Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:14][C:13]([C:6]1[CH:7]=[C:8]([CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:9]([OH:11])=[O:10])=[O:15])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Product: C=CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
5-Nitroisophthalic acid (5 g) was converted to the mono allyl ester using one equivalent of allyl bromide (2 ml) using a similar method to that described in example 1. The required acid (2.7 g) was extracted from the organic phase with aqueous NaHCO3. The organic layer contained the di-allyl ester (2.7 g). The mono acid, 3-allyloxycarbonyl-5-nitrobenzoic acid, was obtained as a white solid. Nmr (CDCl3): 4.87 (d, 2H); 5.3-5.5 (q, 2H); 5.97-6.15 (m, 1H); 9.01 (t, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:31]=[C:30]([Cl:32])[C:29]([F:33])=[CH:28][C:14]=1[C:15]([CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]>O>[Cl:12][C:13]1[CH:31]=[C:30]([Cl:32])[C:29]([F:33])=[CH:28][C:14]=1[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Reaction time: 3 h
Yield: 78.6 %

Procedure:
0.15 g of p-toluenesulphonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluorobenzoylmalonate (3) in 50 ml of water. The mixture is heated to boiling, with thorough stirring, for 3 hours, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution, dried with Na2SO4 and the solvent is distilled out in vacuo. Fractionation of the residue under high vacuum provides 21.8 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate (4) of boiling point 127°-142° C./0.09 mbar.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:6]1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)(Cl)(Cl)Cl>C1COCC1>[C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:6]1[N:36]=[N+:37]=[N-:38])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1,3,4,6-Tetra-O-acetyl-2-O-trifluormethanesulfonyl-β-D-mannopyranose (6) (53 mg, 0.11 mmol) was dissolved at 25° C. in 3 mL of THF. Trimethylsilyl azide (19 μL, 0.15 mmol) was added via syringe followed by TBAF (150 μL, 0.15 mmol). The solution was stirred at 25° C. for 22 h. The reaction mixture was filtered through a plug of silica gel and concentrated in vacuo to give a yellow oil which was chromatographed (2:1, hexane/EtOAc) to afford 30 mg (73%) of β-anomer as a colorless oil. IR (CCl4) 2113, 1762; 1H NMR (CDCl3) 5.56 (d, J=8.8), 5.10 (t, J=9.5), 5.05 (t, J=9.5), 4.31 (dd, J=4.8, 12.5), 4.09 (dd, J=12.5), 3.79 (ddd, J=9.5, 4.8, 2.0), 3.65 (dd, J=9.5, 8.8), 2.18 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H). The spectra for the anomeric mixture has been previously reported (Vasella, A. et al., Helv. Chim. Acta 74:2073-2077 (1991)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=3)[S:10][C:3]=12.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH2:27])=[CH:22][CH:21]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:12]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:27][C:23]3[CH:24]=[C:25]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([CH3:17])=[CH:26]4)[CH:8]=2)=[CH:15][N:14]=[CH:13]1
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cncn5C)sc34)ccc2[nH]1
Yield: 16.5 %

Procedure:
7-Chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine (600 mg, 2.40 mmol) and 2-methyl-5-aminoindole (422 mg, 2.89 mmol) were dissolved in 20 mL of tert-butanol and 20 mL of dichloroethane and heated to 85° C. The solvent was allowed to evaporate overnight and was replaced the following day with the same amounts as in the initial reaction mixture along with an additional 90 mg of the indole. The solution was heated an additional 24 hours and allowed to go dry as before. Chromatography of the residue with 30-5-% methanol:ethyl acetate afforded 142 mg (16%) of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine. 1H NMR (400 MHz, CD3OD) δ8.14 (d, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.40 (s, 1H), 7.34 (d, 1H), 7.29 (s, 1H), 6.99 (d, 1H), 6.72 (d, 1H), 6.17 (s, 1H), 3.84 (s, 3H), 2.44 (s, 3H). LC-MS: 360, 361 (MH+); HPLC RT: 3.96 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([C:5]3[S:6][C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[CH:3][CH:4]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(-c3ccc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyridine (example E.87) (0.25 g, 0.626 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.152 g, 0.689 mmol) according to the general procedure VI. Obtained as a light brown solid (0.055 g, 21%). MS (ISP) 412.1 [(M+H)+], 414.2 [(M+2+H)+] and 416.2 [(M+4+H)+]; mp 180° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2].C(O)(=O)C>O>[CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of 1.9 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 28 ml of 75% v/v aqueous acetic acid was stirred at 60° C. for 2 hours. At the end of this time, the reaction mixture was diluted with 7 ml of water and cooled to room temperature. Precipitated trityl alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The syrupy residue was crystallized in diisopropyl ether, to give 1.21 g of the title compound, melting at 166°-167° C.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:12](I)([CH3:14])[CH3:13].O.[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[OH:28])[O:24][C:23]([CH3:30])([CH3:29])[CH2:22][C:21]2=[O:31]>>[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH:12]([CH3:14])[CH3:13])[O:24][C:23]([CH3:29])([CH3:30])[CH2:22][C:21]2=[O:31]
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1O)C(=O)CC(C)(C)O2
Temperature: 130 °C
Yield: 90 %

