Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:31]1[C:40]2[CH2:39][CH2:38][NH:37][CH2:36][C:35]=2[CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:37]3[CH2:38][CH2:39][C:40]4[N:31]=[CH:32][CH:33]=[CH:34][C:35]=4[CH2:36]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: c1cnc2c(c1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ncccc3C2)no1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with 5,6,7,8-tetrahydro[1,6]naphthyridine dihydrochloride (Chem.Pharm.Bull.; 32; 7; 1984; 2522-2529) (0.79 g, 3.80 mmol) and triethylamine (1.27 ml, 9.13 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (90:10) gradually changing to dichloromethane:ethyl acetate (50:50) to afford the title compound (281 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].[Na].CO>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:22][OH:23])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
178.7 g (628 mmol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carbonitrile and 65.5 g (941 mmol) of hydroxylamine hydrochloride were added to a solution prepared from 17.3 g (753 mmol) of sodium and 1.5 l of methanol. The reaction mixture was stirred at room temperature overnight and subsequently diluted with 1 l of water. The suspension obtained was suction filtered and the crystals were dried. There were obtained 169.7 g (85%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamidoxime of decomposition point 269°.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[NH:9][C:10]3[C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([CH2:42][CH2:43][CH2:44]Br)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:44][CH2:43][CH2:42][CH:38]3[CH2:39][CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:37]3)[C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:10]=3[N:9]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(OCc2nc3cccc(OCc4ccccc4)c3[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCBr)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCc4ccccc4)cccc32)C1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for thirty minutes and then (RS) 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the reaction mixture. The resulting mixture was stirred at 70° C. for three hours. The reaction was quenched by the addition of water (1×30 ml). The aqueous fraction was extracted with diethyl ether (1×30 ml). The organic fractions were combined, washed with water (1×30 ml), then brine (1×30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 38% yield.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)=[O:12].P(Br)(Br)[Br:22].C(=O)(O)[O-].[Na+]>CCOCC>[Br:22][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12]
Reactant: O=C(CCCCCCCO)c1ccc2ccccc2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CCCCCCCBr)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
To a solution of 7-(2-naphthoyl)-1-heptanol 71 (175 mg, 0.606 mmol) in ether (5 mL) at 0° C. was added a solution of phosphorous tribromide (86 μL, 0.908 mmol) in ether (1 mL) dropwise and the reaction mixture was stirred at room temperature for 6 hours. Saturated sodium bicarbonate solution was added slowly and the mixture was extracted with ether (2×20 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvents were removed in vacuo to give the title compound 72 (141 mg, 70%). 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.12 (m, 1H), 7.99 (m, 3H), 7.62 (m, 2H), 3.50 (t, 2H), 3.11 (t, 2H), 1.65 (m, 2H), 1.55 (m, 2H),1.31 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][O:21][CH3:22])=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=3[N:13]=2)[CH:8]=1.[CH3:23][O:24]COC1C=CC(C=NC2C(C)=CC=CC=2O)=CC=1>>[CH3:23][O:24][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=3[N:13]=2)=[C:6]([O:19][CH2:20][O:21][CH3:22])[CH:5]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(C)cccc2o1
Reactant: COCOc1ccc(C=Nc2c(C)cccc2O)cc1
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(C)cccc2o1

Procedure:
2-(4,5-dimethoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F9) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) by using 2-[(4-methoxymethoxybenzylidene)amino]-3-methylphenol (F6) (3.31 g, 10 mmol) instead of 2-[(5-methoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F4) in 62% (2.07 g): 1H-NMR (400 MHz, CDCl3) δ2.66 (s, 3H), 3.58 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 5.28 (s, 2H), 6.84 (s, 1H), 7.12 (d, 1H, J=8.0 Hz), 7.21 (t, 1H, J=8.0 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.63 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol) in N,N-dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102 mmol, 1.5 eq). The mixture was stirred for 30 min. A solution of methyl iodide (4.17 mL, 67.0 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to provide 10.2 g (92%) of methyl 2-amino-3-methylbenzoate. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:34])[CH:15]([C:17]1[N:18]=[N:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:21]=1)Br)([CH3:3])[CH3:2].[N-:35]=[N+]=[N-].[Na+].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:35][CH:15]([C:17]1[N:18]=[N:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:21]=1)[C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[O:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCn1nnc(C(Br)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCCCCn1nnc(C(N)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 24 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl -2H-tetrazol-5-yl)-2-bromoacetamide (1 g, 1.87 mmol) from Example 1 (e) was added to a solution containing sodium azide (0.24 g, 3.7 mmol) in ethanol (20 mL). The solution was stirred for 72 hours at 24° C. Sodium borohydride (0.07 g, 1.87 mmol) was added to the reaction mixture in one portion. The suspension was stirred for 12 hours at 24° C., then concentrated in vacuo. The resulting residue was triturated with ethyl acetate, filtered, and the filtrate was concentrated in vacuo leaving a viscous liquid. The liquid was dissolved in 10 mL of 50% ethyl acetate/ 50% hexane and purified by silica gel chromatography (elution with 50% ethyl acetate/50% hexane) to give (±)-2-amino-N-(2,6-diisopropylphenyl)-2-(2-dodecyl -2H-tetrazol-5-yl)-acetamide (0.58 g, 66%) as a colorless liquid;
Reaction SMILES: C(O[C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.[CH3:13][O:14][C:15](=[O:17])[CH3:16].[Na]>>[CH2:10]([O:9][CH:5]([O:6][CH2:7][CH3:8])[C:4](=[O:12])[CH2:16][C:15]([O:14][CH3:13])=[O:17])[CH3:11]
Reactant: COC(C)=O
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Na]
Product: CCOC(OCC)C(=O)CC(=O)OC
Temperature: 0 °C

