Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[F:32])[OH:6])[CH3:2].I[CH3:35]>>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:29])([CH3:31])[CH3:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]=1[F:32])[O:6][CH3:35])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Reactant: CI
Product: CCOC(=O)C(OC)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F

Procedure:
(RS)-[3-(tert-Butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-methoxy-acetic acid ethyl ester was prepared in analogy to example 173 from (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester and iodomethane. Yellowish oil. MS 484.2 (4, [M+]+); 427.1 (29, [M−tBu]+); 411.2 (14, [M−COOEt]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)cc2)N1
Reaction time: 22 h
Yield: 78.5 %

Procedure:
To a stirred solution of racemic tryptophan methyl ester (3 g ) and 4-hydroxybenzaldehyde (1.84 g) in anhydrous dichloromethane (50 mL) cooled at 0° C. was added dropwise trifluoroacetic acid (1.27 mL) and the solution was allowed to react at ambient temperature. After 22 hours, the solution was washed with a saturated solution of NaHCO3, then with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography eluting with ethyl acetate to give the title compound (3.48 g) as an off-white solid m.p.:233-235° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH2:31]1[O:39][C:38]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=2[O:32]1>>[O:32]1[C:33]2[CH:34]=[CH:35][C:36]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)[NH:20][C:19]4=[O:29])=[CH:37][C:38]=2[O:39][CH2:31]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccc5c(c4)OCO5)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3,4-methylenedioxyphenylboronic acid in step C. (ESI): mass calcd. for C19H12N4O5, 376.1; m/z found, 377.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.96 (br s, 2H), 8.97 (s, 1H), 8.29-8.25 (m, 2H), 8.11 (dd, J=8.5, 2.2 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.38 (d, J=1.7 Hz, 1H), 7.27 (dd, J=8.1, 1.8 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.10 (s, 2H).
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]([N+:18]([O-:20])=[O:19])([CH3:17])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][CH:10]=1.[OH-].[K+]>CN(C=O)C>[CH3:1][N:9]1[CH:10]=[C:6]([CH2:5][C:4]([CH3:3])([N+:18]([O-:20])=[O:19])[CH3:17])[N:7]=[C:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: CC(C)(Cc1c[nH]c(-c2ccccc2)n1)[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(CC(C)(C)[N+](=O)[O-])nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
Methyliodide (1.4 g) was added dropwise to a mixture of 4-(2-methyl-2-nitro-propyl)-2-phenyl-1H-imidazole (1.6 g) and fine powdered potassium hydroxide (2.19 g) in DMF (20 ml) at 20-25° C. The reaction mixture was stirred at RT for 4 h, quenched with ice/water and extracted with ethyl acetate. The organic phase washed with water and brine, dried over magnesium sulphate and concentrated. The residue was purified on silica gel using methylene chloride/methanol 2 and 5% as eluent to obtain the desired product (1.40 g) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:18]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:21]([O:20][C:18](=[O:19])[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)[CH:27]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)Nc1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-(N-Boc-amino)phenylboronic acid gives “A82”; method 1: HPLC/MS: 1.56 min, [M+H]=406.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N.[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31](O)[CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(Cl)(Cl)Cl>[N+:35]([C:34]1[CH:29]=[CH:30][C:31]([O:19][C:18](=[O:20])[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:32][CH:33]=1)([O-:37])=[O:36]
Reactant: O=C(O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Yield: 83.3 %

