Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:14](=O)[NH:13][C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:11][C:5]=1[NH:6]2.O=P(Cl)(Cl)[Cl:25].C(Cl)(Cl)Cl.CO.CCOCC>C(Cl)(Cl)Cl.CO>[Cl:25][C:14]1[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][C:5]=2[N:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Solvent: CCOCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Temperature: 115 °C
Yield: 70 %

Procedure:
To 9 (2 g, 6.274 mmol) was added 30 mL of POCl3 in a 250 mL round bottom flask. The reaction mixture was refluxed at 110-120° C. for 4 hours. After this the POCl3 was evaporated and the mixture was neutralized using NH4OH. The aqueous mixture was filtered (the ppt being the compound). The filtrate too contained some compound. Therefore it was extracted using chloroform and ethyl acetate. The ppt. obtained was dissolved in chloroform and methanol. Both the dissolved ppt. and extracted filtrate were dried using sodium sulfate overnight. To the solution was added silica and solvent was removed under reduced pressure to provide a silica gel plug. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform, 1% methanol in chloroform and 5% methanol in chloroform. Fractions containing the product 10 (TLC) were pooled and evaporated to give a solid. The overall yield was 70%. TLC Rf 0.86 (chloroform-methanol 5:1), m.p. 245.6-246.1° C., 1H NMR: δ 1.24 (s, 9H, pivaloyl); 7.37-7.63 (m, 3H, phenyl); 10.32 (s, 1H, 9-NH, exch); 12.96 (s, 1H, 2-NH, exch). Anal. Calculated (C15H14Cl2N4O. 0.25 (C2H5)2O): C, 54.02; H, 4.67; N, 15.74. Found: C, 54.14; H, 4.56; N, 15.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]([NH2:14])=O)[O:8][C:7]=2[CH:15]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]#[N:14])[O:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)OC(C(N)=O)=CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)OC(C#N)=CO2

Procedure:
1.76 g (8.52 mmol) of the amide obtained in Step A and 4.62 g (30 mmol) of phosphorus oxychloride are dissolved in 40 ml of anhydrous pyridine. The reaction medium is then heated at reflux for 1 hour under an inert atmosphere; the solvent is then evaporated in vacuo. The residue obtained is slowly hydrolysed with a saturated solution of sodium hydrogen carbonate; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrate in vacuo. The title nitrile is obtained pure in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 10/60).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][C:8]1([OH:25])[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH:12]([N:10]1[CH2:9][C:8]([CH2:7][NH:6][C:3](=[O:4])[CH2:2][Cl:1])([OH:25])[CH2:11]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.846 mL) was added dropwise over 30 minutes to a vigorously stirred mixture of 3-(aminomethyl)-1-benzhydrylazetidin-3-ol (example 33, step c) (2.1 g) in ethyl acetate (100 mL) and potassium carbonate (3.03 g) in water (100 mL) at 0° C. The mixture was stirred for a further 30 minutes at 0° C. and then extracted with ethyl acetate, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.6 g.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])[N:8]=2)[CH2:2][CH2:3]1
Reactant: CNOC
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1coc(C2CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
To a solution of 2-cyclopropyloxazole-4-carboxylic acid (0.1 g, 0.653 mmol) in dry dichloromethane (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.25 g, 1.3 mmol) and hydroxybenzotriazole (0.175 g, 1.3 mmol) at 0° C. portion wise. N,O-dimethylhydroxylamine (64 mg, 0.653 mmol) was then added followed by triethylamine (0.26 mL, 1.95 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with ethyl acetate and washed with water and brine solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by preparative TLC (25% ethyl acetate in petroleum ether) to afford 2-cyclopropyl-N-methoxy-N-methyloxazole-4-carboxamide (100 mg, 83%). MS (ES+) (M+H) 197.25; LCMS retention time: 2.82 min (Method S).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][S:5][CH3:6].C1C(O)=CC=CC=1C.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:4][S:5][CH3:6]
Reactant: CSC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1cccc(F)c1
Solvent: Cc1cccc(O)c1
Product: CSC[C@@H](COc1cccc(F)c1)NC(=O)OC(C)(C)C

Procedure:
By the operation similar to that in Step 2 of Example 15 except that t-butyl (1R)-2-hydroxy-1-[(methylsulfanyl)methyl]ethylcarbamate (1 g) obtained in Step 1 was used as a starting material and m-cresol was changed to 3-fluorophenol, the title compound (300 mg) was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO.O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/CCCO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.5 %

