Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][O:41][CH3:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:39][CH2:40][O:41][CH3:42])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(OCc3ccccc3)cc1OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (A2 from 2,4-bis-benzyloxy-5-isopropyl-benzoic acid (Preparation B10) and 5-hydroxyisoindoline) (100 mg, 0.2 mmol), 1-chloro-2-methoxy-ethane (23.6 mg, 0.25 mmol) and K2CO3 (34.5 mg, 0.25 mmol) in DMF (4 ml) were combined and stirred for 2 hours at room temperature. A further 0.25 mmol of 1-chloro-2-methoxy-ethane and K2CO3 was added then heated at 90° C. for 16 hours. Reaction cooled to room temperature and diluted with EtOAc then filtered. The filtrate was reduced in vacuo then purified by flash column chromatography, eluting with 100% petroleum ether to 100% ethyl acetate to afford 115 mg of the title compound as a colourless gel. MS: [M+H]+ 552
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:52][CH2:51][CH:45]([C:46]([O:48]CC)=[O:47])[CH2:44][CH2:43]1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([N:42]2[CH2:52][CH2:51][CH:45]([C:46]([OH:48])=[O:47])[CH2:44][CH2:43]2)=[O:36])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N3CCC(C(=O)O)CC3)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and ethyl isonipecotate (31 mg, 0.20 mmole) were processed as in Example 279A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6 δ12.05-12.35 (br.s, 1 H), 8.95 (s, 1 H), 7.23 (m, 8 H), 7.03 (m, 1 H), 6.94 (m, 4 H), 6.69 (dd, 1 H), 6.49 (m, 2 H), 4.20 (d, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (t, 2 H), 3.77 (d, 1 H), 3.05 (t, 1 H), 2.91 (s, 3 H), 2.70 (t, 1 H), 2.47 (m, 1 H), 2.43 (m, 2 H), 2.39 (s, 3 H), 1.90 (m, 2 H), 1.79 (m, 2 H), 1.45 (m, 1 H), 1.34 (m, 1 H); MS (APCI+) m/z 686.4 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.Cl[CH2:7][Cl:8].OC[CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]2[O:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]1=[O:23]>C(N(CC)CC)C>[Cl:8][CH2:7][CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]2[O:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]1=[O:23]
Reactant: Cc1cc2c(=O)n(CCCO)ccc2o1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(=O)n(CCCCl)ccc2o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methane sulfonyl chloride(0.24 ml) was added to a dichloromethane solution(10 ml) of 5-(3-hydroxypropyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and triethylamine(0.45 ml). The mixture was stirred at room temperature for two days. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:4→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound(0.16 g) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=2[C:27]([N:29]([CH3:33])[CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=2[C:27]([N:29]([CH3:33])[CH2:30][C:31]#[CH:32])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: C#CCN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: C#CCN(C)C(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-N-prop-2-ynyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (40 mg, 22%). LCMS (m/e) 519 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.94 (bs, 1H), 8.38 (d, 1H, J=8.3 Hz), 8.08 (s, 1H), 7.60-7.37 (m, 2H), 7.33 (s, 1H), 7.24 (d, 1H, J=8.1 Hz), 7.21-7.12 (m, 1H), 7.02 (d, 1H, J=8.1 Hz), 6.90 (s, 1H), 4.50-4.00 (m, 2H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 3.17 (bs, 3H), 2.95-2.84 (m, 4H), 2.79-2.68 (m, 6H), 2.40-2.28 (m, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.[O:6]1CCC[CH2:7]1.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:17]=1>>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:17]=[C:12]([CH:7]=[O:6])[CH:13]=[N:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: COc1cccc(C#Cc2cncc(Br)c2)c1
Agent: CC(C)[Mg]Cl
Product: COc1cccc(C#Cc2cncc(C=O)c2)c1
Yield: 82 %

