Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[CH:5][N:4]=1.[Mg]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)C1=C(c2ccnc(OC)c2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Mg]
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccnc(OC)c1

Procedure:
To a MeOH solution (0.1 M) of 1-(1,1-dimethylethyl) 3-ethyl 2′-(methyloxy)-5,6-dihydro-4,4′-bipyridine-1,3(2H)-dicarboxylate (1 eq.) from the previous step was added magnesium turnings (3.3 eq.). The suspension was evacuated and back-filled with N2. Finally, the reaction mixture was sonicated at RT for 3.5 h during which the magnesium turnings disappeared. The reaction was then quenched with the addition of diethyl ether and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 90:10 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][Si](C=[N+]=[N-])(C)C>CO.C(OCC)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([O:35][CH3:39])=[O:34])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(Sc3cccc(C(=O)O)c3)ccc2O1)C[C@H](O)c1cccnc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Sc2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2cccnc2)C(=O)OC(C)(C)C)O3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To 650 mg (1.25 mmol) of 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid (Example 173) dissolved in 10 mL 1:1 methanol/ethyl acetate, was added 3 mL of 2M trimethylsilyl diazomethane dropwise. The resulting solution was then allowed to stir at room temperature for 16 hours. The solution was then diluted with ethyl acetate, washed with water and brine, and concentrated in vacuo. The crude mixture was purified by Biotage with 75% ethyl acetate/hexanes to obtain 223 mg (33% yield) of product; MH+ 551.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([C:13]2[C:14]([F:20])=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:6]([N+:21]([O-])=O)[CH:5]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:5]=[C:6]([NH2:21])[C:7]([C:13]2[C:14]([F:20])=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:8]([NH2:10])[CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-c2cc(C)cnc2F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(-c2cc(C)cnc2F)c(N)c1
Yield: 98.8 %

Procedure:
Compound 128 (2.02, 6.03 mmol) was stirred in MeOH (150 mL) with 10% Pd/C (200 mg) under a balloon of hydrogen for 1.5 h. The reaction was filtered through Celite and concentrated to give 1.64 g (99%) of the title compound as a brown solid. MS (ES) [m+H] calc'd for C14H14FN3O2, 276; found 276.
Reaction SMILES: [O:1]=[C:2]([CH:24]=[CH2:25])[CH:3]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]1[S:38][C:37]([CH:39]=[O:40])=[N:36][CH:35]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[O:1]=[C:2]([CH2:24][CH2:25][C:39](=[O:40])[C:37]1[S:38][C:34]([CH2:33][O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:35][N:36]=1)[CH:3]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:22][CH:23]=1)[CH2:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution of tert-butyl 4-[2-oxo-1-(tetrahydro-2H-pyran-4-ylmethyl)but-3-en-1-yl]benzoate (1.50 g) in ethanol (15 mL) were added 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (1.20 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (130 mg) and triethylamine (260 μL), and the mixture was stirred with heating under reflux for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.37 g, yield 95%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 488 (MH+).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=[CH:6][N:5]=1>N1C=CC=CC=1>[Br:1][C:6]1[N:5]=[C:4]([CH3:3])[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=1
Reactant: BrBr
Reactant: Cc1ccnc(C)c1O
Solvent: c1ccncc1
Product: Cc1cc(Br)nc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of bromine (4.2 mL, 81.2 mmol) in anhydrous pyridine (80 mL) was added dropwise to a solution of 2,4-dimethyl-3-hydroxypyridine (10.0 g, 81.2 mmol) in anhydrous pyridine (160 mL). The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure and then further dried under vacuum. The residue was taken up in water (100 mL) and the resulting mixture was stirred for 0.5 hour at room temperature. The precipitated solid was collected by filtration, washed with water and air dried overnight to afford 8.7 g (53%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](C=O)=[CH:7][CH:8]=1.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].[C:19]([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:19]=[C:15]1[C:16](=[O:17])[O:18][C:11]([CH3:12])=[N:14]1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)NCC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1C=C1N=C(C)OC1=O
Temperature: 100 °C
Yield: 52.8 %

