Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>C(O)(=O)C.C(Cl)Cl>[N:23]1([C:21]([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH:31]=[CH:35][CH:34]=[CH:33]3)=[CH:7][C:6]=2[NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1
Reactant: COC1CCC(OC)O1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1ccc(-n2cccc2)cc1NS(=O)(=O)c1cccc2nsnc12)N1CCCCC1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
To a stirred solution of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-amino-2-(piperidine-1-carbonyl)-phenyl]-amide (EXAMPLE 24; 25 mg, 0.06 mmol) in glacial acetic acid (3 mL) was added 2,5-dimethoxytetrahydrofuran (8 μL, 0.06 mmol). The reaction mixture was heated to 120° C. for 45 min after which it was cooled to room temperature. The mixture was taken up in 4 mL of DCM and washed with water. The organic layer was removed, dried, and purified by preparative reversed-phase HPLC to afford the title compound (12 mg, 0.02 mmol, 43%). MS (ESI): m/z 468 [M+H]+, 490 [M+Na]+. HPLC (reversed-phase): RT=9.71 mm (single peak). 1H NMR (400 MHz, CDCl3): (rotameric broadening) 9.15 (s, 1H), 8.26 (dd, J=7.0, 1.0 Hz, 1H), 8.22 (dd, J=8.8, 1.0 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.67 (dd, J=8.8, 7 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.05 (m, 3H), 6.35 (t, J=2.2 Hz, 2H), 3.23 (bs, 4H), 1.61 (m, 2H), 1.48 (bs, 4H).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:2]=[CH2:3].[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)[NH2:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:26][C:8]2[N:7]=[C:6]3[N:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]3=[CH:10][N:9]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Reactant: Cc1cc(N)ccc1N1CCN(C)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(C)c3)nc2n1-c1ccccn1

Procedure:
17.0 mg of the entitled compound was obtained as a!yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 29-1 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](Cl)=[O:36])=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:35](=[O:36])[CH2:34][CH2:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(CCC(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CCC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 72 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 3-(4-methoxyphenyl)propionyl chloride, the title compound was synthesized according to Example 1b. Yield: 72%. Melting point: 188-191° C. (Ethyl acetate-hexane).
Reaction SMILES: C1C(CC2CCC(N)CC2)CCC(N)C1.[NH2:16][C:17]([NH2:30])([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[NH2:16][C:17]([NH2:30])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(N)(C1CCCCC1)C1CCCCC1
Agent: NC1CCC(CC2CCC(N)CC2)CC1
Product: NC(N)(c1ccccc1)c1ccccc1

Procedure:
Instead of the pure 4,4'-diaminodicyclohexylmethane, mixtures of the diaminodicyclohexylmethane position isomers which are composed of 70 to 99 mol % of the 4,4'-diamino isomer, 1-30 mol % of the 2,4'-diamino isomer, 0-2 mol % of the 2,2'-diamino isomer and, if appropriate, diamines with a correspondingly higher degree of condensation and which are obtained by hydrogenation of diaminodiphenylmethane of technical quality can also be used. Up to 30% of the isophthalic acid can be replaced by terephthalic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCO[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCOCC>CCCCCC>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=CNc1ccccc1CC)C(=O)OCC
Temperature: 80 °C
Yield: 94.9 %

Procedure:
A mixture of 2-ethylaniline (11.7 g) and diethyl ethoxymethylene malonate (25.0 g) were warmed together at 80° C. for one hour. After cooling, the mixture was poured with stirring into a mixture of 150 ml of ether and 75 ml of hexane. After cooling the solution in an ice bath colorless needles precipitated and were collected by filtration. There was obtained 26.7 g (95%) of the title product; tlc, Rf =0.73, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>ClCCl>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][C:11]=1[F:17])#[N:14]
