Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH:11](Br)[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][OH:19]>>[Br:1][CH:2]1[CH:11]([O:19][CH3:18])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: CO
Reactant: O=C1c2ccccc2C(Br)C(Br)c2sccc21
Product: COC1c2sccc2C(=O)c2ccccc2C1Br

Procedure:
A suspension of 20 g of 9,10-dibromo-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one in 400 cc of methanol is boiled at reflux for 5 hours. 9-Bromo-9,10-dihydro-10-methoxy-4H-benzo[ 4,5]cyclohepta[1,2-b]thiophen-4-one (M.P. 103°-106°) is obtained.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(O)cc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(N)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 73 %

Procedure:
A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-methoxyphenol (0.74 g, 6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 ml) was heated at 100° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound (1.1 g, 73%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.CCO.[CH3:17][NH2:18]>>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:18][CH3:17])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CNCc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
4-(bromomethyl)-1-methoxy-2-nitrobenzene (276 mg, 1.122 mmol) was dissolved in methanamine in EtOH (33% w/w, 8 ml, 64.5 mmol) and stirred at RT for 1.5 hours. The mixture was evaporated to dryness and diluted with WATER/brine. The aqueous phase was extracted twice with EtOAc. NaHCO3 sat. sol. was added until basic pH, and the aqueous phase was extracted twice with DCM. The combined organic layers were dried and evaporated under vacuum to give 1-(4-methoxy-3-nitrophenyl)-N-methylmethanamine (220 mg, 1.121 mmol, 100% yield, MS/ESI+ 197.1 [MH]+) that was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.CN([CH:24]=[O:25])C>C1COCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: c1cc2sccc2cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2cnccc2s1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
A solution of thieno[3,2-c]pyridine (500 mg, 3.70 mmol) in anhydrous THF (10 mL) was stirred under argon and maintained at −78° C. while a solution of 1.6 M n-butyllithium in hexane (2.5 mL, 4.07 mmol) was added dropwise. The resulting wine red solution was stirred for 5 min. then DMF (573 μL, 7.4 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was treated with 10% aqueous HCl, made alkaline with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×50 mL) The combined organic fractions were concentrated in vacuo to give an oily residue which was subjected to flash chromatography on silica gel (70% ethyl acetate:hexanes) to give the title compound as a white solid (41.5%): 1H-NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.19 (d, J=5.6 Hz, 1H); MS (ES) m/e 164 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:21](#[N:23])[CH3:22]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:5]1[C:21]([CH3:22])=[N:23][N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20])[CH3:2]
Reactant: CC#N
Reactant: CCOC(=O)/C=C(\Nc1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1c(C)nn(-c2ccccc2)c1-c1ccccc1
Yield: 88 %

Procedure:
According to AVV A, (Z-3-phenyl-3-phenylamino acrylic acid ethylester (267.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into acetonitrile (3.0 ml, 57.1 mmol, 57.1 equiv.) for 21 hours at 110° C. The blue-green raw product (389.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→0:100). The product was obtained in the form of a white solid (269.3 mg, 0.88 mmol, 88%).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.I.CS[C:14]1[NH:23][CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[CH:2]1([NH:1][C:14]2[NH:23][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CSC1=Nc2ccccc2C(c2ccccc2)N1
Reactant: NC1CCc2ccccc21
Agent: I
Product: c1ccc(C2NC(NC3CCc4ccccc43)=Nc3ccccc32)cc1

Procedure:
The title compound (MS: m/e=340.3 [M+H+]) was prepared in analogy to example 1 (b) from (+/−)-1-aminoindan and 2-methylsulfanyl-4-phenyl-3,4-dihydro-quinazoline hydroiodide. 2-Methylsulfanyl-4-phenyl-3,4-dihydro-quinazoline hydroiodide can be prepared by the method of Kosasayama, A.; Higashi, K.; Ishikawa, F. Chem. Pharm. Bull. 1979, 27(4), 880-892.
Reaction SMILES: [C:1]1([CH:7]([CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]12[CH2:26]C[CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[C:8]([O:10][C@@H:11]2[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(CCn1cccn1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(CCn1cccn1)c1ccccc1
Yield: 60.3 %

