Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:8][CH:9]=1)([O-])=O.Cl>C(O)C.O>[C:20]1([C:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:11]#[C:10][C:7]3[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:15][CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Reaction time: 0.5 h

Procedure:
A solution of 1,2,3,6-tetrahydro-1-[4-(5-nitro-2-pyridinyl)-3-butynyl]-4-phenylpyridine (Example 9) (2.0 g, 0.006 mol), reduced iron (3.1 g), and 0.10 mL of concentrated hydrochloric acid in 30 mL of 95% ethanol and 10 mL of water is heated at 80° C. with vigorous stirring for 30 minutes. The hot solution is filtered through diatomaceous earth (Celite), and the filter cake is washed with 300 mL of hot ethanol. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound, containing 0.3 mol of water; mp 135.5°-137° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:31]([O:33]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:37][NH2:38]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:37][NH:38][C:31](=[O:33])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg) in 85% hydrazine monohydrate (1 mL) and methanol (10 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The crude was purified by flash chromatography to give the title compound (72 mg, yield 37%). LC-MS (ESI) m/z: 439 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.18 (d, 3H), 1.19 (d, 3H), 2.26 (s, 6H), 2.79-2.83 (m, 1H), 3.51 (d, 2H), 4.27 (d, J=8.0 Hz, 1H), 4.73 (d, J=8.0 Hz, 1H), 6.98-7.00 (m, 2H), 7.05-7.07 (m, 2H), 7.18-7.22 (m, 3 H), 7.25-7.27 (m, 2H), 7.54-7.56 (m, 1H), 7.56-7.59 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6]Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]#[N:23].[OH-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:8]([N:4]1[CH2:5][CH2:6][C:21]([C:22]#[N:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:2][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Temperature: 65 °C
Yield: 101.6 %

Procedure:
To a mixture of N,N-bis-(2-chloroethyl)benzylamine (Szarvasi, E., Eur. J. Med. Chem. Chem. Ther. 11(2), 115-124, 1976) (60 g, 22 mmol), 2-pyridylacetonitrile (2.51 mL, 22 mmol) and tetrabutylammonium hydrogen sulfate (0.26 g, 0.7 mmol) in toluene (10 mL), sodium hydroxide solution (2.43 g in 4.86 mL H2O) was added over a 20 minute period. The reaction mixture was heated at 65° C. for 4 hours. The reaction mixture was cooled to room temperature, 10 mL of water was added and the solution partitioned between ethyl acetate (45 mL) and water. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane: EtOAc, 2:3) gave 6.2 g (87%) of the title compound as a red solid; 1H-NMR (CDCl3): δ2.05 (d, J 13.1 Hz, 2H), 2.30 (t, J=13.2 Hz, 2H), 2.48 (t, J=13.2 Hz, 2 H), 2.97 (d, J=12.1 Hz, 2 H), 3.57 (s, 2 H), 7.19-7.27 (m, 6 H), 7.30 (d, J=7.6 Hz, 1 H), 7.60 (t, J=7.6 Hz, 1 H ), 8.58 (d, J=4.6 Hz, 1 H).
Reaction SMILES: F[C:2](F)(F)C1(F)OC1(F)F.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=O>>[F:11][C:12]([F:20])([F:19])[C:13](=[CH2:2])[C:15]([F:18])([F:17])[F:16]
Reactant: FC(F)(F)C1(F)OC1(F)F
Reactant: O=C(C(F)(F)F)C(F)(F)F
Product: C=C(C(F)(F)F)C(F)(F)F

