Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][NH:17][C:16](=[O:19])[N:15]1[CH3:20])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[H-].[Na+].Cl>CN(C=O)C.ClCCl.CO.ClCCl.CCOCC>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][N:17]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:16](=[O:19])[N:15]1[CH3:20])=[O:13]
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)N(CCN2CCOCC2)CC1C(=O)NCc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
A mixture of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (100 mg, 0.33 mmol) (prepared as described in Example 28) and potassium carbonate (91 mg, 0.66 mmol) in DMF (1 ml) was stirred at room temperature for 10 minutes and 4-(2-chloroethyl)morpholine hydrochloride (61 mg, 0.33 mmol) was added. The mixture was stirred for 30 minutes and then heated at 60° C. for 3 h and 80° C. for 2 h. The mixture was cooled to room temperature and sodium hydride (40 mg, 60% dispersion in oil, 1 mmol) was added and the mixture heated at 50° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC to give two components with same molecular ion. Each component was converted to the corresponding HCl salt by dissolving the product from mass-directed automated HPLC in methanol/dichloromethane, adding an excess of 1M HCl in ether, evaporating the solvent, co-evaporating the residue with methanol and ether. The residue was triturated with ether/heptane and the solid collected and dried to give N-[(2-Chloro-3,4-difluorophenyl)methyl]-3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxamide hydrochloride (22 mg, 15%) (LC/MS [M+H]+=417, retention time=1.40 minutes) and N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxamide hydrochloride (6 mg, 4%) (LC/MS [M+H]+=417, retention time=1.55 minutes).
Reaction SMILES: C([N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([CH3:35])=[CH:27][CH:26]=3)[CH:22]=[C:21]([C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]([CH3:46])=[CH:38][CH:37]=3)[CH:20]=2)=[N:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:46][C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]([C:21]2[CH:20]=[C:19]([C:16]3[N:15]=[N:14][NH:18][N:17]=3)[CH:24]=[C:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([CH3:35])=[CH:27][CH:26]=3)[CH:22]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(-c2cc(-c3nnn(C(c4ccccc4)c4ccccc4)n3)cc(-c3ccc(C)c4ccccc34)c2)c2ccccc12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(-c3nn[nH]n3)cc(-c3ccc(C)c4ccccc34)c2)c2ccccc12
Reaction time: 8 h
Yield: 95.5 %

Procedure:
2-Benzhydryl-5-(3,5-bis(4-methylnaphthalen-1-yl)phenyl)-2H-tetrazole (0.32 g, 0.54 mmol) was dissolved in dichloromethane (2 mL). Anisole (0.3 mL, 2.76 mmol) and TFA (1 mL) were added sequentially. The reaction was stirred overnight, and then concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate:AcOH=30:10:1) to afford 0.22 g (95.5%) of product as a white solid, 1H NMR (DMSO, 500 MHz) δ 8.24 (d, J=1.55 Hz, 2H), 8.25 (d, J=8.15 Hz, 2H), 8.03 (d, J=8.20 Hz, 2H), 7.72 (s, 1H), 7.65 (t, J=7.58 Hz, 2H), 7.60 (t, J=7.44 Hz, 2H), 7.56 (d, J=7.15 Hz, 2H), 7.51 (d, J=7.29 Hz, 2H), 2.74 (s, 6H); 13C NMR (DMSO, 125 MHz) δ 141.58, 136.38, 134.51, 133.81, 132.43, 130.72, 127.15, 127.03, 126.51, 126.32, 126.11, 125.61, 124.76.19.21.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(=O)([O-])O.[Na+].NN.[Cl:18][C:19]1[N:20]=[C:21]2[C:26](=[C:27]3[C:32]=1[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH:25]=[CH:24][CH:23]=[CH:22]2>ClCCl.C(O)C.O>[ClH:18].[CH:25]1[C:26]2[C:21](=[N:20][C:19]([NH:9][NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:10])=[C:32]3[C:27]=2[CH:28]=[CH:29][CH:30]=[CH:31]3)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1nc2ccccc2c2ccccc12
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: NN
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1NNc1nc2ccccc2c2ccccc12
Temperature: 25 °C

