Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[N:10]=[CH:11][NH:12][C:13](=O)[C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:8]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c1nc(-c1ccccc1)n2-c1ccccc1
Product: Clc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
8,9-diphenyl-1H-purin-6(9H)-one obtained in step 3 (22.3 g, 77.4 mmol) was dissolved in POCl3 (70 ml) at 0° C. and the reaction mixture was heated to reflux at 110° C. overnight. After cooled to room temperature, ice-water was added to the resulting reaction mixture and stirred for 30 min at room temperature. The resulting mixture was filtered with water. The collected solid was dried under reduced pressure to obtain the title compound (20 g, 84%) as beige solid.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH3:30])[NH:23][C:22]([CH2:31][O:32][CH2:33][C:34](O)=[O:35])=[C:21]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].N>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH3:30])[NH:23][C:22]([CH2:31][O:32][CH2:33][C:34]([NH2:3])=[O:35])=[C:21]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: N
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCC(N)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Carbonyldiimidazole (9.80 g) was added to a suspension of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetic acid (25.4 g) in tetrahydrofuran (400 ml) and the mixture stirred at room temperature for 2 hours. A stream of gaseous ammonia was passed through the resulting solution with stirring until the reaction was complete (as determined by t.l.c.) The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate and evaporated. The residue was triturated with diethyl ether and the resulting solid collected, recrystallised from diethyl ether/n-hexane and dried to give the title compound (17.0 g), m.p. 127°-128° C.
Reaction SMILES: [C:1](Cl)(=O)C.Cl.[F:6][C:7]([F:37])([F:36])[C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[CH2:11][NH:12][CH:13]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)[C:14]([OH:16])=[O:15].C([O-])(O)=O.[Na+]>CO>[F:37][C:7]([F:6])([F:36])[C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[CH2:11][NH:12][CH:13]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)[C:14]([O:16][CH3:1])=[O:15]
Reactant: O=C(O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a magnetically stirred solution of 100 ml of methanol cooled in an ice-acetone bath at ca. -15° C., was treated dropwise with acetyl chloride (27.3 g, 350 mmol, 35 eq) over a six-minute period as a convenient way to generate HCl in situ. The solution was stirred at ambient temperature for 45 minutes, then solid α-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid was added which formed a dark rose colored solution. After stirring for 22 hours the reaction mixture was poured into 100 mL of saturated NaHCO3 solution containing 100 mL of crushed ice, basified with additional solid NaHCO3 powder until the rose color dissipated and extracted twice with ether. The combined organic extracts were washed with saturated NaHCO3 (1×75 mL), saturated brine (1×100 mL), dried with anhydrous NaSO4 and concentrated in vacuo. Flash chromatography with 100 g of silica gel using ethyl acetate-hexane (1:2) afforded 4.07 g of the title compound as a golden oil.
Reaction SMILES: [CH:1]1([CH:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15][CH3:16])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:3][CH2:2]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CS(C)=[O:44])C=CC=3)NC=2)=CC=1>>[CH:1]1([CH:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15]([CH3:16])=[O:44])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3F)C3CC3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 50 mg (0.15 mmol) of the compound from Example 228 in analogy to the synthesis of the compound from Example 235. 43 mg (82% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].II.[Cl:7][C:8]1[C:9]([CH3:15])=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].O>CO>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([S:1][C:2]#[N:3])=[C:8]([Cl:7])[C:9]=1[CH3:15]
Reactant: Cc1c(N)cccc1Cl
Reactant: N#C[S-]
Agent: II
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1c(N)ccc(SC#N)c1Cl
Yield: 89.3 %

Procedure:
To a stirred solution of ammonium thiocyanate (1.61 g, 0.02 mol) and iodine (1.79 g, 7.1 mmol) in methanol was added 3-chloro-2-methylaniline (0.84 mL, 7.1 mmol) dropwise. The mixture was allowed to stir at room temperature for 2 days after which time water (50 mL) was added and the mixture was extracted with dichloromethane (4×50 mL). The extracts were washed with a 15% aqueous solution of sodium thiosulfate (100 mL) then dried (Na2SO4) and the solvent removed in vacuo to afford 4-amino-2-chloro-3-methylphenyl thiocyanate as a brown solid (1.26 g, 90%). Material was used crude in subsequent steps.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>CN1CCCC1=O>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1C(=O)OC(C)(C)C
Temperature: 140 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
Compound 1a (3.60 g) was dissolved in N-methylpyrrolidin-2-one (14 mL), and diisopropylethylamine (6.55 mL) and 2-fluoro-4-nitrophenol (2.89 g) were added to the solution. The mixture was heated to 140° C. and stirred for 4 hours. To the reaction mixture, distilled water was added on an ice bath, and the precipitate was filtrated, to thereby yield compound 1b (4.71 g, yield: 93%).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:84][C:85]([N:87]1[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]1)=[O:86])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>CN(C=O)C>[CH2:77]([O:84][C:85]([N:87]1[CH2:92][CH2:91][N:90]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:5])=[O:43])[CH2:89][CH2:88]1)=[O:86])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 55 μl DIPEA, 64 mg HATU and 56 mg piperazine-1-carboxylic acid benzyl ester. After stirring for 24 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: O.[P:2]([Cl:6])(Cl)([Cl:4])=[O:3].[CH2:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11]>C(Cl)(Cl)(Cl)Cl>[P:2]([Cl:6])([Cl:4])(=[O:3])[O:12][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCCOP(=O)(Cl)Cl
Reaction time: 18 h
Yield: 102.9 %

