Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[C:7]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)[CH:2]=[C:3]([Cl:9])[N:4]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(Cl)nc(N3CCN(C)CC3)n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trichloropyrimidine is added in portions to an ice cooled solution of N-methylpiperazine (40 g) in alcohol (200 ml). The mixture is then heated at 60. for 2 hr. The mixture is concentrated and chromatogtaphed on silica gel with 2 to 5% methanol in methylene chloride to give 2,4-bis-[4-methylpiperazino]-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 hr. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give 2,4-bis[1(4-methylpiperazino)]-6-piperazinopyrimidine. This triamine is stirred in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna- 4,9(11)-diene-3,20-dio ne (7.18 g) and potassium carbonate (2 g) for 20 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is concentrated and chromatographed on silica gel (methylene chloride to 5% methanol and 0.5% ammonium hydroxide/methylene chloride) to give the free base corresponding to the title compound. The free base is dissolved in ethyl acetate and treated with methane sulfonic acid (2.22 g). The product is triturated with ether to give the title compound, bubbled at 110° without obvious decomp.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>[C:15]1([CH:14]=[CH:13][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1ccc2c(Br)ccnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: Clc1ccc2c(C=Cc3ccccc3)ccnc2c1
Temperature: 120 °C
Yield: 50.8 %

Procedure:
A mixture of 4-bromo-7-chloroquinoline (24.3 g, 0.1 mol), styrene (12.0 g, 0.125 mol), tri(o-tolyl) phosphine (0.4 g, 1.3 mmol), palladium acetate (0.2 g, 0.89 mol) and triethylamine (120 mls) was charged into a 300 ml stirred pressure vessel and heated at 120° C. for 17 hours. The mixture was cooled, filtered to remove triethylamine hydrobromide, and the solids washed with ethyl acetate (250 ml). Solvents were evaporated under reduced pressure and the residue dissolved in ethyl acetate (500 ml). The solution was washed with water and brine, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallisation of the residue from ethyl acetate: hexane gave the product (13.5 g, 51%) as an orange solid, mp 120-122° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a white foam (320 mg, 81%).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[CH:25]=O)[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2/[CH:25]=[CH:2]/[C:1]([C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[O:3])[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1
Reactant: CC(=O)c1cccs1
Reactant: COc1ccc(-c2nc3sccn3c2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(-c2nc3sccn3c2/C=C/C(=O)c2cccs2)cc1
Temperature: 27 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2-acetyl thiophene (126 mg, 1.0 mmol) and a 6-(4-methoxyphenyl) imidazo[2,1-b]thiazol-5-carbaldehyde (258 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (16a) as yellow solid (256 mg, 70% yield). Mp: 169-172° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[I:13]Cl.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:13][C:12]1[C:2]([F:1])=[CH:3][C:4]2[O:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=2[CH:11]=1
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(I)cc2N1
Yield: 94.9 %

Procedure:
7-Fluoro-2H-1,4-benzoxazin-3(4H)-one (15.8 g) was mixed with iodine monochloride (15.6 g) in acetic acid (150 ml) and heated to reflux for 36 h. The cooled mixture was treated with saturated aqueous sodium bisulfite until the color was dissipated. The solid was filtered and washed well with water. The solid was air dried and dried further by dissolution in dimethylformamide (100 ml) and evaporated to dryness under reduced pressure to give the desired product (26.3 g) contaminated with some starting material. (The reaction can be taken to completion by addition of more iodine monochloride and refluxing for 24 h longer.) The crude product was used in Step B.
Reaction SMILES: [OH-].[Na+].[C:3]([S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)(=O)N.ClC[C:16]([NH2:18])=[O:17]>O>[C:16]([CH2:3][S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)(=[O:17])[NH2:18]
Reactant: NC(=O)CCl
Reactant: NC(=O)SCc1csc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CSCc1csc(=O)[nH]1
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
9.0 ml of 10N (40%) sodium hydroxide solution are added dropwise to a suspension containing 5.7 g (0.03 mol) of 4-carbamoylmercaptomethyl-2(3H)-thiazolone [compound of the formula (Ib)] in 27 ml of water and 18 ml of ethanol at 25° to 30° C. while bubbling an inert gas through the mixture. After 15 minutes, 3.0 g (0.032 mol) of chloroacetamide are added to the reaction mixture which is then stirred for 16 hours. After filtering off the insoluble material, the filtrate is acidified by adding 5 ml of glacial acetic acid. The crystalline product is filtered, washed with isopropanol and dried to obtain 4.04 g (66.0%) of the named compound, m.p.: 151°-153° C. The active ingredient content of the substance is 99.4% based on titration with alkaline metal hydroxide.
