Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CS(C)=O>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][O:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13]
Reactant: CC(C)=CCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)=CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (7.55 g, 54.6 mmol) was added to a solution of N-hydroxyphthalimide (13.93 g, 85.4 mmol) in 150 mL of DMSO to give a wine-red colored solution. 4-Bromo-2-methyl-2-butene (20 g, 134 mmol) was added to the solution dropwise and the reaction was stirred for 16 hours at room temperature. The reaction was poured into 600 mL of ice water to give a white crystalline solid. The crude crystalline product was filtered, washed with ice water, and air dried. The crystalline product was recrystallized from ethanol to give 15.7 g, m.p. 97°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22]CC=C)=[O:21])=[CH:17][CH:18]=3)[C:13]([CH3:26])=[C:12]2[CH3:27])=[CH:8][CH:7]=1.N1CCOCC1>C1COCC1.C(OCC)(=O)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>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[C:13]([CH3:26])=[C:12]2[CH3:27])=[CH:8][CH:7]=1
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(OCC(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: COC(=O)COc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reaction time: 1.5 h

Procedure:
A solution of the allyl 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (536 mg, 1.3 mmol) and morpholine (1.14 mL, 13.2 mmol) in anhydrous THF was degassed with argon. Then Pd(PPh3)4 (152 mg, 0.13 mmol) was added and the reaction stirred under argon protection for 1.5 h. The reaction mixture was diluted with ethyl acetate, washed with brine, concentrated. The title compound was precipitated in ethyl ether as a beige powder (430 mg, 89%). ESI-MS (m/z): 368 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1.O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:9]2[C:10]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11][S:12][N:13]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1cncc(-c2nsnc2OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of cyclopropylcarbinol (360 mg, 5 mmol) and sodium hydride (110 mg, 5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 400 mg (69%) of the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[NH2:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.C(OCC)C>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:41][CH2:42][C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1C
Yield: 74.7 %

