Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([O:7][C:8](Cl)=[O:9])=[CH:3][CH:2]=1.[CH3:12][O:13][N:14]=[CH:15][C:16]1[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:12][O:13][N:14]=[CH:15][C:16]1[CH2:17][N:18]([C:8]([O:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)=[O:9])[CH2:19][CH2:20][CH:21]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: CON=CC1=CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=CC1=CCCN(C(=O)Oc2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
A solution of p-tolylchloroformate (1.5 mL, 10.3 mmoles) in dichloromethane (15 mL) was added under nitrogen at 0° C. to a stirred solution of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime (1.3 g, 9.3 mmoles) and triethylamine (1.3 mL, 2.3 mmoles) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 20 minutes, the solvent was evaporated and the residue was partitioned between water and ethylacetate. The organic layer was dried (Na2SO4) and evaporated. The solid was triturated with cyclohexane to afford 2.3 g (91%) of a white solid with mp 70°-71° C.
Reaction SMILES: C([O:4][C@@H:5]([CH3:40])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([NH:23][C:24]([C:26]3([C:29](=[O:38])[NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:18][C:17]=2[F:39])[CH:12]=[CH:11][N:10]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:22][C:20]1[CH:21]=[C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[CH3:40])[CH:14]=2)[C:17]([F:39])=[CH:18][C:19]=1[NH:23][C:24]([C:26]1([C:29]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[O:38])[CH2:28][CH2:27]1)=[O:25]
Reactant: CC(=O)O[C@@H](C)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@H](O)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.2 %

Procedure:
To a solution of (S)-1-((4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl acetate (180 mg, 0.323 mmol) in a solution of MeOH—H2O (3:1, 20 mL) was added potassium carbonate (111.6 mg, 0.809 mmol), the mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated and purified by prep-TLC to give (S)—N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 60% yield). 1H NMR (400 MHz, Methanol-d4): δ 8.21-8.16 (m. 2H), 7.78 (d, J=2.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.28-7.24 (m, 1H), 7.10-7.05 (m, 2H), 6.76-6.74 (dd, J=6.0, 2.4 Hz, 1H), 4.23 (q, J=6.8 Hz, 1H), 1.75-1.67 (m, 4H), 1.39 (d, J=6.8 Hz, 3H); MS (ESI): m/z 515.2 [M+H]+.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Br[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=1>>[CH3:16][O:15][C:13]1[CH:14]=[C:9]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[OH:7])[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: C1CCC2OC2C1
Product: COc1cc(OC)cc(C2CCCCC2O)c1

Procedure:
Preparation 106 is prepared from cyclohexene oxide and 1-bromo-3,5-dimethoxybenzene in a manner similar to preparation 10. 1H NMR (CDCl3): 6.41 (s, 2H), 6.35(s, 1H), 3.79 (s, 6H), 3.65 (m, 1H), 2.37 (m, 1H), 2.1 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H)1.6-1.2 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:38]2[CH:37]=[C:15]([CH:14]=[CH:13][C:39]=2[CH3:40])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=2)=[O:17])[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=12
Reactant: C#Cc1cnc2cnccn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-a]pyrazine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. The product was obtained as a solid: 533 m/z (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@H:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[CH2:26][C:27]([NH:29][C:30]([CH3:35])([C:32]([OH:34])=O)[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:56]C=2C=1.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@H:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=3)[CH2:26][C:27]([NH:29][C:30]([CH3:35])([C:32]([NH2:56])=[O:34])[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)C[C@H](NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(NC(=O)C[C@H](NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 50 mg (75 μmol) of the compound of Example 39, 29 mg (0.15 mmol) of EDC and 20 mg (0.15 mmol) of HOBt in 2 ml of DMF was stirred at RT for 20 min and then poured into 5 ml of ammonia (35% strength solution in water). The reaction mixture was stirred at RT for 30 min and then concentrated on a rotary evaporator, acidified with 2.5 N hydrochloric acid and separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 42 mg (84% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1.[C:22](Cl)(=O)[CH2:23][CH3:24]>>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:15])[C:12]#[N:13])=[CH:7][CH:6]=3)[C:22]([CH2:23][CH3:24])=[N:1][C:2]=2[CH:19]=1
Reactant: CCC(=O)Cl
Reactant: CC(C)(C#N)c1ccc(Nc2cc(Cl)c(Cl)cc2N)cc1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(C(C)(C)C#N)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-[4-(2-amino-4,5-dichloroanilino)phenyl]-2-methylpropanenitrile (step 2) and propionyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[NH:21][C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc1)n2C
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)NC3=O)cc1)n2C

