Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:3]1=[O:21].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23].C(Cl)Cl>>[OH:28][C:22]([C:24]([F:27])([F:26])[F:25])=[O:23].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:3]1=[O:21]
Reactant: Cc1ncccc1N1CC(C(=O)OC(C)(C)C)N(C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1N1CC(C(=O)O)N(C)C1=O

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3.00 mmol) (prepared as described in step (iii) of Example 13) and 3-bromo-2-methylpyridine (515 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (738 mg, 85%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (738 mg, 2.53 mmol) in TFA/DCM (1:2, 12 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.5 mmol) which was used in the next step.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=[O:8].Cl.[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:1][C@H:2]3[CH2:6][CH2:5][CH2:4][C@H:3]3[C:7]([OH:9])=[O:8])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 84.2 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 322.9 mg (2.5 mmol) of cis-2-amino-1-cyclopentane-carboxylic acid with 960.7 mg of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride provided 927.7 mg of cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in 84% yield. MS: 441.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:34](=[O:33])[CH2:35][OH:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)c1

Procedure:
The title compound was prepared analogous to the method described in Example 21 starting from (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a) (511 mg, 1.31 mmol), and Acetoxyacetyl chloride (155 μL, 1.44 mmol). Yield 429 mg (73%).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([NH:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)NC(C)Cc1ccc(CCCC(=O)O)cc1
Reaction time: 1.25 h
Yield: 96.2 %

Procedure:
Four and two-tenths g (0.015 moles) of 4-[4-[2-(Acetylamino)propyl]phenyl]-4-oxobutanoic acid was shaken under fifty lb/in2 of hydrogen pressure in 200 ml of acetic acid in the presence of one gram of 10% Pd/C in a Parr apparatus. Reduction was complete in approximately 1.25 hours. After removal of the catalyst by filtration, the solvent was distilled in the rotary evaporator leaving 3.8 g of a colorless syrup. An aliquot of the syrup was rubbed under acetonitrile whereupon it crystallized. Recrystallization from acetonitrile yielded white crystals of mp 114°-117°.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[OH:18])[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O>S(=O)(=O)(O)O.O>[C:1]([O:18][C:17]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[F:8])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Yield: 79.4 %

Procedure:
6.40 ml of acetic anhydride was added to 5.00 g (32.00 mM) of 3-fluoro-4-hydroxybenzoic acid. Under stirring at room temperature, two drops of concentrated sulfuric acid was added thereto (the mixture solidified as soon as the concentrated sulfuric acid was added), followed by heat-stirring for 10 minutes at 107°-111° C. on an oil bath (the mixture became transparent and melted by heating). After the reaction, the reaction mixture was poured into 150 ml of iced water to precipitate a crystal. The crystal was recovered by filtration and recrystallized from 20 ml of methanol to obtain 5.04 g of 4-acetoxy-3-fluorobenzoic acid (Yield: 79.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]([CH3:25])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: Clc1ccc2cc(-c3cncc(OCc4ccccc4)c3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(OCc3ccccc3)c2)cc2ccc(Cl)cc21
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1H-indole (Example 98, 0.435 g, 1.29 mmol), dimethyl carbonate (0.328 mL, 3.89 mmol), potassium carbonate (0.098 g, 0.714 mmol) and DMF (3 mL). The reaction mixture is stirred at 150° C. overnight. It is then cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo, to give a residue which is purified by flash chromatography (heptane-ethyl acetate, 1:1) to afford 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.70 (s, 3H), 5.31 (s, 2H), 6.67 (d, J=0.8 Hz, 1H), 7.10 (dd, J=8.3, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.41-7.47 (m, 2H), 7.49-7.55 (m, 3H), 7.57 (d, J=8.3 Hz, 1H), 7.64 (dd, J=2.5, 1.8 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H); HRMS (ESI) m/z 349.1108 [(M+H)+ Calcd for C21H18ClN2O: 349.1108].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14].[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][CH2:14][CH:13]1[CH2:12][CH2:11][CH:10]([C:4]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:15]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCC(O)c1cc(F)ccc1OC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCC(CBr)O1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
To a solution of 1-(2′-methoxy-5′-fluorophenyl)pent-4-en-1-ol (3.24 g, 18.0 mmol) in dry CH2Cl2 (50 mL) at 0° C. was added portionwise N-bromosuccinimide (NBS, 3.56 g, 20.0 mmol) portionwise and the reaction was warmed to room temperature for 12 h. Solvent was then removed in vacuo and the residue was purified by flash column chromatography (10% EtOAc in Hexane, Rf=0.28) to give the product (2.28 g, 44%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][NH:5][CH:6]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C)C=O.[Cu](I)I>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)c1c[nH]cc1C
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccccc2)cc1C
Yield: 35 %