Reactant: N#Cc1ccc(Nc2ncccc2N)cc1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nc2cccnc2n1-c1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 4-[(3-aminopyridin-2-yl)amino]-2-fluorobenzonitrile (C15) (300 mg, 1.31 mmol) and triethylamine (270 mg, 2.67 mmol) in dichloromethane (20 mL) was added ethyl chloro(oxo)acetate (220 mg, 1.61 mmol), and the solution was stirred at 0° C. for 2 hours. After addition of water (20 mL), the mixture was extracted with dichloromethane (3×20 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative thin layer chromatography on silica gel (Eluent: 10:1 dichloromethane/methanol) to afford the product as a yellow solid. Yield: 40 mg, 0.13 mmol, 10%. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.55 (d, J=5 Hz, 1H), 4.46 (q, J=7 Hz, 2H), 1.43 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[C:36]([NH:44][C:45]1[N:53]=[CH:52][N:51]=[C:50]2[C:46]=1[NH:47][CH:48]=[N:49]2)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>ClCCl>[C:16]([O:15][C@@H:8]1[C@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@H:9]1[N:49]1[CH:48]=[N:47][C:46]2[C:50]1=[N:51][CH:52]=[N:53][C:45]=2[NH:44][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred suspension of the anomeric mixture 33 (5.0 g, 10.3 mmol) and 6-N-benzoyladenine (3.76 g, 15.7 mmol) in anhydrous dichloromethane (200 cm3) was added N,O-bis(trimethylsilyl)acetamide (15.54 cm3, 61.8 mmol). The reaction mixture was stirred at reflux for 1 h and then cooled to room temperature. Trimethylsilyl triflate (7.0 cm3, 38.7 mmol) was added dropwise and the mixture was refluxed for 20 h. The reaction mixture was allowed to cool to room temperature and the volume of the mixture was reduced to ¼ under reduced pressure. Dichloromethane (250 cm3) was added, and the solution was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×50 cm3) and water (50 cm3). The organic phase was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 58 as white solid material (3.65 g, 52%). δH (CDCl3) 9.25 (1H, br s, NH), 8.71 (1H, s, 8-H), 8.24 (1H, s, 2-H), 8.0 (2H, d, J 7.5, Bz), 7.60-7.23 (13H, m, Bn, Bz), 6.35 (1H, d, J 4.6, 1′-H), 5.99 (1H, dd, J 4.9, 5.3, 2′-H), 4.78 (1H, d, J 5.6, 3′-H), 4.64-4.42 (5H, m, Bn, 1″-Ha), 4.25 (1H, d, J 12.1, 1″-Hb), 3.72 (1H, d, J 10.1, 5′-Ha), 3.56 (1H, d, J 10.1, 5′-Hb), 2.07 (3H, s, COCH3), 2.02 (3H, s, COCH3). δC (CDCl3) 170.42, 169.72 (COCH3), 164.60 (NHCO), 152.51 (C-6), 151.45 (C-2), 149.46 (C-4), 141.88 (C-8), 137.04, 137.00, 133.50, 132.60, 128.86, 128.66, 128.53, 128.41, 128.38, 128.18, 128.06, 127.91, 127.88, 127.79, 127.63, 123.26 (Bz, Bn, C-5), 86.38 (C-1′), 86.25 (C-4′), 77.74, 74.74, 74.44, 73.48 (C-2′, C-3′, 2×Bn), 70.11 (C-1″), 63.42 (C-5′), 20.70, 20.54 (COCH3). FAB-MS m/z 666 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(#N)C.[OH:23][S:24]([O-:26])=[O:25].[Na+:27]>O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[S:24]([O-:26])(=[O:25])=[O:23])=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1.[Na+:27]
Reactant: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(C(O)S(=O)(=O)[O-])cc1)N1CCN(C2CC2)CC1
Temperature: 50 °C

Procedure:
A 100 mL flask was charged with 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (2.58 g, 10.0 mmol, 1.0 eq), acetonitrile (30 mL), and water (1.0 mL) under nitrogen atmosphere. The reaction mixture was heated to 50° C. A solution of NaHSO3 (1.14 g, 11.0 mol, 1.1 eq) in water (2.0 mL) was added dropwise over 5 min. The reaction mixture was then cooled to 17° C. The product was collected by filtration as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[C:9]([C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1.[OH-].[K+]>CO.O>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: COC(=O)c1cccc2c1CC(C)(C)CC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CC(=O)c2cccc(C(=O)O)c2C1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A solution of 2.5 g (11 mmol) of methyl 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (J. Org. Chem. 17 (1976), 2918) and 1.8 g (33 mmol) of potassium hydroxide in 50 ml of methanol and 5 ml of water was allowed to stand at room temperature overnight. After distilling off the methanol in vacuo, the residue was taken up in 40 ml of water and the mixture was acidified with dilute hydrochloric acid. The precipitated product was filtered off with suction and dried in vacuo, and 2.3 g of 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid were obtained; m.p. 167-168° C.
