Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:13])([C:8]#[C:9][CH:10]([CH3:12])[CH3:11])[C:3]([O:5]CC)=[O:4].O.[OH-].[Na+].Cl>C1COCC1>[OH:1][C:2]([CH3:13])([C:8]#[C:9][CH:10]([CH3:11])[CH3:12])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(O)C#CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C#CC(C)(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a stirred solution of ethyl 2-hydroxy-2,5-dimethyl-3-hexynoate from the previous step (0.35 g, 1.9 mmol) in 2 mL THF was added H2O (2 mL) and 1 N NaOH solution (2 mL). The reaction was stirred at ambient temperature for 3 h. The mixture was acidified with 1N HCl (2 mL) and extracted twice with Et2O (10 mL). The organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed on a rotary evaporator to give 2-hydroxy-2,5-dimethy-3-hexynoic acid as a white solid (0.272 g, 92%). 1H NMR, 400 MHz, CDCl3, 4.81 ppm (br, s, 1H); 2.56-2.62 ppm (m, 1H); 1.70 ppm (s, 3H); 1.17 ppm (d, J=3.18 Hz, 6H).
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]C>>[CH2:30]([C:21]1[C:20]2[C:19]([F:22])=[CH:18][C:17]([F:23])=[CH:16][C:15]=2[N:14]=[C:13]2[C:24]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:27])[C:8]1[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=1[CH:25]=3)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: CCCCCCCCCCC=O
Product: CCCCCCCCCCc1c2c(nc3cc(F)cc(F)c13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 100 is treated with undecanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[NH2:14]>CO.O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: Nc1cc(Nc2ncc(F)c(Nc3ccc([N+](=O)[O-])c(N)c3)n2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-nitroaniline (184 mg, 1.2 mmol) was added and the mixture was refluxed for 3 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 8.21 (d, 1H, J=2.9 Hz), 7.89 (m, 3H), 7.56 (d, 1H, J=2.3 Hz), 7.01 (m, 1H), 6.81 (dd, 1H, J=2.3, 9.4 Hz); LCMS: purity: 91.1%; MS (m/e): 401.00 (M+, 100).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].O.Cl>ClCCl>[C:1]([NH:5][C@H:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C[C@H](N)c1cccc(F)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C[C@H](NC(C)=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (7.9 ml, 111 mmol) in dichloromethane (50 ml) was added dropwise to a cold (0° C.) solution of ethyl (3S)-3-amino-3-(3-fluorophenyl)propanoate (WO99/31099, Scheme 3 page 97) (25.2 g, 102 mmol) in dichloromethane (200 ml). The reaction was stirred for 2 hours at 0° C., then water (100 ml) was added. The reaction mixture was adjusted to pH1 with 2 N hydrochloric acid and the organic layer separated. The dichloromethane layer was washed with saturated sodium hydrogencarbonate solution (50 ml), water (50 ml) and then dried (MgSO4). Solvent was evaporated under reduced pressure to afford a thick oil which was purified by column chromatography (silica gel, eluting with diethyl ether) to give the title compound as a clear, colourless oil, 25.1 g.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(C)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ncc2cn[nH]c(=O)n12