Procedure:
N,N-dibenzyl-L-phenylalanine hydrochloride (7.64 g, 20.0 mmol) was added to 50 ml of chloroform, and 20.0 ml of 10% aqueous ammonia were added dropwise to the suspension for neutralization. The organic layer was separated, washed with 20 ml of water, then dried over magnesium sulfate, and filtered. The filtrate was concentrated, the resulting residue was dissolved in 50 ml of chloroform, and 2.89 g (20.4 mmol) of p-nitrophenol and 4.13 g (20.0 mmol) of N,N′-dicyclohexylcarbodiimide were added to the solution in this order while being cooled with ice. The mixture was reacted overnight. To the reaction solution were added 30 ml of ethyl acetate, and the N,N′-dicyclohexylurea which precipitated was removed by filtration. The filtrate was washed with a 10% potassium carbonate aqueous solution. The organic layer was separated, and concentrated. The resulting residue was redissolved in 30 ml of ethyl acetate, and the insoluble materials which precipitated were removed by filtration. The filtrate was concentrated, and the resulting crude product was purified through silica-gel column chromatography to obtain 7.77 g (16.65 mmol) of the above-mentioned compound (Ib).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:32][C:31]1([CH3:49])[CH3:48].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:9][O:8][C:6]([C:4]1[N:3]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40](=[O:41])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:32][C:31]2([CH3:49])[CH3:48])[CH:2]=[N:1][CH:5]=1)=[O:7]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)CN(C(=O)c2ccccc2)c2ccccc2C1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2N(C(=O)c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
methyl 4-imidazolecarboxylate (55 mg, 0.44 mmol), PS-triphenylphosphine (2.15 mmol/g, 0.20 g, 0.43 mmol) are added to a solution of (4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (80 mg, 0.28 mmol) in THF (10 mL) at room temperature. The mixture is stirred at room temperature for 5 minutes and then Cooled to 0° C. DIAD (0.083 mL, 0.43 mmol) is added, and then the mixture is stirred at room temperature. After 3 h, the reaction mixture is filtered to remove resin and washed with ethyl acetate. The ethyl acetate solution is washed with brine, and dried over anhydrous sodium sulfate. After concentration, the residue is purified by reverse phase HPLC (CH3CN:H2O=20 to 90% over 20 mins) and yields the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.74 (s, 3 H), 1.15 (s, 3 H), 3.52 (d, J=13.4 Hz, 1 H), 3.87 (d, J=13.1 Hz, 1 H), 3.92 (s, 3 H), 5.30 (s, 1 H), 6.40 (s, 1 H), 6.95-6.99 (m, 1 H), 7.01-7.06 (m, 1 H), 7.11-7.16 (m, 1 H), 7.28-7.33 (m, 2 H), 7.38-7.44 (m, 2 H), 7.45-7.50 (m, 1 H), 7.52-7.56 (m, 2 H). HRMS: calculated for C23H24N3O3: 390.1818. Found: 390.1800
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25]CNC[CH2:21]1>C1(C)C=CC=CC=1>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:1][N:2]([CH2:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:3][CH2:21]1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1
Yield: 96.9 %

Procedure:
To a solution of 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (258 mg, 1.39 mmol) (prepared in Example 1(a)) in toluene (10 mL) was added 1-(pyridin-2-yl)piperazine (233 mL, 250 mg, 1.53 mmol). The mixture was heated at reflux over night. Heating was discontinued and when the reaction temperature had reached room temperature the solid was filtered off and dried in vacuo to give 3-[4-(pyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine as a colourless solid (395 mg, 93%). δH (300 MHz, CDCl3) 2.50 (4H, m, piperazinyl), 3.46 (4H, m, piperazinyl), 3.68 (2H, s), 6.61 (1H, dd, J=5.1 and 6.9), 6.78 (1H, d, J=8.6), 7.06 (1H, dd, J=4.7 and 7.8), 7.39 (1H, s), 7.51 (1H, dd, 6.9 and 8.6), 8.10 (1H, d, J=8.1), 8.12(1H, d, J=7.8), 8.22(1H, d, J=4.6),11.49(1H, br s); ESMS 294 (MH+)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH:40]C(OC(CC)(C)C)=O)[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]>CCOCC>[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
Trifluoroacetic acid (3 ml) was added under ice-cooling to 7-[2-methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added ether and precipitating powder was collected by filtration and dissolved in a mixture of water (20 ml) and an 1 N aqueous solution of sodium hydroxide to adjust to pH 12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and methylene chloride. Excess methylene chloride in the aqueous layer was thoroughly removed by bubbling of nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and ice-cooling to precipitate powder. The powder was collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.128 g)
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@:7]12[CH2:15][CH2:14][C:13]3[C:16]4[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=4[CH2:22][CH2:23][C:12]=3[C@@H:11]1[CH2:10][CH2:9][C:8]2=[O:26])[CH:4]([CH3:6])[CH3:5].C(O)(=O)C>CO>[CH2:3]([C@:7]12[CH2:15][CH2:14][C:13]3[C:16]4[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=4[CH2:22][CH2:23][C:12]=3[C@@H:11]1[CH2:10][CH2:9][C@@H:8]2[OH:26])[CH:4]([CH3:6])[CH3:5]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]12
Reaction time: 1 h

