Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=O.C(Cl)(Cl)Cl.[CH3:9][CH2:10][C@:11]1([OH:65])[C@H:20]([OH:21])[C:19]2[C:14](=[C:15](O)[C:16]3[C:31](=[O:32])[C:30]4[C:25](=[C:26](O)[CH:27]=[CH:28][C:29]=4[OH:33])[C:23](=[O:24])[C:17]=3[C:18]=2[OH:22])[C@@H:13]([O:36][C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)C(=O)CC4)[C@@H](O)C3)[C@@H](N(C)C)C2)[CH2:12]1>CO>[CH3:9][CH2:10][C@:11]1([OH:65])[C@H:20]([OH:21])[C:19]2[C:18]([OH:22])=[C:17]3[C:23](=[O:24])[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([OH:33])[C:30]=4[C:31](=[O:32])[C:16]3=[CH:15][C:14]=2[C@@H:13]([OH:36])[CH2:12]1
Reactant: CC[C@@]1(O)C[C@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]3C[C@H](O)[C@H](O[C@H]4CCC(=O)[C@H](C)O4)[C@H](C)O3)[C@H](C)O2)c2c(O)c3c(c(O)c2[C@H]1O)C(=O)c1c(O)ccc(O)c1C3=O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)=O
Product: CC[C@@]1(O)C[C@H](O)c2cc3c(c(O)c2[C@H]1O)C(=O)c1cccc(O)c1C3=O

Procedure:
The resulting broth (about 12 liters) was similarly subjected to acid hydrolysis, acetone extraction from the mycelia and chloroform extraction, and finally 9.8 g of a crude powder containing β-isorhodomycinone. The whole amount of the crude powder was dissolved in 100 ml of methanol and the insoluble materials were centrifuged off. After concentration, the soluble fraction was applied on a silica-gel column (diameter: 78 mm) packed with 300 g of the above-mentioned silica-gel C-200 in chloroform, and eluted with 500 ml of chloroform, 100 ml of a mixture solution of chloroform/methanol (500/1), 3400 ml of the mixture solution (400/1) and 1000 ml of the mixture solution (300/1) in this order. β-isorhodomycinone was eluted with a mixture of chloroform/methanol (400/1). The β-isorhodomycinone-containing fractions were collected and evaporated to dryness followed by washing with ether The yield of β-isorhodomycinone was 0.62 g. The identification of this compound was carried out by means of 1H--M=NMR and 13C--NMR spectra and UV and FD mass spectra thereof, referring chemical data described in the literature (Chem. Ber., Vol. 98, page 3145, 1965).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1>CO.O>[OH:17][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: CC(=O)c1ccc(C2=CCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(C2=CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7 g of sodium borohydride in 300 ml of methanol and 80 ml of water is cooled to 5°C and 50 g of p-(1-cyclohexenyl)-acetophenone are stirred in portionwise. The batch is stirred on for 2 hours at room temperature, the solution is concentrated to half its volume in a rotary evaporator, mixed with 1 litre of water and extracted with 3 × 500 ml of methylenechloride. The methylenechloride residue is recrystallized from petroleum ether and furnishes 1-hydroxy-1-[p-(1-cyclohexenyl)-phenyl]-ethane melting at 60°-62°C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:12].[ClH:30]>ClCCl.CCOCC>[ClH:30].[ClH:30].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][NH:20][CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 1B (8.5 g) in dichloromethane (80 mL) was added 2N HCl in ether (80 mL). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 2-chloro-1H-benzo[d]imidazole (10 g), 4-bromophenol (56.7 g) and TEA (45.5 mL) was stirred at 150° C. overnight. The mixture was quenched with water at room temperature and extracted with AcOEt. The extract was washed with 1 M NaOH aqueous solution, dried over Na2SO4, and concentrated under reduced pressure. The precipitate was crystallized from AcOEt/hexane to give the title compound (11.9 g).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:48]=[CH:49][CH:50]=1)[C:34]([NH:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][N:43]([CH3:47])[CH2:44]2)=[CH:39][CH:38]=1)=[O:35]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH:29][CH2:30][C:31]1[CH:50]=[CH:49][CH:48]=[C:33]([C:34](=[O:35])[NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][N:43]([CH3:47])[CH2:44]3)=[CH:39][CH:38]=2)[CH:32]=1)=[O:9]
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Reactant: COc1ccc(C(=O)O)cc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(C)CC4)c2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-chloro-4-methoxybenzoic acid dihydrochloride (29 mg, 150 mmol), EDC (30 mg, 150 mmol), HOBt (22 mg, 150 mmol), and TEA (0.057 mL, 408 mmol) in anhydrous DMF (5 mL) was stirred at room temperature for 30 min. To this was added 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide. (50 mg, 136 mmol) and the solution stirred at room temperature for 24 h. The reaction was diluted EtOAc (100 mL) and quenched with sat. NH4Cl (100 mL). The organic fraction was dried (Na2SO4). The residue was purified by flash chromatography using a methanol/methylene chloride gradient to provide 31 mg of 3-chloro-4-methoxy-N-[3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray, 464 (M+H).
Reaction SMILES: O[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)([Cl:15])=O.CN(C)C=O.Cl>C1(C)C=CC=CC=1.O.O1CCOCC1>[Cl:15][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](Cl)Cc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
1,4-Dioxane (200 ml) was added to 20.4 g (122.8 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S)), 43.8 g (368.4 mmol) of thionyl chloride was added dropwise, and the mixture was stirred at 40° C. for 2 hours. To that solution was added 1.8 g (24.6 mmol) of dimethylformamide, and the mixture was stirred at 40° C. for 6 hours. This reaction mixture was cooled and, while maintaining the temperature at 20° C., 70 ml of water was added dropwise and, after about an hour of stirring, the mixture was extracted with 200 ml of toluene. Water (70 ml) was added to the organic phase and, after pH adjustment to 9.0 with a 30% aqueous solution of sodium hydroxide, the organic phase was removed by phase separation. To the aqueous phase obtained was added 200 ml of toluene, the pH was adjusted to 1.0 with 35% aqueous hydrochloric acid, and the aqueous phase was removed by phase separation. The toluene was distilled off under reduced pressure from the thus-obtained toluene phase to give 19.1 g (103.3 mmol, yield 84%) of (2R)-2-chloro-3-phenylpropionic acid. The optical purity of the product as determined by the same method as in Example 12 was 99.7% ee (R) (rate of configurational inversion 99.7%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:21])=[O:2]
Reactant: COC(=O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1 g (3.07 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 20 ml of dioxan. 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 50° C. for 3 h, and stirred at RT for 16 h. 5 ml water was added, followed by concentrated hydrochloric acid to give a pH of 1 to 2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([NH:9][CH2:10][C:11](=[O:17])[NH:12]2)=[CH:7][CH:6]=1.OO.C(O)(=O)C>O>[CH3:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([N:9]=[CH:10][C:11](=[O:17])[NH:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1OC)NC(=O)CN2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)[nH]c2c1OC
Yield: 65.8 %

