Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:3]([O:5][CH3:6])=[O:4].C(O[C:29]([CH3:32])([CH3:31])[CH3:30])(=O)C.Cl(O)(=O)(=O)=O>>[C:29]([O:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 64.8 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (142 mg, 0.435 mmol) in tert-butyl acetate (2.94 mL, 21.76 mmol) was treated with perchloric acid (0.075 mL, 0.870 mmol), and then kept in the refrigerator without stirring for 2 days. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (108 mg, 0.282 mmol, 64.9% yield) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.71 (br. s., 1H), 7.39-7.31 (m, 2H), 7.30-7.24 (m, 2H), 7.18 (t, 1H), 6.09 (t, J=2.5 Hz, 1H), 5.38 (s, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H), 0.94 (s, 9H); LCMS (m/z) ES+=383 (M+1).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=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>CN(C=O)C.O>[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(F)c2)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine-2HCl (70.6 mg, 0.209 mmol), (3-fluorophenyl)acetic acid (32.2 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base (0.146 mL, 0.836 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The solid was filtered and dried to afford a white solid as the product. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (t, J=8.46 Hz, 2H), 3.73 (s, 3H), 3.92 (s, 2H), 4.19-4.26 (m, 2H), 7.08-7.11 (m, 1H), 7.12-7.17 (m, 2H), 7.23 (d, J=8.34 Hz, 1H), 7.25 (s, 1H), 7.31 (s, 1H), 7.36 (s, 1H), 7.39 (d, J=6.82 Hz, 1H), 8.10-8.17 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N+:11]([O-])=O)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.O=[Pt]=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)Oc1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)Oc1cccc(N)c1

