Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CN(C)CCN(C)C.CCCCCC.CN(C)[CH:34]=[O:35].[NH4+].[Cl-]>CCOCC>[CH:34]([CH:7]1[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[CH2:6]1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
tert-butyl 8-azaspiro[4.5]decane-8-carboxylate (Intermediate 71, 6 g, 25.07 mmol) dissolved in 150 ml of Et2O was cooled to −78° C., then N,N,N′,N′-tetramethyl ethylendiamine (9.08 ml, 60.16 mmol) and secBuLi 1.4M in hexane (42.95 ml, 60.16 mmol) were added. After 10 minutes at −60° C., the temperature was raised to −20° C. for 60 minutes, then the reaction was cooled to −78° C. and dimethylformamide (4.47 ml, 60.16 mmol, dissolved in 5 ml of Et2O) was added. After 30 minutes a saturated aqueous solution of NH4Cl (30 ml) was slowly added, then reaction was allowed to reach room temperature. Reaction was extracted with Et2O (3×100 ml), the organic solvent was dried (Na2SO4) and evaporated to obtain 4 g of the title compound as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1>CC#N.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([OH:22])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-(7-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (71) was prepared by the method of Example 67 skipping step 7 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate. 1H-NMR: 400 MHz, (CD3OD) δ: 7.71 (m, 2H), 7.58 (m, 3H), 7.52 (dd, J=9, 2 Hz, 1H), 7.33 (m, 2H), 5.15 (s, 1H), 2.59 (s, 3H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.67.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)[CH:14]=[CH:13][C:12]=2[O:25][CH3:26])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:24][C@H:19]1[NH:20][C@@H:21]([CH3:23])[CH2:22][N:17]([C:15]2[CH:14]=[CH:13][C:12]([O:25][CH3:26])=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:29][O:28][CH3:27])[CH:35]=4)=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=2)[CH2:18]1
Reactant: COCc1cccc(B(O)O)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COCc1cccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3OC)s2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-thiophenesulfonamide (E122) (100 mg, 0.22 mmol) and {3-[(methyloxy)methyl]phenyl}boronic acid (83 mg, 0.5 mmol) in DME (3 ml) was added potassium tert-butoxide (210 mg, 1.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then concentrated in Genevac and residues passed over SCX. Basic fractions were re-concentrated in Genevac and the residue purified using mass directed autoprep HPLC to afford the title compound (E123). MS (ES+) m/e 502 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[N+:11]([O-])=O.C(Cl)Cl.[H][H]>[Pd].CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1cc2cn[nH]c2cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To the product of Step (c) (530 mg, 2.93 mmol, 1 equiv) and 10% Pd/C (200 mg) was added CH2Cl2 (10 mL) and MeOH (40 mL). The atmosphere was replaced with hydrogen gas and the solution was stirred at room temperature and atmospheric pressure for 2 hours. The reaction mixture was filtered through a plug of celite and rinsed with MeOH and CH2Cl2. The residue was purified by flash chromatography (linear gradient, 40→70% EtOAc/hexanes) affording 330 mg (75%) of the title compound as a pale purple solid. MS (ES+) m/e 152 [M+H].
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C([O:9][C:10](=[O:41])[CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH2:27][N:28](C(OCC2C=CC=CC=2)=O)[CH2:29][CH3:30])[C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)C.[Li+].[OH-]>C1COCC1>[CH:1]1([C:4]([N:28]([CH2:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:14]2[C:15]([O:18][CH3:19])=[CH:16][CH:17]=[C:12]([CH2:11][C:10]([OH:41])=[O:9])[CH:13]=2)[CH2:29][CH3:30])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: O=C(Cl)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-186) was prepared by reacting(2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride according to the procedure described in Example 1, Step 6 and then hydrolyzing the ester with aqueous LiOH in THF at room temperature
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Na+].Cl[CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])=[O:15])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 4-(n-octylamino)benzoic acid (4.97 g.) in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and then 1-chloro-2,3-propanediol in the manner described in Example 2 to produce white crystals of 2,3-dihydroxypropyl 4-(n-octylamino)benzoate.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)[CH:28]=[N:27]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)cn1
Temperature: 100 °C

