound (Yield: 97%).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 15 %

Procedure:
As described for example 301, [6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran to the title compound (18 mg, 15%) which was obtained as a white solid. MS: m/e=415.1 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]([OH:18])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:30][C:31]1[CH:32]=[C:33]([CH:52]=[CH:53][CH:54]=1)[O:34][C:35]1[CH:49]=[CH:48][C:38]2[N:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[S:41][C:37]=2[C:36]=1[C:50]#[N:51]>O1CCCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:8]([C:16]([NH:30][C:31]2[CH:54]=[CH:53][CH:52]=[C:33]([O:34][C:35]3[CH:49]=[CH:48][C:38]4[N:39]=[C:40]([NH:42][C:43]([CH:45]5[CH2:47][CH2:46]5)=[O:44])[S:41][C:37]=4[C:36]=3[C:50]#[N:51])[CH:32]=2)=[O:18])[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(C(=O)O)c1-c1ccccc1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of 1-tert-butyl-5-phenyl-1H-pyrazole-4-carboxylic acid (67 mg, 0.274 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (29 μL, 0.338 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (80 mg, 0.228 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (73 mg, 55%) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([CH:16]3[CH2:17][CH2:18][N:13]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:12])[CH2:14][CH2:15]3)=[CH:20]2)[CH:30]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1cncc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4cccnc4)c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution containing 1.2 g (52 mmol) of 3-bromomethyl-benzoic acid methyl ester in 10 mL of anhydrous dichloromethane was added dropwise over a solution of 1.5 g (5 mmol) 3-piperidin-4-yl-1-pyridin-3-ylmethyl-1H-indole and 0.8 mL (55 mmol) of triethylamine in 35 of anhydrous dichloromethane. After stirring at room temperature for 5 hours, the crude mixture was washed with water, saturated solution of sodium hydrogencarbonate and water. The organic phase was dried and the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography over silica gel affording 0.95 g (43% of yield) of 3-[4-(1-pyridin-3-ylmethyl-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester. This ester was dissolved in 15 mL of methanol and hydrolised with NaOH 1N at room temperature for 12 hours. The crude mixture was neutralised with HCl 1N and then the solvent was removed under reduced pressure. The solid residue was washed with water and dichloromethane and the corresponding acid (0.6 g, 77% of yield) was isolated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:16](I)([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)N1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 77.5 %

Procedure:
A mixture of 34.16 g (0.165 mol) of the 4-(4-fluorobenzoyl)piperidine, 33.80 g (0.199 mol) of isopropyl iodide and excessive sodium bicarbonate in 600 mL of acetonitrile was heated at reflux for 14 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo to give a solid. This was recrystallized from CH2Cl2 /hexane to give 31.89 g (77.6%) of crystalline solid, mp 120°-121° C.
Reaction SMILES: CS([Cl:5])(=O)=O.[N+:6]1([O-])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>>[Cl:5][CH:14]1[C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: [O-][n+]1cccc2c1CCCC2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ClC1CCCc2cccnc21
Temperature: 20 °C

Procedure:
At ambient temprature, 3 ml of methane sulfonyl chloride were added slowly to 1.49 g of 5,6,7,8-tetrahydroquinoline-N-oxide with stirring under an inert atmosphere. The mixture was heated for 4 hours at 80° to 82° C., then cooled to 20° C. and poured into 20 ml of a saturated solution of sodium bicarbonate. Then, sodium bicarbonate was added until an alkaline pH was obtained and after extracting with methylene chloride, washing with water, drying the re-united organic solutions and distilling to dryness under reduced pressure, 1.53 g of 8-chloro-5,6,7,8-tetrahydroquinoline were obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].[BH4-].[Na+]>C(O)C>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:16][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CNCC(OC)OC)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
3--Fluoro-4-methoxybenzaldehyde (5.0 g, 0.0324 mole) was added to aminoacetaldehyde dimethyl acetal (3.53 ml, 0.0324 mole) and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled in ice, diluted with ethyl alcohol (50 ml) and sodium borohydride (1.23 g, 0.0324 mole) was added and the mixture was stirred overnight at 25° C. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and the solution was washed with water and brine and then dried with sodium sulfate. The mixture was filtered and the solvent removed under reduced pressure to give N-(3-fluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal as an oil (6.68 g, 85%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]12([C:23]([C:26]3[C:31](O)=[CH:30][C:29]([OH:33])=[CH:28][C:27]=3[Cl:34])=[N:24][OH:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:13]12([C:23]3[C:26]4[C:27]([Cl:34])=[CH:28][C:29]([OH:33])=[CH:30][C:31]=4[O:25][N:24]=3)[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: ON=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Oc1cc(Cl)c2c(C34CC5CC(CC(C5)C3)C4)noc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
Diethylazodicarboxylate (0.92 g, 1.7 eq) in THF (20 ml) was added to a mixture of 1-adamantyl (2-chloro-4,6-dihydroxyphenyl)methanone oxime (1 g, 3.1 mmoles), triphenyl phosphine (1.4 g, 1.7 eq) in THF (20 ml) at 0° C. The mixture was stirred 2 h at 0° C., poured into water, extracted with ethylacetate, dried over Na2SO4 and concentrated under vacuum to give the crude product. Flash chromatography (AcOEt/toluene 1/9) and crystallisation from EtOH yielded the expected product (230 mg, 23%). mp 215° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][C:5]1[C:6]([NH2:28])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:13]=2)=[N:9][C:10]=1[NH2:11].[H-].[Na+].I[CH3:33].Cl>CN(C)C=O>[NH2:11][C:10]1[C:5]([N:4]([CH3:33])[C:3](=[O:29])[O:2][CH3:1])=[C:6]([NH2:28])[N:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[N:13]=2)[N:9]=1
Reactant: COC(=O)Nc1c(N)nc(-c2nn(CC3CCCCC3)c3ncccc23)nc1N
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1c(N)nc(-c2nn(CC3CCCCC3)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
24 mg (61 μmol) of the compound of Example 1 were initially charged in 1 ml of dimethylformamide, and about 2.7 mg (70 μmol) of sodium hydride (60% in mineral oil) were added. The resulting mixture was stirred at RT for 10 min, 6 μl (9 μmol) of iodomethane were then added and the reaction was stirred overnight. 0.5 ml of 1N hydrochloric acid was added, and the entire mixture was separated by HPLC (Method 5). The appropriate fractions were concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 8 mg (32% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([O:7][CH:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][CH2:10][N:11]([CH3:25])[C:12]([CH2:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:13])=[CH:5][CH:4]=1.[ClH:36]>CCOC(C)=O>[ClH:36].[F:1][C:2]([F:34])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][CH2:10][N:11]([CH3:25])[C:12](=[O:13])[CH2:14][CH2:15][CH2:16][NH2:17])=[CH:32][CH:33]=1
Reactant: CN(CCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1)C(=O)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(CCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1)C(=O)CCCN
Reaction time: 3 h

Procedure:
tert-Butyl 3-(N-(3-(4-(Trifluoromethyl)phenoxy)-3-phenylpropyl)-N-methyl carbamoyl)propylcarbamate (AN-229) was prepared as described in WO 2005/092392. AN-229 (0.5 mmol) was added to a solution of HCl in EtOAc (35 ml) and the resulting mixture was stirred for 3 hours. The solvent was thereafter evaporated and the product, AN-227, was obtained in quantitative yield.