Procedure:
Anisaldehyde (11.3 g), N-acetylglycine (9.8 g) and sodium acetate (8.2 g) were dissolved in acetic anhydride (200 ml) and the mixture was heated at 100° C. for 10 hr. After cooling, the precipitated yellow crystals were collected by filtration to give the title compound (9.52 g), melting point 151–153° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1)=O.[NH3:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH2:13][CH2:1][C:3]1[CH:4]=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C=O)cc(B(O)O)c1
Reactant: N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(CN)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-Formyl-5-methylphenylboronic acid (1 eq, 3.05 mmol, 0.5 g) in dry DCM (5 ml) under an inert atmosphere of argon is treated with ammonia solution 35% (1.1 eq, 3.35 mmol, 0.185 ml) followed by acetic acid (1.1 eq, 3.35 mmol, 0.192 ml) and NaBH(OAc)3 (1.2 eq, 3.66 mmol, 0.776 mg) and the resulting mixture is stirred at room temperature overnight. The reaction is quenched by addition of acetonitrile and filtered under vacuum. The filtrate is concentrated in vacuo to afford the title compound which is used without further purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:19][C:20]([O:22]CC)=[O:21])[C:10]=2[CH3:25])=[CH:6][CH:5]=1.O.Cl>C1COCC1>[Cl:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:19][C:20]([OH:22])=[O:21])[C:10]=2[CH3:25])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)O

Procedure:
A solution of 2M sodium hydroxide (3 ml) was added to a stirred mixture of the product from step (ii) (0.36 g), water (10 ml) and THF (10 ml). After 2 h the solution was acidified with 2M hydrochloric acid and extracted with diethylether. The organics were washed with water, dried and evaporated under reduced pressure. The residue was recrystallised from diethylether/isohexane. Yield 138 mg
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([C:8]#[N:9])([CH3:7])[CH3:6])C.[H][H]>[Ni].CO>[CH3:1][O:3][C:4](=[O:10])[C:5]([CH3:7])([CH3:6])[CH2:8][NH2:9]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)C#N
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(C)(C)CN
Yield: 94.7 %

Procedure:
A mixture of 10 g of Raney-nickel 2800 was transferred to a 500 mL hydrogenation vessel and washed three times with 40 mL of methanol. Then, 180 mL of methanol and 25.0 g (0.177 mole) of 2-cyano-2-methylpropanoic acid ethyl ester was added and the mixture agitated on a Paar hydrogenator under a 50 psi atmosphere of hydrogen for 24 hours. The mixture was filtered through Celite, washing the filter pad with methanol, and then concentrated under reduced pressure to give 21.98 g of 3-amino-2,2-dimethyl-propanoic acid methyl ester, which was used without further purification.
Reaction SMILES: BrCC(C1C=CC(S(NC2CC2)(=O)=O)=CC=1)=O.[CH2:18]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](=[O:55])[NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([S:46](=[O:54])(=[O:53])[NH:47][CH:48]3[CH2:52]CC[CH2:49]3)=[CH:42][CH:41]=2)[N:39]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](=[O:55])[NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([S:46](=[O:53])(=[O:54])[NH:47][CH:48]3[CH2:52][CH2:49]3)=[CH:42][CH:41]=2)[N:39]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1nc(-c2ccc(S(=O)(=O)NC3CCCC3)cc2)cs1)C1CCCN1C(=O)OCc1ccccc1
Agent: O=C(CBr)c1ccc(S(=O)(=O)NC2CC2)cc1
Product: O=C(Nc1nc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cs1)C1CCCN1C(=O)OCc1ccccc1