Procedure:
A 27.2 gm. portion of 3-(2-methyl-4-imidazolylmethylene)carbazic acid ethyl ester in 200 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product m.p. 303°-305.5° C.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[C:14]=2[C:18](=[O:32])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[F:31][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:27]([F:30])([F:28])[F:29])[CH2:20][NH:19][C:18]([C:14]1[C:15]2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9](=[O:34])[C:10]=2[CH:11]=[CH:12][C:13]=1[CH3:33])=[O:32]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1C(=O)NCc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(5-(3-fluoro-4-(trifluoromethyl)benzyl-carbamoyl)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (0.47 g, 0.00093 mol), potassium carbonate (0.22 g, 0.0016 mol) and methanol (100 mL, 2 mol). The reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC to afford the desired product as a an off white solid.
Reaction SMILES: [CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>COCCOC>[CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:27][CH:26]=[CH2:25])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=C(c1ccccc1)c1ccc(O)cc1)C1CCCC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCOc1ccc(C(=C(CC)C2CCCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.92 g (10 mmol) of pure E- or Z-isomer of 2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenyl-1-butene in dry DME was added under nitrogen atmosphere to a stirred suspension of sodium hydride in DME (0.6 g of 50-60% dispersion from which the oil had been removed by washing with dry DME). After stirring for 30 minutes at room temperature, 1.44 g (12 mmol) of allyl bromide was added. The mixture was refluxed for 3 hours. Ice water was added. The water layer was extracted with ether and the combined organic layers washed with diluted sodium hydroxide and water and dried. After evaporation of the solvent the residue was 3.1 g. In the case of the E-isomer the semisolid product was purified by chromatography over silica gel using methylene chloride as eluent. The Z-isomer was purified by recrystallization from methanol, mp. 82°-84° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O.[F:10][C:11]([C:37](F)([F:39])[F:38])([O:15][C:16]([F:36])([F:35])[C:17]([F:34])([C:30]([F:33])([F:32])[F:31])[O:18][C:19]([F:29])([F:28])[C:20]([F:27])([C:25]#[N:26])[C:21]([F:24])([F:23])[F:22])C(F)=O>>[F:38][C:37]([F:39])=[C:11]([F:10])[O:15][C:16]([F:36])([F:35])[C:17]([F:34])([C:30]([F:31])([F:32])[F:33])[O:18][C:19]([F:28])([F:29])[C:20]([F:27])([C:25]#[N:26])[C:21]([F:24])([F:23])[F:22]
Reactant: N#CC(F)(C(F)(F)F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)(C(=O)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Product: N#CC(F)(C(F)(F)F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)=C(F)F
Yield: 92 %

Procedure:
A bed (8 × 90 cm) of finely divided dry sodium carbonate held at 250°-270°C. in a vertical glass tube was fluidized with a minimum flow of preheated (300°C.) nitrogen from the bottom, and the exit gases passed out the top and through a series of three dry-ice cooled traps. Perfluoro(8-cyano-2,5-dimethyl-3,6-dioxanonanoyl) fluoride (215 g) was added at 0.59 ml/minute to the preheated nitrogen entering the bed. After all of the acid fluoride had been added, the traps were washed out with the aid of ethyl ether and the combined trap contents distilled to give 172 g (95%) of perfluoro(8-cyano-5-methyl-3,6-dioxa-1-nonene).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH:6]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([N+:19]([O-])=O)[CH:11]=2)[CH2:5][C:4]([CH3:24])([CH3:23])[NH:3]1.[H][H]>C(O)C.[Pd]>[NH2:19][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([NH2:16])[CH:13]=1)[C:9]([NH:8][CH:6]1[CH2:5][C:4]([CH3:24])([CH3:23])[NH:3][C:2]([CH3:1])([CH3:25])[CH2:7]1)=[O:22]
Reactant: CC1(C)CC(NC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC(C)(C)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(NC(=O)c2cc(N)cc(N)c2)CC(C)(C)N1
Yield: 79.6 %

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidyl)-3,5-dinitrobenzamide (1.0 g.) is dissolved in ethanol (50 ml.) and 10% palladium on charcoal (.1 g.) is added. The reduction is carried out in a Parr apparatus for 2 hours at 40 psi of hydrogen. The catalyst is removed by filtration, washed with a few ml. of ethanol and the filtrate taken to dryness under reduced pressure leaving a tan solid. Recrystallization from ether gives a cream colored product (6.6 g., m.p. 188°-190°C., 79.6% yield).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([C:14](Cl)=[O:15])[O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].B.[Na]>>[OH:15][CH2:14][C:12]1[O:13][C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:9]=2[C:10](=[O:17])[CH:11]=1
Reactant: CS(=O)(=O)Nc1cc2oc(C(=O)Cl)cc(=O)c2cc1Oc1ccccc1
Agent: B
Agent: [Na]
Product: CS(=O)(=O)Nc1cc2oc(CO)cc(=O)c2cc1Oc1ccccc1