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step D (8.0 g, 15 mmol) and dimethyl sulfoxide (5.3 mL, 75 mmol) in dry acetonitrile (90 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (3.1 mL, 30 mmol) and the reaction mixture was heated to reflux for 48 hours. The cooled mixture was concentrated in vacuo, the oily residue redissolved in ethyl acetate (400 mL), washed with 1M sodium hydroxide (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a red foam. Purification by flash chromatography using a solvent gradient of 50 to 100% ethyl acetate in hexane gave a pale yellow foam. Trituration with hot diethyl ether (150 mL) afforded the title compound (5.9 g, 75%) as a pale yellow solid, m.p. 147-149° C. Alternatively, the title compound could be purified by HPLC (normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane, m.p. 148-150° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O1CCCC1.C(N(C(C)C)C(C)C)C.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[N+:39]([C:30]1[CH:31]=[C:32]([S:35](=[O:37])(=[O:36])[NH2:38])[CH:33]=[CH:34][C:29]=1[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Reaction time: 18 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.0 g), tetrahydrofuran (50 ml), N-ethyl-N-isopropylpropan-2-amine (5.61 mL) and N,N-dimethylformamide (10 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (1.212 g) and the mixture was stirred for 18 hours. The crude product was isolated by concentration and was the material was purified on silica gel, and was eluted with a 30, 50, and 75% ethyl acetate in hexane step gradient to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(N)cc(C)c1C=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(C)c(C=O)c(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 4-amino-2,6-dimethylbenzaldehyde (600 mg) and bromoacetic acid methyl ester (0.4 mL) in DMF (20 mL) was added K2CO3 (1.4 g) and the suspension was heated at 80° C. After 1 h, additional bromoacetic acid methyl ester (0.4 mL) was added and this process was continued until the starting material was consumed (check by LC/MS). The reaction mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated and the residue was purified by flash chromatography using hexanes/ethyl acetate (2:1) to give (4-formyl-3,5-dimethylphenylamino)-acetic acid methyl ester as a yellow solid. MS (ESI)m/z 222 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[C:27]2[C:34](O)=[O:35]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:34]([C:27]3[C:26]4[C:31](=[CH:32][CH:33]=[C:24]([CH3:23])[CH:25]=4)[N:30]=[CH:29][CH:28]=3)=[O:35])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: Cc1ccc2nccc(C(=O)O)c2c1
Agent: Cl
Product: Cc1ccc2nccc(C(=O)N3CCCC[C@@H]3COc3cccc4c3C(N)=NS(=O)(=O)N4)c2c1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 6-methylquinoline-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.53 (m, 2H), 1.59-1.86 (m, 4H), 2.01 (s, 3H), 3.01 (m, 1H), 3.20 (m, 1H), 4.19 (dd, 1H, J=10.1, 3.2 Hz), 4.95 (t, 1H, J=10.6 Hz), 5.46 (m, 1H), 6.67 (d, 1H, J=8.1 Hz), 7.01 (d, 1H, J=8.3 Hz,), 7.34 (s, 1H), 7.48-7.56 (m, 2H), 7.60-7.68 (m, 1H), 7.92 (d, 1H, J=8.7 Hz), 7.99 (br s, 1H), 8.27 (br s, 1H), 8.87 (d, 1H, J=4.4 Hz), 10.94 (s, 1H). MS 480 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:11](O)=[O:12])[C:7](=[O:19])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]([F:17])([F:18])[F:16])[C:11]([NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:28]3[CH2:27][O:26][C:25]([CH3:37])([CH3:24])[O:29]3)[N:32]=2)=[O:12])[C:7](=[O:19])[CH:6]=1
Reactant: O=C(O)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid (144 mg, 0.41 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 97 mg, 0.49 mmol) in N,N-dimethylformamide (4 mL). To this mixture was added N,N-diisopropyethylamine (200 μL, 1.23 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (271 mg, 0.62 mmol) and stirred for 16 h at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), dried over sodium sulfate, and then concentrated with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide (168 mg, 77%) as a white foam: HR-ES-MS m/z calculated for C23H24N4O5ClF3 [M+H]+ 529.1460, observed 529.1457.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([N:15]([CH3:35])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([CH3:36])=[CH:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].O.[Li+].[OH-].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([N:15]([CH3:35])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]4)[C:12]([CH3:36])=[CH:11][N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ncc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCc1ccc(-c2ncc(C)c(N(C)CCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 343, 140 mg, 0.290 mmol) in a mixture of THF (5 mL), water (5 mL), and EtOH (2.5 mL) was added LiOH (27.5 mg, 1.15 mmol). After vigorously stirring for 24 h, the reaction mixture was acidified to pH ˜5 using HCl (1 N aqueous solution) and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and then concentrated under reduced pressure to give the product (118 mg, 89%) as a white foam. 1H NMR (400 MHz, acetone-d6) δ 1.26 (t, 3H), 1.70-1.76 (m, 1H), 2.18-2.21 (m, 2H), 2.37 (s, 3H), 2.33-2.42 (m, 2H), 2.67-2.85 (m, 5H), 3.28 (s, 3H), 3.44-3.45 (m, 1H), 3.86 (t, 2H), 4.07 (t, 2H), 6.71 (d, 1H), 6.78 (s, 1H), 7.12 (d, 1H), 7.27 (d, 2H), 8.08 (s, 1H), 8.35 (d, 2H); LC-MS: RT=2.53 min, (M+H)+ 460.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:17])[CH3:16])[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=1.Cl>CC(O)C.O1CCOCC1>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([Cl:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]2[CH:32]=[CH:31][C:23]3[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Yield: 77.7 %

Procedure:
1-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-ethanone (37.0 mg, 0.132 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (27.7 mg, 0.146 mmol) were slurried in iPrOH (1.5 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated in a microwave reactor (sealed vessel) at 120° C. for 40 min. After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed with iPrOH (2×2 mL) water (4×2 mL) and iPrOH (2×2 mL) to afford product (44.7 mg, 78%) as a white powder that had the following properties: m.p.=215-217° C.; LC/MS (ESI+): 436 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 11.79 (s, 1H), 9.60 (s, 1H), 8.90 (m, 1H), 8.30 (s, 1H), 8.13 (d, 1H, J=8.1), 7.65-7.59 (m, 2H), 7.57 (s, 1H), 7.25-7.20 (m, 2H), 3.22 (s, 3H), 2.70 (s, 3H), 2.58 (m, 2H), 2.16 (m, 2H), 2.04 (m, 2H).
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:41][CH2:40][O:39][CH:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH2:49])=[CH:44][CH:43]=1.C(OC(OCC)CCCN)C>>[O:37]1[CH2:41][CH2:40][O:39][CH:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][NH:49][C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:12][O:11][C:10]3[CH:9]=[C:8]([C@@H:7]([NH:25][C:26](=[O:27])[O:28][C@@H:29]4[CH:34]5[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]5)[CH2:30]4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:15]=2)=[O:18])=[CH:46][CH:47]=1
Reactant: NCc1ccc(C2OCCO2)cc1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: CCOC(CCCN)OCC
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)NCc3ccc(C4OCCO4)cc3)cc2)c1)O[C@H]1CN2CCC1CC2

