Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.C1COCC1.[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.39 g, 0.73 mmol) in 2.0 M dimethylamine in THF (10 mL, 20 mmol) was stirred for 16.5 hours at 80° C. in a sealed tube. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 35 minutes to give dimethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine a light brown-orange semi-solid (0.257 g, 86.2%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a buff-colored foam (0.254 g). Mass Spectrum (+EI, [M+H]+) m/z 410. 1HNMR (500 MHz, DMSO-d6): δ10.25 (s, 1H), 8.74-8.76 (m, 1H), 8.51 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26-8.28 (m, 1H), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 2H), 7.56-7.66 (m, 2H), 7.39 (d, 1H, J=2.08 Hz), 7.22 (dd, 1H, J=9.28 Hz and 2.32 Hz), 4.39-4.42 (m, 2H), 4.05 (s, 3H), 3.50-3.52 (m, 2H), 2.83 ppm (s, 6H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C.O>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][N:52]([C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[Br:20])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
HOBt (4 g, 29.6 mmol) and DIEA (8.7 g, 67.7 mmol) were added to a stirred solution of 2-bromo benzoic acid (5.6 g, 28.3 mmol) in DMF (50 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (7.76 g, 40.48 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (5 g, 26.9 mmol) were added. Then reaction mixture was stirred at the room temperature overnight. Water was added and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4, and removed under reduced pressure to afford 9 g (90%) of 4-(2-bromo-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR: (DMSO-d6): δ 7.58 (d, 1H), 7.38 (t, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 3.85 (m, 1H), 3.7 (m, 1H), 3.55 (t, 2H), 3.5 (m, 1H), 3.3 (m, 3H), 3.15 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH:11]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C([BH3-])#N.[Na+]>>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: N#Cc1ccc(C=CC=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 8 %

Procedure:
Prepared from 3-(4-cyano-phenyl)acrolein and 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine by reductive amination with sodium cyanoborohydride. Yield: 8% of theory, Melting point: 199°-205° C. (decomp).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:3]=[C:4]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Reactant: Nc1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(Nc4ccccc4)cnc32)cc1
Yield: 172.7 %

Procedure:
Put 750 mg of 5-bromo-1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridine in 19 cm3 of toluene, 54 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 970 mg of caesium carbonate, 280 mg of aniline and 40 mg of tri(dibenzylideneacetone)dipalladium(0) in a microwave oven reactor. Irradiate the reactor in a microwave oven for forty-five minutes at 150° C. After cooling, filter the reaction mixture, then reduce to dryness under vacuum in a rotary evaporator. Combine the brown residue with another two residues obtained similarly, then purify by flash chromatography on a silica column with dichloromethane eluent to give 1.34 g of 1-[(4-methylphenyl)sulphonyl]-N-phenyl-1H-pyrrolo[2,3-b]pyridin-5-amine in the form of a beige powder with the following physical characteristics:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:39])(=[O:38])[NH2:37])[CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:27][N:28]=[C:29]([C:30]4[CH:31]=[C:32]([S:36]([NH2:37])(=[O:38])=[O:39])[CH:33]=[CH:34][CH:35]=4)[N:40]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)n2)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.31) (188 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a light yellow solid (120 mg, 43%). MS (ISN) 552.9 [(M−H)−]; mp 251° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Oc1ccccc1Cl
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3Cl)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-chloro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-chloro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 352(MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH2:13][CH:14](C)C)=[CH:8][N:7]=1)=[O:5])[CH3:2].BrC1C=C(C)C(Br)=CN=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH2:13][CH3:14])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c(CC(C)C)cn1
Agent: Cc1cc(Br)ncc1Br
Product: CCOC(=O)c1cc(C)c(CC)cn1

Procedure:
5-Ethyl-4-methyl-pyridine-2-carboxylic acid ethyl ester is prepared in analogy to 5-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester starting from 2,5-dibromo-4-picoline; LC-MS: tR=0.70 min, [M+1]+=193.99; 1H NMR (CDCl3): δ 1.25 (t, J=7.8 Hz, 3H), 1.45 (t, J=7.0 Hz, 3H), 2.39 (s, 3H), 2.72 (q, J=7.5 Hz, 2H), 4.48 (q, J=7.0 Hz, 2H), 7.92 (s, 1H), 8.49 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[Cl:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Cl
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1Cl