Procedure:
7-Methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid chloride was reduced by sodium boron hydride to obtain 2-hydroxymethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([S:32]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Product: CCCCS(=O)(=O)Oc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 24 mg (0.15 mmol) of butanesulfonyl chloride. 48 mg (72% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:29]1[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[C:31]([CH2:41][S:42][C:43]2[S:44][C:45]([CH2:48][CH3:49])=[N:46][N:47]=2)[N:30]=1)[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:17]=1)[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].O1CCCC1>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:29]1[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[C:31]([CH2:41][S:42][C:43]2[S:44][C:45]([CH2:48][CH3:49])=[N:46][N:47]=2)[N:30]=1)[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:17]=1)[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)Nc1cccc(C(CCC(=O)OC)N(C(=O)OC(C)(C)C)c2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(CCCO)N(C(=O)OC(C)(C)C)c2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-[N-tert-butoxycarbonyl-N-{3-methoxycarbonyl-1-[3-(2-propenyloxycarbonylamino)phenyl]propyl}amino]-6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholinopyridine (100 mg) obtained in Example 138-(2) was dissolved in tetrahydrofuran (3 ml), and a 2 M lithium borohydride-tetrahydrofuran solution (0.1 ml) was added thereto, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the above identified compound (66 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)[NH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2cccnc2Cl)c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.2 g, 4.32 mmol) and hydrazine hydrate (6.27 mL) in ethanol (50 mL) was heated at 80° C. for 24 hours. The reaction was concentrated and the residue was neutralized to pH 7 with 1N HCl, extracted with ethyl acetate. The combined ethyl acetate was dried, concentrated and purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]=[C:44]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>C(Cl)(Cl)Cl>[CH3:58][C:56]([CH3:59])([O:55][C:54]([NH:53][C:44]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[N:45][C:46]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:52])=[O:60])[CH3:57]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCN)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)NCCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
1.05 g (8.10-3 mol) of monoethyl malonate are dissolved in 15 ml of anhydrous chloroform, the solution is then cooled to 0° C. and 1.65 g (8.10-3 mol) of 1,3-dicyclohexylcarbodiimide and 0.108 g (0.8.10-3 mol) of 1-hydroxybenzotriazole hydrate are added. After stirring for 0.5 hour at 0° C., a solution of 1.5 g (4.19.10-3 mol) of bis(1,1-dimethylethyl) [[(6-aminohexyl)imino]methylene]biscarbamate in 5 ml of anhydrous chloroform is added. The mixture is then stirred for 48 hours at room temperature, after which the reaction medium is concentrated under reduced pressure. The crude product obtained is purified by medium pressure chromatography on silica using a hexane/ethyl acetate mixture (1/1 v/v) as the eluent to give 1.95 g (yield=99%) of the expected product in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 300 mg, 0.84 mmol) and triphenylphosphine (288 mg, 1.09 mmol) in methylene chloride (6.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (192 mg, 1.09 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyridine (220 mg, 1.68 mmol) and 2,6-lutidine (0.42 mL, 3.36 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL) and water (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (265 mg, 67%) as a white foam: [α]23589=−35.71° (c=0.35, chloroform); EI-HRMS m/e calcd for C21H22Cl2N2O4S (M+H)+ 469.0750, found 469.0754.
Reaction SMILES: [C:1]([C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][O:45][NH2:46]>>[CH3:44][O:45][N:46]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Cc1ccccc1
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(=O)Cc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:34])[O:25][CH:26]1[CH:33]2[CH:29]([O:30][CH2:31][CH2:32]2)[O:28][CH2:27]1)[C@H:9]([OH:22])[CH2:10][NH:11]C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[NH2:11][CH2:10][C@@H:9]([OH:22])[C@@H:8]([NH:23][C:24](=[O:34])[O:25][C@@H:26]1[C@H:33]2[C@H:29]([O:30][CH2:31][CH2:32]2)[O:28][CH2:27]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COC2OCCC12)OCc1ccccc1
Solvent: CO
Product: NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Yield: 95 %