Procedure:
A solution of 3-isopropoxynitrobenzene (8.5 g, 50 mmol) and PtO2 (0.3 g) in 200 ml of ethanol was shaken under 40 psi hydrogen at room temperature for 1.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to provide 7.08 g of light oil (3-isopropoxyaniline). The oil was added to isatoic anhydride (7.35 g, 45 mmol) along with 15 ml of ethyl acetate. The mixture was heated in a 90° oil bath under nitrogen for two hours. The product crystallized from the reaction mixture upon the addition of hexanes. Filtration of the reaction mixture provided 10.19 g (83%) of 2-amino-N-(3-isopropoxyphenyl)benzamide as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc(I)cc1N
Temperature: 65 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
4-Iodo-2-nitroaniline (35.2 g, 0.133 mol) was added in batches via an open funnel over 25 min to a heated (65° C.) mixture of SnCl2.2H2O (106.86 g, 0.465 mol) and 12N HCl (200 ml). An additional 12N HCl (30 ml) was added and the reaction mixture was heated at 65° C. for an additional 1 h, and stirred at room temperature for 1 h. It was placed in a refrigerator for 15 h, and the precipitate was filtered. The resultant solid was transferred into a flask containing water (210 ml), cooled (ice/water), and a solution of NaOH (aq) (35 g in 70 ml of water) was added to it over 10 min with stirring. The cooling bath was removed, and vigorous stirring was continued for 45 min. The mixture was filtered and the solid was washed with water and dried in vacuo to provide 4-iodobenzene-1,2-diamine as a tan solid (25.4 g). The product was used in the next step without further purification. 1H NMR (DMSO-d6, δ=2.5 ppm, 500 MHz): 6.79 (d, J=2, 1H), 6.63 (dd, J=1.9, 8.1, 1H), 6.31 (d, J=8.1, 1H), 4.65 (br s, 2H), 4.59 (br s, 2H). LC/MS: Anal. Calcd. for [M+H]+ C6H8IN2: 234.97; found: 234.9.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([C:37]([CH:39]2[CH2:41][CH2:40]2)=[O:38])[CH3:36])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:39]1([C:37]([N:35]([CH2:34][C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH3:36])=[O:38])[CH2:41][CH2:40]1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)C2CC2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(C)C(=O)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3R*,4R*)-3-[(cyclopropanecarbonyl-methyl-amino)-methyl]-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (154 mg, 0.267 mmol) in 3 mL CH2Cl2, TFA (309 μL, 4.01 mmol) is added. The mixture is stirred 4 h at RT, and poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on Isolute SPE Flash NH2 column (eluent: CH2Cl2/MeOH 100:0 to 95:5) to give the title product. TLC, Rf (SiO2—NH2, CH2Cl2/MeOH 95:5)=0.1. MS (LC-MS): 476.1 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.10 min.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][CH:33]1[O:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[O:35][CH2:34]1>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]([CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[N:19]=1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: ClCC1COc2ccccc2O1
Product: Cc1c(-c2nn(CC3COc4ccccc4O3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 2-chloromethyl-2,3-dihydro-benzo[1,4]dioxine using the procedure described in example 14. MS: ESI (negative): 514, 516 (M−H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH:26]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=O.C[Si]([C:43]#[N:44])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:43]#[N:44])[CH:21]=[C:22]([CH:26]([O:28][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[CH:30]([CH3:32])[CH3:31])[CH3:27])[C:23]=1[O:24][CH3:25]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: COc1cc(C=O)cc(C(C)O[Si](C(C)C)(C(C)C)C(C)C)c1OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc(C(C)O[Si](C(C)C)(C(C)C)C(C)C)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After adding 0.99 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 2.607 g of 3,4-dimethoxy-5-(1-triisopropylsilanyloxyethyl)benzaldehyde, 1.7 g of MS3A and 1.6 ml of trimethylsilyl cyanide to a solution of 350 mg of Yb(OTf)3 in 14 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of [3,4-dimethoxy-5-(1-triisopropylsilanyloxyethyl)phenyl][4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][Si:26]([C:29]#[C:30][C:31]1[NH:35][C:34]([C@@H:36]2[CH2:41][C@@H:40]3[C@@H:38]([CH2:39]3)[NH:37]2)=[N:33][CH:32]=1)([CH3:28])[CH3:27].[CH3:42][O:43][C:44]([NH:46][C@@H:47]([CH:51]([CH3:53])[CH3:52])[C:48](O)=[O:49])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:52][CH:51]([CH3:53])[C@H:47]([NH:46][C:44](=[O:45])[O:43][CH3:42])[C:48](=[O:49])[N:37]1[C@H:36]([C:34]2[NH:35][C:31]([C:30]#[C:29][Si:26]([CH3:27])([CH3:28])[CH3:25])=[CH:32][N:33]=2)[CH2:41][C@@H:40]2[C@H:38]1[CH2:39]2
Reactant: C[Si](C)(C)C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
HATU (428 mg, 1.125 mmol) was added to a stirred solution of (1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (212 mg, 0.865 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (197 mg, 1.125 mmol) in DMF (3 mL) and DIPEA (1.2 mL, 6.9 mmol) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and then purified with a BIOTAGE® Horizon (25 g SiO2, 40-60% EtOAc/hexanes) to yield methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (203 mg) as a yellow glass. LC-MS retention time 3.095 min; m/z 403.29 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 7.17 (br. s., 1 H), 5.04-5.11 (m, 1 H), 4.54 (d, J=6.8 Hz, 1 H), 3.65 (s, 3 H), 3.54-3.61 (m, 1 H), 2.82 (s, 1 H), 2.39-2.50 (m, 1 H), 2.27-2.36 (m, 1 H), 2.04-2.15 (m, 1 H), 1.94-2.04 (m, 1 H), 1.11 (dt, J=8.7, 5.6 Hz, 1 H), 0.95 (d, J=6.8 Hz, 3 H), 0.90 (d, J=6.8 Hz, 3 H), 0.73-0.79 (m, 1 H), 0.21 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([CH3:10])[CH3:9])[N:5]=[C:4]([NH:12][CH:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[N:1][C:2]2[N:7]=[C:6]([C:8]([F:11])([CH3:9])[CH3:10])[N:5]=[C:4]([NH:12][CH:13]([CH:23]3[CH2:24][CH2:25]3)[CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(F)c1nc(N)nc(NC(CCCc2ccccc2)C2CC2)n1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(F)c1nc(N=Cc2ccc(Cl)cc2)nc(NC(CCCc2ccccc2)C2CC2)n1

Procedure:
A mixture of 2.5 g (7.28 mmol) of 2-amino-4-(1-fluoro-1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine, 1.08 g (7.70 mmol) of p-chlorobenzaldehyde and 100 mg of p-toluenesulfonic acid in 80 ml of toluene are boiled for 10 hours in a water separator. When cold, all volatile constituents are distilled. The crude product is purified by column chromatography (eluent:toluene/ethyl acetate=85:15). This gives 3.0 g (89% of theory) of 2-(4-chloro-6-benzylideneamino)-4-(1-fluoro-1-methylethyl-)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C@@H:7]1[C@:15]2([CH3:16])[C@@:10]([OH:23])([CH2:11][C@@H:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:14]2)[CH2:9][CH2:8]1.[N+:24]([O-:27])(O)=[O:25].[C:28](N1C(C)=CC(C)=N1)(=[NH:30])[NH2:29]>C(O)C>[N+:24]([O:23][C@@:10]12[CH2:11][C@@H:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14][C@:15]1([CH3:16])[C@@H:7](/[CH:6]=[N:5]/[O:4][CH2:3][CH2:2][NH:1][C:28]([NH2:30])=[NH:29])[CH2:8][CH2:9]2)([O-:27])=[O:25]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: O=[N+]([O-])O
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2/C=N/OCCN
Solvent: CCO
Product: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O[N+](=O)[O-])CC[C@@H]2/C=N/OCCNC(=N)N
Yield: 43.9 %

