Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][CH:13]([CH:16]3[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C2CCC(C3CCC4(CC3)OCCO4)CC2)cc1
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: CCCc1ccc(C2CCC(C3CCC(=O)CC3)CC2)cc1

Procedure:
190.5 g (0.55 mol) of 8-[4-(4-propylphenyl)cyclohexyl]-1,4-dioxaspiro[4.5]-decane are stirred vigorously for 19 h together with 480 ml of formic acid in 900 ml of toluene. Water is added, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to completion. The crude product is recrystallised from n-heptane.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:22]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:7][CH2:6]1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (76 mg, 0.378 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.24 mL, 1.70 mmol), and 4-pentylbenzene-1-sulfonyl chloride (140 mg, 0.567 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (148 mg, 95%). 1H NMR (400 MHz, CD3OD) δ 7.77 (d, 2H, J=7.6 Hz), 7.35 (d, 2H, J=7.3 Hz), 4.00 (q, 2H, J=6.7), 2.69 (t, 2H, J=7.0 Hz), 2.57 (s, 2H), 2.46-2.36 (m, 2H), 2.20-2.02 (m, 7H), 1.68-1.60 (m, 4H), 1.41-1.25 (m, 4H), 1.20 (t, 3H, J=6.4 Hz), 0.89 (t, 3H, J=6.7 Hz); MS ESI 411.3 [M+H]+, calcd for [C21H34N2O4S+H]+ 411.58.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])C.[OH-].[K+]>CCO.O>[CH3:30][C:5]([CH3:31])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 74.1 %

Procedure:
To a solution of 209j (11.63 g, 25.6 mmol) in EtOH and H2O (3:1, 200 mL) was added powdered KOH (85%, 4.31 g, 65.3 mmol). The resulting mixture was refluxed for 19 h and concentrated in vacuo until all of the EtOH was removed. Water (200 mL) was added and the resulting mixture was extracted with Et2O (2×200 mL). The aqueous phase was acidified with aqueous HCl (4 M) to pH˜1 and extracted with Et2O (3×200 mL). The combined Et2O layers of the latter extraction were dried over anhydrous Na2SO4 and evaporated in vacuo. The remaining white solid was recrystallized from heptane/iPr2O to give 210j (7.56 g, 74%) as white crystals. Mp 74.3-77.3° C. 1H NMR (CD3OD): δ (ppm): 2.43 (t, J=7.3, 4H), 1.57-1.50 (m, 8H), 1.33-1.21 (m, 16H), 1.14 (s, 12H). 13C NMR (CD3OD): δ (ppm): 214.5, 182.1, 43.6, 43.2, 42.0, 31.2, 30.4, 30.38, 26.2, 25.9, 25.0. HRMS: Calcd for C23H42O5 (M+): 398.3028, found: 398.3032.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH:39]=2)[C:35]([O:37][CH3:38])=[O:36])=[CH:27][N:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14]([NH:23][C:24]3[S:25][C:26]([O:29][C:30]4[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH:39]=4)[C:35]([O:37][CH3:38])=[O:36])=[CH:27][N:28]=3)=[O:16])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(Oc2cnc(N)s2)ccc1C
Reactant: O=C(O)C(O[C@@H]1CCOC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)ccc1C
Yield: 85.5 %

Procedure:
The compound of example A3 was obtained by similar method described in example A2 using 2-(4-Cyclopropanesulfonyl-phenyl)-2-[(R)-(tetrahydro-furan-3-yl)oxy]-acetic acid (preparation 5, 0.200 g, 0.613 mmol), methyl 5-(2-aminothiazol-5-yl)oxy-2-methyl-benzoate (preparation 26; 0.194 g, 0.736 mmol), HOBt (0.099 g, 0.736 mmol), and EDCl (0.140 g, 0.736 mmol), N-methyl morpholine (0.0154 g, 1.53 mmol) in DCM (8 mL) to provide the title compound (0.3 g).