Procedure:
To a solution of (E)-ethyl 6-(tert-butyldimethylsilyloxy)hex-2-enoate (7) (27.2 g, 0.1 mol) in THF and MeOH was added LiOH (6.6 g, 0.3 mol) in 50 mL H2O, the mixture was stirred at RT for 5 hours. After removal of the solvent, the residue was poured into 3N HCl to the pH value was adjusted to 4-5, then extracted with DCM (250 mL×2), and the organic layers were washed with water (250 mL×3) and brine (3×200 mL), dried over Na2SO4 and concentrated to give the desired compound of (E)-6-(tert-butyldimethylsilyloxy)hex-2-enoic acid (8) (12.1 g, 50%) as a yellow oil after purification by column chromatography on silica gel (eluent: PE:EA=5:1). 1H NMR (300 MHz, CDCl3): δ 0.0021 (S, 6H), 0.0857 (S, 9H), 1.600 (m, 2H), 1.197 (t, 3H), 2.240 (q, 2H), 3.586 (t, 2H), 5.832 (d, J=15.6 Hz, 1H), 6.936-6.885 (m, 1H); LC-MS found 245 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30](=[O:37])[O:31][C@H:32]1[CH2:36][CH2:35][O:34][CH2:33]1)[C@H:9]([OH:28])[CH2:10][N:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]=[P:39](Cl)(Cl)Cl.Cl.[OH2:44].[OH2:45].C([O-])(=O)C.[Ca+2:50].C([O-])(=O)C>O.C(C(C)=O)C(C)C.N1C=CC=CC=1>[CH3:26][CH:25]([CH2:24][N:11]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:10][C@@H:9]([O:28][P:39]([O-:38])([O-:45])=[O:44])[C@@H:8]([NH:29][C:30]([O:31][C@@H:32]1[CH2:33][O:34][CH2:35][CH2:36]1)=[O:37])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:27].[Ca+2:50]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: CC(=O)CC(C)C
Product: CC(C)CN(C[C@@H](OP(=O)([O-])[O-])[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc(N)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
Mixture of 100 g (0.186 mol) (3S)-tetrahydro-3-furyl N-[(1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitrobenzene sulphonamido)propyl]carbamate (IV) and 200 ml pyridine was cooled to 0-10° C. and 70.0 g (0.456 mol) of POCl3 was added and stirred at ambient temperature for 4 hours, 400 ml methyl isobutyl ketone was added, cooled and 1:1 conc. HCl-water was added. Mixture was heated to 50° C. for 1 hour, cooled to 25-30° C. Organic layer was separated, washed with water and partially concentrated; 500 ml water and 31.5 g sodium bicarbonate was added and stirred. The organic layer was separated and 100 ml ethylacetate, 400 ml methanol and 5.0 g Pd/C was added. The reaction mass was stirred under hydrogen pressure for 4 hours at 30° C. The mixture was filtered, catalyst washed with methanol. The filtrate was heated to 50° C. and 33.0 g (0.186 mol) calcium acetate monohydrate in 100 ml water was added and stirred for 30 minutes. Cooled to 30° C. and stirred. Solid was filtered, washed with 1:1 mixture of methanol-water and dried to obtain crude fosamprenavir calcium.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH2:25]([NH2:28])[C:26]#[CH:27].[I-].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:28][CH2:25][C:26]#[CH:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2
Reactant: C#CCN
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 19, 8-fluoro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-fluoro-1-[[(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 22 8-(Trifluoromethyl)-1-[[(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][C:16](=[O:17])[O:15]1.N1CCCC1C(O)=O.[CH3:31][S:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[CH:39]2>C(#N)C>[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH:18]([CH:11]([C:39]2[C:38]3[C:42](=[C:34]([CH2:33][S:32][CH3:31])[CH:35]=[CH:36][CH:37]=3)[NH:41][CH:40]=2)[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:16](=[O:17])[O:15]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CSCc1cccc2cc[nH]c12
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc4ccccc4c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
694 mg (4.44 mmol) of naphthalene-2-carbaldehyde, 640 mg (4.44 mmol) of Meldrum's acid and 24 mg (0.21 mmol) of D,L-proline were added to a solution of 750 mg (4.23 mmol) of the compound from Example 8A in 35 ml of acetonitrile. The reaction mixture was stirred at RT overnight. Then a further 35 ml of acetonitrile were added, and the mixture was stirred at RT for two days. It was concentrated, the residue was stirred in water, and the precipitate was filtered off with suction and dried in vacuo at 50° C. for 1 h. The crude product was stirred in acetonitrile, and the precipitate was filtered off with suction and dried under high vacuum to result in 882 mg (45% of theory) of the title compound which were reacted without further purification.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O[C@H]1CC[C@H](Nc2ncc3ccc(F)cc3n2)CC1
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1

