Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: COc1ccc(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1

Procedure:
The title compound, MS: m/e=425.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-methoxyphenyl-isocyanate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 1, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.76 mmol) was reacted with benzoyl chloride (0.25 g, 1.76 mmol) to provide N1-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 203-206° C. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.47 (broad s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.32 (q, J=6.0 Hz, 2H), 2.95 (q, J=7.0 Hz, 2H), 1.87 (quintet, J=7.0 Hz, 2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H); MS (EI) m/e 387.2058 (387.2059 calcd for C23H25N5O).
Reaction SMILES: [C:1]([N:4]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)(=[O:3])[CH3:2].[I:19](O)(=O)=O.II>C(O)C>[C:1]([N:4]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[C:7]([I:19])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2ccccc2)nn1C(C)=O
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CC(=O)Nc1c(I)c(-c2ccccc2)nn1C(C)=O
Temperature: 50 °C

Procedure:
A suspension of N-(2-acetyl-5-phenyl-pyrazol-3-yl)acetamide (25.1 g, 0.103 mol), iodic acid (4.5 g, 0.026 mol) and iodine (15.7 g, 0.062 mol) in ethanol (250 mL) was heated at 50° C. for 3 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and 2 M Na2S2O3 aq. solution. The layers were separated and the organic washed with brine, dried (phase separator cartridge), and concentrated in vacuo to provide a mixture of the title compound and starting material (2.2:1, 30.3 g). The mixture was put in reaction again using iodic acid (1.6 g, 9.6 mmol) and iodine (9.7 g, 0.038 mol) in ethanol (250 mL) under the same conditions, to provide the title compound as a solid (31.9 g).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH2:18]([NH:21][S:22]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:24])=[O:23])[CH:19]=[CH2:20]>>[CH2:18]([NH:21][S:22]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:30][CH:31]=1)(=[O:24])=[O:23])[CH:19]=[CH2:20]
Reactant: C=CCNS(=O)(=O)Cc1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: C=CCNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-allyl-4-aminophenylmethane sulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.3 (t, 1H), 7.1 (d, 1H), 5.8 (m, 1H), 5.2 (d, 1H), 5.1 (d, 1H), 4.4 (s, 2H), 3.6 (t, 2H); APCI−MS m/z 427 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[N:18]2[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][O:21][C:16]3=[C:17]2[C:12](=[CH:13][CH:14]=[CH:15]3)[NH:11]1.C(#N)C>C(O)(=O)C>[Br:1][C:15]1[C:16]2[O:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[N:18]3[C:10](=[O:9])[NH:11][C:12]([C:17]=23)=[CH:13][CH:14]=1
Reactant: NC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC#N
Product: NC(=O)C1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a solution of 2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide, acetonitrile (5 mL) and acetic acid (3 mL) and cooled to 0° C. The reaction mixture was stirred for 1 h and then concentrated to remove residual acetic acid. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.040 g. 60%). LCMS calculated for C15H12BrN4O3 (M+H)+: m/z=375.1, 377.1. found: 375.0, 376.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[C:11](OCC)=[O:12].Cl>CO>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH:7]([CH2:11][OH:12])[CH2:8][C:9]1=[O:10]
Reactant: CCOC(=O)C1CC(=O)N1Cc1ccc(OC)cc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(CN2C(=O)CC2CO)c(OC)c1
Yield: 96.1 %

Procedure:
47.6 g (0.162 mole) of ethyl 1-(2,4-dimethoxybenzyl)-4-oxo-2-azetidine-carboxylate prepared according to paragraph e) of Example 1 are reacted with 12.4 g (0.327 moles) of sodium-[tetrahydro-borate(III)] in 200 ml of methanol under external ice-cooling. The reaction takes place within about half an hour. The solution is made neutral by adding diluted hydrochloric acid, the methanol is distilled off and the oil precipitated from the aqueous mixture is extracted five times with 50 ml of ethyl acetate each. The united ethyl acetate layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. Thus 39.1 g of 1-(2,4-dimethoxy-benzyl)-4-(hydroxymethyl)-2-azetidinone are obtained. Yield: 96%.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1nnn2-c1ccccc1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
Sodium hydride (38.5 mg, 0.96 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (200 mg, 0.40 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (Intermediate AP2) (107 mg, 0.40 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-chloropyridin-2-yl)propanamide (290 mg, 99%). m/z (ES+), (M+H)+=728.38: HPLC tR=3.91 min Intermediate AP5: 6-chloro-N4-o-tolylpyrimidine-4,5-diamine
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH2:24][CH:25]=O)=[CH:16]1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1.[OH-].[Na+]>ClCCl.C(O)(=O)C>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH2:24][CH2:25][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]2)=[CH:16]1
Reactant: O=CCc1coc2ccccc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(CCc2coc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
13 ml of acetic acid and 61 g of sodium triacetoxyborohydride are added in succession to a solution of 33 g of 2-(benzofuran-3-yl)acetaldehyde and 41.3 g of tert-butyl 4-piperidylcarbamate in 1.4 litres of dichloromethane. After 24 hours' stirring at room temperature, a 20% sodium hydroxide solution is added. After 10 minutes, the reaction mixture is decanted and the organic phase is washed, dried and concentrated. Chromatography over silica gel (cyclohexane/ethyl acetate 30/70) enables the expected product to be isolated.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@H:19]([C:20]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=[CH:29]4)[CH2:25][CH2:24][CH2:23][N:22]5[CH:21]=3)[C:18](=[O:32])[NH:17][C:16]2=[O:33])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd]>[C:20]1([C@H:19]2[C@H:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16](=[O:33])[NH:17][C:18]2=[O:32])[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][CH2:23][N:22]3[CH:21]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(O)cc1
Yield: 44.1 %