Procedure:
To a stirred solution of sodium borohydride (6.0 g.) in methanol (500 cc. under nitrogen) add 13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (17 g.). Gently heat the reaction mixture for one minute to initiate the reaction and then allow to stand for one hour at room temperature. After adding cautiously glacial acetic acid (20 cc.), concentrate the solution in vacuo to 1/3 of its volume followed by addition of water. Extract the product with ether. Wash the ethereal solution successively with water, sodium bicarbonate, and water, and dry. Evaporate the ether to obtain 13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol as a gum, (17.0 g.; 99%); ultraviolet absorption peak at 278 mμ (ε14,560).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[C:33]([C:44]([OH:46])=O)=[CH:32]1)([CH3:30])[CH3:29].[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1>C(Cl)Cl>[S:49]1[CH:50]=[CH:51][N:52]=[C:48]1[NH:47][C:44]([C:33]1[C:34]2[C:39](=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=2)[N:31]([CH:28]([CH3:30])[CH3:29])[CH:32]=1)=[O:46]
Reactant: CC(C)n1cc(C(=O)O)c2ccc(C(F)(F)F)cc21
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of triphenylphosphine (377 mg, 1.44 mmol) in methylene chloride (4 mL) cooled to 0° C. was treated with N-bromosuccinimide (256 mg, 1.44 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid (300 mg, 1.11 mmol). The reaction was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-aminothiazole (255 mg, 2.54 mmol) and stirred at 25° C. for 24 h. At this time, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, diethyl ether) afforded 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (43 mg, 11%) as a light pink solid: mp 246-247° C.; EI-HRMS m/e calcd for C16H14F3N3OS (M+) 353.0810, found 353.0801.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:65]1([C:71](=[O:79])[CH2:72][N:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[CH:9]([C:28]([N:76]3[CH2:77][CH2:78][N:73]([CH2:72][C:71]([N:65]4[CH2:66][CH2:67][O:68][CH2:69][CH2:70]4)=[O:79])[CH2:74][CH2:75]3)=[O:30])[NH:10][CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood, 44 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 63 mg.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>>[F:12][C:13]([F:17])([F:16])[CH2:14][O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cnc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a mixture of methyl 5-chloropyrazine-2-carboxylate (1 g, 5.79 mmol) and 2,2,2-trifluoroethanol (2.111 ml, 29.0 mmol) was added potassium carbonate (0.801 g, 5.79 mmol). The reaction was stirred at ambient temperature for 16 hrs. The reaction was partitioned between ethyl acetate and water. The organic portion was concentrated and purified in 10-60% EtOAc/Heptane to give the title compound (1.1 g, 4.66 mmol, 80%). MS m/z=237.1 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[C:29]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36])(=O)[CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[CH3:28][C:4]1[C:3]([N:2]2[C:35](=[O:36])[C:34]3[C:33](=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=[C:29]2[CH3:30])=[CH:27][N:6]2[C:5]=1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=1)=[C:9]([C:25]#[N:26])[CH:8]=[N:7]2
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1c(-n2c(C)nc3ccccc3c2=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (10.4 mg, 0.027 mmol), 2-acetylamino benzoic acid (7 mg, 0.04 mmol), PyBOP (21 mg, 0.04 mmol) and DIEA (8.6 mg, 0.067 mmol) in 1.2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 375 as a yellow film (5.8 mg, 42%). [M+H]+=498.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[CH:11]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:4][C:2]([C:5]1[CH:26]=[CH:25][C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[CH:11]([C:13]([F:18])([F:19])[C:14]([F:17])([F:16])[F:15])[O:12][C:7]=2[CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)OC(C(F)(F)C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 23.3 h
Yield: 51.7 %