Procedure:
Sodium hydroxide (0.18 g, 4.42 mmol, 2.0 eq) is added at room temperature to a stirred solution of 7,8-dimethoxy-3,4-dihydro-1H-quinoxalin-2-one (0.46 g, 2.21 mmol, 1.0 eq) in water (5 mL), followed by 3% hydrogen peroxide (5 mL, 14.69 mmol, 6.65 eq). The reaction mixture is heated under reflux for 3 hours, then acidified with acetic acid to pH 5. The precipitate is collected by filtration, dried under vacuum to afford 7,8-dimethoxy-quinoxalin-2-one as a brown solid (0.3 g, 65% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:7][N:6]=[N:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:7][N:6]=[N:5][CH:4]=1)=[O:22]
Reactant: CS(=O)(=O)c1cc(Cl)cc(C(=O)O)c1
Reactant: CNc1cnncc1-c1ccccc1C
Product: Cc1ccccc1-c1cnncc1N(C)C(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Yield: 44 %

Procedure:
The title compound was prepared in analogy to example 1, from methyl-(5-o-tolyl-pyridazin-4-yl)-amine and 3-chloro-5-methanesulfonyl-benzoic acid. A second purification step using preparative HPLC (Gemini NX column) with a gradient of acetonitrile:water with 0.05% formic acid (80:20 to 98:2) gave the desired compound as a colorless solid (44%). MS (ESI+): m/z=416.083 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[N:20][CH:21]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cncc(Cl)c2)c(-c2ccccc2)n1
Yield: 10.4 %