Procedure:
A solution of o-tolylhydrazine hydrochloride (7.6 g, 47 mmol) in dichloromethane (450 ml) is extracted by shaking three times each with saturated aqueous sodium hydrogencarbonate solution (90 ml each time) and demineralized water. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness. Yield: 4.9 g (86%). The hydrazine (4.8 g, 39 mmol) is dissolved in ethanol (100 ml) and admixed under argon with 6-chlorophenanthridine (A. G. Mikhailovskii, V. S. Shklyaev, Chem. Heterocycl. Comp. 1992, 445) (7.0 g, 33 mmol). The mixture is stirred under reflux for 16 h. After cooling to room temperature, the resulting precipitate is filtered off and washed with ethanol and petroleum ether. Yield: 9.3 g (85%).
Reaction SMILES: O.[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([S:18][CH3:19])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH2:20][CH3:21])[N:6]([CH2:22][CH2:23][OH:24])[N:5]=1)[CH3:3].[OH:25]OS([O-])=O.[K+]>ClCCl>[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([S:18]([CH3:19])=[O:25])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH2:20][CH3:21])[N:6]([CH2:22][CH2:23][OH:24])[N:5]=1)[CH3:3]
Reactant: O=S([O-])OO
Reactant: CCc1nn(CCO)c(CC)c1Oc1cc(C#N)cc(SC)c1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1nn(CCO)c(CC)c1Oc1cc(C#N)cc(S(C)=O)c1
Temperature: 25 °C

Procedure:
Wet alumina was prepared by adding water (1 ml) to Brockman grade I alumina (5 g). To a stirred solution of the sulphide from Example 250 (134 mg, 0.40 mmol) in dichloromethane (2 ml) was added of wet alumina (400 mg) followed by Oxone® (123 mg, 0.4 mmol) and the mixture was heated at reflux. After 1 hour a second portion of oxone (123 mg, 0.40 mmol) was added and the mixture was heated for a further 2 hours. After cooling to room temperature the reaction mixture was filtered and the resulting solids were washed with dichloromethane (20 ml). The filtrate was concentrated and was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (a gradient from 99:1 to 90:10, by volume) to provide the title compound (92 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:31][C:14]2[N:15]=[CH:16][C:11]3[CH:10]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=3[N:13]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NC3CCCCC3)nc21
Temperature: 134 °C

Procedure:
A mixture of 0.100 g (0.26 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.300 g (3.00 mmol) of cyclohexylamine was heated to the boiling point (134° C.). The resulting solution was heated at reflux for 2 minutes. Most of the excess amine was evaporated at reduced pressure. The remaining gum was dissolved in 2 mL of ethyl acetate hot. Petroleum ether (2 mL) was added, and the crystals that separated from the cooled solution were filtered and washed with water; wt 0.090 g. Recrystallization from ethyl acetate gave pure crystalline product; 0.048 g; mp 242°-244° C.
Reaction SMILES: [O-2].[Zn+2:2].[CH3:3][C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5]>O>[Zn:2].[CH3:3][C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5]
Reactant: [Zn+2]
Agent: CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [O-2]
Solvent: O
Product: [Zn]
Temperature: 70 °C

Procedure:
184.8 grams (2.28 moles) zinc oxide was slurried at 20 percent by weight in water and heated to 70° C. An aqueous solution containing 316 grams (1.52 moles) etidronic acid was diluted to 20 percent by weight and heated to 70° C. The zinc oxide slurry was pumped into the etidronic acid solution over 45 minutes with continuous stirring of both the slurry and the solution. A precipitate formed after the addition of about 20 percent of the zinc oxide. The slurry formed was stirred for 4 hours at 60°-70° C. to allow the salt-forming reaction to take place. The slurry was then cooled and filtered on a Buchner funnel. The solid obtained was washed 4 times with distilled water using 2 liters of water each time to wash the salt free of etidronic acid. The wet filter cake was broken up and oven dried at 110° C. to obtain about 500 grams of zinc etidronate as a while solid with needle-like crystals. The solubility of the zinc etidronate was measured by slurrying it in distilled water, centrifuging and measuring the dissolved metal ion content. The metal ion content was 0.165 grams per liter, indicating a pigment solubility of 0.5 grams per liter.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([N:13]([CH3:23])[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)[CH:10]=[CH:11][CH:12]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:52])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH4+].[Cl-]>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH:39]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14](=[O:22])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=3)[CH3:23])[CH:16]=2)[OH:52])[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Reactant: CN(C(=O)c1cccc(I)c1)c1cccc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cccc(C(O)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
n-Butyllithium (1.61 mL of 1.92 M solution; 3.10 mmol) was added to a mixture of N-(3-fluorophenyl)-3-iodo-N-methylbenzamide (1.0 g; 2.82 mmol) and 4-[3-(tert-butyl-dimethyl-silanyloxy)benzoyl]-piperidine-1-carboxylic acid tert-butyl ester (1.182 g; 2.82 mmol) in THF (150 mL) at −78° C. under nitrogen in one portion. The reaction was stirred under nitrogen overnight while the temperature warmed to room temperature. Saturated NH4Cl solution (25 mL) was added to the reaction mixture, followed by the addition of 25 mL of water. The mixture was extracted by ether (300 mL×2). The ether layer was washed by water (200 mL×2) and brine (200 mL×1), dried by Na2SO4 and concentrated to give 2.03 g of crude product, which was purified by silica gel column chromatography eluted with 30% EtOAc in pentane to give 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (763 mg; 42%). 1H NMR (600 MHz, DMSO-d6) δ 7.34 (bs, 1H), 7.29 (s, 1H), 7.23-7.16 (m, 3H), 7.09 (m, 2H), 6.94 (m, 2H), 6.85 (m, 2H), 6.60 (d, 1H, J=7.0 Hz), 5.25 (s, 1H), 3.88 (m, 2H), 3.35 (s, 3H), 2.60 (bs, 2H), 2.34 (m, 1H), 1.37 (s, 9H), 1.36 (m, 2H), 1.16 (m, 2H), 0.91 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:16][CH2:17][CH:18]=C)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C(NCCC=C)=CC=CN=1.CC([O:36]C(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[O:36]=[C:18]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][N:3]=2)[N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[CH2:16][CH2:17]1
Reactant: C=CCCN(C(=O)OC(C)(C)C)c1cccnc1Br
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=CCCNc1cccnc1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
tert-butyl (2-bromopyridin-3-yl)(but-3-en-1-yl)carbamate. To a solution of 2-bromo-N-(but-3-en-1-yl)pyridin-3-amine (1 eq.) and DCM (0.2 M) is added (Boc)2O (1.5 eq.). The solution is stirred at room temperature until judged complete by TLC. The solution is concentrated in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]([C:19]([OH:21])=[O:20])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH2:17][CH3:18])[CH:8]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][C@H:5]([C:19]([OH:21])=[O:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH2:17][CH3:18])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOc1ccc(C=C(NC(C)=O)C(=O)O)cc1OCC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOc1ccc(C[C@H](NC(C)=O)C(=O)O)cc1OCC
Yield: 69.5 %