Procedure:
In the form of the present invention starting from hexafluoropropylene oxide, a vapor stream of hexafluoropropylene oxide is fed at any convenient flow rate, e.g., in the range of about 0.04 to about 0.06 g-mole/hr to a reactor maintained at a temperature in the range of about 400° to about 650° C. and containing a fluorinated catalyst (hereinafter described) for a residence time sufficient to for a vapor stream comprising hexafluoroacetone which is not isolated but forwarded directly to a heating zone of the reactor for conversion to hexafluoroisobutylene.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:27]([N:29]1[C@H:33]([C:34](=[O:46])[NH:35][C@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][CH2:38][CH2:37]2)[CH2:32][Si:31]([CH3:48])([CH3:47])[CH2:30]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:49]>C(Cl)Cl>[NH2:8][C@H:9]([C:27]([N:29]1[C@H:33]([C:34](=[O:46])[NH:35][C@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][CH2:38][CH2:37]2)[CH2:32][Si:31]([CH3:48])([CH3:47])[CH2:30]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1.[ClH:49]
Reactant: COC(=O)c1ccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(C[C@H](N)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4′-((S)-2-((tert-butoxycarbonyl)amino)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)-[1,1′-biphenyl]-4-carboxylate (30 mg, 0.045 mmol) in DCM (2 mL) was added HCl (4.0 M solution in dioxane) (0.34 mL, 1.34 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo to give the title compound HCl salt as a light yellow solid (25 mg, 92%). MS(ESI+) m/z 570.5 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:22][CH:21]=2)=[CH:16][C:15]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:13])(=[O:10])=[O:9])(=O)C.[OH-].[Na+]>CO.O1CCCC1>[OH:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][N:29]([CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:24][CH:25]=2)=[CH:16][C:15]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:13])(=[O:10])=[O:9]
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of 3-[[[[4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-3-isopropoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (221 mg) in methanol (2.21 ml) and tetrahydrofuran (1.11 ml) was added 1N sodium hydroxide (0.950 ml) and the mixture was stirred at room temperature for 1 hour. Methanol and tetrahydrofuran were removed by evaporation under reduced pressure and to the residue was added water (50 ml). The mixture was acidified with 1N hydrochloric acid (pH=5.4) and extracted with ethyl acetate (50 ml×2). The combined organic layer was washed with water and brine, and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave tert-butyl [3-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-isopropoxy-4-biphenylyl]propyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (212 mg) as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)NC=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[S:22]1C2C=CC=CC=2C(C(Cl)=O)=[N:23]1>>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:22][N:23]=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: O=C(Cl)c1nsc2ccccc12
Product: O=C(NCC12CCN(CC1)CC2)c1nsc2ccccc12

Procedure:
N-(quinuclidin-4-ylmethyl)benzo[d]isothiazole-3-carboxamide was prepared in a similar manner to N-((quinuclidin-4-yl)methyl)-1H-indole-3-carboxamide, substituting benzo[d]isothiazole-3-carbonyl chloride as the electrophile.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=2)[C:9]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8]1.[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28]>C1(C)C=CC=CC=1>[C:20]1([CH2:19][CH2:18][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[N:26][NH:27][N:28]=4)[CH:11]=3)[NH:7][N:8]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(CCc1ccccc1)nn2C1CCCCO1
Solvent: Cc1ccccc1
Product: c1ccc(CCc2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 37 %

Procedure:
The title compound was prepared as described in Example 167, using 1-perhydro-2H-pyran-2-yl-3-(2-phenylethyl)-1H-indazole-5-carbonitrile (0.117 g, 0.35 mmol), azidotributyl tin (0.353 g, 0.292 mL, 1.06 mmol) in toluene (5 mL). After hydrolysis of the protecting group under acidic conditions, the compound was purified by acid/base extraction. The residue was partitioned between 6.0N NaOH and ethyl acetate. The aqueous phase was then acidified with 6.0 N aqueous hydrogen chloride, to pH 3–4, resulting in the formation of a white precipitate that was collected by filtration, washed with small portions of cold water and dried under vacuum (0.038 g, 37% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.05 (br s, 1H), 8.5 (s, 1H), 8.0 (d, 1H), 7.65 (d, 1H), 7.3 (m, 4H), 7.15 (m, 1H), 3.3 (m, 2H), 3.1 (m, 2H); ES-MS (m/z) 291 [M+1]+.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[N:11]=[C:12]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 4 %

Procedure:
To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100 mg, 0.241 mmol) in DMSO (5 mL) was added methyl sulfonamide and K2CO3 (76.5 mg, 0.554 mmol). The reaction was stirred at 120° C. for 24 h. The reaction was then cooled to room temperature, quenched with water and extracted with Et2O. The organic layers were dried over MgSO4, and concentrated in vacuo. The crude residue was then passed through a plug of silica gel eluting with 1:1 Hex:EtOAc to 9:1 CH2Cl2:MeOH to afford N-[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]methanesulfonamide as a white solid (4.4 mg, 4%): LCMS RT: 2.45, MH+: 475.2.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC=C)(=O)C.C(Cl)Cl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1CCC[C@@H](OCc2ccccc2)C1
Solvent: C=COC(C)=O
Solvent: ClCCl
Product: OC1CCCC(OCc2ccccc2)C1
Reaction time: 26 h

