Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[CH:24]=1>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[CH:3][C:2]([C:31]#[C:30][C@@:28]([OH:32])([C:25]5[CH:24]=[C:23]([CH3:22])[O:27][N:26]=5)[CH3:29])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C4CC4)n2CCO3)no1

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-cyclopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound. MS+419.2. 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=2.2 Hz, 1H), 7.42 (br s, 1H), 7.31 (dd, J=8.5, 2.2 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.95 (br s, 1H), 6.45 (s, 1H), 6.35 (s, 1H), 4.50 (m, 4H), 2.40 (s, 3H), 1.80 (s, 3H), 1.76 (m, 1H), 0.98 (m, 2H), 0.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].C[Mg+].[Br-].[CH2:20](OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([C:9]([CH3:20])=[CH:8][CH2:7][C:6]2([CH3:16])[CH3:15])=[CH:11][C:12]=1[CH3:13]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1C)C(C)=CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
General Procedure F CeCl3.7H2O (2.6 g, 6.9 mmol) was heated in an oil bath at 140-150° C. under high vacuum without stirring for 1 h, and then with stirring for 2 h. Argon was then introduced, and the flask was cooled to room temperature. Tetrahydrofuran (15 mL) was added, and the resulting slurry solution was stirred at room temperature under the argon atmosphere for 16 h. A solution of 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 30, 1.0 g, 4.6 mmol) and 5 mL of tetrahydrofuran was added, and the reaction mixture was stirred for 1 h, then cooled to 0° C. A solution of 3 M MeMgBr in diethyl ether (2.3 mL, 6.9 mmol) was added, and the ice bath was removed. After 1 h, the reaction was poured into concentrated sulfuric acid in ice, extracted with ethyl acetate, washed with NaHCO3 1 N, brine, dried over MgSO4, and filtered. The solvent was removed to give 1.0 g (100%) of the title compound as an orange oil. PNMR (300 MHz, CDCl3) δ 1.52 (s, 6 H), 2.28 (s, 3 H), 2.42 (d, 2 H, J=3.4 Hz), 2.49 (s, 1 H), 4.07 (s, 3 H), 5.86 (t, 1 H, J=2.5 Hz), 7.08 (s, 1 H), 7.30 (s, 1 H). 4-Ethyl-7-methoxy-1,1,6-trimethyl-1,2-dihydro-naphthalene (Compound 32)
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[NH:9][C:8]=2[C:22]([F:25])([F:24])[F:23])[CH:3]=1.[Br:26]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[NH:9][C:8]([C:22]([F:23])([F:24])[F:25])=[C:7]([C:4]3[C:3]([Br:26])=[C:2]([Br:1])[S:6][CH:5]=3)[C:11]=2[N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1Br

Procedure:
A solution of 3-(5-bromo-3-thienyl)-5-(p-chlorophenyl)-4-nitro-2-(trifluoromethyl)pyrrole (0.50 g, 1.1 mmol), bromine (0.20 g, 1.3 mmol) and sodium acetate (0.11 g, 1.3 mmol) in acetic acid (10 mL) is heated overnight at 50° C. and poured into water. The solids are collected and recrystallized from 1,2-dichloroethane to give the title product as a yellow solid, mp 241°-242° C.