Procedure:
To a solution of trans-4-[(7-fluoroquinazolin-2-yl)amino]cyclohexanol (800 mg, 3.06 mmol) in MeOH (25 mL) was added sodium methoxide powder (1.65 g, 30.62 mmol) and the solution heated to reflux for 16 hours under nitrogen. The mix was cooled and the solvents evaporated. The residue was diluted with water (100 mL), brine (50 mL) and extracted with DCM (4×150 mL), and the combined organics were dried over MgSO4, filtered and stripped. The residue was purified via Biotage flash chromatography (40M) eluting with 2-6% MeOH/DCM over 1300 mL to yield the title compound as an off white solid, 830 mg, 99%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.86 (1H, s) 7.63 (1H, d, J=8.84 Hz) 7.08 (1H, d, J=6.57 Hz) 6.78 (2H, dd, J=8.72, 2.15 Hz) 4.55 (1H, d, J=4.55 Hz) 3.86 (3H, s) 3.71-3.84 (1H, m) 3.35-3.50 (1H, m) 1.76-2.02 (4H, m) 1.14-1.42 (4H, m); MS (API+) for C15H19N3O2 m/z 274.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[I:12][CH3:13]>CC(C)=O>[I-:12].[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([CH3:13])=[CH:7]2
Reactant: CI
Reactant: Nc1cccc2cnccc12
Solvent: CC(C)=O
Product: C[n+]1ccc2c(N)cccc2c1
Product: [I-]
Reaction time: 2 h

Procedure:
To a solution of 5-aminoisoquinoline (14.4 g, 100 mmol) in acetone (300 ml) was added iodomethane (14.4 ml). The solution was briefly stirred and then allowed to stand for 2 h. The yellow precipitate was then filtered, washed with acetone and dried to afford the title compound as a yellow solid (18.8 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:7]=1.[C-:18]#[N:19].[Na+]>C(O)C>[C:18]([C:7]1[N:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:5](=[O:16])[NH:4][C:3](=[O:17])[CH:2]=1)#[N:19]
Reactant: Cc1ccccc1Nn1cc(Br)c(=O)[nH]c1=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1Nn1c(C#N)cc(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
To 1.35 mmol of 5-bromo-1-(2-methylanilino)-2,4-pyrimidinedione in 5 ml of 50% aqueous ethanol is added 1.41 mmol of sodium cyanide. The mixture is heated to reflux for 4 hours, after which it is cooled to RT, filtered and recrystallized from ethanol to give 6-cyano-1-(2-methylanilino)-2,4-pyrimidinedione.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[C:6](O)([CH3:9])[CH:7]=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[C:6](/[CH3:9])=[CH:7]/[CH2:8][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH3:2]
Reactant: C=CC(C)(O)C(NC=O)C(=O)OCC
Reactant: CCOP(OCC)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(NC=O)/C(C)=C/CP(=O)(OCC)OCC

Procedure:
The starting material is manufactured as follows: 5-Methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester, b.p. 65°-75° (13 Pa) is obtained by reaction of isocyanoacetic acid ethyl ester with methyl vinyl ketone in a manner analogous to that described in Example 30. By hydrolysis of the 5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 1, 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-3 methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester in the form of a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](OC(C)(C)C)=[O:19])=[N:9][N:10]([CH3:12])[CH:11]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1)=C=O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:41][CH:40]=3)=[O:19])=[N:9][N:10]([CH3:12])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cn1cc(Cc2ccc(Cl)cc2)c([C@H]2CCCN2C(=O)OC(C)(C)C)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cc(Cc2ccc(Cl)cc2)c([C@H]2CCCN2C(=O)Nc2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4-chlorobenzyl)-1-methyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (39 mg, 0.1 mmol) was dissolved in 4M HCl in 1,4-dioxane (2 mL), stirred for 2 hr and then concentrated in vacuo. The resulting residue was then suspended in dichloromethane (2 mL) and DIEA (34 μL, 0.2 mmol) before 1-isocyanato-4-(trifluoromethyl)benzene (28 μL, 0.15 mmol) was added. After 16 h of stirring, the reaction mixture was concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-2-(4-(4-chlorobenzyl)-1-methyl-1H-pyrazol-3-yl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamide (12 mg, 26%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH2:3][CH2:2]1.C[N:16](C)[CH:17]=[O:18].COC(OC)N(C)C.[C:28]([CH2:30][C:31](N)=O)#[N:29]>C(OCC)C.O>[C:28]([C:30]1[C:17](=[O:18])[NH:16][C:11]([C:12]2[CH:13]=[CH:14][CH:9]=[CH:7][C:6]=2[O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:10][CH:31]=1)#[N:29]
Reactant: CN(C)C=O
Reactant: O=C(COCC1CC1)c1ccccc1
Reactant: N#CCC(N)=O
Agent: COC(OC)N(C)C
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(-c2ccccc2OCC2CC2)[nH]c1=O
Temperature: 140 °C