Procedure:
100.0 g of cis-3-benzyloxycyclohexan-1-ol were dissolved in 170 ml of vinyl acetate and 630 ml of methylene chloride, admixed with 5.0 g of Novozym 435 and stirred at 20–23° C. for 26 h. The enzyme was filtered off, and a sample was withdrawn and concentrated by evaporation under reduced pressure. The enantiomeric excess of (1S,3R)-3-benzyloxycyclohexan-1-ol was >99% (HPLC on Chiralpak AD-H 250×4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN+0.1% TFA), and the enantiomeric excess of the (1R,3S)-acetate was 90% (HPLC on Chiralcel OD 250×4.6; 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 717.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[CH3:25][C:26]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:27][OH:28].C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:28][CH2:27][C:26]([CH3:29])([N+:30]([O-:32])=[O:31])[CH3:25])=[O:11]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(CO)[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.8 g, 0.01 mole) in acetone (10 ml) was added 2-methyl-2-nitropropanol (1.19 g, 0.01 mole) in acetone (10 ml) followed by triethylamine (1.01 g, 0.01 mole) in acetone (5 ml). The temperature rose and a white precipitate formed. The reaction was heated to reflux for 2.5 hours and then stirred overnight at room temperature. After dilution with water (75 ml), the solution was extracted twice with methylene chloride (25 ml @). The organic solution was then washed with 5% sodium hydroxide and finally with a brine solution. The dried solution was concentrated to give an amber oil 2.83 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Cl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1CCC(Nc2cc(N)ncc2Cl)CC1
Yield: 66.6 %

Procedure:
A solution of N-(5-chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (0.609 g, 1.87 mmol) in 6M HCl (5 mL) was heated under microwave irradiation at 105° C. for 50 min. The solution was basified with Na2CO3 and extracted with ethyl acetate (3×20 mL). The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.300 g, 66%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][CH:18]([O:20][CH3:21])[CH:17]([O:22][CH3:23])[CH2:16]2)[CH:11]=[CH:12][C:13]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CO.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[CH:11]=[CH:12][C:13]=1[C:25]#[C:24][C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CN(c2ccc(I)c(Cc3ccccc3)c2)CC1OC
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)c2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Then, a mixture of 340 mg of (3R,4S)-1-(3-benzyl-4-iodophenyl-3,4-dimethoxypyrrolidine, 134 mg of (3R)-3-ethynyl-3-quinuclidinol (Production Example 22), 9 mg of tetrakis(triphenylphosphine)palladium (0), 8 mg of copper (I) iodide, 0.22 ml of triethylamine and 0.8 ml of methanol was stirred under nitrogen atmosphere at room temperature for 4 hours. After ethyl acetate and methanol were added to the reaction mixture for dissolution, NH-silica gel was added thereto and the reaction mixture was evaporated. The residue was subjected to column chromatography using NH-silica gel with 50% ethyl acetate/hexane and 0–2.5% methanol/ethyl acetate, to give 220 mg of the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[N:20]4)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[Cl:32]CCl.C(OCC)(=O)C>CN1CCCC1=O.O1CCOCC1.COC(C)(C)C>[Cl:32][C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: ClCCl
Reactant: O=S(=O)(Oc1nc(-c2ccc(N3CCOCC3)nc2)cc2ncccc12)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: Clc1nc(-c2ccc(N3CCOCC3)nc2)cc2ncccc12

Procedure:
400 mg Trifluoromethanesulfonic acid 7-(6-morpholine-4-yl-pyridine-3-yl)-[1,6]-naphthyridine-5-yl ester (6.5) in 5 mL N-methyl-2-pyrrolidinone was treated with 1.6 mL (4N) hydrochloric acid in dioxane for 30 min at 70° C. 2 mL dichloromethane, 20 mL ethyl acetate and 10 mL methyl-tert-butylether was added and the precipitate isolated and dried at 50° C. under vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])#[C-:18].C(P(C#N)(CC)=O)C.N12CCCN=C1CCCCC2>CN(C)C=O.C(N(CC)CC)C>[CH3:23][O:22][C:20]([C:19]1[N:17]=[CH:18][O:16][C:14]=1[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:21]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ncoc1CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A mixture of 33.5 g of N-benzyloxycarbonyl-β-alanine, 15 g of methyl isocyanoacetate, 31.8 g of diethylphosphorylcyanide, 23 g of 1,8-diazabicyclo[5.4.0]undec-7-ene, 42 ml of triethylamine and 300 ml of dimethylformamide was stirred at room temperature overnight. Then, the solvent was removed, and ethyl acetate was added to the mixture. The mixture was washed and dried, and then the solvent was removed. The residue was purified by silica gel chromatography and crystallized from isopropyl ether, followed by recrystallization from an ethyl acetate-isopropyl ether mixed solution, to obtain 22.6 g of 4-methoxycarbonyl-5-{2-(benzyloxycarbonylamino)ethyl}oxazole.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[Cl:23])(=[O:15])=[O:14])[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:13]([CH:10]1[CH2:11][CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]1)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)C1CCC(S(=O)(=O)c2ccc(F)cc2Cl)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCC(S(=O)(=O)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120 %

Procedure:
To a mixture of Rac-(1S,3S)-3-(2-Chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid tert-butyl ester (278 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (1.34 g). The reaction mixture was stirred overnight at room temperature and the volatiles were removed in vacuo to afford the title compound (282 mg, quant.) as light brown oil, used in the next step without further purification. MS (EI): 305.1 (M−H)−.