Procedure:
A mixture of methyl (RS)-2-phenyl-4-(1H-pyrazol-1-yl)butanoate (see Preparation 17) (0.37 g), (R)-3-quinuclidinol (0.24 g) sodium hydride (15 mg, as an 80% dispersion in oil) in toluene (15 ml) as refluxed with continuous removal of distillate and, when necessary, replacement with fresh toluene, for 11/2 hours. The cooled mixture was successively washed with water then saturated brine and extracted with 2M hydrochloric acid. The aqueous layer was washed with ethyl acetate, basified with potassium carbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated to give the title compound (0.31 g, 61%) as a yellow oil
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>O1CCCC1>[CH:9]1([C:5]2[CH:6]=[C:7]([F:8])[C:2]3[NH:1][C:31](=[O:32])[N:12]([CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]4)[C:3]=3[CH:4]=2)[CH2:11][CH2:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C3CC3)cc(F)c2N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(F)cc(C4CC4)cc32)CC1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-cyclopropyl-3-fluorophenyl)amino]-1-piperidine-carboxylate (D27, 0.80 mmol, 280 mg) was dissolved in 4 ml of tetrahydrofuran and CDI (1,1′-(oxomethanediyl)bis-1H-imidazole) (2.5 eq., 2.0 mmol, 0.33 g) at room temperature and the mixture was stirred at 50° C. for one overnight under argon. Extra CDI (1 eq., 0.13 g, 0.80 mmol) was added and the mixture was refluxed for two extra hours. The mixture was cooled to room temperature and the solvent was evaporated to afford the crude compound which was purified by chromatography (ethyl acetate (50)-n-hexane (50)) to yield the title compound, 102 mg, 36%, M−−H=374.
Reaction SMILES: [OH-].[Li+].[C:3]([C:6]#[C:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)([OH:5])=[O:4].[CH3:25]O>>[CH3:25][O:4][C:3]([C:6]#[C:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:5]
Reactant: CO
Reactant: Cc1c(-c2cccnc2)n(CC#CC(=O)O)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)C#CCn1c(-c2cccnc2)c(C)c2ccccc21

Procedure:
Treatment of 33 mg of 1-(3-methoxycarbonylprop-2-ynyl)-3-methyl-2-(3-pyridyl)indole in 1 ml of methanol with 0.3 ml of aqueous 1 N lithium hydroxide at room temperature yields 1-(3-carboxyprop-2-ynyl)-3-methyl-2-(3-pyridyl)indole; IR 1720 cm1.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1
Reactant: Cn1nnc2c3nc(O)c(O)nc3ccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1nnc2c3nc(O)c(O)nc3cc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 82.9 %

Procedure:
Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was added portionwise to a stirred solution of 7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6 mmol) in 20 ml of conc. sulfuric acid at 0° C. After 1 h the ice bath was removed and the mixture was stirred over night at room temperature. Then an additional amount of potassium nitrate (0.47 g) was added and stirring was continued over night at room temperature. The solution was poured into ice/water and the precipitated solid was collected, washed with water, and dried to give 1.0 g (83%) of the pure nitro compound; m.p. >300° C.; IR (KBr): 1710 cm-1 ; 1H-NMR (DMSO-d6): 4.50 (s, 3H, CH3), 8.18 (s, 1H, ArH), 12.13 (broad s, 1H, OH), 13.17 (broad s, 1H, OH).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12]C)=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][N+:22]([O-])=O)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]2[C:3]3=[CH:2][NH:1][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:4]=43)[C:10](=[O:12])[NH:22][CH2:21]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Product: COc1ccc(C2CNC(=O)c3cccc4[nH]cc2c34)cc1

Procedure:
In a manner similar to that described for the preparation of Example Q, methyl indole4-carboxylate and p-methoxy nitrostyrene were condensed and the resulting nitro alkane was reduced/cyclized to give, after recrystallization (CH2Cl2/MeOH/hexanes), (rac)-3-(4-methoxyphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 16.9 mh (50%) as a white solid: m.p. 221-223° C.; 1H NMR (300 MHz, d4-MeOH) 3.57 (br m, 5H), 5.15 (br s, 1H) 6.62 (m, 2H), 6.86 (m, 2H),7.08 (app t, J=7.8 Hz, 1H), 7.11 (s, 1H),7.37 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H). Anal. (C19H16N2O2.0.25 H2O) C, H, N.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([O:20][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:19]
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1C
Reactant: O=C(O)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1C
Yield: 80.3 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.08 mmol), 2,6-dichlorobenzoic acid (0.4 g; 2.09 mmol), and triethylamine (0.3 mL; 2.08 mmol) in 20 ml of toluene was allowed to react at 90°-100° C. for 15 hours and at 100° C. for 19 hours, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flesh chromatography to afford 0.66 g (80%) of 2-(2,6-dichlorophenylcarbonyloxy-methyl)-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =methyl) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J24) (1.0 mg, 3.05 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K24) (1.22 g, 3.05 mmol) according to the general procedure M. Obtained as a light brown foam (620 mg, 31%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:14]2[CH2:19][CH2:18][N:17]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CCS(=O)(=O)Cl
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Compound 2 (150 mg, 0.41 mmol) was dissolved in DCM and cooled to 0° C. Ethanesulfonyl chloride (62.2 mg, 0.49 mmol) was added, followed by DIEA (0.21 mL, 1.22 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was diluted with DCM and washed with saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by normal phase chromatography eluting with 10-50% methanol/DCM gradient to provide Compound 91 as a white solid (0.13 g, 69%). MS: m/z 462.34 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH:7]2[CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.O>CC(O)C.[C].[Pd]>[ClH:1].[ClH:1].[N:3]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: c1ccc(CN2CCC(N3CCC3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: C1CN(C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 185.1 %