Reaction SMILES: CN(C=O)C.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([N:28]=[N+:29]=[N-:30])=[CH:16][C:15]=1[CH:31]([CH3:33])[CH3:32])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][O:35][C:36](=[O:54])[C:37]#[C:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:53])([CH3:52])[O:46][SiH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:41][CH:40]=1.CCOC(C)=O>O>[CH3:34][O:35][C:36]([C:37]1[N:30]=[N:29][N:28]([C:17]2[CH:16]=[C:15]([CH:31]([CH3:33])[CH3:32])[C:14]([O:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:19][C:18]=2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:38]=1[C:39]1[CH:40]=[CH:41][C:42]([C:45]([CH3:53])([CH3:52])[O:46][SiH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:43][CH:44]=1)=[O:54]
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)C#Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
A DMF solution (2.5 ml) containing 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (373 mg, 1 mmol) and [4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-propynoic acid methyl ester (277 mg, 0.91 mmol) was degassed at RT by means of three vacuum-nitrogen cycles. [Cp*RuCl]4 (49 mg, 0.045 mmol) was then added and other three cycles were done. The reaction was stirred at RT until completion (monitored by TLC). AcOEt and water were then added. After standard work-up, the crude reaction mixture was purified by column chromatography (PE/AcOEt:60/40) to get the desired adduct as an oil.
Reaction SMILES: [CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>O1CCOCC1.CO.O>[C:22]([O:21][C:19]([N:6]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]1[CH2:1][CH2:2][CH2:3][CH3:4])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCC1c2cc(C(=O)OC)ccc2CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CCCCC1c2cc(C(=O)O)ccc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a solution of 2-tert-butyl 7-methyl 1-butyl-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate prepared in step 2 (347 mg, 1.0 mmol) in 2:1:1 dioxane/methanol/water (6.6 mL) was added lithium hydroxide monohydrate (125 mg, 3.0 mmol) and the reaction mixture stirred 24 h at room temperature. The reaction mixture was concentrated under reduced pressure and the solid residue partitioned between ethyl acetate and water. The aqueous phase was acidified with 1 N hydrochloric acid to pH 1 and extracted several times with 3:1 chloroform/2-propanol. The combined organic phases were washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 2-(tert-butoxycarbonyl)-1-butyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (205 mg). ESI MS m/z 332 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](Cl)(=O)[CH3:11].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1>[Cu]>[N:14]1([CH:6]([O:7][CH2:10][CH3:11])[C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: [Cu]
Product: CCOC(c1ccc(Cl)cc1)n1cncn1

Procedure:
The diethyl acetal of p-chlorobenzaldehyde (4.28 g) was reacted with acetyl chloride (2.34 g) in the presence of a trace of copper bronze. The product was reacted with 1,2,4-triazole (2.8 g) to give the title compound as a viscous oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:16]([O:27][C:28](=[O:45])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[OH:43])[C:30]=3[OH:44])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.Cl.[C:47](Cl)(=[O:57])[O:48][C@@H:49]1[CH:54]2[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]2)[CH2:50]1>CC#N>[CH:28]([OH:45])=[O:27].[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:16]([O:27][C:28](=[O:45])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]([C:47]([O:48][C@@H:49]4[CH:54]5[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]5)[CH2:50]4)=[O:57])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[OH:43])[C:30]=3[OH:44])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:2][CH2:3]1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccc(CNc2ccccc2O)c1O
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CC#N