Procedure:
To a tap water cooled solution of 79 g of phosphorous oxychloride in 200 ml of carbon tetrachloride is added dropwise with stirring a solution of 50 g of 1-pentanol in 125 ml of carbon tetrachloride. The temperature rises to 30° C. and stirring is continued for 18 hours. The solvent is evaporated and the syrup evaporated with toluene several times. The residue is distilled rom a Kugelrohr still to give 108.7 g of the desired product as a colorless oil, B.P. 85°-90° C./0.3 mm.
Reaction SMILES: ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:9]([O:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)[CH3:10].[Br:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][CH:26]=[CH:25]2>C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][CH:26]=[C:25]2[C:15](=[O:17])[CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:18]
Reactant: CCOC(=O)CCC(=O)O
Reactant: Brc1cccc2cc[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1c[nH]c2c(Br)cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (50 mL) solution of aluminum chloride (6.80 g), succinic acid monoethyl ester chloride (8.39 g) was added under ice cooling and the mixture was stirred for 30 minutes. To the mixture, 7-bromoindole (5.0 g) was added, followed by stirring at room temperature for 5 hours. To the reaction mixture, ice water and ethyl acetate were added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was washed with diisopropyl ether to obtain the titled compound having the following physical properties (6.04 g).
Reaction SMILES: [C:1]([O:6][C@H:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])[OH:19])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])(O)=O.[Na+:29]>O.C(#N)C>[Na+:29].[C:1]([O:6][CH:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[O-:20])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCP(=O)(O)CCCNC(=O)O[C@@H](OC(=O)C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCP(=O)([O-])CCCNC(=O)OC(OC(=O)C(C)C)C(C)C
Reaction time: 0.17 h

Procedure:
Compound 39 was dissolved in a mixture of water and acetonitrile, an aqueous solution of 1 eq. NaHCO3 was added, the mixture stirred for about 10 min, and lyophilized to afford the title compound (213). 1H-NMR (400 MHz, CDCl3): δ 6.55 (d, J=4.8 Hz, 1H), 3.10 (t, J=6.4 Hz, 2H), 2.53-2.56 (m, 1H), 1.97-2.00 (m, 1H), 1.79-1.83 (m, 2H), 1.70-1.74 (m, 2H), 1.53-1.58 (m, 2H), 1.37-1.43 (m, 2H), 1.15 (t, J=6.8 Hz, 6H), 0.90 (t, J=7.2 Hz, 9H).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23]N)=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.O1CCOCC1.N(OCCC(C)C)=O.N[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].Cl>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NN
Reactant: CCOC(=O)CCN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a solution of Boc-Leu-DTrp-NHNH2 (39 mg) obtained in Example 1-(2) in DMF (0.5 ml) was added 3.1 M HCl/1,4-dioxane (81 μl) at -60° C. The temperature of the solution was raised to -20° C. and isoamyl nitrite (15 μl) was added. The reaction mixture was stirred at -20° C. to -15° C. for 1.5 h and cooled at -60° C. A solution of βAla-OEt.HCl (17 mg) in DMF (0.5 ml) and TEA (50 μl) were added. The reaction mixture was stirred at 5° C. overnight and concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=30/1 for development to give the product (41 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([O:15][C:16](=[O:23])/[CH:17]=[CH:18]/[C:19]([F:22])([F:21])[F:20])[CH3:14]>>[CH:10]([C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:23])[CH:18]([C:19]([F:20])([F:22])[F:21])[O:1]2)=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1ccc(C=O)c(O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Product: CCOC(=O)C1=Cc2ccc(C(C)C)cc2OC1C(F)(F)F

Procedure:
This salicylaldehyde (Step 1) was condensed with Ethyl-4,4,4-triflurocrotonate via a similar method to that of Example 4a, Step 1 producing the ethyl ester (8.21 g, 84%) as yellow solid. This ester was of suitable purity to use without further purification: ESLRMS m/z 315 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][OH:10])[O:7][CH2:6][CH2:5][O:4]1)C.[CH3:11][O:12]CC(=O)CC(OC)=O>>[CH3:11][O:12][CH2:1][C:3]1([CH2:8][CH2:9][OH:10])[O:4][CH2:5][CH2:6][O:7]1
Reactant: COCC(=O)CC(=O)OC
Reactant: CCC1(CCO)OCCO1
Product: COCC1(CCO)OCCO1
Yield: 50 %

Procedure:
The same procedure as in the step (39a) and (39b) of Example 39 was repeated using methyl 4-methoxyacetoacetate to obtain the title compound (5.3 g, 2 steps: 50%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1([CH2:13]O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.CCOCC.C(#N)C.[I:52]I>>[CH2:1]([N:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1([CH2:13][I:52])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN(Cc1ccccc1)CC1(CO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CN(Cc1ccccc1)CC1(CI)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 63.8 %