Procedure:
To a suspension of N-acetyl-3-(3,4-diethoxyphenyl)dehydroalanine (100.2 g) in acetic acid (1000 ml) is added 10% palladium-carbon (4 g), and the mixture is subjected to hydrogenation at 40° C. under 3 atms of hydrogen gas for 7 hours. The catalyst is removed by filtration, and the filtrate is concentrated. The residue is crystallized from ether to give N-acetyl-3-(3,4-diethoxyphenyl)alanine (70.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:14][O-:15].[Na+].[Na]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([O:15][CH3:14])[CH:6]=[CH:5]2
Reactant: Cc1cc(Br)cc2ccc(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccc2cc(Br)cc(C)c2n1

Procedure:
A solution of 6-bromo-2-chloro-8-methylquinoline (10.7 g) in methanol (80 cm3) was heated under reflux with a solution of sodium methoxide [made from sodium 2.76 g) in methanol (50 cm3)]for 24 hours. The cooled solution was then evaporated in vacuo and the residue was partitioned between chloroform (100 cm3) and water (50 cm3). The aqueous phase was further extracted with chloroform (2×50 cm3) and the combined and dried (MgSO4) organic phases were evaporated in vacuo to give a solid which was recrystallised from ethyl acetate:hexane, 1:9, to afford 6-bromo-2-methoxy-8-methylquinoline, m.p. 89°-91° (8.3 g).
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([NH:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1.I[CH3:29].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:29][N:21]([CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:19]([C:16]1[N:8]2[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=[C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)[C:7]2=[N:18][CH:17]=1)=[O:20]
Reactant: CI
Reactant: O=C(NC1CCOCC1)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(1,3-oxazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide (55 mg) and iodomethane (18 μL) in DMF (2 mL) was added 60% sodium hydride (8.7 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (47 mg).
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:42]I>C(Cl)Cl>[I:42][CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Yield: 103.5 %

Procedure:
A dry 50 mL r-flask was charged with (S)-4-(3-hydroxy-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (1.0 g, 4.2 mmol), PPh3 (2.2 g, 8.5 mmol), imidazole (0.58 g, 8.5 mmol) and dissolved with CH2Cl2 (25 mL). Iodine (2.2 g, 8.4 mmol) was then added in small portions over 4 h period. After the last addition the reaction was poured onto SiO2 and filtered. Concentration under reduced pressure yielded the crude title compound (1.5 g), which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(I)cc1
Temperature: 70 °C
Yield: 61.8 %