Procedure:
To a solution of 5-iodo-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P1) (500 mg, 1.1 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (272 mg, 1.31 mmol) in a mixture of ethanol and water (4:1, 10 mL) were added dichlorobis(triphenylphosphine)palladium(II) (41 mg, 58 μmol) and potassium carbonate (447 mg, 3.23 mmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. It was then heated at 100° C. for 18 hours. After concentration in vacuo, the residue was purified via chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.48 mmol, 44%. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 5.57 (s, 2H), 3.90 (s, 3H), 3.50-3.58 (m, 6H), 3.20-3.27 (m, 4H), 0.83 (dd, J=8.0, 7.9 Hz, 2H), −0.09 (s, 9H).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>O>[CH2:3]([O:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(OCc2ccccc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
To a methanol (20.0 mL) solution of 6-benzyloxy-pyridine-3-carbaldehyde (2.00 g, 9.38 mmol) described in Manufacturing Example 12-1-2 was added sodium borohydride (426 mg, 11.3 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (1.84 g, 91.1%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].N1CCCCC1.[C:13]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])/[CH:14]=[CH:15]/[CH3:16]>>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH:15]([CH3:16])[CH2:14][C:13]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COC(=O)CS
Reactant: C/C=C/C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Product: COC(=O)CSC(C)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
A mixture of methyl thioglycolate (0.8 mL, 8.9 mmol), piperidine (0.12 mL, 1.2 mmol) and 2 g (14 mmol) of t-butyl crotonate was stirred at room temperature for 12 hours, followed by distillation under reduced pressure. The reaction solution was purified by column chromatography to give 2.05 g (8.2 mmol) of the title compound in a yield of 92%.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:8]([O:15][CH2:16][CH:17]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1)=[O:6])C=C.N1CCOCC1>C1COCC1.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>[C:13]([C:10]1[N:9]=[C:8]([O:15][CH2:16][CH:17]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[CH2:19][CH2:18]2)[C:7]([C:5]([OH:6])=[O:4])=[CH:12][N:11]=1)#[N:14]
Reactant: C=CCOC(=O)c1cnc(C#N)nc1OCC1CCC2(CC1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: N#Cc1ncc(C(=O)O)c(OCC2CCC3(CC2)CC3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a 2-cyano-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid allyl ester (0.096 mmol) in THF (1.0 mL) are added Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium) (0.0096 mmol) and morpholine (0.19 mmol) at room temperature. The reaction mixture is stirred at room temperature for 0.5 h and the reaction is quenched by the addition of sat. aq. NaHCO3. The mixture is extracted with ether. The aqueous layer is acidified to pH 2 with sat. aq. KHSO4. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(C)cc2[N+](=O)[O-])sc2ccccc12
Yield: 100.9 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxlate (4.0 g), 4-fluoro-3-nitrotoluene (3.3 g) and dimethyl sulfoxide (55 ml), ethyl 2-(4-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.5 g) was obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCCC4)cc3c2)cc1

Procedure:
The product from Example 1C and pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.7 (m, 5H), 7.50 (d, J=8.7 Hz, 1H), 7.42 (dd, J=8.7, 1.5 Hz, 1H), 6.51 (s, 1H), 3.1 (m 2H), 2.95 (m, 2H), 2.65 (m, 4H), 1.9 (m, 4H); MS (DCI) m/z 317 (M+H)+;
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=4[CH3:30])[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[C:5]1=[O:31])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[N:11]=[CH:10][C:9]([N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:31])=[CH:14][CH:13]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)nc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cn3)CC2)c(C)c1
Yield: 36.5 %

Procedure:
To a mixture of 1-acetyl-3-{6-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]pyridin-3-yl}imidazolidin-2-one (70 mg) described in Example 388 and potassium carbonate (35 mg) was added methanol (5 mL), and the mixture was stirred with heating under reflux for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (23 mg).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.O[CH2:6][CH:7]([CH2:9][OH:10])O>>[C:9]([O:10][CH3:1])(=[O:10])[C:7]1[CH:6]=[CH:7][C:2]([C:1]([O:4][CH3:2])=[O:4])=[CH:9][CH:6]=1
Reactant: OCCO
Reactant: OCC(O)CO
Product: COC(=O)c1ccc(C(=O)OC)cc1
Yield: 490.7 %