Procedure:
Ethyldiethoxyacetate (32 g.) and methylacetate (25 g.) are placed in a flask equipped with stirrer and reflux condenser and heated to reflux. Metallic sodium wire (6.5 g.) is introduced into the flask in small portions and heating continued until the sodium is completely dissolved. Methylacetate (25 g.) and metallic sodium wire (6.5 g.) are then added and heating continued until the solution is clear. The mixture is cooled, a large volume of ice water cautiously added and the mixture extracted with ether. The aqueous solution is acidified with hydrochloric acid at 10° C. to 15° C. and the desired product extracted with ether. The ethereal extract is dried (Na2SO4), the ether removed and the residue distilled in vacuo to give methyl γ,γ-diethoxyacetoacetate.
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.[O:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](O)=[O:34])[CH2:28]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]([CH:29]5[CH2:30][CH2:31][CH2:32][O:27][CH2:28]5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1CCCOC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCCOC1

Procedure:
The title compound, off-white solid (91 mg, 83%), MS (ISP) m/z=441.4 [(M+H)+], mp 222° 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 dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1>ClCCl>[C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:2]([O:1][S:44]([C:40]5[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=5)(=[O:46])=[O:45])=[CH:3][CH:4]=4)[CH2:9]3)=[O:30])=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NCCCCN1CCc2ccc(O)cc2C1)c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1CCc2ccc(OS(=O)(=O)c3cccnc3)cc2C1)c1ccc(-c2ccccc2)cc1
Reaction time: 18 h
Yield: 8.5 %

Procedure:
To a stored solution of 7-hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (05 g, 1.3 mmol) and triethylamine (0.21 ml; 1.5 mmol) in dichloromethane (20 ml) was added pyridine-3-sulfonyl chloride (0.25 g, 1.4 mmol). The mixture was stirred for 18 h, then partitioned between dichloromethane (4×30 ml) and saturated aqueous NaHCO3 (100 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica using 0-5% methanolethyl acetate gradient elution gave the title compound (0.06 g, 12%) as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Br[C:15]1[C:16]([NH2:33])=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:33][C:16]1[C:15]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[N:20][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][N:17]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(NC(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
tert-Butyl N-pyrrolidin-3-ylcarbamate (43.14 mg, 0.2316 mmol) was added to a stirred solution of 3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (75 mg, 0.2105 mmol) and DIPEA (29.93 mg, 40.34 μL, 0.2316 mmol) in NMP (1 mL) and the reaction mixture heated to 100° C. under microwave conditions for 90 minutes. The reaction mixture was partitioned between EtOAc/water and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether). The fractions were collected concentrated in vacuo and freeze-dried to give the title compound as a yellow solid (46 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 1.40 (s, 9H), 1.79-1.82 (m, 1H), 2.08-2.17 (m, 1H), 3.30-3.38 (m, 1H), 3.42-3.44 (m, 2H), 3.60-3.71 (m, 2H), 4.06-4.12 (m, 1H), 6.22 (s, 2H), 7.16 (d, 1H), 7.83 (d, 2H), 8.18 (d, 2H) and 8.20 (s, 1H) ppm; (ES+) 462.3.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][CH2:33][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=3)[CH:36]=[CH:35]2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][N:34]2[CH2:33][CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:29]2)=[CH:38][CH:39]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2ccn(CCC3CNC3)c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(CCn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.43 g, 0.79 mmol), 1-(2-azetidin-3-yl-ethyl)-6-fluoro-1H-indole (0.25 g, 0.95 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (10% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.3 g of the (S)-enantiomer of the title compound as a brown oil. The hydrochloride salt was prepared in ethyl acetate and collected as a yellow solid: m.p. 115° C. (dec).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:7]=1[CH3:21])=[O:4].[CH3:22][C:23]1([CH3:33])[N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:26]2[C:25](=[O:32])[NH:24]1.C(N(CC)CC)C>CN(C)C=O>[CH3:21][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:30]1[CH2:29][CH2:28][N:27]2[C:23]([CH3:33])([CH3:22])[NH:24][C:25](=[O:32])[CH:26]2[CH2:31]1
Reactant: CC1(C)NC(=O)C2CNCCN21
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCN2C(C1)C(=O)NC2(C)C
Temperature: 70 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
A mixture of 13.36 parts of 2-chloro-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]acetamide, 6.76 parts of hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one, 7.8 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated. The residue was taken up in water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 11.66 parts (66.8%) of N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]hexahydro-3,3-dimethyl-1-oxoimidazo-[1,5-a]pyrazine-7(8H)-acetamide; mp. 223.8° C. (int. 1).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([C:22]([O:24]CC)=[O:23])=[CH:10]2)=[O:5].[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([C:22]([OH:24])=[O:23])=[CH:10]2)=[O:5]
Reactant: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Temperature: 90 °C