Procedure:
A stirred mixture of 2-(cyclopropylmethoxy)-acetophenone (15 g), dimethylformamide (45 ml) and dimethylformamide dimethylacetal (12.75 ml) was heated at 140° C. for 25 hours, then cyanoacetamide (8.29 g) was added and the mixture was heated for a further 18 hours. The cool mixture was added to water (200 ml) and diethyl ether (100 ml) and the solid was collected by filtration, washed with water then with ethanol. Digestion with acetonitrile give the title compound, 6.1 g, m.p. 250°-252° C. (from acetonitrile).
Reaction SMILES: [NH2:1][C@H:2](C(N)=O)[CH2:3][C:4]1C=CC(O)=C[CH:5]=1.Cl.C([N:17]([CH2:20]C)[CH2:18][CH3:19])C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>>[N:17]1[C:18]2[CH:19]=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH:20]=1
Reactant: CCN(CC)CC
Reactant: NC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.1 %

Procedure:
To a 0° C. crude solution of compound 2 (4.1 g, 15.34 mmol) and triethylamine (6.4 mL, 46.02 mmol) in dicholoromethane (200 mL) was added pentafluorophenyl trifluoroacetate (6.35 mL, 36.82 mmol) via syringe over 3 min. After another 5 min, the ice bath was removed and the reaction mixture stirred while warming to room temperature for another 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue purified by flash chromatography (silica gel, hexanes/ethyl acetate=1:0, 50:1) to give compound 3 (3.5 g, 50% yield).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[C:10]([OH:12])=O.[CH3:28]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[OH:50][C@@H:51]([CH2:81]O)[CH2:52][N:53]1[CH:57]=[CH:56][C:55]([NH:58]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:54]1>ClCCl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[C:10]([NH:58][C:55]1[CH:56]=[CH:57][N:53]([CH2:52][C:51]([OH:50])([CH3:81])[CH3:28])[N:54]=1)=[O:12]
Reactant: O=C(O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CC3CCC2C3)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
In a round bottom flask under argon was placed 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (73 mg, 0.19 mmol) in dichloromethane (5 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (38 μL, 0.21 mmol) and 1-hydoxybenzotriazole (27 mg, 0.20 mmol) and was stirred at 25° C. for 2 h. After this time period, 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 36 mg, 0.23 mmol) was added and stirred for 16 h at 25° C. After this time, the mixture was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL), a saturated aqueous sodium bicarbonate solution (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 40% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (40 mg, 40%) as a light orange solid as a mixture of diastereomers: HR-ES-MS m/z calculated for C27H32N4O4F2 [M+H]+ 515.2465, observed 515.2464; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.10-2.10 (m, 11H), 2.15 (br. s., 2H), 3.89 (s, 2H), 4.28 (d, J=19.3 Hz, 1H), 4.57-4.65 (m, 1H), 4.67 (s, 1H), 472-486 (2×m, 1H), 5.04 (s, 1H), 6.41-6.49 (m, 1H), 7.29-7.51 (m, 3H), 7.54 (s, 1H), 10.81 (2×s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([Br:32])[CH:31]=1)[NH:28][C:27](=[O:33])[CH2:26]2>>[Br:32][C:30]1[CH:31]=[C:23]([F:22])[CH:24]=[C:25]2[C:29]=1[NH:28][C:27](=[O:33])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 87 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-7-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (57 mg, 87.0%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.O>N1CCCCC1.CC(O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: O
Product: O=C1Nc2cccc(Br)c2/C1=C/c1ccc[nH]1
Temperature: 85 °C

Procedure:
A mixture of 4-bromo-1,3-dihydro-2H-indol-2-one (0.2 g, 0.94 mmol) (see Kosuge et al., supra), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85° C. for 2 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%).