Procedure:
6-(5-Chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 5-chloropyridine-3-ylboronic acid (0.20 g, 1.30 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][CH2:17][C@H:18]4[CH:22]([CH2:23][OH:24])[O:21][C@@H](C5C=CC=CC=5)[O:19]4)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:31]3[C:36]([F:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=3[F:42])[C:7]2=[O:43])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][CH2:17][C@H:18]([OH:19])[C@@H:22]([OH:21])[CH2:23][OH:24])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:31]3[C:36]([F:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=3[F:42])[C:7]2=[O:43])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(NC[C@@H]4O[C@H](c5ccccc5)OC4CO)nc3N(C3CCCC3)C2=O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC[C@H](O)[C@@H](O)CO)nc3N(C3CCCC3)C2=O)c1F
Temperature: 25 °C
Reaction time: 9 h
Yield: 56.8 %

Procedure:
(S,S)-1-Cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-[(5-hydroxymethyl-2-phenyl-[1,3]dioxolan-4-ylmethyl)-amino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.57 g, 0.95 mmol) was dissolved in 90 mL methanol containing 12 mL 10% HCl acid. The mixture was stirred at room temperature for 9 hours. Adjusted pH=12 by adding 1 M NaOH. Stripped the solvent. The residue was dissolved in methanol. Insoluble NaCl was removed by filtration. The filtrate was evaporated to dryness and the residue was purified by column chromatography (5:1 dichloromethane/methanol) to give 0.275 g (57%) (S,S)-1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-(2,3,4-trihydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as white solid: mp=160° C (dec.); MS (APCI) m/z 510.1, 511.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1>[NH4+]=S>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([NH2:9])=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(O)n1
Product: Nc1nc(N)c(N)c(O)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A suspension of the compound of example 99 (15 g, 96.7 mmoles) in an ammonium sulfide solution (20% in water, 200 ml) was stirred overnight at 50° C. The reaction mixture was cooled down in the refrigerator and the precipitate was filtered off, providing the title compound as a yellow powder (11.33 g, yield: 83%). The spectral data are identical with literature data (Landauer et al. cited supra).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[CH:13]([O-])([O-])[O:14][CH2:15][CH3:16].C(OC(=O)C)(=O)C>>[CH2:15]([O:14][CH:13]=[C:4]([C:5](=[O:9])[CH:6]([CH3:8])[CH3:7])[C:3](=[O:10])[C:2]([F:11])([F:12])[F:1])[CH3:16]
Reactant: CCOC([O-])[O-]
Reactant: CC(C)C(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C(C)C)C(=O)C(F)(F)F
Yield: 52.4 %

Procedure:
A mixture comprising 213 g (1.17 mol) of 1,1,1-trifluoro-5-methyl-2,4-hexanedione, 242 g (1.64 mol) of ethyl orthoformate and 166 g (1.63 mol) of acetic anhydride, was heated and refluxed for 6 hours. The solvent was distilled off under reduced pressure to obtain 146 g (yield: 67%) of 3-ethoxymethylene-1,1,1-trifluoro-5-methyl-2,4-hexanedione.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Br:7].[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: BrC1=C(Br)CCC1
Product: BrC1=C(c2ccccc2)CCC1
Yield: 40.8 %