Procedure:
Prepare essentially as described in EXAMPLE 90 using a 1 M solution of isopropylmagnesium chloride in tetrahydrofuran (2.98 mL, 2.98 mmol), 3-bromo-5-(3-methoxyphenylethynyl)-pyridine, (prepared as described in PREPARATION 20), (430 mg, 1.49 mmol) to give the title compound (290 mg, 82%).
Reaction SMILES: C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.[C:30]([OH:37])(=O)[CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35].[CH2:38]([O:41][C@H:42]1[C:50]2[C:45](=[CH:46][C:47]([O:51][CH:52]([CH3:54])[CH3:53])=[CH:48][CH:49]=2)[C@@H:44]([NH:55][CH2:56][C@@H:57]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[C@@H:58]([NH2:63])[CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:43]1)[CH:39]=[CH2:40]>>[CH2:38]([O:41][C@H:42]1[C:50]2[C:45](=[CH:46][C:47]([O:51][CH:52]([CH3:54])[CH3:53])=[CH:48][CH:49]=2)[C@@H:44]([NH:55][CH2:56][C@@H:57]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:66])[CH3:67])[C@@H:58]([NH:63][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH2:59][CH:60]([CH3:61])[CH3:62])[CH2:43]1)[CH:39]=[CH2:40]
Reactant: C=CCCCC(=O)O
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)CC(C)C)c2cc(OC(C)C)ccc21
Agent: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Product: C=CCCCC(=O)N[C@@H](CC(C)C)[C@@H](CN[C@H]1C[C@@H](OCC=C)c2ccc(OC(C)C)cc21)O[Si](C)(C)C(C)(C)C

Procedure:
Step EQ (1): Hex-5-enoic acid (240 mg, 2.1 mmol) and (2R,3S)-N1-((1S,3R)-3-(allyloxy)-6-isopropoxy-2,3-dihydro-1H-inden-1-yl)-2-(tert-butyldimethylsilyloxy)-5-methylhexane-1,3-diamine (1.1 g, 2.2 mmol, from Preparation BH) were coupled using a procedure analogous to Step CA (1) to afford N-((2R,3S)-1-((1S,3R)-3-(allyloxy)-6-isopropoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(tert-butyldimethylsilyloxy)-5-methylhexan-3-yl)hex-5-enamide. LC-MS (M+H)+=587.47.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:38])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:39])=[O:4])[CH2:12][CH2:11]2)=[CH:18][CH:17]=1)=[O:38])=[O:25]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4)oc3C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1C(=O)NCCC(=O)Nc1ccc([C@H]2CC[C@H](CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (59.6 mg, 1.5 mmol) was added to trans-[4-(4-{3-[(5-methyl-2-phenyloxazole-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (75 mg, 0.15 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was stirred with acetonitrile and filtered, then eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified. Therefore, the desired compound as a white solid was obtained.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:24][NH:25][CH3:26].Cl>C1(C)C=CC=CC=1.O.C(OC)(C)(C)C>[CH3:24][N:25]([CH3:26])[C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a 40% aqueous solution of dimethylamine hydrochloride (20 mL, 0.18 mol) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over (Na2SO4), filter, evaporate the filtrate in vacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as a white solid; mp 57-59° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22](Cl)[N:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22]([NH:16][CH:14]([C:8]2[N:7]3[C:13]4[C:3]([O:4][CH2:5][CH2:6]3)=[C:2]([F:1])[CH:12]=[CH:11][C:10]=4[N:9]=2)[CH3:15])[N:21]=[CH:20][N:19]=1
Reactant: CC(N)c1nc2ccc(F)c3c2n1CCO3
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)c3c2n1CCO3
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (108 mg, 0.49 mmol), 4-amino-6-chloro-5-cyanopyrimidine (75 mg, 0.49 mmol) and DIPEA (171 μL, 0.98 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in MeOH and acidified with TFA, at which point the solution became homogenous. The reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo and the resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-8% 2M NH3/MeOH in DCM) to afford 434 as a pale yellow solid (125 mg, 75%). LCMS (Method K): RT 2.49 min [M+H]+ 340.1. 1H NMR (DMSO, 400 MHz): δ 8.02 (1H, s), 7.74 (1H, d, J=7.4 Hz), 7.27 (2H, br s), 7.09 (1H, dd, J=8.7, 3.3 Hz), 6.95 (1H, dd, J=12.3, 8.8 Hz), 5.60 (1H, dq, J=7.4, 6.8 Hz), 4.50-4.41 (2H, m), 4.36-4.27 (2H, m), 1.58 (3H, d, J=6.8 Hz)
Reaction SMILES: [C:1]([S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6]CC(O)=O)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[S].[C:41](OC(=O)C)(=[O:43])[CH3:42]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:41]([O:3][CH:1]1[S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:2]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)S[C@H](CCC(=O)O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [S]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1