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[CH2:3][C@@H:4]1[CH2:8][N:7]([CH2:9]O)[C:6](=[O:11])[CH2:5]1.S(Cl)([Cl:16])=O>ClCCl>[Cl:1][C:2]([F:13])([F:12])[CH2:3][C@@H:4]1[CH2:8][N:7]([CH2:9][Cl:16])[C:6](=[O:11])[CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: O=C1C[C@H](CC(F)(F)Cl)CN1CO
Solvent: ClCCl
Product: O=C1C[C@H](CC(F)(F)Cl)CN1CCl
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A solution of (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (0.281 g, 1.32 mmol, 1.5 eq) in dichloromethane (25 ml) is treated with thionyl chloride (382 μl, 5.27 mmol, 6 eq). The mixture is stirred for 1 h at 22° C. and concentrated in vacuo to obtain (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-one a18R. The resulting liquid is then added to a solution of anhydrous zinc chloride (0.239 g, 1.76 mmol, 2 eq) and 2-[methoxy(2H2)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a44 (0.210 g, 0.88 mmol, 1 eq) in dioxane. The mixture is stirred at 80° C. for 4 days. Some more (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (1.5 eq) are then added and the mixture is stirred for another 24 h. (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (2 eq) is added again and the mixture stirred for another 3 days. The mixture is then diluted with dichloromethane and washed with water (2×25 ml). The organic layer is dried over magnesium sulphate and concentrated under reduced pressure to afford 1.28 g of a brown oil. The mixture is purified by reverse phase HPLC (X-bridge C18, eluent: MeCN/H2O/NH3) to afford (4R)-4-(2-chloro-2,2-difluoroethyl)-1-({2-[methoxy(2H2)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl}methyl)pyrrolidin-2-one 31 as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=2)=[C:12]([CH2:26][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:28][CH3:29])[CH:11]=1)[C:2]1C=CC=CC=1.S(=O)(=O)(O)O.[CH3:46][CH2:47]O>>[CH2:1]([O:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:46][CH3:47])=[O:24])[CH:21]=2)=[C:12]([CH2:26][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:28][CH3:29])[CH:11]=1)[CH3:2]
Reactant: CCO
Reactant: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cncc(-c2ccc(C(=O)OCC)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
3-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-carboxymethyl-pyridin-3-yl)-benzoic acid benzyl ester (1.74 g, 3.2 mmol) in EtOH (200 mL) was treated with sulfuric acid (2 mL), and the reaction was stirred at 95° C. for 2 hours. The mixture was cooled to room temperature and concentrated, and the residue was partitioned between EtOAc and H2O. The solution was extracted with EtOAc, and the combined organic layers were washed with 1N aqueous HCl and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-ethoxycarbonylmethyl-pyridin-3-yl)-benzoic acid ethyl ester.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH:14]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12]2)(=[O:7])[CH3:6].S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[C:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12]2)(=[O:7])[CH3:6]
Reactant: COC(=O)CC1CCc2cc(NC(C)=O)ccc2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC1=Cc2ccc(NC(C)=O)cc2CC1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
Sodium borohydride (72.4 mg, 1.91 mmol) was added to a methanol solution (10 ml) of methyl [6-(acetylamino)-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]acetate (527 mg, 1.91 mmol) obtained in Reference Example 100 under ice-cooling, which was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; ethyl acetate). Concentrated sulfuric acid (0.14 ml) was added to an acetic acid solution (7 ml) of the oil (404 mg, 1.46 mmol), which was stirred at 40° C. for 5 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give the titled compound (251 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3].[N:25]1([C:32]2[S:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:32]3[S:33][C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)[CH2:26][CH2:27]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3]
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Reactant: CCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCCNC(=O)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-propylamide and 2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[CH:19]=[O:20])=[N:11]2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[CH2:19][OH:20])=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
Solid sodium borohydride (2.5 g) was added in portions to a stirred suspension of crude 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl]benzaldehyde (5.8 g) in methanol (200 ml). The mixture was filtered and the filtrate was concentrated to ca 70 ml and diluted with hot water to give crystals, m.p. 141° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][C:23]#[N:24]>>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1/[C:22](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:23]#[N:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1nc2ccccc2s1