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.07 g of 5-{4-(3,7-dimethyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 41) and 16 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent. The product was crystallized by trituration with ethyl acetate, to give 0.28 g of the title compound, melting at 205-207° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:18]/[C:19](=[N:39]\[OH:40])/[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C(F)(F)F)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 3-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-(2-trifluoromethyl-phenyl)-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI−): m/z=521.2 ([M−H]−).
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC(C[O:15][C:16]2[CH:17]=[C:18]([CH3:24])[C:19]([CH:22]=[CH2:23])=[N:20][CH:21]=2)=CC=1>C1(OC)C=CC=CC=1>[CH3:24][C:18]1[CH:17]=[C:16]([OH:15])[CH:21]=[N:20][C:19]=1[CH:22]=[CH2:23]
Reactant: C=Cc1ncc(OCc2ccc(OC)cc2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=Cc1ncc(O)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.25 mL, 5 times) was added to a stirred solution of 5-((4-methoxybenzyl)oxy)-3-methyl-2-vinylpyridine (250 mg, 0.00098 mmol) in anisole (0.5 mL). The reaction mixture was stirred for 2 h at ambient temperature. After completion of the reaction, the reaction mixture was concentrated and quenched with saturated NaHCO3 solution (2 ml). The reaction mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was triturated with pentane to afford 5-methyl-6-vinylpyridin-3-ol as an off white solid (100 mg, 76%). MS m/z=136.15 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][CH2:6][N:7]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8](=[O:21])[NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=O)C.O.C(OCC)(=O)C>N>[SH:4][CH2:5][CH2:6][N:7]([CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:8](=[O:21])[NH:9][C@@H:10]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:11]([OH:13])=[O:12]
Reactant: CC(=O)SCCN(CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(CCS)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
(2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-3-phenylpropionic acid (Compound No. 7-30, 646 mg) is dissolved in 28% aqueous ammonia (15 ml) under a nitrogen atmosphere, and the solution is stirred at room temperature for one hour. To the reaction mixture are added water and ethyl acetate, and the aqueous layer is separated from the organic layer. To the aqueous layer is added 6 N hydrochloric acid under ice cooling to acidify it, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 415 mg (81%) of the titled compound (Compound No. 11-1).
Reaction SMILES: [I:1]Cl.[OH:3][CH2:4][CH:5]([CH2:16][OH:17])[CH2:6][CH2:7][N:8]1[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]>CO>[OH:3][CH2:4][CH:5]([CH2:16][OH:17])[CH2:6][CH2:7][N:8]1[CH:15]=[C:14]([I:1])[C:12](=[O:13])[NH:11][C:9]1=[O:10]
Reactant: ClI
Reactant: O=c1ccn(CCC(CO)CO)c(=O)[nH]1
Solvent: CO
Product: O=c1[nH]c(=O)n(CCC(CO)CO)cc1I
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
Iodine monochloride (500 mg, 3.08 mmol) was added to a solution of 18 (360 mg, 1.68 mmol) in dry methanol (25 ml) and the reaction mixture was stirred at 50° C. for 90 min. and then the methanol was removed in vacuo. The dry residue was treated with 5.0 ml of conc. ammonium hydroxide in 25 ml of methanol with stirring at 50° C. for 1 h. The crude reaction mixture was purified by elution from a column of silica gel by using dichloromethane-methanol (92:8, v/v) as eluent. The product 19 was obtained in 59.2% yield as a colorless gum.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:44])[C@@H:35]([NH2:43])[CH2:36][C:37]1[S:38][C:39]([Br:42])=[CH:40][CH:41]=1>>[Br:42][C:39]1[S:38][C:37]([CH2:36][C@H:35]([NH:43][C:26]([C:15]2[N:16]=[C:17]([CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[C:10]([O:9][C:8]2[CH:29]=[CH:30][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)[CH:19]=3)=[O:27])[C:34]([OH:33])=[O:44])=[CH:41][CH:40]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)s1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccc(Br)s4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 87.7 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester HCl (40.1 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 66.9 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([OH:17])=O)[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C:29]1=[O:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[C:29](=[O:34])[CH2:30]1)=[O:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: CN1CCNCC1=O
Reactant: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)O)c2cc1OC
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)N3CCN(C)C(=O)C3)c2cc1OC
Yield: 69.1 %

Procedure:
4-{[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]acetyl}-1-methylpiperazin-2-one is prepared by following the procedure described in example 93, but using 0.1 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]acetic acid and 0.039 g of 1-methylpiperazin-2-one. 0.088 g of 4-{[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]acetyl}-1-methylpiperazin-2-one is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20]C)=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[NH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([NH2:22])=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1cccc2oc(-c3ccc(OC)cc3)nc12
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1

