Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]([CH3:27])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][N:20]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[N:17]([CH3:27])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][N:20]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cn1c(-c2ccccc2)cnc1I
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc(-c2ccccc2)n1C
Yield: 52 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted [using 2-iodo-1-methyl-5-phenyl-1H-imidazole (prepared from 1-methyl-5-phenyl-1H-imidazole according to J. Org. Chem. (43) 4381, 1978) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 88 mg, 52%) which was obtained as a light brown solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8].Cl.[NH2:13][C:14]([NH2:16])=[NH:15].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[CH:7]([C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:15]=[C:14]([NH2:16])[N:13]=1)([CH3:9])[CH3:8]
Reactant: COCC(=O)CC(=O)C(C)C
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCc1cc(C(C)C)nc(N)n1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a stirred solution of 1-methoxy-5-methylhexane-2,4-dione (1.08 g, 6.8 mmol) in EtOH (15 mL) was added guanidine hydrochloride (1.3 g, 13.7 mmol). 5 min later, a solution of Na2CO3 (1.45 g, 13.7 mmol) in H2O was added and the resulting mixture was heated to reflux for 20 h. The reaction was cooled to room temperature and the solvent was removed. The residue was dissolved in EtOAc (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexanes) to provide 4-isopropyl-6-(methoxymethyl)pyrimidin-2-amine (482 mg, 39%). 1H NMR (CDCl3): d 6.43 (s, 1H), 6.11 (s, 2H), 4.16 (s, 2H), 3.26 (s, 3H), 2.56-2.66 (m, 1H), 1.03 (d, J=6.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[N:10][OH:11])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:20]#[C:21][CH2:22][CH3:23]>CCOCC>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:9]2[CH:20]=[C:21]([CH2:22][CH3:23])[O:11][N:10]=2)=[CH:5][N:6]=1
Reactant: ON=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: C#CCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1cc(-c2cnc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5,6-Dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (0.85 g, 3.8 mmol) was dissolved with stirring in ether (60 mL) and a solution of triethylamine (0.8 g, 7.9 mmol) in ether (50 mL) added dropwise to the solution while 1-butyne was bubbled through the reaction mixture. The mixture was stirred at room temperature overnight, filtered, and the filtrate evaporated to dryness under reduced pressure. Recrystallisation of the residue from hexane gave the desired product (0.83 g, 90%) as a cream solid, melting point. 98-9° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.CCOCC>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:6]=[N:7][C:2]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:3][C:4]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(N2CCOCC2)nnc1Nc1ccc(I)cc1F
Temperature: 135 °C

Procedure:
To mixture of 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (34 mg, 0.09 mmol) in DMF was added morpholine (37.7 mg, 0.43 mmol). The mixture was heated at 135° C. for 3.5 h. The mixture was diluted with ether and extracted with NaOH (1N). The aqueous layer was acidified by concentrated HCl. The desired product was precipitated and was collected by vacuum filtration. LC/MS [5.51 min; 445 (M+1)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([OH:15])=O)=[CH:7]1.Cl.Cl.[NH:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][NH:24]/[C:23]/1=[N:32]\[C:33]([C:35]1[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=1)=[O:34].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([N:29]2[CH2:30][CH2:31][C:26]3([NH:22]/[C:23](=[N:32]/[C:33]([C:35]4[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=4)=[O:34])/[NH:24][CH2:25]3)[CH2:27][CH2:28]2)=[O:15])=[CH:7]1
Reactant: O=C(O)c1ccc(=O)n(Cc2ccc(F)c(F)c2)c1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4ccc(=O)n(Cc5ccc(F)c(F)c5)c4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3,4-Difluoro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.15 mmol) in NMP (0.5 ml) is added to a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (0.049 g, 0.15 mmol) and N-methyl morpholine (0.033 ml, 0.30 mmol) in NMP (1 ml), followed by a solution of HATU (0.11 g, 0.3 mmol) in NMP (0.5 ml). The reaction mixture is shaken at room temperature overnight. The reaction mixture is purified by mass-directed preparative HPLC. Fractions containing pure product are eluted through SCX-2 cartridges (Biotage 1 g/6 ml cartridge), and the cartridge is washed with MeOH (4 ml), followed by 3M NH3 in MeOH solution (4 ml) to afford the title compound; [M+H]+ 572.0