Procedure:
The title was prepared as described in Example 5 Step 1 with 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid and (4-(1,3-dioxolan-2-yl)phenyl)methanamine replacing 1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylic acid and 4-aminobutyraldehyde diethyl acetal respectively.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][C:14]([N:18]1CCCCC1)([CH3:17])[CH2:15][NH2:16].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26]C=1>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:18][C:14]([CH3:17])([CH3:13])[CH2:15][N:16]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:24]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Oc1ccccc1
Reactant: CC(C)(CN)N1CCCCC1
Product: CC(C)(CN1CCCCC1)Nc1ccnc2cc(Cl)ccc12
Yield: 31.6 %

Procedure:
4.57 g of 4,7-dichloroquinoline, 7.5 g of 2-methyl-2-(piperidin-1-yl)-propylamine and 0.75 g of phenol were reacted at 180° C. for 16 hours. The crude reaction product, isolated as in the preceeding Example, was purified on 200 g of aluminium oxide (activity grade II) prior to recrystallization; a 1:1 mixture of toluene and acetone was used as the eluent. After a fore-run, which contained unreacted 4,7-dichloroquinoline, the product was eluted and, after recrystallization from 5 ml of acetonitrile, yielded 0.8 g of colourless crystals, m.p.: 143°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2ncc(Cl)c(Cl)c2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2ncc(Cl)c(N3CCCC3)c2c1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
A mixture of methyl 3,4-dichloroquinoline-6-carboxylate (100 mg), pyrrolidine (33 mg), and NMP (2 mL) was heated under stirring at 180° C. for 10 minutes under microwave irradiation. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 3-chloro-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (40 mg).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=O)[C:18]1=[O:26].[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH2:37].O>CN(C)C=O>[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH:37][C:23](=[O:25])[CH2:22][N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[C:18]1=[O:26]
Reactant: O=C(O)CN1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.30 g of dicyclohexylcarbodiimide dissolved in 6 ml of dimethylformamide are added dropwise at 0° to 1.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid and 1.03 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine dissolved in 20 ml of dimethylformamide. The mixture is left to stir at room temperature for 4 days, treated with 0.23 g of ion-free water and evaporated in a water-jet vacuum. The residue is treated five times with toluene and in each case again evaporated. The constituents of the residue which are soluble in chloroform are chromatographed on 60 g of aluminum oxide (activity grade III, neutral). The alcohol eluate is again chromatographed on 15 g of aluminum oxide (activity grade III, neutral). The fractions which are eluted with acetonitrile and ethanol contain, according to the gas chromatogram and mass spectrum, (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](SC)[N:15]=1.O[O:27][S:28]([O-:30])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:40]([O-])(O)=O.[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:28]([CH3:40])(=[O:30])=[O:27])[N:15]=1
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1

Procedure:
To a cold 0° C. solution of 2-(2-chlorobenzyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 7, (460 mg, 1.23 mmol)) in THF/MeOH (20 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (3.0 g, 4.9 mmol) in H2O (15 mL). After stirring the reaction for 1.5 hours at room temperature, the solution is poured into aqueous saturated NaHCO3. The aqueous phase is extracted three times with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 316 mg of the desired product which is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.CN(C=O)C.[H-].[Na+].[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[N:35]=[C:34](S(C)(=O)=O)[N:33]=1>C(O)(=O)C.O>[O:8]([C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([O:15][C:34]1[N:35]=[C:36]([O:38][CH3:39])[CH:37]=[C:32]([O:31][CH3:30])[N:33]=1)[C:11]([O:13][CH3:14])=[O:12])[C:1]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 24.5 %

Procedure:
4.4 g (15.4 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (Compound 1.1) are dissolved in 40 mol of DMF, and 0.46 g (18.4 mmol) of sodium hydride is added. The mixture is stirred for 1 hour and then 3.4 g (15.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added. The mixture is stirred at room temperature for 24 hours and then cautiously hydrolyzed with 10 mo of water, the pH is adjusted to 5 with acetic acid, and the solvent is removed by distillation under high vacuum. The residue is taken up in 100 mo of ethyl acetate, washed with water, dried over sodium sulfate and distilled to remove solvents. 10 ml of methyl t-butyl ether are added to the residue, and the precipitate is filtered off with suction. Drying results in 1.6 g of a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[C:15](=N)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
L-phenylalanine methyl ester hydrochloride (5.95 g) and benzophenonimine (5.00 g) were added to methylene chloride (100 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, diethyl ether (100 ml) was added to the residue. The solid was filtered off again, and the ether layer was then washed with water (100 ml), and dried over anhydrous magnesium sulfate. After magnesium sulfate was removed, the ether solution was concentrated to obtain desired N-(diphenylmethylene)-L-phenylalanine methyl ester (9.44 g) in a yield of 99.6%.