Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[C:26](Cl)=[CH:25][C:23]([NH2:24])=[C:22]([N+:28]([O-:30])=[O:29])[CH:21]=1>CS(C)=O>[Cl:19][C:20]1[C:26]([O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[Cl:1])=[CH:25][C:23]([NH2:24])=[C:22]([N+:28]([O-:30])=[O:29])[CH:21]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-(trifluoromethyl)phenol (2 g, 10.18 mmol) in DMSO (250 ml) was added potassium carbonate (4.2 g, 30.17 mmol). The resulting solution was stirred overnight at room temperature, then 4,5-dichloro-2-nitroaniline (2.1 g, 10.14 mmol) was added. The resulting solution was stirred for an additional overnight at 90° C. and then quenched with water (1000 ml) and extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with saturated aqueous brine (3×1000 ml), dried by anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column, eluting with 1% to 1.5% ethyl acetate in petroleum ether to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroaniline as a yellow solid (450 mg, crude). Next, to a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroaniline (450 mg, crude) in ethanol (10 ml) was added hydrochloric acid (conc) (0.484 ml) and Zn (478 mg, 7.35 mmol) in several batches at room temperature. The resulting solution was stirred for 10 min at room temperature and 2 h at 80° C. The reaction was concentrated under vacuum and dissolved in water (200 ml), pH adjusted to 8 with potassium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Prep-HPLC to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a off-white solid (150 mg, 61%). Finally, a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (50 mg, 0.15 mmol) in trifluoroacetic acid (5 ml) and conc. HCl (1 ml) was refluxed overnight. The reaction was then quenched with water (100 ml), pH value adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Prep-TLC with 12.5% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenoxy]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (36.4 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>ClCCCl>[Br:11][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Solvent: ClCCCl
Product: Cc1[nH]c(=O)c(C#N)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 181.1 %

Procedure:
A mixture of 6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (26.23 g, 95.5 mmol) and N-bromosuccinimide (36.54 g, 205 mmol) in 1,2-dichloroethane (500 mL) heated to reflux for 18 hours, cooled to room temperature, and filtered. The solid was treated with water (1 L), stirred for 2 hours, filtered, washed with water, and dried under vacuum to provide 36.85 g (88%) of the desired product of sufficient purity for subsequent use. MS (DCI/NH3) m/z 230 (M+NH4)+; 1H NMR (DMSO-d6) δ 12.96 (br s, 1H), 8.34 (s, 1H),2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([C:9]2[C:19]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(OCC)(=O)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([C:9]2[C:19]3[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-c2cccc3c2OCCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of tert-butyl 9-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (210 mg, 0.534 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (121 mg, 68.8%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:30]([OH:34])[C:31]([OH:33])=[O:32]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:30]([OH:34])[C:31]([OH:33])=[O:32])=[O:19])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Temperature: 4 °C
Reaction time: 48 h

Procedure:
2.26 g of the p-nitrophenyl ester of benzyloxycarbonyl-L-asparagine and 1.89 ml (13.6 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 900 mg (3.9 mmol) of (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid hydrochloride in 15 ml of dimethylformamide, and the mixture was stirred at 4° C. for 2 days. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with 1N aqueous hydrochloric acid to cause crystallization. The crystals were collected by filtration and washed first with water and then with ethyl acetate, to give 1.52 g of the title compound as colorless crystals, melting at 225°-227° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.N.CS(C)=[O:34]>>[NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:34])[N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(C)=O
Reactant: Nc1nc(Sc2ccc3ccccc3c2)nc2c1nc(Br)n2Cc1ccccc1
Agent: Cl
Agent: N
Product: Nc1nc(Sc2ccc3ccccc3c2)nc2c1nc(O)n2Cc1ccccc1
Yield: 35 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-naphthylthio)purine (33 mg, 0.043 mmol) in a mixture of concentrated hydrochloric acid (20 ml) and dimethyl sulfoxide (7 ml) was refluxed for 6 hours under heating. The reaction mixture was made basic with 28% aqueous ammonia, and the resulting crystals were filtered, washed with water and the crude product was purified by thin-layer chromatography to give the subject compound (6 mg, yield 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([C:17]([N:21]=[C:22]=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([N:14]=[C:15]=[O:16])([CH2:12][CH3:13])[CH3:11]>CCCCC>[N:8]([C:17]([NH:21][C:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([NH:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])([CH2:12][CH3:13])[CH3:11]
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Reactant: Nc1ccccc1
Solvent: CCCCC
Product: CCC(C)(N=NC(C)(CC)NC(=O)Nc1ccccc1)NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4.44 grams (0.0476 moles) of aniline in 30 ml of pentane in a 50 ml erlenmeyer flask cooled in a water bath was added 5.33 grams (0.0236 moles) of 2,2'-azobis (2 -isocyanatobutane) (from Example XXXVI) dropwise over 20 minutes while holding the reaction temperature below 30° C. After the addition was complete, the reaction was stirred for an additional 60 minutes at room temperature and filtered. The filter cake was washed with pentane and dried. The dry white solid weighed 1.5 grams (15% crude yield) and melted at 118°-120° C. The product had a strong carbonyl band at 1680 cm-1 and NH peaks at 3220 and 3420 cm-1 in its infrared spectrum and there was no isocyanate band at 2200 cm-1.
Reaction SMILES: CO[C:3](=[O:25])[CH2:4][CH2:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH2:26]([NH2:29])[CH:27]=[CH2:28].[Cl-].[NH4+]>>[CH2:26]([NH:29][C:3](=[O:25])[CH2:4][CH2:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=2)=[CH:11][CH:12]=1)[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCNC(=O)CCC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C