Procedure:
A mixture of (±)-trans-3-[4-(benzyloxy)phenyl]-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrolidine-2,5-dione (0.2 g) and Pd/C (10% w/w, 0.076 g) was stirred under 1 atmosphere of hydrogen gas overnight. The catalyst was filtered off through a pad of celite and concentrated. The residue was purified by column chromatography on silica gel eluting with 30-40% ethyl acetate in hexane to provide (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(4-hydroxyphenyl)pyrrolidine-2,5-dione 0.07 g as a light yellow solid. Mp 105-107° C.; 1H NMR (acetone-d6) 400 MHz δ: 10.27 (s, 1H), 8.34 (s, 1H), 7.17-7.21 (m, 4H), 6.80-6.91 (m, 4H), 4.39 (d, J=7.0 Hz, 1H), 4.22 (d, J=7.0 Hz, 1H), 4.13 (d, J=5.6 Hz, 2H), 2.92 (d, J=5.2 Hz, 2H), 2.15-2.19 (m, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1.[B:14](OC)([O:17]C)[O:15]C.Cl>C1COCC1>[CH3:13][C:9]1[CH:8]=[C:7]([B:14]([OH:17])[OH:15])[CH:12]=[CH:11][CH:10]=1
Reactant: COB(OC)OC
Reactant: Cc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
n-Butyllithium (15 mL, 2.5M in hexane, 37.4 mmol) was added dropwise to a solution of 3-bromotoluene (5.8 g, 34.0 mmol) in 50 mL of THF cooled to -78° C. The resulting suspension was stirred at -78° C. for 30 min, treated with trimethyl borate (10.6 g, 102.2 mmol), stirred -78° C. for 10 min, and allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours, then cooled in an ice bath and acidified to pH 6 with 2N HCl. The mixture was extracted with methylene chloride, and the organic extract was washed with bdne, dried over Na2SO4, and concentrated to yield 4.24 g of 3-methylphenyl boronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C.CCOC(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCNc1ccccn1
Temperature: 0 °C

Procedure:
2-Aminopyridine (3-1, 1.97 g, 20.9 mmol) in 10 mL DMF was added to a suspension of NaH (60% in oil, 1.00 g, 25 mmol) in 80 mL DMF cooled to 0° C. After warming to RT for 45 min, ethyl 5-bromopentanoate (4.2 mL, 25 mmol) was added dropwise. This mixture was heated at 75° C. overnight, then cooled to RT, diluted with EtOAc, washed with water (2×), sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 50% then 70% EtOAc/hexane) provided 3-2 as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][CH2:15][CH3:16])/[C:10]([OH:12])=[O:11])=[C:6]([O:17]C)[C:5]([O:19][CH3:20])=[C:4]([O:21][CH3:22])[C:3]=1[O:23]C>CCOCC>[CH3:22][O:21][C:4]1[C:3](=[O:23])[C:2]([CH3:1])=[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][CH2:15][CH3:16])/[C:10]([OH:12])=[O:11])[C:6](=[O:17])[C:5]=1[O:19][CH3:20]
Reactant: CCCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)O
Solvent: CCOCC
Product: CCCC/C(=C\C1=C(C)C(=O)C(OC)=C(OC)C1=O)C(=O)O

Procedure:
Compound 10e was prepared from 9e (0.015 g, 0.044 mmol) as described above for 10a to give 0.005 g (0.018 mmol, 40%) of the product as a red solid following flash chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1B(O)O>>[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(F)c(Br)n1
Reactant: COc1ccc(F)c(B(O)O)c1F
Product: COc1ccc(F)c(-c2nc(C)ccc2F)c1F
Yield: 60 %