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:15][C:16]1[C:29]([NH:30][NH2:31])=[CH:28][C:19]2[N:20]([CH2:25][C:26]#[CH:27])[C:21](=[O:24])[CH2:22][O:23][C:18]=2[CH:17]=1>O>[F:15][C:16]1[C:29]([NH:30][N:31]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[CH:28][C:19]2[N:20]([CH2:25][C:26]#[CH:27])[C:21](=[O:24])[CH2:22][O:23][C:18]=2[CH:17]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(NN=CC(=O)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 8.0 g (97.2 mmol) of sodium acetate and 50 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the reaction was allowed to proceed at 80° C. for 30 minutes. Then, the reaction mixture was cooled to 0° C., to which 4.4 g (18.7 mmol) of 7-fluoro-6-hydrazino-4-propargyl-2H-1,4-benzoxazin-3-one was added, and the reaction mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed twice with 10 ml of water, and dried, which afforded 6.3 g (18.37 mmol) of 7-fluoro-6-trifluoroacetylmethylidenhydrazino-4-propargyl-2H-1,4-benzoxazin-3-one [another name: 3,3,3-trifluoro-2-oxopropanal 1-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-ylhydrazone)], m.p. 190.6° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][N:31]([CH3:30])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCOS(C)(=O)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCN(C)c1ccccc1

Procedure:
A solution of 4.36 g. of 5-chloro-2-{3-[(methylsulfonyl)oxy]propyl}-3-phenylisoindole-1-carboxylic acid ethyl ester in 25 ml. of hexamethylphosphoric acid triamide is treated with 25 ml. of N-methylaniline and heated at 80° C. for 24 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue treated with 250 ml. of ice-water. The oily precipitate is taken up in methylene chloride and the extract washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is purified by chromatography on 150 g. of aluminum oxide [neutral; Brockmann activity I]. By elution with methylene chloride and evaporation of the solvent, there is obtained 5-chloro-2-[3-(N-methylanilino)propyl]-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 108°-110° C. Crystallization from ether/hexane gives almost colorless crystals of the same melting point.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.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>[C:24]1([C:30]#[C:31][C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2s1
Yield: 8 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, Pd(PPh3)2Cl2, triethylamine, and phenylacetylene in 1 mL of anhydrous DMF was reacted according to the procedure of Example 213 to give 0.008 g (8%) of the desired compound. LC/MS 322 (M+1); LC retention time 3.65 min.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[OH-].[Na+].[H][H]>O.[Pd]>[OH:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13]
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
A solution of 3-benzyloxy-2-methylbenzoic acid (50 g, 0.21 mol) and sodium hydroxide (9 g, 0.225 mol) in 700 g of water and 2 g of 5% Pd/C catalyst (50% water-moist) are added to a 21 steel autoclave with an aerating stirrer. 10 bar of hydrogen are injected at a temperature of 50° C. and a stirring speed of 800 rpm. Consumed hydrogen is replaced by repeated injection. After 20 min, the absorption of hydrogen falls off. The catalyst is filtered off at room temperature by means of a pressure filter. 760.7 g of a crude solution are obtained, from which 7.7 g of toluene are separated off in a separating funnel. A total of 22.2 g of hydrochloric acid (37% strength) are added to the crude solution, then the solution is cooled to 0° C. The precipitated solid is filtered off with suction and washed twice with 50 g of water. After drying, 18.0 g of 3-hydroxy-2-methylbenzoic acid having a melting point of 147° C. are obtained. After concentration of the mother liquor, a further 9.6 g of substance can be obtained, such that the total yield is 27.6 g or 88.1% of theory.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(NC(C)C)(C)C>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=2)[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1ncc(B(O)O)cn1