Product: COc1ccc(/C=C(\C#N)c2nc3ccccc3s2)cc1OC
Yield: 89.2 %

Procedure:
3,4-Dimethoxybenzaldehyde (191 mg) was condensed with 2-benzothiazoleacetonitrile (200 mg) through Method B (production step 2), to thereby yield the target product (yield: 330 mg, 89%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[C:18]([NH2:20])[CH:19]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1cccc(Sc2ccc(C)cc2N)c1
Product: Cc1cccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (267 mg, 1.56 mmol) was reacted with the product from Example 48b (358 mg, 1.56 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (116 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.10 (s, 3H) 2.38 (s, 3H) 2.76 (s, 3H) 6.27 (d, J=7.35 Hz, 1H) 7.00 (m, 3H) 7.40 (m, 3H) 7.78 (d, J=8.82 Hz, 1H) 8.37 (d, J=6.99 Hz, 1H) 8.92 (d, J=8.82 Hz, 1H) 11.08 (br. s., 1H) 14.45 (br. s., 1H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.Cl>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:12][NH:1]2)=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: Oc1n[nH]c2cc(F)ccc12
Reaction time: 0.5 h

Procedure:
2-Amino-4-fluorobenzoic acid (25 g, 161.2 mmol) were suspended in 250 ml of water and 39 ml of conc. hydrochloric acid. At 0° C., sodium nitrite (11.2 g, 161.2 mmol) in 30 ml of water were added dropwise at below 10° C. After 30 min at room temp., sodium sulfite (69 g, 400 mmol) in 250 ml of water were added. After stirring for 2 h, 30 ml of conc. hydrochloric acid were added, and the mixture was left to stand overnight. It was then heated under reflux for 9 h, cooled and adjusted to pH 5.5 with sodium bicarbonate. The precipitate was filtered off with suction and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Yield: 94 %

Procedure:
[3-(1H-Indol-6-yl)-3-(3-methoxy-phenyl)-propyl]-methyl-amine XXXIII (100 mg, 94% yield) was prepared as a hydrochloride salt from 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-N-methyl-propionamide using the procedure described for [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (see Example 4). MS (M+H)=295.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(CC)CC)C.CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([F:9])[C:7]=1[C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14]
Reactant: COc1cc(OC)c(F)c(I)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(F)c(C#C[Si](C)(C)C)c1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (740 mg, 2.47 mmol), (trimethylsilyl)acetylene (0.697 mL, 4.93 mmol), copper(I) iodide (38 mg, 0.20 mmol), and triethylamine (0.52 mL, 3.7 mmol) in N,N-dimethylformamide (DMF) (4 mL, 50 mmol), bis(triphenylphosphine)palladium(II) chloride (86 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 70 hours. The reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (630 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[C:22]([OH:24])=[O:23])=[O:15])[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[C:22]([O:24][CH2:31][CH3:32])=[O:23])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C3CCCCC3C(=O)O)ccc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCCC1C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
A solution of 3.42 g (10 mmoles) of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]cyclohexane carboxylic acid, described in Example III, in 100 cm3 of ethyl alcohol containing 0.1 cm3 of 98% sulfuric acid, is heated for 12 hours at reflux. The solution is concentrated under reduced pressure and the resulting crude ester is dissolved in 100 cm3 of ethyl ether. The ether solution is washed with sodium bicarbonate and then with water, dried on sodium sulfate and evaporated to dryness. After drying, 3.6 g of ethyl 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]cyclohexane carboxylate are obtained in the form of a colorless thick oil.
Reaction SMILES: C(OC([N:8]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=2[C:35]#[N:36])[CH2:21][CH2:20]1)[C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:37].C(OCC)C>C(Cl)Cl>[ClH:37].[ClH:37].[C:35]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:26]=1[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:8][C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)[C:30]([OH:32])=[O:31])#[N:36]
