Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][OH:21])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.I[CH3:23]>C1COCC1>[CH3:23][O:21][CH2:20][C:19]#[C:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][O:3]1)[N:10]=[CH:11]2
Reactant: CI
Reactant: OCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Sodium hydride (60% in mineral oil, 0.42 g, 10.5 mmol) was added to a solution of 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-ol (1.01 g, 3.94 mmol; Intermediate 16) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then iodomethane (1.67 g, 11.8 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1:30) to afford the title compound (0.714 g, yield 67.3%). 1H NMR (DMSO-d6, 300 MHz): δ 8.21 (s, 1H), 7.93 (s, 1H), 7.73 (d, 1H), 7.47-7.45 (m, 1H), 5.85-5.83 (m, 1H), 4.38 (s, 2H), 3.76-3.71 (m, 2H), 3.35 (s, 3H), 2.40-2.37 (m, 1H), 2.03-1.94 (m, 2H), 1.73-1.72 (m, 1H), 1.57-1.55 (m, 2H). LCMS: 271 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[CH:14]1([NH:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH:14]1([NH:19][NH:20][C:8](=[O:10])[C:7]2[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=2[O:11][CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1nccc(I)c1C(=O)O
Reactant: NNC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nccc(I)c1C(=O)NNC1CCCC1
Yield: 27.6 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (1.95 g) obtained in Step C of Example 6, cyclopentylhydrazine hydrochloride (1.05 g), EDCI hydrochloride (0.58 g), HOBt (2.01 g) and triethylamine (1.06 g) in DMF (30 mL) was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (697 mg).
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([O:8][CH:9]([C:11]([O:14][CH2:15][C:16]([C:19]([OH:21])=[O:20])([F:18])[F:17])([F:13])[F:12])[F:10])([F:7])([F:6])[F:5].[NH3:22]>>[C:4]([O:8][CH:9]([C:11]([O:14][CH2:15][C:16]([C:19]([O-:21])=[O:20])([F:18])[F:17])([F:12])[F:13])[F:10])([F:7])([F:6])[F:5].[NH4+:22]
Reactant: O=C(O)C(F)(F)COC(F)(F)C(F)OC(F)(F)F
Reactant: N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C(F)(F)COC(F)(F)C(F)OC(F)(F)F
Product: [NH4+]

Procedure:
This mixture was subjected to hydrolysis with a 6 N aqueous solution of sodium hydroxide, and the hydrolysis product was lyophilized and then neutralized with 12 N hydrochloric acid. The thus-obtained CF3OCHFCF2OCH2CF2COOH was neutralized with aqueous ammonia and the neutralization product was lyophilized to give 45.7 g of CF3OCHFCF2OCH2CF2COONH4.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[O:18][C:19]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[C:20]=4[C:21]=3[CH3:22])=[CH:11][C:9]=2[CH:10]=1)=O)C.[C-]#[N:40].[Na+].C(Cl)Cl.CO>N>[CH3:22][C:21]1[C:20]2[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([NH2:40])=[O:3])=[CH:10][C:9]=2[CH:11]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(COc2ccc3oc(C(N)=O)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Yield: 100.9 %

Procedure:
The compound in Example 36 (12 mg, 0.022 mmol) and NaCN (1 mg) in saturated NH3 anhydrous MeOH solution was heated at 70° C. in a sealed flask overnight. Silica gel column chromatography (CH2Cl2/MeOH=20/1 to 10/1) gave desired product (10 mg, 88%) as a colorless solid. FAB-MS: m/z 486 (MH+); 1H-NMR (CD3OD): δ 2.01 (2H, m); 2.26 (3H, s), 2.80 (1H, t, J=6.9 Hz), 3.78 (2H, s), 4.10 (1H, t, J=5.9 Hz), 5.04 (2H, s), 5.80 (1H, brs), 6.50 (1H, brs), 6.52 (1H, d, J=7.6 Hz), 7.04-7.20 (5H, m), 7.33 (1H, d, J=8.9 Hz), 7.39 (1H, s), 8.41 (1H, brd, J=4.5 Hz), 8.49 (1H, brs).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([O:34]CC)=[O:33])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([OH:34])=[O:33])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Yield: 46.7 %