Reactant: O=C(O)c1cc(Cl)nc(-c2ccc(F)cc2F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1ncc(-c2cc(C(=O)O)cc(-c3ccc(F)cc3F)n2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-6-(2,4-difluorophenyl)isonicotinic acid (0.10 g, 0.37 mmol) in DMF (1.9 mL) and water (0.6 mL) were added (2-methylpyrimidin-5-yl)boronic acid (0.31 g, 2.23 mmol), palladium(II)acetate (12.5 mg, 0.06 mmol), 3,3′,3″-phosphinidynetris(benzenesulfonic acid) trisodium salt (95.0 mg, 0.17 mmol) and diisopropylamine (0.19 mL, 1.30 mmol). The mixture was heated to 80° C. After 2 h, the mixture was filtered and the filtrate was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid). To the product fractions was added HCl (2.0 M in ether) and the mixture was concentrated to give the hydrochloride salt of the title compound. MS 328.1 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1ccccn1
Agent: Cl
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 7 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound in 7% yield; NMR spectrum (DMSO-d6) 1.18 (d, 3H), 1.83 (s, 3H), 2.84 (s, 3H), 4.19-4.43 (m, 2H), 5.14-5.24 (m, 1H), 5.30 (s, 2H), 7.16-7.27 (m, 2H), 7.32-7.38 (m, 2H), 7.45-7.50 (m, 1H), 7.58 (d, 1H), 7.72 (t, 1H), 7.87 (t, 2H), 8.43 (s, 1H), 8.59 (d, 1H), 9.53 (s, 1H); Mass spectrum MH+ 492.3.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[N:36][CH:35]=[N:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:40][CH2:39][CH:38]([N:33]6[CH:37]=[N:36][CH:35]=[N:34]6)[CH2:43][CH2:42]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:31])[F:32])[CH:3]=1
Reactant: c1ncn(C2CCNCC2)n1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(n3cncn3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-[1,2,4]triazol-1-yl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-[1,2,4]Triazol-1-yl-piperidine following General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Br:24]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]([Br:24])[C:8](=[O:21])[C:9]([CH3:19])([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
36.6 g (0.1 mol) of 1,4-bis-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were dissolved in 250 ml of chloroform, and 16.6 g (0.1 mol) of bromine were added dropwise at 20° C. in a manner such that continuous decolorization occurred. After the addition, the mixture was subsequently stirred at room temperature for 30 minutes and was then concentrated by distilling off the solvent in vacuo. 43.2 g (quantitative conversion) of 1,4-bis-(4-chlorophenoxy)-1-bromo-3,3-dimethyl-butan-2-one were obtained as an oil, which was further reacted directly.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[Li]CCCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]([OH:32])([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc2nccc(Br)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2nccc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: -78 °C
Yield: 66.6 %

Procedure:
To a solution of 8-bromo-2-methoxy-[1,5]naphthyridine (1 g, 4.18 mmol, prepared as in WO 2006/032466) in dry THF (20 mL) at −78° C. was added dropwise n-BuLi (2.5 M in hex, 5 mL, 1.2 eq). The mixture was stirred at −78° C. for 1 h before the dropwise addition of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.833 g, 4.2 mmol) in THF (5 mL). The mixture was stirred at −78° C. for another h and then slowly warmed to rt. The mixture was quenched by the addition of sat. aq. NH4Cl solution (10 mL) and extracted with EA. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by CC (hex/EA 1:1 to EA) to give the desired intermediate (1.0 g, 66.5%) as yellow oil.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:26])[C:22]=1[N+:23]([O-:25])=[O:24])[C:17](O)=[O:18].CN>O1CCCC1>[CH3:1][NH:3][C:17](=[O:18])[C:16]1[CH:15]=[C:14]([CH3:13])[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([CH3:26])[CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1′-Carbonyldiimidazole (914 mg) is added to a suspension of 3,5-dimethyl-4-nitrobenzoic acid (1 g) in tetrahydrofuran (10 mL). The mixture is stirred for 3 hours at room temperature, methylamine (7.7 mL, 2 M in tetrahydrofuran) is added and the mixture is stirred for further 30 minutes. After concentration the mixture is diluted with ethyl acetate and washed with hydrochloric acid (0.2 M), saturated aqueous NaHCO3 solution and brine. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 1 g; LC (method 20): tR=4.82 min; Mass spectrum (ESI+): m/z=209 [M+H]+.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)([O-:17])=[O:16].[N+](C1C=CC=CC=1F)([O-])=O>ClC1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(NCCO)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=[N+]([O-])c1ccccc1F