Procedure:
In 80 ml of N,N-dimethyl formamide 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.2 g (2.5 ml, 25 millimoles) of isopropyl iodide are added. The reaction mixture is heated at 130° C. for 6 hours, poured into 200 ml of water and extracted with 100 ml of carbon tetrachloride. To the aqueous layer 50 ml of an 5% sodium hydroxide solution are added and the mixture is cooled below 5° C. The mixture is acidified with concentrated hydrochloric acid, the precipitated crystalline substance is filtered off and crystallized from methanol. Thus 4.5 g of the desired compound are obtained, yield 90%, mp.: 138°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[O:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.S(=O)(=O)(O)O.[N+:29]([O-])([OH:31])=[O:30]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:19])[C:13]3[CH:14]=[C:15]([N+:29]([O-:31])=[O:30])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[O:9]2)=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)Nc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(c2ccc(Cl)cc2)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Yield: 32 %

Procedure:
To a stirred suspension of 4-(4-chlorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.15 g, 18.80 mmol) in a mixture of glacial acetic acid (15 mL) and concentrated sulfuric acid (15 mL) was slowly added concentrated nitric acid (3 mL). After 10 minutes the reaction was poured over ice and brine (100 mL) and filtered. Trituration of the solid with ethyl acetate/ether gave 4-(4-chlorophenyl)-4-methyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one as a tan solid (1.92 g, 32%). 1H NMR (DMSO-d6): δ 11.04 (s, 1H), 8.29 (m, 2H), 7.47 (dd, J=6.6, 2.0 Hz, 2H), 7.32 (dd, J=6.7, 2.1 Hz, 2H), 7.13 (d, J=9.5 Hz, 1H), 2.06 (s, 3H); MS (ESI) m/z [M+H]+(319/321); MS (ESI) m/z [M−H]− (317/319); Anal. calcd for C15H11ClN2O4: C, 56.53; H, 3.48; N, 8.79. Found: C, 55.43; H, 3.37; N, 8.78.
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28](O)=[O:29])=[CH:20]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:2][CH2:1][CH:3]([NH:6][C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2([CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]2)[CH:20]=1)=[O:29])[CH2:4][CH3:5]
Reactant: CCC(N)CC
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C(=O)O)c3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-ethylpropylamine (0.5 mL) was added to a stirred solution of compound (C4) (0.50 g, 1.52 mmol), EDAC.HCl (0.6 g, 3.00 mmol), HOBt (0.31 g, 2.32 mmol) in DMF (10 mL) and the solution was stirred at room temperature for 2 h. The solution was poured into water (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage SP1 on silica gel eluting with 5-70% EtOAc in hexanes to provide tert-butyl 3-(pentan-3-ylcarbamoyl)spiro[inden-1,4′-piperidine]-1′-carboxylate (F1) as a white solid (0.6 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 399 (M+1), Rt 3.66 minutes. 1HNMR (500 MHz, DMSO-d6) δ 7.78 (d, 1H), 7.55 (m, 1H), 7.43 (d, 1H), 7.23 (br m, 1H), 4.07 (m, 2H), 3.75 (m,1H), 3.15 (m, 2H), 1.98 (d, 2H), 1.55 (m, 2H), 1.45 (s, 9H), 1.25 (m,2H), 0.88 (m, 6H).