Procedure:
Using 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (55 mg, 0.20 mmol) and methyl 2-chloro-4-hydrazinocarbonylbenzoate (50 mg, 0.22 mmol) as the starting materials, the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (86 mg, yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:11]([N+:13]([O-:15])=[O:14])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1ccc2c(c1[N+](=O)[O-])C(=O)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
To a solution of 6-methoxy-1-indanone (30.0 g, 185 mmol.) in conc. sulfuric acid (130 mL) was added a solution of potassium nitrate (24.3 g, 0.24 mol.) in conc. sulfuric acid (100 mL), while maintaining the inner temperature below 0° C. The mixture was stirred for 20 minutes at the same temperature, which was then poured into ice-water, followed by extraction with ethyl acetate. The extract solution was washed with water and an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to afford the title compound (yield 21.7 g, 58%).
Reaction SMILES: [Br-].[Li+].[H-].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]=2[N:17]=1.[CH2:18](Br)[CH:19]=[CH2:20]>CN(C)C=O.O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:20][CH:19]=[CH2:18])[C:11]=2[N:17]=1
Reactant: C=CCBr
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ccc(OC)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Lithium bromide (514 mg, 5.92 mmol) and subsequently sodium hydride (55%, oily, 258 mg, 5.92 mmol) were added under cooling on ice to a solution of 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.00 g, 5.64 mmol) in N,N-dimethylformamide (30 ml) and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled on ice again, allyl bromide (0.537 ml, 6.20 mmol) was added thereto and the mixture was stirred for 3 hours while gradually raising the temperature to room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 1.20 g (98%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Reactant: Cn1cc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(NC(=O)c2ccc(OCc3c(-c4ccc(Cl)cc4)noc3CO)nc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and 1-methyl-1H-pyrazol-4-ylamine (26.9 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) to afford the title compound (101 mg, 83%) as a white solid. MS: m/e=440.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])=[O:16])=[CH:9][CH:8]=1)=O.[CH3:30][NH2:31]>CO>[CH3:29][N:17]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]=1[CH3:28])[C:15](=[O:16])/[CH:14]=[CH:13]/[C:10]1[CH:11]=[N:12][C:7]([NH:6][CH2:5][C:3]([NH:31][CH3:30])=[O:2])=[CH:8][CH:9]=1
Reactant: CN
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Solvent: CO
Product: CNC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Reaction time: 72 h
Yield: 100 %

Procedure:
To (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide (0.7 g, 1.8 mmole) was added a solution of 2.0 M methylamine in MeOH (50 mL). After stirring for 72 h the reaction was concentrated to dryness. The residue was triturated with Et2O, filtered, and dried under vacuum to give the title compound (0.703 g, 100%) as an off-white solid: MS (ES) m/e 392.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:16])([F:15])[C:11]([O:13]C)=O)[N:8]=1)([O-:3])=[O:2]>CN(C=O)C>[OH:13][CH2:11][CH2:10][CH2:9][CH2:7][NH:8][C:11](=[O:13])[C:10]([F:16])([F:15])[CH2:9][C:7]1[N:8]=[C:4]([N+:1]([O-:3])=[O:2])[NH:5][CH:6]=1
Reactant: COC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Solvent: CN(C)C=O
Product: O=C(NCCCCO)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
To a solution of methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionate (1.0 g, 4.2 mmol) in DMF (10 ml), n-butanolamine (500 mg, 5.6 mmol) was added and stirred for 6 hours at a room temperature. Then, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 3-(2'-nitroimidazolyl)-2,2-difluoropropionic acid hydroxybutylamide (450 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:29])[CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].Cl>CO>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([CH3:29])[CH2:20][NH2:21])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C#Cc2ccc(C(C)CNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CO
Product: CCCOc1ccc(C#Cc2ccc(C(C)CN)cc2)cc1
Temperature: 25 °C

Procedure:
To 0.70 g (1.78 mmol) tert-butyl 2-(4-((4-propoxyphenyl)ethynyl)phenyl)propyl-carbamate (I61.1) in 5 mL MeOH are added 4.27 mL (5.34 mmol) HCl (1.25M in MeOH). The mixture is stirred at r.t. over night. The solvent is removed in vacuo and the crude product is treated with aq. NaHCO3 solution. The precipitate is filtered, washed with water and dried at 50° C. in vacuo.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[F:15]>C1COCC1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:1])([OH:14])[CH3:13])=[CH:7][C:6]=1[F:15]
Reactant: C[Mg]Br
Reactant: CC(=O)Cc1ccc(Cl)c(F)c1
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc(Cl)c(F)c1
Temperature: 76 °C
Yield: 88.1 %