Procedure:
The ester from Step 3 (1.58 g 4.20 mmol) was dissolved in THF (3 mL) and ethanol (3 mL), treated with 2.5 N sodium hydroxide (2 mL, 5 mmol), and stirred at room temperature for 23.3 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl yielding a suspension. The solid was collected by filtration and was recrystallized from ethanol-water to yield a yellow solid (0.76 g, 52%): mp 171.0–173.5° C. 1H NMR (acetone-d6/300 MHz) 7.93 (s, 1H), 7.39 (d, 1H, J=8.1 Hz), 7.18 (dd, 1H, J=8.1 Hz 1.8 Hz), 7.02 (s, 1H), 6.01 (dd, 1H, J=23.1 Hz 3.2 Hz), 1.32 (s, 9 H). FABLRMS m/z 351 (M+H). EIHRMS m/z 350.0945 (M+, Calc'd 350.0941). Anal. Calc'd for C16H15F5O3: C, 54.86; H, 4.32. Found: C, 54.88; H, 4.32.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[CH3:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH2:16]Br)=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH2:16][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1
Reactant: O=Cc1ccc[nH]1
Reactant: COc1cc(CBr)c([N+](=O)[O-])cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cn2cccc2C=O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a suspension of sodium hydride (0.724 g, 60% suspension in oil) in N,N-dimethylformamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. It was then cooled to 0° C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate (450 mL), washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was triturated with water, filtered and washed with water. This material was dried over anhydrous potassium carbonate in vacuo to provide the title compound as a yellow crystalline solid (4.97 g), m.p. 109-112° C., which was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:6](=[O:12])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:4](=[O:21])[C:3]=1[NH:22][C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([S:33]([C:36]2[C:37]([CH3:43])=[N:38][N:39]([CH3:42])[C:40]=2[Cl:41])(=[O:35])=[O:34])[CH3:32])=[CH:27][CH:26]=1.[OH-].[Na+]>CO>[CH:9]1([CH2:8][N:7]2[C:2]3[N:1]=[C:23]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[S:33]([C:36]5[C:37]([CH3:43])=[N:38][N:39]([CH3:42])[C:40]=5[Cl:41])(=[O:35])=[O:34])=[CH:29][CH:30]=4)[NH:22][C:3]=3[C:4](=[O:21])[N:5]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]2=[O:12])[CH2:11][CH2:10]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)N(C)c1ccc(CC(=O)Nc2c(N)n(CC3CC3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 50 °C
Yield: 50 %

Procedure:
To a solution of N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-{4-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-methyl-amino]-phenyl}-acetamide (0.119 mmol) in methanol (2 mL) was added 10% w/v aqueous sodium hydroxide solution (1 mL) and the mixture heated to 50° C. for 1.5 hrs. The methanol was removed in vacuo and the aqueous residue acidified to pH=4 with 1.0M aqueous hydrochloric acid. The aqueous suspension was extracted with chloroform, the combined chloroform extracts washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. the residue was triturated with acetonitrile to give 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide as a colorless solid (50%); (ES)+-HRMS m/e calculated for C29H29ClFN7O4S (M+Na)+ 648.1566, found 648.1566.