Procedure:
119 mg (0.31 mmol) of ethyl 5-[(3,3-dimethylbutanoyl)amino]-1-phenyl-1H-indole-2-carboxylate from Example LVIII are dissolved in each case in 2 ml of methanol and THF, and 0.31 ml (0.63 mmol) of a 2 M lithium hydroxide solution is added. The mixture is heated at 90° C. for one hour. After cooling, the mixture is, for work-up, diluted and extracted with aqueous hydrochloric acid and ethyl acetate. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl>[O:1]([CH2:8][CH2:9][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: O=S(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: ClCCOc1ccccc1
Temperature: 0 °C
Yield: 101.7 %

Procedure:
Into a three-necked flask fitted with a stirrer, dropping funnel, thermometer and reflux condenser, was added 34.7 g 2-phenoxy-ethanol, 75 g dichloromethane and 1.25 g benzyl-trimethyl-ammonium chloride. The mixture was cooled to about 0° C. and 34 g thionyl chloride was added dropwise over a period of 45 minutes. After this addition, the mixture was warmed to room temperature, stirred for an hour and then heated to reflux (50° C.) for an additional three hours. At the end of the reaction (determined by GLC) the mixture was washed with water, an aqueous 10% sodium hydroxide solution and then again with water. The solvent was distilled off to afford 40 g of 2-phenoxy-ethyl chloride in a concentration of 95%.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1COCC1>[C:15]([NH:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13])(=[O:17])[CH3:16]
Reactant: NC[C@H](O)CCl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H](O)CCl
Reaction time: 0.08 h

Procedure:
Triethylamine (10.5ml, 75.3 mmol, 1.11 eq) is added to a slurry of (S)-1-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 9,938 g, 68.059 mmol) in THF (80 ml) at −40° and the mixture stirred for 5 min at −40°. Acetic anhydride (6.78 ml, 71.86 mmol, 1.056 eq) is then added at −40° and the mixture allowed to warm to 20-25° over 1.5 hrs. The precipitate is removed by filtration with reduced pressure and washed with THF. The filtrate is treated with magnesol (5.69 g), which is removed by filtration with reduced pressure and washed with THF (2×60 ml). The filtrate is then concentrated under reduced pressure. The concentrate is purified by flash chromatography (silica gel; eluting with a gradient of 75-100% ethyl acetate/cyclohexane) to give the title compound, NMR (CDCl3) 2.03, 3.32, 3.50-3.57, 3.55, 3.91-4.13, 5.01 and 7.09δ; CMR (CDCl3) 23.00, 43.31, 46.52, 70.65 and 172.40δ; MS (CI, NH3), M/Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152 (48.1); [α]25D=−7.44 (c=1.00, H2O).
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4](Br)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>C(O)(=O)C>[C:14]([O:17][C:4]12[CH2:3][C:2]3([CH3:1])[CH2:12][CH:6]([CH2:7][C:8]([CH3:11])([CH2:9]3)[CH2:10]1)[CH2:5]2)(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC12CC3CC(C)(CC(C)(C3)C1)C2
Temperature: 0 °C

Procedure:
2.486 (10.2 mmoles) of 3,5-dimethyl-1-bromoadamantane is refluxed for 16 hours with 2.034 g (20.7 mmoles) of potassium acetate in 10 mL of acetic acid. The solution is poured over 100 grams of ice, allowed to melt, and extracted with 3×10 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, then dried over sodium sulfate. The solvent is removed under vacuum, yielding 1.521 (67%) of the desired product, a colorless oil. TLC: Rf=0.68 (silica plate: eluant hexane 90%, ethyl acetate 10%). 1HNMR (CDCl3, 500 Mhz): 0.858 (s, 6H), 1.115 (d, 2H, J=12.4 Hz), 1.177 (d, 2H, J=12.4 Hz), 1.260 (d, 2H, J=12.3 Hz), 1.367 (d, 2H, J=12.3 Hz), 1.714 (d, 2H, J=11.6 Hz), 1.766 (d, 2H, J=11.6 Hz), 1.939 (s, 2H), 1.976 (s, 3H), 2.191 (m, 1H).