Procedure:
To a solution of methylmagnesium bromide (100 mL, 100.0 mmol, 1.0 M in THF) was added a solution of 1-(4-chloro-3-fluorophenyl)propan-2-one (9.00 g, 48.20 mmol) in THF (20 mL) dropwise at 0° C. under N2 and the reaction mixture was heated at 76° C. for 12 h. It was then cooled to rt and quenched with saturated NH4Cl aqueous solution (50 mL) and the mixture was poured into water (200 mL). The resulting mixture was extracted with EtOAc (100 mL×4) and the combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 (50 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as yellow liquid (8.61 g, 88.2%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]([CH3:33])=[C:29]([CH2:31]O)[N:30]=2)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:31][C:29]2[N:30]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[O:27][C:28]=2[CH3:33])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(Cl)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 21 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with [2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanol (R. C. Self, W. E. Barber, J. P. Machin, J. M. Osbond, C. E. Smithen, B. P. Tong, J. C. Wickens, D. P. Bloxham, D. Bradshaw, C. H. Cashin, B. B. Dodge, E. J. Lewis, D. Westmacott, J. Med. Chem. 1991, 34, 772-777) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1.[CH:16]([C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:13]([C:10]2([NH:9][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:8])[CH2:11][CH2:12]2)=[O:15])=[CH:24][CH:23]=1)([CH3:18])[CH3:17]
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: CC(C)c1ccccc1Oc1ccc(CN)cc1
Product: CC(C)c1ccccc1Oc1ccc(CNC(=O)C2(NC(=O)c3cncnc3)CC2)cc1
Yield: 89 %

Procedure:
Analogously to Example (7c) the title compound was prepared from 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and 4-(2-isopropyl-phenoxy)-benzylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([CH3:22])[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[N:27]1([CH2:26][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([CH3:22])[N:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 68 %

Procedure:
The 2-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-6-methylpyridine (4 g, 14 mmol), N-(2-chloroethyl)pyrrolidine hydrochloride (2.3 g, 14 mmol), and powdered K2CO3 (9.5 g, 68 mmol) were stirred in 250 mL methyl ethyl ketone and refluxed 18 h. The reaction mixture was worked up and purified by prep. chromatography (EtOH/ CH2Cl2 gradient), triturated with Et20, filtered, and dried in vacuo to give 3.7 g (71% yield) of white product: mp 63°-64° C.; 1H NMR (CDCl3) d 1.79-1.83 (comp, 4H, pyrrolidine), 2.60-2.64 (comp, 7H, Pyr-CH3 and pyrrolidine), 2.86-2.90 (t, 2H, J=6 Hz, NCH2), 3.81 (s, 3H, ArOCH3), 4.07-4.11 (t, 2H, J=6 Hz, OCH2), 6.78-6.82 (m, 4H, ArH), 7.06-7.30 (comp, 5H, ArH), 7.55-7.58 (d, 1H, J=8 Hz, ArH); MS(FD) 388(M+). Anal. Calcd for C25H28N202: C, 77.23; H, 7.26; N, 7.21. Found: C, 77.12; H, 7.48; N, 7.00.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([O:23]CC4C=CC=CC=4)=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:31][CH3:32])[C:15]=2[CH3:33])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>CN(C)C=O.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([OH:23])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:31][CH3:32])[C:15]=2[CH3:33])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCc4ccccc4)cccn23)ccc1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(O)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
The mixture of 2.0 g (4.5 mmol) of methyl 2-amino-5-{[8-(benzyloxy)-1-methoxy-2-methylindolizin-3-yl]carbonyl}benzoate and 0.42 g (6.75 mmol) of ammonium formate in the presence of 1.0 g of palladium-on-charcoal (10%) in 20 ml of N,N-dimethylformamide is stirred for 12 hours at ambient temperature under argon. The mixture is filtered under nitrogen and concentrated to dryness so as to obtain 1.51 g of a red oil. The product decomposes on contact with air.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:30])[CH2:17][N:18](CC1C=CC=CC=1)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=2[O:31]CC1C=CC=CC=1)=[O:6].CO.O1CCCC1>C(O)(=O)C>[C:5]([OH:6])(=[O:4])[CH3:7].[CH3:1][O:2][CH2:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([CH:16]([OH:30])[CH2:17][NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=[CH:11][C:10]=2[OH:31])=[O:6]
Reactant: COCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COCOC(=O)c1cc2c(C(O)CNC(C)(C)C)ccc(O)c2[nH]1
Yield: 189.4 %

Procedure:
617 mg of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid methoxymethyl ester is combined with 10 ml of methanol, 40 ml of absolute tetrahydrofuran, and 0.3 ml of acetic acid and hydrogenated and worked up as described in Example 31(E), thus obtaining 450 mg of 7-hydroxy-4-(1-hydroxy-2-tert-butylaminoethyl)indole-2-carboxylic acid methoxymethyl ester acetate, decomposition point 165°-170° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.O1CCCC1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Br:12])=[CH:14][CH:15]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(NC(=O)Nc2ccc(Br)cc2)c1
Reaction time: 72 h
Yield: 80.5 %

Procedure:
A mixture of 3-cyanophenyl isocyanate (3.76 g, 26.1 mmol) and 4-bromoaniline (4.5 g, 26.1 mmol) in 1:1 tetrahydrofuran:chloroform (100 mL). After 72 h at ambient temperature, product was isolated by filtration, the filtrate was washed with cold chloroform and air dried to give 6.6 g of N-(3-cyanophenyl)-N′-(4-bromophenyl)urea (21 mmol).