Procedure:
To a solution of methyl 4-methyl-1H-pyrrole-3-carboxylate (1.70 g) in N,N-dimethylformamide (1.5 mL) were added iodobenzene (1.50 mL), potassium carbonate (2.19 g), L-proline (273 mmg) and copper iodide (232 mg), and the reaction was carried out in a microwave reactor (Emrys Optimizer manufactured by Personal Chemistry, 70° C., 1 hr). The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless solid (yield 925 mg, 35%).
Reaction SMILES: I[CH2:2][CH3:3].[Cl:4][C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:4][C:5]1[C:6]([O:13][CH2:2][CH3:3])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9]
Reactant: O=Cc1cccc(Cl)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(Cl)cccc1C=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
Iodoethane (1.54 mL, 19.2 mmol) was added to a stirring solution of 3-chloro-2-hydroxy-benzaldehyde (2.01 g, 12.8 mmol) and K2CO3 (3.90 g, 28.2 mmol) in DMF (25 mL). The mixture was heated to 50° C. and stirred for 2.5 h. The heat was removed and reaction stirred at room temperature for 18 h. The reaction was quenched with H2O (70 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (2.16 g, 91%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.85 (dd, J=7.8, 1.5 Hz, 1H), 7.72 (dd, J=7.8, 1.8 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15](OC)=[O:16])[CH:11]=2)=[CH:6][CH:5]=1.[NH2:21][NH2:22].O>CCO>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([NH:21][NH2:22])=[O:16])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of methyl 5-(4-(trifluoromethoxy)phenyl)isoxazole-3-carboxylate (6.50 g, 22.6 mmol) in EtOH (200 mL) was added NH2NH2.H2O (80%, 7 mL, 113 mmol) and the mixture was stirred at RT for 3 h. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography (Petroleum ether:EtOAc=1:2) to give the ttitle compound as a white solid (4.4 g, 67.8%). MS (ES+) C11H8F3N3O3 requires: 287. found: 288 [M+H]+.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8][C:7](=[O:16])[C:6]1=[O:17])=[O:4].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:3]([CH:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:16])[C:6]2=[O:17])=[O:4])=[CH:21][CH:20]=1
Reactant: COC(=O)C1Cc2ccccc2NC(=O)C1=O
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccccc2CC(C(=O)Nc2ccc(Br)cc2)C1=O
Temperature: 25 °C

Procedure:
To the boiling suspension of 4.0 g of 2,3,4,5-tetrahydro-1-benzazepine-2,3-dione-4-carboxylic acid methyl ester in 130 ml of xylene, 3.85 g of 4-bromoaniline are added while stirring and the mixture refluxed for 6 hours under nitrogen. It is cooled to room temperature, filtered and the residue recrystallized from acetonitrile-acetic acid, to yield the 4-(4-bromophenylcarbamoyl)-2,3,4,5-tetrahydro-1-benzazepine-2,3-dione melting at 226°-228°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>CC#N>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C=Cc1ccncc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2ccncc2)cc1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a CH3CN solution of 1-iodo-4-nitrobenzene (498 mg, 2 mmol) and 4-vinylpyridine (262 mg, 2.5 mmol) was added TEA (350 μL, 2.5 mmol) and Pd(OAc), (0.45 mg, 0.2 mmol). The mixture was heated to 100° C. for 48 hr in a capped Pyrex tube. It was then cooled to room temperature, quenched with 1N HCl (20 mL) and concentrated under reduced pressure. The mixture was filtered and the solid was taken up in EtOAc (30 mL) and washed with 1N NaOH (30 mL). The organic layer was concentrated, dried over Na2SO4 and concentrated to give 4-[2-(4-nitro-phenyl)-vinyl]-pyridine as yellow solid (160 mg, 37%).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH4+].[Cl-].C(Cl)Cl>C1(CCO)C=CC=CC=1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:14]=[CH:15][CH:16]=1)=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: OCCc1ccccc1
Solvent: ClCCl
Product: CN1CCC2(C)c3cc(C(=O)C(=O)OCCc4ccccc4)ccc3N(C)C12
Temperature: 25 °C
Yield: 151.4 %