Procedure:
D-glutamic acid (1) was treated with sodium nitrite in hydrochloric acid to produce (R)-1,4-butyrolactone-4-carboxylic acid (2). Compound 2 was then reduced by borane-dimethyl sulfide complex in THF to give the corresponding (R)-4-(hydroxymethyl)-4-butyrolactone (4), which was subsequently treated with tert-butyldiphenylsilyl chloride in methylene chloride using imidazole as a catalyst to afford (R)-5-O-tert-butyldiphenylsilyl-4-hydroxymethyl-1,4-butyrolactone (53). The protected lactone 53 was opened with sodium hydroxide in ethanol and then converted to the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(R)-hydroxypentanoic acid (54) by reaction with dimethyl sulfate in dimethyl sulfoxide. Compound 54 was transformed into the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(S)-iodopentanoic acid (55) by treatment with triphenylphosphine, imidazole and iodine. Displacement of the iodo group in compound 55 by thioacetate in toluene occurred readily to give the methyl ester of 4-(R)-(acetylthio)-5-[(tert-butyldiphenylsilyl)oxy]pentanoic acid (56). Compound 56 was then treated with 2 equivalents of diisobutylaluminum hydride (DIBAL) in toluene to reductively deprotect the sulfur and reduce the methyl ester to an aldehyde, thereby producing the thiolactol via spontaneous cyclization. The thiolactol was acetylated with acetic anhydride in pyridine to give 1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (57): 1HNMR (CDCl3) delta 7.67 (m, 4H, ArH), 7.40 (m, 6H, ArH), 6.10 (m, 1H, 1-H), 3.70 (m, 1H, 4-H), 3.52 (m, 2H, 5-H), 2.20 (m, 2H, CH2), 2.00 (2 s, 3H, CH3CO-), 1.92 (m, 2H, CH2), 1.08 (s, 9H, tert-butyl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNS(=O)(=O)c1ccc(Br)cc1
Yield: 87 %

Procedure:
4-Bromo-N-[2-(methoxy)ethyl]benzenesulfonamide (512 mg, 87%) was prepared as a white solid from 4-bromobenzenesulfonyl chloride (511 mg, 2 mmol), 2-(methoxy)ethylamine (0.174 mL, 2 mmol) and triethylamine (0.836 mL, 6 mmol) in CH2Cl2 (10 mL) in a manner similar to Example 108, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.77-7.67 (m, 2H), 7.66-7.59 (m, 2H), 4.86 (t, 1H, J=5.7 Hz), 3.45-3.34 (m, 2H), 3.25 (s, 3H), 3.14-3.04 (m, 2H); LRMS (ESI), m/z 294/296 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O>CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:1]=[C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]3[CH:12]=2)=[CH:16][CH:17]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccn2cc(-c3ccc(F)cc3)nc12
Yield: 36.4 %