Procedure:
{1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.737 g, 1.42 mmol), potassium hydroxide (0.260 g, 4.63 mmol) in THF (9 mL) and water (9 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from acetonitrile and drying at 88° C. furnished the title compound as a white solid (0.326 g, 47%), mp: 206-207° C. Mass spectrum (+APCI, [M+H]+) m/z 492; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.3 (br s, 1H), 8.75 (s, 1H), 8.5 (s, 1H), 8.25 (s, 2H), 8.1 (s, 1H), 7.75 (s, 2H), 7.25-7.35 (m, 5H), and 5.6 ppm(s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].O>CN(C=O)C.CCOC(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]1[CH:18]([C:23](=[O:24])[NH2:25])[CH2:19][CH2:20][CH2:21][CH2:22][C:9]=1[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)C1CCCCc2c1c1c(O)cccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1cccc2c1c1c(n2Cc2ccccc2)CCCCC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A slurry of 5-benzyl-1-hydroxy-5,6,7,8,9,10-hexahydro-cyclohepta[b]indole-10-carboxylic acid amide (Part F; 275 mg; 0.822 mmol) and Cs2CO3 (670 mg; 2.06 mmol) in 8 mL of DMF was treated with methyl bromoacetate (0.100 mL; 1.07 mmol). After stirring overnight at ambient temperature, the reaction mixture was poured into water and EtOAc (20 mL each). The layers were separated, and the organic phase was washed with water (3×20 mL), dried over Na2SO4 and concentrated in vacuo. Purification by radial chromatography (CHCl3) afforded 205 mg (0.504 mmol; 61%) of the title ester as a white foam. ES-MS: 407 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:28](=[O:29])[CH2:27][O:26][CH2:25][CH2:24][O:23][CH3:22])[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: COCCOCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCOCC(=O)N[C@H](CC(=O)OC)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [0.75 g, Reference Example 7(c)], 2-(2-methoxyethoxy)acetic acid (0.3 ml), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.02 g), diisopropylethylamine (0.9 ml) and dimethylformamide (25 ml) was stirred at ambient temperature 2 hours. The reaction mixture was poured into water (150 ml) and the resultant solid collected. The resulting fawn solid (1.5 g) was dissolved in dichloromethane (15 ml) and the solution was treated with trifluoracetic acid (3 ml). After stirring at ambient temperature for 2 hours the reaction mixture was evaporated. The residue was treated with toluene (50 ml), concentrated to dryness and the resultant material treated with ethyl acetate (50 ml). The resultant suspension was treated with saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate, and then evaporated to give the title compound (0.5 g) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[CH2:25][CH2:24]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(CC(=O)O)cc2)cc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(-c2ccc(CC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)cc2)cc1
Reaction time: 12 h
Yield: 67 %

Procedure:
[4-(4-Acetylphenyl)phenyl]acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (2.5 g) were suspended in DMF (50 mL), and triethylamine (2.1 mL), EDC hydrochloride (1.6 g) and HOBt (1.3 g) were added-to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (2.5 g) as a white solid. melting point: 184° C.
Reaction SMILES: CNC1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:15])[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5](=[O:22])[C:4]=1[C:23]([NH:25]C(=O)OCC)=[S:24].[CH3:31][N:32]([CH3:35])[CH:33]=[O:34].C(N(CC)CC)C.Cl>O>[SH:24][C:23]1[C:4]2[C:5](=[O:22])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7](=[O:15])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:31]=2[N:32]([CH3:35])[C:33](=[O:34])[N:25]=1
Reactant: CCOC(=O)NC(=S)c1c(NC)n(-c2ccccc2)c(=O)n(-c2ccccc2)c1=O
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(=O)nc(S)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude ethyl (6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thiocarbonyl)-carbamate 23 (1.58 g) obtained in Step 4 was added N,N-dimethylformamide (8.4 ml), triethylamine (0.63 ml) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 min. Water (25 ml) was added, the mixture was stirred, 1N hydrochloric acid (5.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration, washed with water and dried to give crude 5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 24 (1.53 g, over weight) as yellow crystals, which were used for the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33].C(N(CC)CC)C>C(#N)C>[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][N:24]([CH2:28][C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[CH:32]=[O:33])[CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1
Reactant: O=Cc1cccc(CBr)c1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C=O)c4)CC3)C2)cs1