Reaction SMILES: [CH2:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[C:21]2[S:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(C(OCC)=O)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+]>O>[C:21]1([C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])=[CH:15][CH:16]=2)=[O:26])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(CC)(C(=O)OCC)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 16.8 parts of diethyl 2-ethyl-2-[p-(2-thenoyl)phenyl]malonate, 4 parts of sodium hydroxide and 80 parts of water is stirred and refluxed for 6 hours. The reaction mixture is poured onto water and the whole is extracted with ether. The aqueous phase is separated and acidified with hydrochloric acid solution: the product is separated as an oil which solidifies. It is extracted with ether. The extract is washed three times with water, dried, filtered and evaporated. The solid residue is crystallized from 24 parts of acetonitrile at room temperature, yielding 2-[p-(2-thenoyl)phenyl]butyric acid, also named p-(2-thenoyl)-α-ethyl-phenylacetic acid; mp. 122.8° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]([CH3:22])[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].CCCCCC>C1COCC1>[CH3:22][N:10]([CH3:9])[NH:11][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12](=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)N1C(=O)c2ccccc2C1=O
Reactant: Br[Mg]c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)NC(=O)c1ccccc1C(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of phenylmagnesium bromide in THF (11.6 mmol) was slowly added to a solution of phthalimide 16 (10.5 mmol) in THF (110 ml) at −78 ° C. and stirred under argon for 15 minutes. The mixture was then progressively warmed to −30 ° C. for 1 hour. The reaction was quenched with a saturated aqueous solution of NH4Cl (15 ml) and the aqueous layer extracted with Et2O. The combined organic layers were washed with brine (20 ml), dried over MgSO4 and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography with (1:2) EtOAc:hexane, to give 80% yield of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol) and TBTU (90 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (216 μL, 1.26 mmol). Then 4-aminotetrahydropyran (28 mg, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (92 mg, 89%) as a white solid. MS: m/e=413.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]O)[CH:21]=2)[CH:19]=1)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Br:54][CH2:26][C:22]1[CH:21]=[C:20]([C:18]2[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])[C:15]3[CH:30]=[N:29][N:28]([CH:31]([CH3:32])[CH3:33])[C:16]=3[N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3-(hydroxymethyl)phenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (2.1 g, 4.7 mmol) in DCM (35 mL), triphenyl phosphine (5 g, 19.06 mmol) was added and stirred it at room temperature for 10 min. Finally CBr4 (6.2 g, 18.69 mmol) was added portion wise to it and resulting solution was stirred at room temperature for overnight. After completion of reaction, solid was filtered and dried to obtain the desired compound (1.2 g, 52.2%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ncccn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)Cc3ncccn3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using pyrimidin-2-yl-acetic acid and 3 (S)-benz yl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.67 min, [M+1]+ 461. Potency class B.
Reaction SMILES: [C:1]1([C:11]2[S:12][C:13]3[CH:36]=[C:35]([O:37]C)[CH:34]=[CH:33][C:14]=3[C:15]=2[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]1([C:11]2[S:12][C:13]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:14]=3[C:15]=2[C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:22][CH:23]=2)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc4ccccc34)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cccc3ccccc23)sc2cc(O)ccc12
Yield: 53.4 %