Procedure:
To a solution of 2-amino-3-nitropyridine (1.3 g, 9.3 mmol) in N,N-dimethylformamide (20 mL) was added 2-bromo-4′-fluoroacetophenone (2 g, 9.3 mmol) and the reaction mixture was heated at reflux for 6 hours. The resulting mixture was concentrated to a solid in vacuo. This residue was dissolved in dichloromethane and the organic phase was washed with aqueous sodium bicarbonate and an aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered through a silica gel pad and concentrated to give a solid. This solid was recrystallized from methanol to give 870 mg (36%) of 2-(4-fluorophenyl)-8-nitroimidazo[1,2-α]pyridine as a brown solid. 1H NMR (d6-DMSO): δ 8.98 (d, 1H), 8.69 (s,1H), 8.32 (d, 1H), 8.10 (q, 2H), 7.36 (t, 2H), 7.15 (t, 1H); 19F NMR (DMSO-d6) δ −113.7; MS m/z 258 (M+1).
Reaction SMILES: ClC1C=CC(C(NC2C=CC(C)=C(I)C=2)=O)=CN=1.C(N[C@@H]1CCNC1)(OC(C)(C)C)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:61])[NH:52][C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[C:55]([I:60])[CH:54]=3)=[CH:47][N:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:38])[NH:39][C@@H:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:61])[NH:52][C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[C:55]([I:60])[CH:54]=3)=[CH:47][N:46]=2)[CH2:41]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Agent: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc2)cc1I

Procedure:
{(R)-1-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester was prepared from 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide and (+)-(R)-3-(Boc-amino)pyrrolidine following a method similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was isolated after a silica gel column purification and a precipitation out of THF with excess of hexanes. HRMS m/z calcd for C22H27N4O3I [M+H]+: 523.1201. Found: 523.1201.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1B(O)O.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cccc(-c2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 80 °C
Yield: 64.8 %

Procedure:
Diethyl 2-(3-bromophenyl)propanedioate (3.75 g), 2-chloro-4-(trifluoromethyl)phenyl boronic acid (4.0 g), dioxane (10 mL), 2M aqueous sodium carbonate solution (5 mL) and dichlorobis(triphenylphosphine)palladium(II) (422 mg) were added to a vial, and the reaction mixture was heated at 80° C. for 30 minutes. The reaction mixture was then cooled, poured into water, extracted with ethyl acetate, and the organic phase was separated and concentrated under vacuum in the presence of Celite® (diatomaceous earth) to yield a crude solid. The crude solid was purified by medium pressure liquid chromatography on silica gel eluting with a gradient of ethyl acetate in hexanes to yield 3.2 g of the title compound. 1H NMR (CDCl3) δ 7.74 (s, 1H), 7.57 (d, 1H), 7.37-7.50 (m, 5H), 4.57 (s, 1H), 4.23 (q, 4H), 1.27 (t, 6H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Yield: 48.9 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.55 g, 1.21 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (1.67 g, 3.03 mmol) at room temperature, the solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.250 g, 0.592 mmol, 49%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc([N+](=O)[O-])cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, yellow solid (41 mg, 47%), MS (ISP) m/z=347.5 [(M+H)+], mp 312° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].B(O)(O)O.[C:15]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[C:22](O)=O)([CH3:18])([CH3:17])[CH3:16]>C1(C)C(C)=CC=CC=1>[C:29]([C:26]1[CH:25]=[C:21]([C:22]2[O:1][C:2]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=3[N:4]=2)[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:27]=1[OH:28])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(O)c(N)c1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: COc1ccc2oc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)nc2c1
Yield: 122.4 %

Procedure:
A solution of 2-hydroxy-5-methoxyaniline (36.9 mmole, 5.13 g), boric acid (36.9 mmole, 2.23 g) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (36.9 mmole, 9.23 g) in xylene (550 ml) was refueled using a Dien Stark trap for approximately two days. The reaction mixture was then concentrated in vacuc to an oil. The oil was treated with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate (3×200 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 15.96 g of a black oil. The material was subjected to preparatory chromatography eluting with 15 to 30% ethyl acetate: hexane over a 30 minute period. Fractions containing title compound were combined and concentrated in vacuo to afford 5.18 g of a solid.