Procedure:
A solution of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.408 g), 3-(bromomethyl)benzaldehyde (0.205 g) and triethylamine (0.36 mL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed twice with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a yellow gum. Yield 0.325 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]3C=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8].ClC1C(F)=C(C=CC=1)C[NH:47]C([C@@H]1C[C@@H](F)CN1C(=O)CN1C2C(=CC(O)=CC=2)C(C(=O)C)=C1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].ClCC1N=CC=CN=1>CS(C)=O>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]3[N:47]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccn3)cc12
Agent: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ncccn3)cc12

Procedure:
The title compound was prepared according to procedure described for the preparation of Example 589 (2S,4R)-1-{2-[3-acetyl-5-(pyridin-2-ylmethoxy)-indol-1-yl]-acetyl}-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide from (2S,4R)-1-[2-(3-acetyl-5-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 579 (23.0 mg, 0.047 mmol), cesium carbonate (61 mg, 0.188 mmol) and 2-(chloromethyl)pyrimidine (0.012 mg, 0.070 mmol) in DMSO (2 mL). White solid. MS (LC/MS): 582/583 [M+H]+; tR (HPLC conditions k): 3.19 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][N:10]=[CH:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[C:4]([F:18])[CH:3]=1.N1CCCCC1.[CH3:25][CH:26](C(O)=O)[C:27](O)=[O:28].C(O)(=O)C>N1C=CC=CC=1>[F:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[N:9]1[C:27](=[O:28])[C:26]([CH3:25])=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:10]1
Reactant: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Reactant: CC(C(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
Under a stream of nitrogen gas, 0.295 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone), compound 3-1 was dissolved in 2.0 ml of pyridine. To this solution were added 0.113 ml of piperidine and 0.295 g of methylmalonic acid, and the mixture was heated to 70° C. and stirred for 2.5 hours. Then, 2.0 ml of acetic acid was added, and stirring was further continued at 130° C. for 7 hours. The reaction solution was left cooling to room temperature and concentrated under reduced pressure. The residue was diluted with 100 ml of diethyl ether. The diluted solution was washed twice with 20 ml of 3 N hydrochloric acid and once with 30 ml of saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 0.184 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one, compound 5-1.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([O:32]C)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[C:1]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)c1ccccc1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
In 50 ml of methanol, 4.4 g of methyl N-benzoylphenylalanyltyrosinate was dissolved. After addition of 23 ml of 1 N sodium hydroxide, the solution was stirred for one hour. The reaction mixture was neutralized with hydrochloric acid, concentrated and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 3.8 g of N-benzoylphenylalanyltyrosine with a mp. 191°-192° C, in a yield of 87%. Analysis, calculated for C25H24O5N2C 69.43, H 5.59, N 6.48, found C 68.98, H 5.72, N 6.37.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:20][CH3:21])[N:6]2[CH2:16][CH2:17][CH2:18][OH:19].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>CN1C(=O)CCC1>[CH3:29][S:30]([O:19][CH2:18][CH2:17][CH2:16][N:6]1[C:5]([O:20][CH3:21])=[N:4][C:3]2[C:7]1=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=2[NH2:1])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCO)c2n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCOS(C)(=O)=O)c2n1
Temperature: 5 °C