Procedure:
Synthesized from 4-(2-bromo-acetyl)-N-cyclopropyl-benzenesulfonamide (150 mg, 0.57 mmol) following multi-step procedure for Example 354 (Compound 5354). MS: 527.1 (M+H+); H1 NMR (MeOH-d4): δ(ppm) 8.18 (dd, 2H), 7.91 (dd, 2H), 8.03 (d, 1H), 7.28 (m, 2H), 7.11 (m, 2H), 5.09 (m, 2H), 3.48 (m, 1H), 2.76 (m, 2H), 2.98 (m, 3H), 1.29 (m, 1H), 0.51 (brs, 1H).
Reaction SMILES: CC(OC(=O)[NH:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(C)C.F[C:25](F)(F)[C:26]([OH:28])=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:28][CH2:26][C:25]2[CH:18]=[CH:17][CH:16]=[CH:8][CH:9]=2)=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A solution of the product from Example E ((S)-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester) (6.0 g, 14.1 mmol) in CH2Cl2 (28 mL) was treated with trifluoroacetic acid (28 mL). The resulting solution was stirred for 20 minutes and then concentrated. The residue was diluted with EtOAc (300 mL), washed with saturated bicarbonate solution (2×300 mL) and brine (300 mL), dried over Na2SO4, and concentrated to give 4.2 g (91%) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH:17]=[O:18])[NH:8][C:7]=1[CH3:19])=[O:5])C.CO.[OH-].[K+]>O>[CH:17]([C:9]1[NH:8][C:7]([CH3:19])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
5-Formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester was dissolved in water (100 mL) and methanol (45 mL) with stirring. Added KOH (2 eq. 1.9 g) and heated in 100° C. After 2.5 h, cooled to room temperature and the remaining ester was removed by extracting into ethyl acetate (200 mL), dried and concentrated. The water layer was acidified to pH=3 using 2N HCl. The white solid was removed by filtration, rinsing with water. The solid was re-concentrated from toluene, triturated with hexanes and dried to afford 2 g (52%) of an off-white solid. 1H NMR (360 MHz, DMSO-d6) δ 12.46 (br s, 1H, CO2H), 11.95 (s, 1H, NH), 9.08 (s, 1H, CHO), 7.36 (s, 5H, ArH) 2.49 (s, 3H, CH3). MS m/z (relative intensity %, ion) found 229 (100, M+); calc. 229.2.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]([CH:31]1[CH2:33][CH2:32]1)([CH3:30])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[CH:31]1([C:21]([NH:20][C:10]([C:7]2[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([CH3:30])[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)CC(C)(N)C1CC1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C)(CC(=O)OC(C)(C)C)C2CC2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and tert-butyl 3-amino-3-cyclopropyl-butanoate (example 229b) as starting materials and isolated (467 mg, 56%); MS (ESI, m/z): 457.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH3:40][C:41]1([CH2:46][CH2:47][C:48](O)=[O:49])[O:45][CH2:44][CH2:43][O:42]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:40][C:41]1([CH2:46][CH2:47][C:48]([NH:1][C:2]2[CH:3]=[N:4][C:5]3[C:10]([C:11]=2[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:49])[O:45][CH2:44][CH2:43][O:42]1
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Reactant: CC1(CCC(=O)O)OCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NNc1c(NC(=O)CCC2(C)OCCO2)cnc2ccccc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (4.50 g, 16.4 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.93 g, 20.5 mmol), 4-methylmorpholine (2.29 mL, 20.5 mmol), and 4-dimethylaminopyridine (0.100 g, 0.82 mmol) in pyridine (120 mL) was chilled to 0° C. under an atmosphere of nitrogen. The mixture was treated drop-wise with a solution of 3-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid (3.28 g, 20.5 mmol) in pyridine (30 mL). The reaction mixture was allowed to slowly come to ambient temperature. After 18 h, the reaction mixture was concentrated under reduced pressure to give a dark red oil. The oil was dissolved in chloroform (150 mL) and washed with 5% Na2CO3 aqueous solution (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 6.83 g of crude tert-butyl 2-(3-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]amino}quinolin-4-yl)hydrazinecarboxylate as a dark red oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=[C:4](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(/C=C/c2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc(/C=C/c2ccccc2)nc1-c1ccccc1
Yield: 41.2 %

Procedure:
A solution of (E)-methyl 2-(4-methyl-6-phenyl-2-styrylpyrimidin-5-yl)pentanoate (73 mg; 0.189 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and 2N sodium hydroxide solution (0.944 mL; 1.889 mmol) was stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with a 6N hydrochloric acid solution. The formed suspension was extracted twice with ethyl acetate and the organic layers were washed with water and dried by filtration over a phase separater filter (PS1). The crude material was purified first by flash chromatography on silica gel using a linear gradient of methanol (1-10%) in dichloromethane and then by preparative thick layer chromatography on silica gel eluting with 10% methanol in dichloromethane to give 29 mg (40%) of the title compound as a colorless oil. ESI/APCI(+): 373 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1N>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[Cl:14])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Nc1ccccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1Cl
Yield: 5 %