Procedure:
A stirred mixture of 4-iodophenol (0.50 g, 2.27 mmol), methyl 2-bromoacetate (0.382 g, 2.50 mmol), and powdered potassium carbonate (0.314 g, 2.27 mmol) in dry acetone under argon was sealed and heated at 70° C. for 4 hr. The cooled mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography (silica, 40 to 50% methylene chloride in cyclohexane) and the solvent was removed in vacuo to afford the titled intermediate as a white solid (0.41 g, 62%), mp 69°-70° C.
Reaction SMILES: [CH:1](/[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])=[CH:11][CH:10]=2)[N:7]=[N:6][C:5]=1[C:23](O)=[O:24])=[CH:2]\[CH3:3].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH:26]1([NH:29][C:23]([C:5]2[N:6]=[N:7][N:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[O:16])=[CH:11][CH:10]=3)[C:4]=2/[CH:1]=[CH:2]/[CH3:3])=[O:24])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: C/C=C/c1c(C(=O)O)nnn1-c1ccc(C(=O)NCC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: C/C=C/c1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
To a solution of 5-[(1E)-prop-1-en-1-yl]-1-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxylic acid (1.96 g) obtained in Example 1215a) in DMF (22 ml) were successively added cyclopropylamine (0.46 ml), triethylamine (0.92 ml), HOBt (1.01 g) and WSC (1.27 g), and the reaction mixture was stirred at room temperature for 2.5 hr. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as a white powder (1.13 g, 52%).
Reaction SMILES: O[CH:2]([C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:20]1([C:17]2[O:16][C:15]([CH:2]=[CH:3][C:4]3[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C=Cc1cccc(CC(O)c2ccc(-c3ccccc3)o2)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1cccc(C=Cc2ccc(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To acid (28) (9.2 mg, 0.028 mmol) in DCM (1 mL), externally cooled to −78° C., was added methanesulphonyl chloride, (20 mg, 0.17 mmol) and triethylamine (29 mg, 0.29 mmol). The solution was then allowed to warm to ambient temperature and stirred for a further 2 hours. The solvent was concentrated in vacuo and the residue purified by Flash Master Jones Chromatography using a 2 g silica cartridge and eluting with 50% EtOAc in heptane to give the title compound as a white solid. Yield: 3.6 mg, 41%; LC-MS tr 1.77 min; NMR Purity: >85%; MS (ES+) m/z 317 (M+H); 1H NMR (400 MHz; DMSO): δ 6.70-6.80 (m, 2H), 7.15 (d, 1H), 7.25-7.35 (d, 1H), 7.35-7.45 (m, 2H), 7.50-7.60 (m, 4H), 7.65-7.75 (m, 3H), 7.90 (d, 2H), 8.10 (s, 1H)
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O.CO>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3Nc3ccc(OC)nc3)n2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc(-c3cccnc3)ccc2-c2nc(C)nc(N)n2)cn1
Yield: 10.2 %

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)-2,3′-bipyridin-6-amine (276 mg, 0.440 mmol) in TFA (10 mL) was heated to 75° C. for 15 h. about 80% of the TFA was removed in vacuo and the crude oily residue was pipetted into an ice cooled solution of NaHCO3. The resulting suspension was collected by filtration and was washed with water and MeOH. The solid was then dry-packed on silica gel and purified on the ISCO (12 g column, 1-25% MeOH in DCM) to give partially purified product. This was suspended in MeOH and filtered, and the filtercake was dry-packed with silica gel and purified on the ISCO (12 g column, 3-15% MeOH in DCM) to give 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)-2,3′-bipyridin-6-amine (17.2 mg, 0.045 mmol, 10.11% yield) as a brown amorphous solid. m/z (ESI, +ve ion) 387.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.86 (1H, s); 9.26 (1H, d, J=2.0 Hz); 8.88 (1H, d, J=8.0 Hz); 8.66 (2H, d, J=2.9 Hz); 8.41 (1H, dt, J=8.1, 1.8 Hz); 8.21 (1H, dd, J=8.9, 2.6 Hz); 7.89 (1H, br. s.); 7.74 (1H, br. s.); 7.58 (1H, d, J=8.0 Hz); 7.52-7.56 (1H, m); 6.90 (1H, d, J=9.0 Hz); 3.87 (3H, s); 2.45 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:29])=[C:13]([CH2:20][NH:21]C(=O)OC(C)(C)C)[CH:14]=[CH:15][C:16]=2[CH:17]([F:19])[F:18])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][CH2:20][C:13]1[C:12]([F:29])=[C:11]([O:10][C:4]2[CH:5]=[C:6]([CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:8]#[N:9])[C:16]([CH:17]([F:19])[F:18])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(F)F)c(Oc2cc(Cl)cc(C#N)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)F)ccc(CN)c2F)c1

Procedure:
A solution of 1,1-dimethylethyl {[3-[(3-chloro-5-cyanophenyl)oxy]-4-(difluoromethyl)-2-fluorophenyl]methyl}carbamate (0.152 g, 0.356 mmol) and TFA (1.372 ml, 17.81 mmol) in dichloromethane (10 ml) was stirred for 16 h at RT under an atmosphere of nitrogen. The solution was concentrated under vacuum to give the title compound as an orange oil that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40-7.52 (m, 2H), 7.31 (s, 1H), 7.23-7.26 (m, 1H), 6.89 (s, 1H), 6.74 (t, 1H), 4.19 (br. s., 2H).