Procedure:
A solution of the product of Example 1 (1.00 g, 1.92 mmol), ethanethiol (0.45 mL, 6.18 mmol), and aluminum chloride (1.54 g, 11.55 mmol) in anhydrous methylene chloride (40 mL) was stirred for 3.5 hours. The mixture was quenched with saturated potassium sodium tartrate (also known as Rochelle's salt) and extracted with ethyl acetate. The organic layer was washed with saturated sodium potassium tartrate and brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol in methylene chloride) to give 520 mg (53%) of the title product as a dark yellow/green foam: 1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H), 1.65 (m, 4H), 2.54 (m, 4H), 2.73 (t, J=5.4 Hz, 2H), 3.96 (t, J=5.4 Hz, 2H), 6.37 (d, J=8.7 Hz, 2H), 6.88 (dd, J=1.9 Hz, 8.8 Hz, 1H), 7.23-7.29 (m, 2H), 7.37-7.51 (m, 5H), 7.62-7.70 (m, 3H), 8.02-8.05 (m, 1H), 8.28 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ23.3, 24.7, 54.4, 57.0, 64.5, 106.9, 113.0, 115.2, 124.2, 124.3, 125.2, 125.5, 126.1, 127.6, 128.7, 128.7, 130.3, 130.5, 131.2, 131.6, 131.8, 132.8, 133.4, 140.7, 141.1, 154.6, 161.6, 192.1; MS (FD) m/e 508 (MH+); Anal. calc'd. for C32H29NO3S: C, 75.71; H, 5.76; N, 2.76. Found: C, 75.43; H, 6.02; N, 3.03.
Reaction SMILES: NC(N)=O.C=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12]([OH:15])(=[O:14])[CH3:13]>>[NH:7]([CH2:13][C:12]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: NCC(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: NC(N)=O
Product: O=C(O)CNCC(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A 2 L autoclave was charged with urea (V) (60 g, 1.0 mole), Co(OAc) 2.4H2O (66 g, 0.26 mole), and acetic acid (1 L). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H2 (70:30) was established at 25° C. with stirring at 2000 rpm. The contents of the autoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H2 (70:30) was established. After approximately one hour, rapid gas uptake was observed. The reaction mass was cooled to 85° C. and the feed gas was changed to a CO:H2 (90:10) composition. Under a constant 3200 psi (22,069 kPa), 47 Wt. % formalin (320 mL, 5.28 mole) was delivered at 16 mL/min. The reaction was stirred at 85° C. for 90 min. after the formalin addition was complete. Then the reaction was cooled to 25° C., removed from the autoclave, and concentrated to an oil under reduced pressure. The oil was treated with 2 L of 10% HCl at 100° C. for two hours. This resulted in a 13% yield of (XIV) and 5% glycine.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.C([Li])(C)(C)C.[CH:21](=[O:23])[CH3:22]>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH:21]([OH:23])[CH3:22])=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1
Reactant: COCOc1ccc(CC(C)(C)C)nc1
Reactant: CC=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cnc(CC(C)(C)C)cc1C(C)O
Temperature: -78 °C

Procedure:
To a solution of 5-(methoxymethoxy)-2-neopentylpyridine (16.5 g, 79 mmol) and in THF (200 mL)-78° C. is added tert-butyllithium (46 ml, 79 mmol) (1.7 M in pentane) over 2 min via cannula. The reaction was stirred at −78° C. 30 min, and acetaldehyde (11 ml, 197 mmol) was added. The reaction was stirred at −78° C. 10 min, then the reaction was warmed to rt and stirred 3 h. The reaction was quenched by addition of saturated aqueous NH4Cl (400 mL), extracted with EtOAc (3×200 mL), the combined organic layers washed with saturated NaCl (10 mL), dried (Na2SO4), and concentrated to give a orange oil, which was purified by chromatography on an ISCO (330 g SiO2, 10%-50% EtOAc/Hexane) gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol as a clear, light yellow oil.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].N1CCCCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(C#C[Si](C)(C)C)cc2)OC1(C)C
Temperature: 35 °C
Yield: 88.4 %

Procedure:
To a toluene (40 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidine-3-carboxylate (2.0 g, 4.6 mmols) is added ethynyltrimethylsilane (451 mg, 4.6 mmols), copper (I)iodide (88 mg, 0.46 mmols, 0.1 equivs), Bis(triphenylphosphine)palladium(II)dichloride (165 mg, 0.23 mmols, 0.05 equivs) and piperidine (782 mg, 9.2 mmols, 2 equivs). The mixture is heated in an atmosphere of nitrogen at 35° C. for six hours. The mixture is filtered through a pad of Celite. The pad of Celite is washed with ethylacetate (2×15 ml). The combined organic filtrates were concentrated using rotary evaporation at reduced pressure to give a crude viscous oil. The oil is purified by flash column chromatography (grading from 100% hexanes to 15% EtOAc) to give the title compound (1.65 g): m/z (Cl) 306 ([M+H]+-Boc).