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:26])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[N:20][C:21](F)=[CH:22][C:23]=4[CH3:24])=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.COC1C=CC(C[NH2:34])=CC=1>O>[NH2:34][C:21]1[N:20]=[CH:19][C:18]([C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[C:6]([CH3:26])=[CH:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:11][CH2:12]2)=[O:17])=[C:23]([CH3:24])[CH:22]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Solvent: O
Product: Cc1cc(N)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
A mixture of [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (1.45 g) described in Preparation Example 140 and 4-methoxybenzylamine (1.12 g) was stirred at 100° C. for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in dichloromethane (10 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.07 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15](=[O:33])[N:16]3[CH2:19][CH2:20][N:21]([CH3:32])[C:22]([O:24]CC3C=CC=CC=3)=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:40](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl.[Pd]>[C:22]([N:21]([CH3:32])[CH2:20][CH2:19][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15]1=[O:33])(=[O:24])[CH3:40]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.023 g, 0.043 mmol) in CH2Cl2 (1.5 mL) was combined with diisopropylethylamine (0.0038 mL, 0.22 mmol), acetic anhydride (0.021 mL, 0.22 mmol) and Pd/C (0.012 g, 10% w/w). The resulting suspension was flushed with nitrogen and evacuated several times the charged with hydrogen under a balloon and stirred at ambient temperature overnight. The reaction mixture was filtered, washed with CH2Cl2, and concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with 1N NaHSO4, and brine, concentrated the organics to afford the title compound as an oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.59 Hz, 3 H), 1.86 (s, 3 H), 2.94 (s, 3 H), 3.50 (t, J=6.86 Hz, 2 H), 4.18 (s, 2 H), 4.28 (q, J=6.83 Hz, 4 H), 7.12 (t, J=8.69 Hz, 2 H), 7.35-7.40 (m, 2 H), 8.02 (d, J=6.40 Hz, 1 H), 8.47 (s, 1 H); ES+ MS: 442 (M+H+).
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH:6]=[C:5]2[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C1COCC1>[Pd].CO>[N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH:5]2[C:10]1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(C2=CCCc3n[nH]cc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(C2CCCc3n[nH]cc32)cc1
Yield: 97.3 %

Procedure:
4-(6,7-dihydro-2H-indazol-4-yl)benzonitrile (3.21 g, 14.5 mmol) is added to THF (10 mL), MeOH (10 mL), and 5% Pd/C (0.2 g) and hydrogenated under a balloon of H2 at room temperature for two hours. The mixture is filtered through a pad of diatomaceous earth and evaporated to dryness. The residue is purified by silica gel flash chromatography eluting with 50%-70% ethyl acetate/hexanes, to give the title compound (3.15 g, 97%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (45.0 mg, 0.200 mmol) using the same procedure employed for Example 2 (2), but with 4-dimethylaminophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a slightly brown solid (34.8 mg, 45%) having the following characteristics.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[O:11][CH2:12][CH3:13]>C1C=CC=CC=1>[C:1]1([CH:3]2[CH2:2][CH:1]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:6][CH2:13][C:12]2=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Solvent: c1ccccc1
Product: O=C1CCC(c2ccccc2)CC1c1ccccc1

Procedure:
The oil was dissolved in 400 mL benzene and added dropwise over 40 minutes to 83 mL (250 mmol) of a 3.0 M solution of phenylmagnesium bromide in ether, cooling so the temperature did not rise above 10° C. The reaction was then allowed to warm and heated to reflux for 14 hours. It was then cooled, quenched with aqueous ammonium chloride solution, then washed with water and brine, dried over sodium sulfate, and evaporated. The yield was 53.9 g (approximately theoretical), and the crude oil was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]([NH2:32])[CH2:29][O:30][CH3:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]([NH:32][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:29][O:30][CH3:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)O
Reactant: COC[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Product: COC[C@H](NC(=O)[C@H](COC(F)F)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
The compound of Formula II(b)(ii) was prepared as an off-white foam in a similar manner as the compound of Formula II(a)(ii), described above, from the compound of Formula IV(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid and the compound of Formula V(b), (S)-2-amino-3-methoxy-propionic acid benzyl ester, hydrochloride salt.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>C1COCC1>[CH:3]1([N:2]([CH3:1])[C:22](=[O:23])[C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To an ice cold stirred solution of N-methylcylohexylamine (20 ml, 0.15 mol) and triethylamine (22 ml) in dry THF (100 ml) under argon was slowly added p-toluoyl chloride (20 ml, 0.15 mol). A white precipitate formed. The ice bath was removed and the mixture stirred at ambient temperature for 24 h. Ice cold 2M hydrochloric acid (100 ml) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine (3×100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give the crude amide, which was crystallised from hexane to give N-cyclohexyl-N-methyl-4-methylbenzamide (30.9 g, 87%) as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[O:22]([NH2:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:23][O:22][N:24]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON=C1CCC(N(C)C(=O)c2ccc3nonc3c2)CC1