Procedure:
A polyester is produced in known manner from 388 g of dimethyl terephthalate, 112 g of ethylene glycol and 75 g of glycerin, and mixed with 273 g of the reaction product of Example A, added thereto in two portions at a temperature of 180°-215° C. Subsequently the reaction product is worked up as described in Example 1, the obtained lacquer is diluted to a solid body content of 27% and the viscosity of 55 seconds, and copper wire is lacquered therewith.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[CH3:14][NH:15][CH:16]([CH3:30])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1>>[C:26]([CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:16]([N:15]([CH3:14])[CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)[CH3:30])=[CH:19][CH:20]=1)([O:28][CH3:29])=[O:27]
Reactant: CNC(C)Cc1ccc(OCC(=O)OC)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Product: COC(=O)COc1ccc(CC(C)N(C)CC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole and N-methyl-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine, followed by reduction and purification of the base on a silica gel column using ethyl acetate/methanol=40:1 as eluant.
Reaction SMILES: [Br:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[NH:9][CH2:8]2)=[CH:4][C:3]=1[CH3:18].[H-].[Na+].I[CH3:22]>CN(C)C=O>[Br:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[N:9]([CH3:22])[CH2:8]2)=[CH:4][C:3]=1[CH3:18]
Reactant: CI
Reactant: Cc1cc(OC2CCS(=O)(=O)NC2)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OC2CCS(=O)(=O)N(C)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(4-Bromo-3,5-dimethyl-phenoxy)-[1,2]thiazinane 1,1-dioxide (110 mg) and sodium hydride (14.5 mg of a 60% mineral oil suspension) are suspended in 2 mL of N,N-dimethylformamide. Iodomethane (0.02 mL) is added and the reaction mixture is stirred at room temperature for 3 h. The solvent is removed, water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→60:40) to give the title compound. Yield: 110 mg.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](OC)=[O:21])[CH:18]=2)[CH:13]=[CH:12]1>C1(C)C=CC=CC=1>[OH:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][N:11]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
Diisobutylaluminum hydride (1M in toluene, 12 mL, 12 mmol) was added to a solution of 1-tert-butyl 6-methyl 1H-indole-1,6-dicarboxylate (1.38 g, 5.00 mmol) in toluene (15 mL) at −50° C. over 10 minutes. After being stirred at −50° C. for 30 minutes, the reaction was quenched with methanol (2.5 mL) and water (2.5 mL). The resulting precipitate was filtered off, and the filtrate was evaporated. The residue was purified by silica gel chromatography, eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford tert-butyl 6-(hydroxymethyl)-1H-indole-1-carboxylate (815 mg, 55% yield) as an oil. LCMS (ESI) m/z 174.3 [M+H−18−56]+, 230.3 [M+H−18]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[O:10][CH2:11][C:12]([OH:14])=[O:13])=[N+:2]=[N-:3].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:13][C:12](=[O:14])[CH2:11][O:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[N:1]=[N+:2]=[N-:3])[CH3:21]
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CO[C@@H]1CCCC[C@H]1N=[N+]=[N-]
Temperature: 0 °C
Yield: 68 %

Procedure:
A solution of trans-2-(2'-azidocyclohexyloxy)-acetic acid (11.16 g, 56 mmoles) and concentrated sulphuric acid (0.8 ml) in anhydrous ethanol (30 ml) was heated for 3 hours at reflux temperature, then the mixture was poured into ice water (150 ml) and extracted with n-hexane (4×60 ml). The combined hexane phases were dried over MgSO4, filtered and the solvent was evaporated. The crude product was distilled in vacuo (boiling point: 129° C./0.67 mbar), yielding 8.6 g (68%) of the title compound in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=3[NH2:14])=[CH:10][N:9]([CH3:23])[C:8]=12.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1.[Na].C(O)(=O)C>ClCCl>[CH:24]1([CH2:27][NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:12]=2[C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:23])[CH:10]=2)[CH2:26][CH2:25]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N)cn(C)c12
Reactant: O=CC1CC1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CC3)cn(C)c12
Yield: 99.6 %

Procedure:
The product from Example 44A (0.1 g, 0.302 mmol), cyclopropanecarboxaldehyde (0.063 g, 0.905 mmol) and sodium triacetoxyhydroborate (0.192 g, 0.905 mmol) were combined in dichloromethane (1.0 mL) and acetic acid (1.0 mL) under nitrogen, stirred for 6 hours and partitioned into water/ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.116 g, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Yield: 70 %

Procedure:
Following the general procedure for Example 11 (step 4), the product from step 1 (0.41 g, 0.94 mmol) was treated with 4M HCl in dioxane (5 mL) to afford the title compound (0.22 g, 70%); 1H NMR (400 MHz, DMSO-d6) δ 1.76 (m, 1H), 1.95 (m, 2H), 2.13 (m, 1H), 3.23 (m, 2H), 3.90 (m, 1H), 4.17 (m, 1H), 4.26 (dd, J1=3.6 Hz, J2=10.4 Hz, 1H), 7.05-7.16 (m, 6H), 7.72 (d, J=8.4 Hz, 2H); MS (m/z) 338.5 (M+1); LC (99.1%); HPLC (99.4%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=1.[CH2:26]([O:28][P:29]([CH2:34][C:35](O)=[O:36])([O:31][CH2:32][CH3:33])=[O:30])[CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:25][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][P:29](=[O:30])([O:31][CH2:32][CH3:33])[O:28][CH2:26][CH3:27])[CH:15]=[CH:14][C:13]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CN)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)NCc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Compound 148 (0.20 g, 0.56 mmol) was dissolved in dry DCM (1 mL) in oven dried glass ware under an argon atmosphere. Diethylphosphonoacetic acid (0.09 mL, 0.56 mmol) was added followed by dropwise addition of dicyclohexylcarbodiimide (0.13 g, 0.61 mmol dissolved in 1 mL dry DCM). The suspension was stirred at room temperature for 7 h after which it was filtered. The filtrate was diluted with 5 mL DCM and washed with 10% aqueous NaHCO3, H2O and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a slightly coloured oil.