Procedure:
Following a synthetic procedure which was similar to the one outlined in Step 2 of Example 1, 4.40 g (19.4 mmol) of 1,2-dibromocyclopentene was reacted with 2.0 g (17.7 mmol) of phenylboronic acid (Aldrich). Purification by silica gel chromatography (Waters Prep-500) with hexane gave 1.61 g (42%) of 1-bromo-2-phenylcyclopentene as an oil: NMR (CDCl3) d 2.01-2.10 (m, 2H) , 2.74-2.82 (m, 2H) , 2.82-2.90 (m, 2H) , 7.27-7.33 (m, 1H) , 7.33-7.41 (m, 2H) , 7.57-7.63 (m, 2H) .
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][CH2:15]Br>CN(C)C=O>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: COCCCBr
Reactant: Oc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 22 g of pyrocatechol in 80 ml of dimethylformamide is added at room temperature, within a period of 30 minutes, to a suspension of 8.4 g of NaH (60% dispersion in mineral oil) in 300 ml of dimethylformamide, and the mixture is stirred for one hour at room temperature. A solution of 49.3 g of 3-bromopropyl methyl ether in 80 ml of dimethylformamide is then added dropwise. The reaction mixture is stirred for a further 80 hours at room temperature and is then concentrated by evaporation under reduced pressure at a bath temperature of 30° C. The residue is partitioned between diethyl ether and water. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by FC (100 g of silica gel, hexane/dichloromethane=5:95), yielding the title compound: Rf (dichloromethane/diethyl ether=96:4)=0.35; HPLC Rt =11.2 minutes.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][CH2:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][CH:37]([CH2:36][CH2:35][OH:34])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OCCC1CCNCC1
Agent: OC1CCNC1
Product: OCCC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 4-(2′-hydroxyethyl)piperidine. A yellow solid 129 was obtained (0.037 g, 73%). 1H NMR (CDCl3, 400 MHz) δ 1.35–1.44 (m, 2H), 1.55–1.60 (m, 2H), 1.84–1.93 (m, 1H), 1.97–2.03 (m, 2H), 3.22–3.30 (m, 2H), 3.74 (t, J=6.2 Hz, 2H), 4.28–4.34 (m, 4H), 4.36–4.42 (m, 2H), 6.91 (d, J=6.6 Hz, 1H), 6.93–6.96 (m, 2H), 7.05 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 8.24 (d, J=6.6 Hz, 1H); MS (APCI) m/z 517 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH3:17]I.O>CN(C)C=O>[CH3:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:13]#[N:14])[CH2:11][CH2:12]2)=[CH:2]1
Reactant: N#CC1(c2c[nH]c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2(C#N)CC2)c2ccccc21
Reaction time: 0.08 h

Procedure:
1-(1H-indole-3-yl)cyclopropanecarbonitrile (183 mg) was dissolved in N,N-dimethylformamide (2 mL) and sodium hydride (60% in oil, 45 mg) was added under ice cooling, followed by stirring for 5 minutes. To the reaction solution, methyl iodide (0.07 mL) was added, followed by stirring at room temperature for one hour. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (parallel separation purification system) to obtain the titled compound having the following physical properties (196 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:48])[C@@H:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=4)=[O:38])=[C:32]([F:47])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:48])[C@@H:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=4)=[O:38])=[C:32]([F:47])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@H](CCC(=O)O)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate (30 mg, 0.046 mmol) in 5 ml of methylene chloride was added 2 ml of TFA. The mixture was stirred at room temperature for 1 hour, and evaporated to dryness. The residue was dissolved in MeOH (3 ml), which was added dropwise into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid as white solid. Yield: 20 mg, 74%.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH2:8][CH:9]2[C:13](=[O:14])[N:12]([CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=O)[C:11](=[O:22])[NH:10]2)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:53]([O:60][NH2:61])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Cl>CN(C=O)C>[CH2:53]([O:60][NH:61][C:16](=[O:18])[CH:15]([N:12]1[C:13](=[O:14])[CH:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:24][CH:23]=2)[NH:10][C:11]1=[O:22])[CH:19]([CH3:21])[CH3:20])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of the compound obtained in step f above (409 mg, 1.020 mmol), NMM (0.4 mL, 3.58 mmol) and HOBt (234 mg, 1.734 mmol) in DMF (10 mL) at −15° C. was added EDCI (214 mg, 1.123 mmol). After the reaction was stirred for 30 minutes, it was allowed to warm to room temperature, BnONH2HCl (179 mg, 1.123 mmol) was then added and the reaction was stirred overnight. The solvent was removed under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the crude product was purified by silica gel column chromatography which gave the title compound as an oil (426 mg, 83% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=O.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:18]([C:3]1[C:2](=[O:1])[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=1)=[O:20]
Reactant: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Reactant: CN
Product: CCCOc1ccccc1-c1ncc(C(=O)NC)c(=O)[nH]1

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(2-propoxyphenyl)pyrimidine-5-carboxylate (1 g, U.S. Pat. No. 4,031,093) was treated with methylamine (33% in industrial methylated spirit, 50 ml) in a pressure vessel (379 kPa) at 120° C. for six hours and then allowed to cool. Solvent was removed under reduced pressure to afford a white solid which was triturated with ether, 0.88 g, m.p. 190°-191° C. This solid together with another sample prepared similarly (0.32 g) was recrystallised from ethanol to afford the title compound, 0.98 g, m.p. 192°-193° C.