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2O)c1O
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A solution of [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl]2-hydroxy-3-[(2-hydroxyanilino)-methyl]benzoate (250 mg, 0.38 mmol) in CH3CN (6 mL) was added (R)-quinuclidin-3-yl carbonochloridate hydrochloride (150 mg, 0.66 mmol) in one portion. The resulting slurry was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound as a pale yellow solid (130 mg, 42%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:24]2[C:29]3[CH:30]=[CH:31][O:32][C:28]=3[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>ClCCCl.CO>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:21]2[CH2:22][CH2:23][N:18]([C:24]3[C:29]4[CH:30]=[CH:31][O:32][C:28]=4[CH:27]=[CH:26][N:25]=3)[CH2:19][CH2:20]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reaction time: 18 h

Procedure:
trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (4.1 g, 17 mmol) was added to a solution under N2 of commercially available 4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (3.1 g, 15 mmol) in 1,2-dichloroethane (40 ml) and MeOH (0.5 ml). The resulting yellow solution was stirred 8 h at room temperature before addition of Na(AcO)3BH (4.9 g, 23 mmol). Stirring was continued at room temperature for 18 h. The reaction mixture was poured on sat. aq. NaHCO3 sol. (130 ml) and the product was extracted with EtOAc (3×100 ml). The combined organic layers were washed with H2O (130 ml) and brine (100 ml). After drying (MgSO4) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield trans-{4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as white crystals (3.4 g, 52%), MS (ISP) m/z=429.4 [(M+H)+].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].CCOCC>ClCCl>[C:1]([O:6][CH2:8][CH2:7][O:9][CH2:10][CH3:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=COCC
Reactant: C=C(C)C(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 20 g methacrylic acid in 50 ml dichloromethane was added 19 g ethyl vinyl ether in 30 ml dichloromethane. The mixture was stirred overnight at room temperature and poured into ether and washed with a saturated aqueous solution of sodium bicarbonate until the solution ceased effervescing. The organic layer was dried with MgO/MgSO4 and concentrated in vacuo. The residue was distilled at 25° C./0.1 torr to give 7.1 g (19% yield) of ethoxyethyl methacrylate. A mixture of 7.0 g ethoxyethyl methacrylate and 0.076 g AIBN in 7 ml MEK was heated to 60° C. for 24 hr and 7 ml MEK was added. This solution (solution E) was used for further evaluation.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20].O>CN(C)C=O>[F:20][CH:19]([F:21])[O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(O)n(C)n1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(F)F)n(C)n1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
67.6 g (0.43 mol) 5-Hydroxy-3-methoxycarbonyl-1-methyl-pyrazole and 299.2 g (2.17 mol) potassium carbonate was dissolved in 1500 ml dimethylformamide and heated to 70° C. At this temperature chlorodifluoromethane was introduced over 2 hours and the mixture stirred at 80° C. for 1.5 hours. The reaction mixture was added to water and extracted 6 times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The reaction solution was concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CSC>[CH3:17][C:14]1[S:13][C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[C:15]=1[CH3:16]
Reactant: Cc1sc(Br)c(C(=O)Nc2ccccc2O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: O
Product: Cc1sc2c(c1C)C(=O)Nc1ccccc1O2
Temperature: 165 °C
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-4,5-dimethyl-3-thiophenecarboxamide (3.3 g) in dimethyl sulfide (50 ml) was added potassium carbonate (2.8 g) and the mixture was stirred at 160-170° C. for 20 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The insoluble matter was filtrated and the filtrate was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 2,3-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.4 g).