Procedure:
To a stirred solution of methyl (benzyl{[1-(hydroxymethyl)cyclopropyl]methyl}-amino)acetate (1.1 g, 0.0042 mol), triphenylphosphine (2.74 g, 0.0104 mol) and 1H-imidazole (0.711 g, 0.0104 mol) in ether (30.0 mL, 0.286 mol) and ACN (10.0 mL, 0.192 mol) at 0° C. was added iodine (2.12 g, 0.00835 mol). The resulting yellow suspension was stirred at 0° C. for 50 min. The reaction was quenched by the addition of 10% aqueous Na2S2O3 (30 ml) and saturated aqueous NaHCO3 (30 mL). The product was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Combiflash chromatography eluting with 0-15% EtOAc/hexanes to afford the desired product (1.0 g). LC/MS: 374.1 (M+1H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si](C=[N+]=[N-])(C)C.CCCCCC>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)([OH:14])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
The compound (0.86 g) obtained in Step 4 was dissolved in methanol (10 mL) and to the solution was added a 2M trimethylsilyidiazomethan-hexane solution (1.3 mL). After completion of the reaction, the residue from which the solvent was removed under reduced pressure was purified by silica gel column chromatography (Chromatorex NH™) (eluent; ethyl acetate:hexane=1:19 to 1:9) to obtain the titled compound (0.8 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15](C)=[N:16]C(C)=CC=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.[CH3:40][N:41]1C(C=O)=CN=[N:42]1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:41]([CH3:40])[N:42]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1nncc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.45 g, 3.37 mmol, Intermediate 47: step d) was added THF (25 mL) at room temp which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol) was added dropwise. The color of the solution became a dark reddish-brown color. After 2 minutes, 1-methyl-1H-1,2,3-triazole-5-carbaldehyde (580 mg, 5.22 mmol, in 3 mL THF, Intermediate 50: step a) was introduced and the color of the mixture went from dark brown to greenish to a yellow color within about 2 minutes. The mixture was allowed to warm to −20° C. over 45 minutes at which time the contents were quenched with aqueous NH4Cl. The mixture was diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a yellowish oil. The crude material was chromatographed on silica gel (5% CH3CN-DCM increasing to 30% CH3CN+2% MeOH) to give the title compound as an off white foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28]OC(=O)C(C)(C)C)[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.[CH2:45]([SH:47])[CH3:46]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH2:28][S:47][CH2:45][CH3:46])[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS
Reactant: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Agent: Cl
Solvent: C1COCCO1
Product: CCSCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 86.8 %

Procedure:
In 10 ml of ethyl mercaptan was dissolved 1.0 g of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine, and 0.01 ml of 5.7 N hydrogen chloride-dioxane solution was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was distilled under reduced pressure, and 50 ml of diisopropyl ether was added to the crystals thus obtained, after which the resulting crystals were filtered. The crystals thus obtained were recrystallized from isopropyl alcohol to obtain 0.8 g (86.8% yield) of white crystalline 1-benzyl-4-{4-[N-ethylthiomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 144° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH2:12]([O+](CC)CC)[CH3:13]>ClCCCl>[F:7][B-:8]([F:11])([F:10])[F:9].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: Cn1ccnc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CCn1cc[n+](C)c1

Procedure:
22.3 ml of N-methylimidazole and 120 ml of 1,2-dichloroethane were introduced into a 250 ml glass flask under an argon atmosphere. 53.2 g of triethyloxonium tetrafluoroborate was added in small portions. The reaction medium was observed to heat up slightly and the solvent was then refluxed for 1 hour 30 minutes. The molten salt formed was colorless, non miscible and denser than the 1,2-dichloroethane. It was separated by simple decanting and drawn under vacuum using a vane pump.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:3][CH2:2]1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(N2CCOCC2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(N2CCOCC2)n1
Yield: 4.91 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-morpholino-1,3-thiazole-4-carboxylic acid (0.229 g, 1.070 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.25 g, 0.892 mmol). The product was purified by Flash-chromatography and triturated using diethyl ether. Yield 4.91%. 1H-NMR (400 MHz; DMSO-d6): δ 1.23 (d, 3H), 3.38-342 (m, 4H), 3.67-3.71 (m, 4H), 4.28-4.45 (m, 3H), 6.95 (d, 1H), 7.39 (s, 1H), 7.83 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 1H), 7.98 (dd, 1H), 8.06 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:28](=[O:30])[CH3:29])[N:12]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCc1nc(-c2ccccc2NC(C)=O)co1
Temperature: 25 °C

Procedure:
Dissolve 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (4.05 g, 14.8 mmol) and triethylamine (2.26 mL, 16.2 mmol) in TI-IF (40 mL) and stir at room temperature. Add acetyl chloride (1.16 mL, 16.2 mmol) and allow the mixture to stir overnight at room temperature. Concentrate the mixture and partition the residue between aq NaHCO3 and EtOAc. Dry the combined extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) which allows for the isolation of 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.51 g, 75%). MS (ES): (M+1)+ 317.2 m/z.