Reactant: CC(C)(C)OC(=O)N(CC1CCN(Cc2ccc(C(=O)O)cc2C#N)CC1)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1cc(C(=O)O)ccc1CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a stirred solution of 4-((4-(((tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid (400 mg, 0.817 mmol) in DCM (5 mL) was added HCl in diethyl ether (5 mL, 0.817 mmol) at 0° C. and stirred at RT for 2 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether (2×10 mL) and dried to afford 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid, dihydrochloride (250 mg, 0.538 mmol, 65.9% yield) as white solid. LCMS (ES) m/z: 390.09 (M+H)+. 1HNMR (400 MHz in D2O): δ 8.489 (bs, 1H) 8.342 (d, J=8 Hz, 1H), 7.866 (d, J=8 Hz, 1H), 7.400-7.291 (m, 3H), 7.209 (d, J=8 Hz, 2H), 4.624 (s, 2H), 3.683 (d, J=10.8 Hz, 2H), 3.269-3.214 (m, 4H), 2.979-2.997 (m, 1H), 2.526-2.577 (m, 1H), 2.107 (d, J=14.8, 3H), 1.528-1.618 (m, 3H), 1.434 (m, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[H-].[Na+].Cl[CH2:15][C:16]1[CH:32]=[CH:31][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[O:21])=[CH:18][CH:17]=1.[I-].[Na+]>C1COCC1.CN(C=O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:32][CH:31]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 0.67 h
Yield: 77.6 %

Procedure:
In an atmosphere of argon, phthalimide (150 mg, 1.0 mmol) was dissolved in THF (10 ml) to which was subsequently added sodium hydride (44 mg, 60%, 1.1 mmol) at room temperature. After 40 minutes of stirring at the same temperature, to this was added a DMF solution (5 ml) containing 4-chloromethyl-N-(2-methoxyphenyl)benzamide (276 mg, 1.0 mmol) and a catalytically effective amount of sodium iodide. After 2 hours of stirring at 80° C. and subsequent removal of the solvent by evaporation, the resulting residue was mixed with water (10 ml) and extracted with an ethyl acetate-methylene chloride (1:2) mixture solution. The resulting organic layer was washed with water and saturated brine and dried on anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was subjected to a silica gel column chromatography (methylene chloride-ether:hexane=2:1) and then washed with ether to obtain 300 mg (77.6%) of the title compound in the form of colorless solid.
Reaction SMILES: [OH:1][CH:2]1[C:7]2=[N:8][C:9]([CH3:16])=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=[C:6]2[CH2:5][CH2:4][CH2:3]1>ClCCl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:16][C:9]1[N:8]=[C:7]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]2=[CH:11][C:10]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc2c(nc1C)C(O)CCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(nc1C)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
Methyl 8-hydroxy-2-methyl-5,6,7,8-tetrahydrocyclohexa[b]pyridine-3-carboxylate (3.95 g, 17.9 mmol) was dissolved in dichloromethane (80.0 ml), and the solution was mixed with activated manganese dioxide (23.29 g) and stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and then purified by a short column chromatography (ethyl acetate) and recrystallization (ethyl acetate-ether) to obtain the title compound (975.1 mg, 24.9%) as pale yellow needle crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:24][C:23](=O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(O)(=O)C>CO.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:23]2[CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:24]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N2CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-benzylpiperazine (0.500 ml) in methanol (25 ml) were added 1-Boc-azetidin-3-one (495 mg), acetic acid (0.182 ml), followed by stirring at room temperature for 5 min. 10% palladium on carbon (308 mg) was added thereto, followed by stirring at room temperature under a hydrogen atmosphere for 15 hr. The catalyst was removed by filtration. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated to provide a crude product of 4-benzyl-1-(1-Boc-azetidin-3-yl)piperazine (ESI-MS (m/z): 332 [M+H]+). This was dissolved in tetrahydrofuran (10 ml). Lithium aluminum hydride (219 mg) was added thereto while stirring in an ice bath. The mixture was stirred under a nitrogen atmosphere in an ice bath for 15 min, at room temperature for 15 min, and was heated to reflux at 100° C. for 3.5 hr. The reaction mixture was cooled in an ice bath. Water (0.22 ml), a 5N aqueous solution of sodium hydroxide (0.22 ml) and water (1.1 ml) were added thereto, followed by stirring in an ice bath for 1 hr. Insoluble matter was removed by filtration. To the filtrate was added a 4N solution of hydrochloric acid in ethyl acetate (2.17 ml), which was concentrated to provide a crude product of 4-benzyl-1-(1-methylazetidin-3-yl)piperazine trihydrochloride (ESI-MS (m/z): 246[M+H]+). This was dissolved in water (25 ml) and 2-propanol (25 ml). 10% palladium on carbon (615 mg) was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was removed by filtration. Concentration of the filtrate provided a crude product of the titled compound as a white solid (382 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:16][N:14]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:4]([OH:3])=[O:5])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1cc2cccnc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (Adams, David Reginald et al., PCT Int. Appl. (2000), WO2000044753) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 301.3 ([M−H]−)