Procedure:
Methyl 2-(4-methoxyphenyl)benzoxazole-4-carboxylate was dissolved in liquid ammonia (30 ml) and sealed in an autoclave. The reaction mixture was left at 55° C., 20 bar for >20 hours. Once the reaction was complete the ammonia was removed and the resulting solid recrystallised from boiling ethyl acetate and petrol.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:21](O)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:32]>C1C=CC=CC=1>[ClH:32].[C:21]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: OCCN1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(C=Cc1ccccc1)OCCN1CCNCC1
Yield: 53 %

Procedure:
In 150 ml of absolute benzene there were dissolved 1.95 g of 1-piperazineethanol and 14.2 g of p-toluene sulfonic acid. To the solution 2.89 g of cinnamic acid was added. The system was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline followed by extraction with ether. After the ethereal layer was dehydrated over a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to give a colorless transparent liquid. The liquid was converted into the hydrochloride thereof. Upon recrystallization from ethanol, 1-piperazineethanol cinnamate hydrochloride was obtained. The melting point of the product was 184°-187° C. The yield was 53%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([F:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([F:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2cc(Cl)cc(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(c2cc(Cl)cc(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3,5-dichlorophenyl)-3-fluoro-pyrrolidin-1-carboxylate (0.45 g, 1.34 mmol), dichloromethane (2 mL), trifluoroacetic acid (2 mL). Stirred for 4 h at ambient temperature. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) followed by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 60:40) and flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.15 g. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 201-202° C.; MS m/z (relative intensity, 70 eV) 235 (M+, 64), 233 (M+, bp), 213 (28), 133 (49), 120 (32).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: Clc1ccc(NCc2ccncc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccncc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A 3.3 g. portion of 4-(4-chlorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature for several days, adding another 0.5 ml. of methanesulfonyl chloride in the process. The mixture was then diluted with dichloromethane, extracted with aqueous sodium bicarbonate and with water, dried over magnesium sulfate and evaporated. The residue was taken up in dichloromethane and chromatographed over silica gel, eluting first with dichloromethane and then with 9:1 dichloromethane:ethyl acetate. The product-containing fractions were combined and evaporated, and the residue was triturated with petroleum ether and diethyl ether to obtain 2.1 g. of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:5]([Cl:17])=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>COCCOC.CCO>[Cl:17][C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:1]=2)[C:6]=1[CH2:8][P:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:16]
Reactant: CCOP(=O)(Cc1nc(N)ccc1Cl)OCC
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cn2c(CP(=O)(OCC)OCC)c(Cl)ccc2n1
Yield: 13 %

Procedure:
Following the procedure for Example 17, the residue from Example 28 was combined with ethyl bromopyruvate (0.468 g, 2.4 mmol) in DME (25 mL). After the resulting salt was refluxed in abs EtOH (30 mL) for 6 h, workup and puricication produced 0./114 g (13% of title compound).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.O[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:29]=1)[C:25]#[N:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:25]([C:24]1[CH:23]=[C:22]([CH:29]=[C:28]([O:30][C:31]([F:32])([F:34])[F:33])[CH:27]=1)[CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:26]
Reactant: N#Cc1cc(CO)cc(OC(F)(F)F)c1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cc(C#N)cc(OC(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (100 mg, 0.386 mmol) and 3-(hydroxymethyl)-5-(trifluoromethoxy)benzonitrile (84 mg, 0.386 mmol) were dissolved in THF (3.0 mL) and cooled to 0° C. Triphenylphosphine (202 mg, 0.771 mmol) and diisopropylazodicarboxylate (DIAD) (0.15 mL, 0.771 mmol) were added. The mixture was warmed to room temperature and stirred for 1 h. Additional DIAD (0.15 mL, 0.771 mmol) and triphenylphosphine (202 mg, 0.771 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 50.8 mg of impure ethyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The material was dissolved in dioxane (1.3 mL) and 1.0 M aqueous LiOH (0.33 mL, 0.33 mmol) was added. The reaction was monitored by HPLC until judged complete and then acidified to pH 2 with 1.0 M HCL. The aqueous mixture was extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by HPLC to give the title compound (1.1 mg). LCMS m/z=431.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 2.11-2.20 (m, 1H), 2.50 (dd, J=15.8, 8.0 Hz, 1H), 2.66-2.84 (m, 4H), 3.51-3.60 (m, 1H), 5.18 (s, 2H), 6.78 (dd, J=8.8, 2.5 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.64 (s, 1H), 7.73 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl[C:27]1[S:28][C:29]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:30]([CH3:32])[N:31]=1>>[CH3:32][C:30]1[N:31]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[S:28][C:29]=1[S:33]([NH2:36])(=[O:35])=[O:34]
Reactant: Cc1nc(Cl)sc1S(N)(=O)=O
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-4-methyl-thiazole-5-sulfonic acid amide (example B.23)(191 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 30%). MS (ISP) 532.1 [(M+H)+]; mp 245–246° C.