Procedure:
A mixture of 101 g of 4-chloro-1,2-dinitrobenzene and 191 g of 2-chloroaniline in 750 ml of 95° EtOH is refluxed for 96 hours. The solvent is evaporated off under vacuum, the residue is extracted with DCM, washed with a 3 N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/hexane mixture (50/50; v/v) as the eluent to give 7 g of the expected product after crystallization from EtOH. M.p.=97° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]SC(C)C)[CH:5]=1)([O-:3])=[O:2].Cl[C:16]1[CH:21]=CC=C(C(OO)=O)[CH:17]=1.[S:26]([O-:29])(O)=[O:27].[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:26]([CH:16]([CH3:21])[CH3:17])(=[O:29])=[O:27])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=S([O-])O
Reactant: CC(C)SCc1cccc([N+](=O)[O-])c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-nitro-3-[(propan-2-ylsulfanyl)methyl]benzene (4.0 g) in DCM (160 mL) was treated at 0° C. with portions of m-chloroperbenzoic acid (9.3 g, 77%). The mixture was stirred at 0° C. for further 30 minutes and then 18 hours at room temperature. The reaction mixture was diluted with DCM before sodium hydrogen sulfite and sodium bicarbonate solution was added and extracted with DCM (2×). The combined organic phases were washed and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 12%-100%) to give the title compound (4.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([Br:10])[N:3]=1.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:11])[CH:5]=[C:4]([Br:10])[N:3]=1
Reactant: OCc1cc(Br)nc(Br)c1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: BrCc1cc(Br)nc(Br)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A solution of 0.5 g of 2,6-dibromo-4-(hydroxymethyl)pyridine in 7 ml of dichloromethane is added dropwise to a solution of 0.95 g of dibromotriphenylphosphorane in 5 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 0° C. The mixture is stirred to a temperature in the region of 20° C. over about 2 hours. The reaction medium is taken up in 100 ml of dichloromethane and then washed with 100 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 37 mm in diameter packed with 50 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (9/1) (v/v), at a flow rate of 8 ml/minute. The fractions between 135 and 200 ml are concentrated under reduced pressure. 0.349 g of 2,6-dibromo-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](OC)=[N:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH2:1]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[NH:13])[CH3:2]
Reactant: [NH4+]
Reactant: CCC1CCCCN=C1OC
Reactant: [Cl-]
Solvent: CO
Product: CCC1CCCCNC1=N
Product: Cl
Yield: 93.5 %

Procedure:
The product of EXAMPLE 58 (600 mg, 3.9 mmol) in 20 mL of MeOH was reacted with ammonium chloride (165 mg, 3.1 mmol) by the method of EXAMPLE 27 to yield 512 mg (93%) of the title material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][C:14](OC)=O)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].BrC[C:26]1C=C[CH:29]=[C:28]([Cl:32])[CH:27]=1>C1COCC1>[Cl:32][C:28]1[CH:29]=[C:13]([CH:14]=[CH:26][CH:27]=1)[CH2:12][S:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[N:7][CH:6]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)CCSc1cnc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
To a cooled solution of methyl 3-[(5,6-dimethoxypyridin-3-yl)sulfanyl]propanoate (Intermediate 7, 257 mg, 1 mmol) in THF (6 ml) at −45° C. was added potassium tert-butoxide (123 mg, 1.10 mmol). After stirring at −45° C. for 20 minutes, 1-(bromomethyl)-3-chlorobenzene (0.16 ml, 1.20 mmol) was added and the reaction mixture was stirred with warming to room temperature for 2 hours. The resulting mixture was partitioned between ethyl acetate (15 ml) and water (15 nil) and the resulting organic layer was washed with brine (15 ml), dried (MgSO4), filtered and concentrated in vacuo to give yellow oil. Purification by column chromatography (SiO2; 0-10% ethyl acetate in petrol) gave 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine as a yellow oil (244 mg, 82%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:21]C1C=C(B(O)O)C=CC=1>>[NH2:21][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COC(=O)CCCc1ccc(-c2ccc(N)cc2)cc1
Product: COC(=O)CCCc1ccc(-c2cccc(N)c2)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using (3-aminophenyl)boronic acid as in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline ES/MS calcd. for C17H20NO2+ 270.2. Found m/z=270.2 (M+H)+.