Procedure:
Methyl-4-oxo-4-[4′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]butanoate (VIII-a-1) (18.2 g, 52 mmol) is treated with allylamine (41.6 g, 730 mmol) and ammonium chloride (1.8 g, 33 mmol) and heated under reflux for 6 h. For work-up, the mixture is poured into ice-cold aqueous HCl (2 M) and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4) and concentrated. The crude product (17.7 g, content: 84.5%, HPLC, 100% method) is recrystallized from toluene.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C(OC([N:35]1[C:39]([C:40]#[N:41])=[CH:38][CH:37]=[C:36]1B(O)O)=O)(C)(C)C>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:36]3[NH:35][C:39]([C:40]#[N:41])=[CH:38][CH:37]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 22.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford a beige solid. UPLC-MS (Condition 3) tR=1.06 min, m/z=474.1 [M+H]+, m/z=472.2 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.81 (m, 1H) 1.81-1.91 (m, 1H) 2.94 (d, J=11.74 Hz, 1H) 3.22-3.28 (m, 1H) 3.32 (d, J=3.42 Hz, 1H) 3.40-3.49 (m, 1H) 4.23 (br. s, 1H) 4.88 (br. s, 1H) 6.30 (d, J=3.67 Hz, 1H) 7.00 (d, J=3.67 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.89 (m, 2H) 8.07 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.17 (s, 1H) 12.60 (br. s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:6]=1[NH2:7].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[C:2]([CH:22]=[CH2:23])=[C:6]([NH2:7])[N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[N:4]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccccc1-n1nc(-c2ccc(F)cc2)c(Br)c1N
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(-c2ccc(F)cc2)nn(-c2ccccc2C)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a solution of 4-bromo-3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine (200 mg, 0.58 mmol) in toluene (10 mL) was added tributylvinyl tin (0.33 mL, 366 mg, 1.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol). The reaction mixture was heated to reflux and stirred for 16 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Silica gel flash chromatography of the residue using 10% EtOAc/Hex afforded 3-(4-fluorophenyl)-1-(2-methylphenyl)-4-vinyl-1H-pyrazol-5-amine (87 mg, 51%):
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1.Br[C:16]1C=CC(N)=NC=1C>>[CH3:16][C:9]1[C:4]([CH:2]2[CH2:3][O:1]2)=[CH:5][CH:6]=[C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:8]=1
Reactant: c1cc(-n2cnnn2)ncc1C1CO1
Reactant: Cc1nc(N)ccc1Br
Product: Cc1nc(-n2cnnn2)ccc1C1CO1

Procedure:
2-Methyl-3-(oxiran-2-yl)-6-(1H-tetrazol-1-yl) pyridine was prepared in a similar fashion to that described for the synthesis of 5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine (INTERMEDIATE 32) starting from 5-bromo-6-methylpyridin-2-amine to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH3:23])[CH:20]([CH2:24][CH3:25])[O:19]1>>[CH3:23][CH:21]1[CH:20]([CH2:24][CH3:25])[O:19][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:22]1
Reactant: CCC1OC(CBr)OC1C
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1OC(CNc2ccccc2OC)OC1C

Procedure:
2-Methoxyaniline (0.05 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4-methyl-5-ethyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4-methyl-5-ethyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([NH:13][CH:10]1[CH2:12][CH2:11]1)[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC1CC1
Product: CCOC(=O)C=C(C)NC1CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of ethyl acetoacetate (5.00 mL, 39.3 mmol) and cyclopropylamine (3.27 mL, 47.1 mmol) is stirred at 40° C. for 3 h. The mixture is concentrated under high vacuum overnight to give the title compound (6.23 g, 94%) of the as an oil, which is used without further purification in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19]C)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC21
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one (100 mg, 0.31 mmol) in dichloromethane (3 mL) at −78° C. was added dropwise boron tribromide (0.79 mL, 0.79 mmol; 1.0M in CH2Cl2). After 5 min, the reaction was warmed to 0° C. and an additional 0.2 mL of boron tribromide (1.0 M in CH2Cl2) was added. After 2 h, the yellow mixture was recooled to −78° C. and quenched with water. The reaction was warmed to room temperature and stirred for 14 h. The mixture was then concentrated, quenched again with aqueous hydrogen chloride (3M), and the resulting yellow solution was concentrated to dryness. The residue was diluted with tetrahydrofuran (10 mL) and saturated aqueous sodium bicarbonate (1 mL). Di-tert-butyl dicarbonate (69 mg, 0.31 mmol) was added, and the mixture was stirred for 1 h. The reaction was then diluted with ethyl acetate and the layers were separated. The organic layer was then dried over sodium sulfate, fitered, and concentrated. The resulting residue was purified by radial chromatography (20% ethyl acetate in hexanes) to give the desired product as an off-white solid (86 mg, 90%). MS (ESI) 305.3 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([O:18]C)[CH:9]=2)[C:4]1=[O:22])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([OH:18])[CH:9]=2)[C:4]1=[O:22])[CH3:2]
Reactant: CCC1C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCC1C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1