Procedure:
To a solution of 3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propan-1-ol (18.0 g, 61.0 mmol) in NMP (146 g) was added triethylamine (9.3 g, 91.4 mmol) and the mixture stirred at 5° C. Methanesulfonylchloride (9.1 g, 79.2 mmol) was added dropwise to the solution and stirred at 5° C. for 30 min. Water (144 g) was added, the mixture stirred for 1 hr and the suspension filtered to give the subtitle compound as water wet cake, which was directly used in the next reaction. Yield 42.4 g as a crude product.
Reaction SMILES: C[O-].[Na+].CO.[Br:6][C:7]1[S:11][C:10]([C:12](=O)[CH2:13][O:14][C:15]2[C:24]([I:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1.[Br-].[CH3:32]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Br:6][C:7]1[S:11][C:10]([C:12]([CH2:13][O:14][C:15]2[C:24]([I:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:29])[C:17]=3[CH:16]=2)=[CH2:32])=[CH:9][CH:8]=1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(OCC(=O)c3ccc(Br)s3)c(I)cc21
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 30% sodium methoxide in methanol (1.65 ml, 8.66 mmol) was added over 8 hours to a mixture of 5-bromo-2-[(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)acetyl]thiophene (4.3 g, 7.9 mmol) and methyltriphenylphosphine bromide (3.8 g, 10.7 mmol) in THF (45 ml). The mixture was stirred for 12 h at room temperature. The mixture was concentrated in a rotary evaporator under vacuum at 40° C. It was extracted with ethyl ether and washed with water. The organic phase was then dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[F:12][CH:13]([F:16])[CH2:14][O:15][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)O)cnc1F
Reactant: OCC(F)F
Product: Cc1cc(C(=O)O)cnc1OCC(F)F
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (1.02 g, an off-white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol (1.06 g, 12.9 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:12][N:11]=[N:10]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:12][N:11]=[N:10]1
Reactant: C1CCNC1
Reactant: Fc1cc(CNc2nnnn2-c2cccc(Cl)c2Cl)ccn1
Solvent: C1CCOC1
Product: Clc1cccc(-n2nnnc2NCc2ccnc(N3CCCC3)c2)c1Cl
Temperature: 60 °C
Reaction time: 48 h
Yield: 14.3 %

Procedure:
To an oven-dried N2-purged, 20-mL scintillation vial containing a magnetic stir bar was added the product of Example 143C (34 mg, 0.10 mmol) and anhydrous tetrahydrofuran (1 mL). Neat pyrrolidine (160 mL, 140 mg, 2.0 mmol) was added via syringe, and the vial was sealed. The reaction mixture was heated to 60° C. and the vial was shaken for 48 hours. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 25% ethyl acetate, 75% hexanes—product Rf˜0.2) to give 5.6 mg (14%) of the title compound as a white powder. MS (ESI+) m/z 390.1 (M+H)+; 1H NMR (DMSO-d6) δ 1.54 (br s, 4H), 3.46 (br s, 4H), 4.61 (d, J=6.1 Hz, 2H), 6.37 (br s, 1H), 6.46-6.48 (m, 1H), 7.39-7.47 (m, 2H), 7.72 (dd, J=7.6, 2.2 Hz, 1H), 8.08 (d, J=5.1 Hz, J=5.1 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(OC2C=CC=CC=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].[CH3:32]I>CS(C)=O>[C:17]1([O:8][C:7]([CH3:32])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: CI
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1ccccc1)(C(=O)c1ccccc1)c1ccccc1
Yield: 82.9 %

Procedure:
18 g benzoin-phenyl ether are reacted in 200 ml DMSO with 25 g of a 10% by weight aqueous sodium hydroxide solution and 11.8 g methyl iodide at 20°C. After working up and filtering through silica gel/benzene, there are obtained, besides 6.2 g of educt, 11.8 g α-methyl-benzoin phenyl ether of m.p. 91.5°C (ethanol).