Reaction time: 8 h
Yield: 70.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), methoxylamine hydrochloride (0.75 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.32 g). Mp=167-168° C., NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.84 (m, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.85-4.70 and 3.80-3.30 (m, 1H); 3.83 (s, 3H); 2.99 and 2.88 (s+s, 3H); 2.60-1.60 ppm (s, 8H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Mg]Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[CH:17](OC(C)=O)[O:18]C(C)=O.Cl.CCCCCCCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH2:17][OH:18])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)OC(C)=O
Reactant: Cc1c([Mg]Cl)cccc1-c1ccccc1
Agent: Cl
Solvent: CCCCCCCC
Solvent: Cc1ccccc1
Product: Cc1c(CO)cccc1-c1ccccc1
Temperature: 53 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Under a nitrogen atmosphere, the reaction mixture from above was decanted into a clean, dry flask, leaving the unreacted magnesium turnings in the first flask. This solution, which contains (2-methyl[1,1'-biphenyl]-3-yl)magnesium chloride, was heated to reflux, and 16.5 g (0.55 mole based on formaldehyde) of polyoxymethylene diacetate (avg. mol. wgt. approx. 50,000, available commercially from E.I. du Pont de Nemours & Co., Inc., Wilmington, Delaware under the trade name Delrin 500 acetal homopolymer resin), milled to about 80 mesh, was added with stirring over three hours. Refluxing was continued for four additional hours after which the reaction mixture was allowed to cool and stand overnight. The mixture was then heated to 53° C. and was poured into a mixture of 100 g of ice, 52 g of concentrated hydrochloric acid, and 200 g of a mixture containing 95% n-octane and 5% toluene (wt/wt). This mixture was filtered and the organic phase separated. The organic solvents were distilled off, boiling range 65°-93° C. During a four hour period the solution was cooled with stirring to approximately 5° C. and was then filtered. The filter cake was washed with 100 mL of cold n-octane and air-dried for 0.5 hour. The filter cake was broken up and dried under a vacuum at 55° C. for four hours, yielding 78.9 g of (2-methyl[1,1'-biphenyl]-3-yl)methanol (89.9% purity), a yield of 70.8% of theory.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][CH2:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43](=[O:44])[CH2:42][O:41][CH3:40]
Reactant: COCC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 55B (0.038 mmol), DEPBT (0.016 g, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.184 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.011 g, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.81 (s, 9 H), 0.84 (s, 9 H), 1.52 (m, 2 H), 2.56 (m, 1 H), 2.74 (m, 3 H), 3.26 (s, 3 H), 3.49 (s, 3 H), 3.66 (m, 1 H), 3.82 (m, 3 H), 4.03 (m, 1 H), 4.16 (m, 1 H), 4.31 (d, J=9.56 Hz, 1 H), 4.83 (d, J=5.88 Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H), 7.14 (m, 8 H), 7.31 (m, 1 H), 7.85 (m, 6 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.CCN(CC)CC.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([NH:17][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:9]=1
Reactant: COC(=O)c1cc(N)cc(-c2ccc(Cl)cn2)c1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
3-Amino-5-(5-chloro-pyridin-2-yl)-benzoic acid methyl ester (1.5 g, 5.71 mmol, from Preparation 2) and Et3N (2.39 mL, 17.13 mmol) were dissolved in 30 mL methylene chloride, and isobutyryl chloride (72 mL, 6.85 mmol) was added. The reaction mixture was stirred at room temperature for two hours, and then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.29 g of 3-(5-chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methyl ester, MS (M+H)=333.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:11]([F:13])([F:14])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH:24][C:28]([NH:27][CH2:25][CH3:26])=[O:29]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]−).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:6]([C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccccc2[N+](=O)[O-])c1C

Procedure:
o-Nitroaniline (15 mmol, 2.1 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (15 mmol, 3.7 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over three silica gel columns to yield the named product, 1H-NMR (CDCl3, ppm): 1.36 t (3H), 2.36 s (3H), 4.31 q (2H), 6.80 s (1H), 7.03-7.66 bm (6H), 7.68 dt (2H) 7.97 dd (1H)