Procedure:
After adding 10% palladium-carbon (600 mg) to a solution of the crude 4-(azetidin-1-yl)-1-benzylpiperidine dihydrochloride (6.55 g) in 2-propanol (50 ml)-water (50 ml), the mixture was stirred for 23 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with 2-propanol, and then the filtrate was concentrated. Ethanol (10 ml)-hexane (50 ml) was added to the residue to produce suspended precipitate. It was then filtered and washed with 10 ml of ethanol. The filtered precipitate was subjected to aeration drying to provide the title compound (4.26 g) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][P:26]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([O:37][CH3:38])[CH:31]=2)(=[O:29])[CH2:25][CH2:24]1)[CH3:22].Cl>COCCO.C(O)C>[CH2:21]([N:23]1[CH2:28][CH2:27][P:26]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=3)=[C:32]([O:37][CH3:38])[CH:31]=2)(=[O:29])[CH2:25][CH2:24]1)[CH3:22]
Reactant: CCN1CCP(=O)(c2ccc(N)c(OC)c2)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: CCN1CCP(=O)(c2ccc(Nc3cc(Nc4ccccc4S(=O)(=O)C(C)C)cnn3)c(OC)c2)CC1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1)=[O:36])[CH3:39]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (6.0 g) in acetonitrile (100 ml) were added ethyl bromoacetate (7.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.4 ml). The resulting mixture was stirred at room temperature for one hour, and the reaction was stopped by addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (6.08 g, yield: 84%).
Reaction SMILES: [C:1]1([C@H:7]([NH:19][C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])[C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=1>>[N:25]12[CH2:26][CH2:27][CH:28]([CH2:29][CH2:30]1)[C@@H:23]([O:22][C:20](=[O:21])[NH:19][C@H:7]([C:8]1[CH:18]=[CH:17][CH:16]=[C:10]([O:11][CH2:12][C:13]([NH:31][C:32]3[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=3)=[O:15])[CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:24]2
Reactant: O=C(O)COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reactant: Nc1ccc(CO)cc1
Product: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1ccc(CO)cc1

Procedure:
The title compound was prepared as described in Example 1 Step 10 with 2-(3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)acetic acid replacing 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl) phenoxy)methyl)benzoic acid and 4-aminobenzyl alcohol replacing 4-(2-hydroxyethoxy)-3-methylbenzaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2([S:11][CH3:12])[CH2:10][CH2:9]2)[CH2:5][C:4](=[O:13])[C:3]=1[C:14](=O)[CH2:15][CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][O:29][NH2:30])=[CH:21][CH:20]=1>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][O:29][N:30]=[C:14]([C:3]2[C:4](=[O:13])[CH2:5][CH:6]([C:8]3([S:11][CH3:12])[CH2:10][CH2:9]3)[CH2:7][C:2]=2[OH:1])[CH2:15][CH3:16])=[CH:23][CH:24]=1
Reactant: NOCC/C=C/c1ccc(Cl)cc1
Reactant: CCC(=O)C1=C(O)CC(C2(SC)CC2)CC1=O
Solvent: CO
Product: CCC(=NOCC/C=C/c1ccc(Cl)cc1)C1=C(O)CC(C2(SC)CC2)CC1=O
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 2.0 g (7.9 mmol) of 3-hydroxy-5-(1-methylthiocyclopropyl)-2-propionyl-2-cyclohexen-1-one, 1.8 g (9.0 mmol) of O-[4-trans-(4-chlorophenyl)-but-3-enyl]-hydroxylamine and 100 ml of methanol was stirred for 24 hours and then evaporated down under reduced pressure. Yield: 100%
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH:12]([Cl:14])[CH3:13]>C(O)C>[Cl:14][CH:12]([CH3:13])[CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: CC(Cl)CBr
Reactant: Oc1ccccc1Br
Agent: [Na]
Solvent: CCO
Product: CC(Cl)COc1ccccc1Br
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0°, and treated, dropwise, with 157.5 g of 1-bromo-2-chloropropane. The last addition requires about 1 hour. The mixture is stirred at 0° for about 2 hours and slowly warmed to reflux during about 2 hours, heated under reflux for about 2 hours, filtered from the precipitated sodium bromide, and the filtrate is concentrated in vacuo at 40° to give about 240.2 g of o-bromophenyl 2-chloropropyl ether as a mobile, colorless liquid.