Procedure:
Method 4 was followed using 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) and 2,6-difluoro-3-methoxyphenylboronic acid (2.0 equiv.) to give 2-(2,6-difluoro-3-methoxyphenyl)-3-fluoro-6-methylpyridine in 60% yield. LC/MS=254.1 (M+H), Rt=0.85 min.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO.C(Cl)Cl>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(OCCN(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
0.68 g (2.27 mmol) of methyl 4-[4-(2-dimethylaminoethoxy)phenyl]benzoate was dissolved in 18 ml of methanol-methylene chloride (5:1 (v/v)). 3.4 ml of a 1N sodium hydroxide aqueous solution was added thereto and the mixture was refluxed under heating for 5 hours. After cooling to room temperature, 3.4 ml of 1N hydrochloric acid was added and stirred. The precipitate thus formed was collected by filtration, washed, and dried to obtain 0.54 g (1.89 mmol) of 4-[4-(2-dimethylaminoethoxy)phenyl]benzoic acid as faint yellowish white powder. ##STR22## Its spectroscopic data are as follows:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([C:30]5[CH:31]=[CH:32][C:27]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)=[CH:28][CH:29]=5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, white solid (112 mg, 88%), MS (ISP) m/z=509.5 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccn(C2CCC(=O)CC2)c(=O)c1
Product: Cc1ccn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c(=O)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-methyl-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(C)(C)C.[K+].COC1C=CC(C[Br:38])=CC=1>CN(C)C=O>[Br:38][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)COC[C@@]2(C)c2cccc(N)c2)cc1
Reactant: COc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)COC[C@@]2(C)c2cccc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-5-(3-amino-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one (1.0 g, 3.7 mmol) in N,N-dimethylformamide was added within 5 minutes at 0° C. to a solution of potassium tert-butanolate (0.636 g, 5.7 mmol). After stirring at 0° C. for 30 minutes the light yellow solution was cooled to −4° C. and treated with a solution of 4-methoxybenzylbromide (1.12 g, 5.6 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was left to warm to room temperature, then the solvent was evaporated at reduced pressure, and the residue treated with saturated ammonium chloride solution (50 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with brine (50 ml), dried over sodium sulfate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. The (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one was obtained as colorless oil (1.19 g, 83% of theory). Mass (calculated) C19H20BrNO3 [390.275]; (found) [M+H]+=390, [M+2-H]+=392.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:21]1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:10][CH2:11][O:12][CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 174 (2.22 g, 6.93 mmol) and THF (30 mL).cooled to 0° C. and maintained under a N2 atmosphere was added NaH (0.333 g, 8.32 mmol, 60% in mineral oil). The ice bath was removed and the solution stirred for 30 min then MeI (0.519 mL, 8.32 mmol) was added and the yellow solution stirred overnight. The reaction was diluted with H2O and extracted with Et2O. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography (SNAP 50) eluting with hexane/EtOAc (4:1) to afford 0.660 g (28%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-methoxypropylcarbamate (176) as a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2OC(=O)[NH:13][C@H:12]2[CH3:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@@H:12]([NH2:13])[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1NC(=O)O[C@H]1c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@H](N)Cc1ccc(C(C)(C)C)cc1

Procedure:
A mixture of 1 g (4.3 mmole)(4S,5S)-5-(4-tert-butylphenyl)-4-methyl-oxazolidin-2-one p(see preparation 4, step 2), 2 g (31.74 mmole) ammonium formate and 0.1 g 10% palladium on carbon in 25 mL methanol was heated under reflux for 2 hrs. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between 10 mL 10% sodium carbonate and 25 mL ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The title compound was isolated as the hydrochloride salt from diethyl ether, 0.93 g (95%), m.p.259.5–261.3° C.
Reaction SMILES: [C:1]1([N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[C:13]2=[O:30])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.Cl>[OH-].[OH-].[Pd+2].CCO>[C:1]1([N:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]2[OH:30])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2=O
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Reaction time: 5 h
Yield: 21.9 %

Procedure:
To a solution of ethyl {[6-(N,N -diphenylcarbamoyloxy)methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]oxy}acetate (100 mg) in a mixed solvent of THF and EtOH (1:4, 5 ml) were added 20% Pd(OH)2 on carbon and catalytic amount of concentrated hydrochloric acid. The mixture was hydrogenated for 5 hours at 3 atm. After removal of the catalyst by filtration, the filtrate was evaporated. The residue was dissolved in EtOAc, washed with saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 2:1) to give ethyl {[(5SR,6RS)-6-(N,N-diphenylcarbamoyloxy) methyl-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]oxy}acetate (22.0 mg) as an amorphous solid.