Agent: [Br-]
Solvent: Clc1ccccc1
Solvent: O
Product: O=C(NCCOc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
20.0 g of 2-benzoylaminoethanol are suspended in 60 ml of chlorobenzene. To the suspension are added 9.7 g of 50% strength sodium hydroxide solution and stirred in for some time until a homogeneous syrup has formed. 1.5 g of tetrabutylammonium bromide are then added, followed dropwise in the course of 15 minutes by 14.3 g of 4-nitrofluorobenzene, and the temperature rises to about 28°-30° C. The yellowish suspension is stirred at 30° for 3 hours and at 45° for a further 5 hours until the conversion of the nitrofluorobenzene is complete. Water is then added to the reaction mixture, the pH value is brought to 5 and the chlorobenzene is driven off in vacuo with water, leaving behind a slightly yellow suspension. After cooling down, it is filtered, and the filtercake is washed with water to give N-[2-(4-nitrophenoxy)-ethyl]-benzamide of Example 3: ##STR37##
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccccn2c1=O
Product: O=c1n(CCC#Cc2ccccn2)nc2ccccn12
Yield: 23.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (70 mg, 0.37 mmol) and 2-bromopyridine (65 mg, 0.41 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (87 μmol, 23%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a yellow solid (M.P.=95.5-96° C.).
Reaction SMILES: [CH:1]1([S:11](=[O:13])(=[O:12])[O:10][CH2:9]C[CH2:7][O:6][S:3]1(=[O:5])=[O:4])[CH3:2].C(O)CCO.C(O)CO>C(Cl)Cl.C1CCCCC1>[CH:1]1([S:3](=[O:4])(=[O:5])[O:6][CH2:7][CH2:9][O:10][S:11]1(=[O:12])=[O:13])[CH3:2]
Reactant: CC1S(=O)(=O)OCCCOS1(=O)=O
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: OCCCO
Product: CC1S(=O)(=O)OCCOS1(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
The reaction procedure described in Example XIII for the preparation of trimethylene 1,1-ethanedisulfonate was followed, substituting for the 1,3-propane diol used in Example XIII, ethylene glycol (5.0 gram, 0.008 mole). The reaction mixture was stirred for 3 hours at room temperature, the solid amine hydrochloride residue removed, and the filtrate roto-evaporated to remove glyme. The crude product obtained was redissolved in a minimum amount of methylene chloride, and subsequent addition of cyclohexane produced white crystals immediately. Several crops of crystals totaling 5.84 grams were obtained after further addition of cyclohexane and refrigeration. Further recrystallization of the material resulted in a total of 4.37 grams of product, representing a 25.2% yield. The product melting point was between 92° C. and 93° C. Product identification was confirmed by IR spectral features relating to CH3CH and SO2 and proton NMR features relating to CH, CH2 and CH3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH:42][C@@H:43]([CH3:46])[CH2:44]O)=[C:26]([CH:41]=1)[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)=[O:28])#[N:21].C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:44][C@@H:43]([NH:42][C:25]1[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:41][C:26]=1[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)=[O:28])[CH3:46]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CO)cc1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CBr)cc1OC
Temperature: 25 °C
Yield: 68.8 %

Procedure:
Triphenylphosphine (156 mg) was added to a mixture of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide (200 mg) and carbontetrabromide (215 mg) in dichloromethane (4 mL), and the mixture was stirred for an hour at ambient temperature. After evaporation of the solvent, the residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (161 mg) as a solid substance.