Procedure:
To a chilled (0° C.) solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (0.76 g) in anhydrous phenylethyl alcohol (18.1 ml) was added titanium (IV) ethoxide (0.22 ml) via syringe under a nitrogen atmosphere. The solution was warmed to room temperature and heated to just under reflux for 3 hours. The solution was then cooled to 0° C. and saturated NH4Cl solution was added slowly until a precipitate formed. Methylene chloride (200 ml) was then added and the mixture extracted twice with 100 ml portions of saturated aqueous NH4Cl solution, twice with 100 ml of saturated aqueous NaHCO3 and once with 100 ml of brine. The organic extracts were dried (Na2SO4), filtered, and the solvent removed on the rotary evaporator. The phenylethyl alcohol was then removed by distillation under high vacuum. The resulting residue was purified using preparative HPLC (silica gel, 4% methanol in ethyl acetate as the loading solvent and eluent). The appropriate fractions were combined, and the solvent removed to yield 0.72 g of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, phenylethyl ester, as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(CO)n1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
1.26 g (10.2 mmol) of 2-amino-6-hydroxymethylpyridine (Journal of Heterocyclic Chemistry, 2001, 38, 173) was dissolved in 5.1 mL of dimethylformamide and 1.7 g (25 mmol) of imidazole was added thereto. Under cooling with ice, 1.8 g (12 mmol) of tert-butyldimethylsilyl chloride was added thereto followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and brine. This was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography to give 1.9 g of the title compound as an orange-colored oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:13][CH2:14][NH2:15].C=O.[C:18](O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:13][CH2:14][NH:15][CH2:18]2
Reactant: NCCc1cccc(OCC2CC2)c1Br
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: ClCCl
Product: Brc1c(OCC2CC2)ccc2c1CCNC2
Temperature: 25 °C

Procedure:
To 40 mg (0.15 mmol) 2-(2-bromo-3-cyclopropylmethoxy-phenyl)-ethylamine (example XXI) and 17 μL (0.22 mmol) formaldehyde (37% solution in water) in 2 mL DCM are added slowly 23 μL (0.30 mmol) TFA and the resulting mixture is stirred at r.t. over night. The reaction mixture is concentrated by evaporation
Reaction SMILES: O.[PH2]([O-])=O.[Na+].C=C.[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.[OH-].[Al+3:26].[OH-].[OH-].[Al+3].[CH2:30]([P:32](CC)(=[O:34])[O-:33])[CH3:31].[CH2:37]([P:39](CC)(=[O:41])[O-:40])[CH3:38].[CH2:44]([P:46](CC)(=[O:48])[O-:47])[CH3:45]>O>[Al+3:26].[CH2:30]([P:32]([O-:34])[O-:33])[CH3:31].[CH2:37]([P:39]([O-:41])[O-:40])[CH3:38].[CH2:44]([P:46]([O-:48])[O-:47])[CH3:45].[Al+3:26]
Reactant: CCP(=O)([O-])CC
Agent: C=C
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CCP([O-])[O-]
Temperature: 100 °C
Yield: 89.7 %

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate are dissolved in 7.5 kg of water and initially charged in a 16 l steel-enamel jacketed pressure reactor. After heating the reaction mixture to 100° C., a reducing valve set to 6 bar was used to introduce ethylene into the reactor up to saturation. While stirring constantly at an ethylene pressure of 6 bar and a temperature of 100-110° C., a solution of 33 g (1 mol %) of sodium peroxodisulfate in 300 g of water is metered in homogeneously. At a conversion of ethylene of 85.3%, the metered addition of sodium peroxodisulfate is stopped and the reactor is decompressed. After cooling to about 90° C., 700 g of concentrated sulfuric acid are metered in within 30 minutes. Subsequently, 364 g (4.67 mol) of aluminum hydroxide are added and the mixture is heated to 150° C. in a closed reactor for 8 h. After cooling to ambient temperature, the resulting solid is filtered off, washed with 2 l of hot water and dried at 130° C. under reduced pressure. The resulting mixture comprises diethylphosphinic acid aluminum(III) salt and ethylphosphonous acid aluminum(III) salt in a ratio of 79.6% by weight of diethylphosphinic acid aluminum(III) salt and 20.4% by weight of ethylphosphonous acid aluminum(III) salt (89.7% yield).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with allyl chloroformate (274 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH2:18]1[C@H:24]2[NH:25][C@H:20]([CH2:21][CH:22](O)[CH2:23]2)[CH2:19]1>>[CH:24]12[NH:25][CH:20]([CH2:19][CH2:18]1)[CH2:21][CH:22]([N:14]1[C:4]3=[N:5][N:6]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]([Cl:1])=[C:3]3[C:16]([CH3:17])=[N:15]1)[CH2:23]2
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Reactant: OC1C[C@H]2CC[C@@H](C1)N2
Product: Cc1nn(C2CC3CCC(C2)N3)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound XIIIa was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and nortropine following the general procedure for the Mitsunobu reaction described in Example 20.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C)C=O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([Br:12])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(COCc2ccc(Br)cc2)cc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a solution of 27.4 g (685 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (425 ml) was added 42.4 g (227 mmol) of 4-bromobenzyl alcohol in an atmosphere of argon, and the mixture was allowed to react at 40-50° C. for 30 min. Then, 62.4 g (250 mmol) of 4-bromobenzyl bromide was added, and the mixture was reacted at room temperature for 15 hours. The reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:1) yielded 72.7 g (204 mmol) of 4-bromobenzyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]>>[CH3:35][CH:34]([CH3:36])[CH2:33][CH2:32][CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: CC(C)CCCBr
Product: CC(C)CCCOc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromo-4-methyl-pentane following the procedure of Example 478: MS (ES) m/z 478.3.