Procedure:
A solution of 0.75 g of (1S,3aS,5S,7aR)-1-[(E)-2-aminoethoxyimino]methyl-5-phenyl-7a-methylperhydroinden-3a-ol (I-am) and 1.05 g of 1-amidino-3,5-dimethylpirazole nitrate in 20 ml of ethanol was heated at reflux for 10 hrs. The solution was evaporated to dryness under reduced pressure and the residue was purified by flash chromatography (SiO2) with chloroform/methanol/28% ammonium hydroxide 78:20:2 as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was ground with diisopropyl ether:ethanol 9:1 to give 0.42 g of the title compound (I-db) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(C)=O)c(-c3ccnn3C)c2)c1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
The N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μL, 3.0 eq) were taken up in 2 mL of dichloromethane and stirred for 15 mins. To this was added acetyl chloride (6.35 μL, 1.2 eq) and the reaction was stirred at room temperature for 18 hrs. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 54.3% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.97 (s, 3H), 3.49-3.56 (m, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.09 (t, J=5.05 Hz, 2 H), 6.36 (t, J=6.32 Hz, 1 H), 6.39 (d, J=2.02 Hz, 1 H), 7.02 (d, J=8.59 Hz, 1 H), 7.09-7.13 (m, 1 H), 7.36-7.45 (m, 2 H), 7.61 (dd, J=9.09, 2.53 Hz, 1H), 7.69 (d, J=1.52 Hz, 1 H), 7.75 (d, J=2.02 Hz, 2 H), 7.85 (s, 1 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C>[Si:21]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.00 g (11.38 mmol) of the crude product from Example 8A (90% pure) are dissolved in 50 ml of dry DMF, and 1.47 g (21.62 mmol) of imidazole and 2.40 g (15.93 mmol) of tert-butyldimethyl-silyl chloride are added. The reaction mixture is stirred at RT for 20 h. 40 ml each of diethyl ether and of saturated aqueous sodium bicarbonate solution are then added to the mixture. After phase separation, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The crude product is used in the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23]([Cl:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[ClH:26].[C:17]1([S:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOCC
Product: CN1CCC(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Product: Cl
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of 2.5 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 50 ml of benzenesulfonyl chloride was heated on a steam bath for 1 hr. The solution was cooled to ambient temperature and then poured into ether. The precipitate was collected and triturated with ethyl acetate to yield a solid. The solid was combined with 1.5 g of solid from another experiment and recrystallized twice from isopropanol to yield 2.3 g (36%) of product, mp 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8].[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:26][CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cc(F)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CN1CCC(O)CC1
Product: CN1CCC(Oc2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2[N+](=O)[O-])CC1

Procedure:
The compound was obtained according to the process of Preparation 2 with 4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinoline-3-carbonitrile and 4-hydroxy-1-methylpiperidine as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH2:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1>CN(C=O)C>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH:50][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere, 1.4 g (8.0 mmol) of N-methoxycarbonyl-(L)-valine, 2.87 g (15 mmol) of EDC and 1.35 g (10 mmol) of HOBT are dissolved in 22 ml of DMF. After 45 min, 4.2 ml (30 mmol) of TEA are added and then a solution of 2.34 g (5.0 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 45 ml of DMF is added dropwise. After 1.5 hours, the reaction mixture is concentrated by evaporation; the residue is taken up in methylene chloride and washed with water, sat. NaHCO3 solution, water and brine. The aqueous phases are extracted 2× with methylene chloride; the combined organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/ethyl acetate 2:1) and crystallisation from ethyl acetate/ether yield the title compound: m.p: 178-179° C.; HPLC20-100 : tRet =15.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:28])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)C(O)=O)[CH:5]=[CH:6][CH:7]=1.C([N:31]([CH2:34]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:43])C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:28][C:34](=[O:43])[NH:31][CH:9]2[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(CC(F)(F)C(F)(F)F)cc2)C(c2cccc(Cl)c2)O1
Yield: 93.1 %

Procedure:
To a solution of (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionic acid (2.75 g, 6.50 mmol) in tetrahydrofuran (70 ml) were added triethylamine (1.36 ml, 9.75 mmol) and diphenylphosphoryl azide (1.54 ml, 7.15 mmol), and the mixture was heated under reflux for 4 hrs. The solvent was evaporated and the residue was diluted with ethyl acetate, washed with water, saturated. aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue as recrystallized from hexane-ethyl acetate to give (4RS,5SR)-5-(3-chlorophenyl)-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidin-2-one (2.54 g, 93%) as colorless crystals.