Procedure:
A suspension of 4.0 g (8.5 mmol) of 3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((1S,2R)-1-benzyl-3-[(benzyloxy)carbonyl]amino-2-hydroxypropyl)carbamate and 0.5 g of 5% Pd(C) in 200 mL of MeOH was subjected to hydrogenation at 45 psi. After 3.5 hours the reaction vessel was purged with nitrogen, catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to afford 2.72 g (95%) of the desired product as a white solid. NMR (DMSO-d6): 7.23-7.04 (m, 6H), 5.45 (d, 1H), 4.91-4.75 (m, 2H), 3.79 (dd, 1H), 3.68 (t, 1H), 3.53 (m, 3H), 3.21 (m, 2H), 3.01 (dd, 1H), 2.74 (q, 1H), 2.57 (dd, 1H), 2.41 (m, 1H), 1.60-1.28 (m, 3H), 1.22 (dd, 1H). MS(ESI): 337(M+H).
Reaction SMILES: C([O:5][CH2:6][C@@H:7]1[O:16][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=O)CC.[OH-].[K+].CO>>[O:16]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:7]1[CH2:6][OH:5]
Reactant: CCC(=O)OC[C@@H]1O[C@@H]1CCCCC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCCC[C@H]1O[C@H]1CO
Yield: 93.6 %

Procedure:
3.4 g of (-)-(2S,3R)-1-propionyloxy-2,3-epoxy-8-methylnonane was hydrolyzed with potassium hydroxide/methanol to yield 2.4 g of (-)-(2S,3R)-2,3-epoxy-8-methyl-1-nonanol.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:33]3[CH:34]=[CH:35][C:36]([CH:39]4[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]4)=[CH:37][CH:38]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Yield: 94.9 %

Procedure:
The title compound was synthesized according to the method of Example A43, except reacting a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (192 mg, 0.446 mmol) with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (190 mg, 0.49 mmol). The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by flash chromatography using EtOAc/hexanes as eluent (1:4 to 7:3) to give the title compound as a yellow solid (239 mg, 80%). 1H NMR (400 MHz, MeOD) δ 7.93-7.90 (m, 3H), 7.36-7.34 (m, 3H), 7.02 (d, J=8.0 Jz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.58 (dd, J=8.0, 4.0 Hz, 1H), 5.55 (s, 1H), 4.39-4.20 (m, 2H), 3.35-3.46 (m, 1H), 3.29 (s, 3H), 2.89-2.79 (m, 2H), 2.76-2.67 (m, 1H), 2.08-2.02 (m 2H), 1.91-1.83 (m, 2H), 1.75-1.61 (m, 2H), 1.51 (s, 9H); MS ESI 565.3 [M+H]+, calcd for [C34H36N4O4+H]+565.27.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([NH2:16])[C:9]([N+:13]([O-])=O)=[CH:10][C:11]=1[F:12].[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([NH2:16])[C:9]([NH2:13])=[CH:10][C:11]=1[F:12]
Reactant: [H][H]
Reactant: CN(C)CCNc1cc(N)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C)CCNc1cc(N)c(N)cc1F

Procedure:
1.29 g of N3-(2-dimethylaminoethyl)-4-fluoro-6-nitrobenzene-1,3-diamine in solution in 30 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 130 mg of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 1 g of N4-(2-dimethylaminoethyl)-5-fluorobenzene-1,2,4-triamine are recovered in the form of a black resin. The product is used as it is for the subsequent stage.