Reaction SMILES: C[O:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[N:23]2CC2C=CC(OC)=CC=2)[CH2:19][C@H:18]2[CH2:20][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:21])[O:17]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[NH:23]2)[CH2:19][C@H:18]2[CH2:20][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:21])[O:17]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C/CCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: O=C1CCCCCC=CCCC[C@@H]2C[C@H](C[C@](O)([C@@H]3CSC(=O)N3)O2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,14R,16R,E)-16-methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH2+:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=2[N:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]3[C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])=[N:23][C:22]=2[CH:24]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1c1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride [see EP 530167 A1 930303] and 2,5-dichloro-1,3-benzoxazole [see J.O.C. (1996), 61(10), 3289-3297]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-(5-chloro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[N:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:23][C:24]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>C(O)C>[Cl:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[N:13][C:14]=4[CH2:15][CH2:16]3)=[N:33]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: COC(=O)c1ccc2c(n1)CCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
In a dried reaction flask, methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylate (1.552 g, 5.44 mmol) and 2-chloro-4-hydrazinobenzonitrile hydrochloride (1.437 g, 7.04 mmol) were dissolved in ethanol (55 mL). In the protection from light and under the nitrogen atmosphere, the solution was stirred at 80° C. for 8 hr and at room temperature for 15 hr, and filtered to obtain a pale yellow solid (0.972 g) in 41.1% yield.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:4][C:3]=2[O:2]1.CC(C)([O-:33])C.[K+].O=O.C(O)(=O)C>CN(C=O)C.O.C(OCC)C>[C:26]([O:25][C:23]([N:11]1[CH2:12][C:13]2[C:14](=[O:33])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Reactant: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2c([nH]c3ccccc3c2=O)C1c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
2-t-Butoxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (4.09 g, 10.4 mmol) (prepared as in Example 9) was dissolved in dry DMF (100 mL). Potassium t-butoxide (2.55 g, 22.7 mmol) was introduced in one portion and the suspension was stirred until a clear solution was obtained. Oxygen gas was then passed through the solution via a syringe needle for 16 h. The reaction was quenched by the addition of glacial acetic acid (25 mmol) and poured into a mixture of diethyl ether and water, which resulted in a precipitate that was collected by filtration. The product was purified by flash chromatography (0-10% MeOH/CHCl3) to yield the product as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:21]C1C=CC=CC=1)[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH2:14])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19].[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>>[CH3:1][NH:2][C:3](=[O:28])[CH:4]([CH3:21])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH:14][C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: COCC(=O)Cl
Product: CNC(=O)C(C)NC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I

Procedure:
This compound is obtained as described in Example 11 from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-alanine methylamide (IV d), m.p. 208°-209° C. (under decomposition), and methoxyacetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([S:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: COc1ccc(S)cc1
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Product: CCCCCCCCCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Yield: 98 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from the corresponding ethyl -2-bromomyristate (5.0 g, 14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of the product was isolated. Yield 98%; Light yellow oil; MS: 393 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10](Cl)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([NH:28][C:29]#[N:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na]>CC(C)=O.O>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[N:13]=[C:12]([N:28]([C:29]#[N:30])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:11]=[C:10]([N:7]([C:8]#[N:9])[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CNc1ccccc1
Reactant: Clc1nc(Cl)nc(N(c2ccccc2)c2ccccc2)n1
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: N#CN(c1ccccc1)c1nc(N(C#N)c2ccccc2)nc(N(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
To a solution of 31.7g (0.10 mole) of a 2-diphenylamino-4,6-dichloro-s-triazine in 325 ml of acetone at room temperature was added dropwise to a solution of 0.20 mole of sodium phenylcyanamide in 100 ml of water over a 30 minute period. After stirring for 1 hour at room temperature, the reaction mixture was heated at reflux overnight. After cooling the reaction mixture was filtered. The residue was washed with water, acetone and dried to give 25.5g of crude product. Recrystallization from 1500 ml of acetonitrile gave 20.9g of pure DPNCT, m.p. 280°-284°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]([OH:19])=[O:18])[N:3]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:19])[CH3:26]
Reactant: CCO
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from the compound of Example 73 by refluxing in ethanol in the presence of concentrated sulphuric acid, mp. 177.5° C.
Reaction SMILES: [N:1]([CH:4]([C:10]1[N:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[CH:12][CH:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:16]([O:15][N:14]1[C:10]([CH:4]([NH2:1])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[CH:11][CH:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(CC)C(N=[N+]=[N-])c1ccnn1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)C(N)c1ccnn1OCc1ccccc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
5-(1-Azido-2-ethylbutyl)-1-(benzyloxy)-1H-pyrazole (0.269 g, 0.90 mmol) was dissolved in THF (20 mL). Distilled water (0.40 mL, 22.5 mmol) was added, followed by triphenyl phosphine (0.590 g, 2.25 mmol). The mixture was refluxed for 2 h, cooled to ambient temperature and concentrated in vacuo. This produced a crude oil that was purified on a Biotage column (hexane/EtOAc, 1:1) to afford the product as a colorless oil (0.188 g, 76%). Mass Spectrum (+ESI): 274.2 (M+H)+.