Procedure:
A stirred mixture of 2-ethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (13.9 g., 0.0415 mole) and aluminum chloride (13.6 g., 0.104 mole) in heptane (120 ml.) is refluxed for five hours then cooled. The heptane is decanted and the residue is treated with ice water (100 ml.) containing hydrochloric acid. The gum which separates is extracted into ether, washed with water dried over magnesium sulfate and the ether evaporated at reduced pressure affording 11.3 g. of 2-ethyl-3-phenyl-5-hydroxy-6,7-dichloro-1-indanone which melts at 220°-2°C. after recrystallization from methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C:12]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][C:12]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@H](O)CN1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
A mixture of (4S)-N-benzyloxycarbonyl-4-hydroxy-2-pyrrolidone (116 g), t-butyldimethylsilyl chloride (81.4 g), imidazole (67.4 g) and dimethylformamide (350 ml) is stirred at room temperature for 17 hours, and the solvent is evaporated in vacuo. To the residue is added ethyl acetate, and the mixture is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, n-hexane : ethyl acetate =4:1 to 2:1) to give (4S)-N-benzyloxycarbonyl-4-t-butyldimethylsilyloxy-2-pyrrolidone (160 g) as colorless needles.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:29])([CH3:28])[CH2:20][NH:21][S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:27][N:25]([CH3:26])[S:22]([NH:21][CH2:20][C:19]([F:29])([C:16]1[CH:15]=[CH:14][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)=[CH:18][CH:17]=1)[CH3:28])(=[O:23])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 0 °C

Procedure:
In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 285 mg of methanesulfonyl chloride is added dropwise to 350 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine (prepared in example 38) and 380 mg of DBU in THF (125 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and then stirred overnight at this temperature. In the morning, the reaction is concentrated under reduced vacuum. The resulting material is taken into ethyl acetate and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum. This crude material is purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:8][C:9](O)([CH3:11])[CH3:10].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:7][C:9]([CH3:11])([CH3:10])[CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Pent-4-ynoic acid (5.0 g, 51.0 mmol), 2-methylpropan-2-ol (7.56 g, 102.0 mmol) and 4-(dimethylamino)pyridine (0.31 g, 2.54 mmol) were dissolved in DCM (17.5 ml), a solution of dicyclohexylcarbodiimide (11.6 g, 56.2 mmol) in DCM (17.5 ml) was added and the mixture was stirred at room temperature overnight. The white solid in the reaction solution was removed by filtration, after which the filtrate was washed with a 0.5 M aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel column chromatography (DCM) to afford the title compound (Compound SP429) (7.15 g, 91.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[OH:12])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16].C>>[OH:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:13](=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2cccnc2c1O
Product: CCCC(=O)Nc1cnc2cccnc2c1O
Yield: 46.3 %

Procedure:
Using the general method of Example 57 Part B, 3-amino[1,5]naphthyridin-4-ol (1.8 g, 11.2 mmol) was reacted with butyryl chloride (1.3 g, 12.3 mmol) to provide 1.2 g of N-(4-hydroxy[1,5]naphthyridin-3-yl)butanamide as a charcoal gray solid, m.p. >360° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:14]1[CH2:15][CH2:16][CH:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH:9]=2)[CH2:12][CH2:13]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cccc(C(=O)NCc4ccccc4)c3)c12
Product: CC(=O)N1CCC(c2cc(-c3cccc(C(=O)NCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 26 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 3-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-benzylbenzamide and acetyl chloride as starting material, 20 mg (26.0%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.88-7.82 (m 2H), 7.62 (d, 1H), 7.55 (t, 1H), 7.36-7.28 (m, 4H), 7.25-7.20 (m, 1H), 6.58 (s, 1H), 4.67-4.59 (m, 3H), 4.06-3.98 (m, 1H), 3.52-3.43 (m, 1H), 3.33-3.24 (m, 1H), 2.78 (td, 1H), 2.20-2.08 (m, 5H), 1.73-1.63 (m, 2H); LC-MS m/z [M+H]+469.3, RT 2.34 min.