Reaction SMILES: C(OC(N1CCN(C2C=CC(NC(C3N=C(C4C=CC=CC=4)OC=3C(F)(F)F)=O)=CN=2)CC1)=O)(C)(C)C.[C:38]1([C:44]2[O:45][C:46]([C:74]([F:77])([F:76])[F:75])=[C:47]([C:49]([NH:51][C:52]3[CH:57]=[CH:56][C:55]([NH:58][C@H:59]4[CH2:63][CH2:62][N:61]([C:64]([CH:66]5[CH2:70][CH2:69][CH2:68][CH:67]5[C:71]([OH:73])=[O:72])=[O:65])[CH2:60]4)=[CH:54][CH:53]=3)=[O:50])[N:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([C:44]2[O:45][C:46]([C:74]([F:76])([F:75])[F:77])=[C:47]([C:49]([NH:51][C:52]3[CH:57]=[CH:56][C:55]([NH:58][C@H:59]4[CH2:63][CH2:62][N:61]([C:64]([C@@H:66]5[CH2:70][CH2:69][CH2:68][C@H:67]5[C:71]([OH:73])=[O:72])=[O:65])[CH2:60]4)=[CH:54][CH:53]=3)=[O:50])[N:48]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Nc1ccc(N[C@H]2CCN(C(=O)C3CCCC3C(=O)O)C2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Product: O=C(Nc1ccc(N[C@H]2CCN(C(=O)[C@@H]3CCC[C@H]3C(=O)O)C2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid was prepared as a mixture of diastereomers. The diastereomeric mixture was purified by chiral supercritical fluid chromatography (the first eluting peak) to yield (1R,2R)-2-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid as a yellow oil. HRMS calcd for C28H27F3N4O5 (M+H) 557.2007, obsd 557.2004
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[OH:48][CH:49]([CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([N+:71]([O-:73])=[O:72])=[CH:67][CH:66]=1)=[O:62])[CH2:50][C:51]([NH:53][C@H:54]1[CH2:58][CH2:57][NH:56][CH2:55]1)=[O:52]>O1CCCC1>[OH:48][CH:49]([CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]([N+:71]([O-:73])=[O:72])=[CH:69][CH:70]=1)=[O:62])[CH2:50][C:51]([NH:53][C@H:54]1[CH2:58][CH2:57][N:56]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:29])[CH2:55]1)=[O:52]
Reactant: O=C(CC(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)CC(O)CNC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (2.87 g) in anhydrous tetrahydrofuran (30 ml), N,N'-carbonyldiimidazole (1.25 g) was added, followed by stirring at 30° C. for one hour. To the reaction mixture, N,N-diisopropylethylamine (1.68 ml) and a solution of (3S)-3-[3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminobutanoylamino]pyrrolidine trifluoroacetate (3.19 g) in anhydrous tetrahydrofuran (30 ml) was added. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated by evaporation under reduced pressure and ethyl acetate was added to the residue. The resulting mixture was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography (dichloromethane-ethyl acetate-methanol) through a silica gel column, whereby 3.81 g of the title compound were obtained as an amorphous substance.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26].C(O)C>[Pd].O>[ClH:26].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:26])[N:10]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cnc(-c2ccc([N+](=O)[O-])cc2)n1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc(Cl)c(CC(=O)O)n2Cc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 1-benzyl-2-(4-nitrophenyl)-5-imidazole-acetic acid (2.1 g, 5.0 mmol), 10% palladium on carbon (0.10 g), 12 M HCl (3.0 ml), 96% ethanol (50 ml) and water (50 ml) was hydrogenated at 55 psi for 1.5 hours on a Parr shaker hydrogenation apparatus. The mixture was filtered through a celite pad and then through a fluted filter paper. Evaporation left the title compound, Compound 12, as 1.0 g orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=C(C#N)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[C:23]([OH:26])(=[O:25])[CH3:24].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:24]([C:23]([OH:26])=[O:25])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CC(=O)O
Reactant: N#Cc1cc(F)c2[nH]nc(-c3ccc4ccccc4c3)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)c2[nH]nc(-c3ccc4ccccc4c3)c2c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To 1.0 g of 7-fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile were sequentially added 5.0 ml of glacial acetic acid, 5.0 ml of water and 10.0 ml of concentrated sulfuric acid, and the mixture was stirred at 120° C. for one day. After standing to cool, 20 ml of water was added to the reaction mixture and the resulting crystals were collected by filtration. The crystals were sequentially washed with water and diethyl ether, to give 1.0 g of the title compound as colorless crystals.