Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=2)[CH:22]=[CH:23][CH:24]=1>ClCCl>[N:31]([C:27]1[CH:26]=[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[N:30]=[CH:29][N:28]=1)=[C:1]=[S:2]
Reactant: COc1cccc(-c2cc(N)ncn2)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cccc(-c2cc(N=C=S)ncn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.970 g, 4.17 mmol) in dichloromethane at room temperature was added 6-(3-methoxyphenyl)pyrimidin-4-amine (0.7 g, 3.48 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak as a major peak. The deep orange solution was concentrated and the remaining residue was filtered. The filtrate was purified by silica gel chromatography (0-10% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.39 g, 4.31 mmol, 46% yield) as a yellow oil. LCMS R.T.=2.91; [M+H]+=244.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
1-fluoro-4-acetyl-benzene was reacted with nitric acid to obtain 2-fluoro-5-acetyl-nitro benzene with a melting point of 56°-58° C. which was reacted as in Example 1 to obtain 0-(4-acetyl-2-nitro-phenyl)-hydroxylamine melting at 132° C.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1.Br[C:24]1[CH:25]=[C:26]([CH2:30][OH:31])[CH:27]=[N:28][CH:29]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[OH:31][CH2:30][C:26]1[CH:25]=[C:24]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)[CH:29]=[N:28][CH:27]=1
Reactant: OCc1cncc(Br)c1
Reactant: C[Sn](C)(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cncc(CO)c3)ccc2n1
Yield: 43.5 %

Procedure:
163 mg of 6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 4), 310 mg of (5-bromopyrid-3-yl)methanol, 66 mg of tetrakis(triphenylphosphine)-palladium and 4 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 20 minutes in a microwave machine set at 150° C. and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with dichloromethane. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 61 mg of 6-[5-(hydroxymethyl)pyrid-3-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1.S(=O)(=O)(O)O.[CH3:23]O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([O:14][CH3:23])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cccc(-c2cc(F)cc(F)c2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(-c2cc(F)cc(F)c2)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-(3,5-difluorophenyl)benzoic acid (2.3 g) in anhydrous methanol (46 ml) was added concentrated sulfuric acid (2.3 ml). The mixture was heated under reflux for four hours. After cooling to ambient temperature, the mixture was concentrated. Ethyl acetate (200 ml) and water (100 ml) were added and the layers were separated. The organic layer was successively washed with 20% aqueous potassium carbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with hexane-ethyl acetate (10:1) as an eluent. The fractions containing the object product were collected and evaporated in vacuo to give methyl 3-(3,5-difluorophenyl)benzoate.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH:33]([F:35])[F:34])=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH:33]([F:35])[F:34])=[C:25]([C:10]2[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:12][N:8]([CH2:7][C:6]([OH:36])=[O:5])[N:9]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of {3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid tert-butyl ester (45.0 g, 86.7 mmol) in dichloromethane (350 mL) was added TFA (100 mL) and the mixture left to stir at room temperature for 18 hours. The solvent was evaporated and the resultant residue triturated with diethyl ether. The resultant solid was collected by filtration, washed with diethyl ether and left to air dry to afford the title compound as a white solid (40.0 g, 99%). LCMS (Method 3) [M+H]+=463.1, RT=2.89 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.86 (s, 1H), 8.78 (dd, 1H), 8.71 (s, 1H), 8.56 (dd, 1H), 8.40 (s, 1H), 7.70 (d, 1H), 7.42 (dd, 1H), 7.30 (s, 1H), 6.99 (dd, 1H), 6.47 (t, 1H), 4.86 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6](O)[C:7](=[CH:9][CH:10]=1)[OH:8])[CH2:2][CH3:3].[C:12]([O-])([O-])=[O:13].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][O:13][CH2:12][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1ccc2c(c1)COO2
Temperature: 117.5 °C

Procedure:
4-Propyl catechol (10.7 g; 70 mmols) was dissolved in a 90:10 (v/v) DMF/dichloromethane mixture (17 ml). The resulting solution was added very slowly to a suspension of anhydrous K2CO3 (14.1 g; 87 mmols) in a 90:10 (v/v) DMF/dichloromethane mixture (85 ml), maintained at 115-120° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:15][C:16](=[O:37])[CH:17]([S:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][S:27][CH:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][O:10][C:9](=[O:11])[CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:23][CH:24]=2)[C:16]([OH:37])=[O:15])=[CH:31][CH:32]=1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Product: CN1CCN(CC(=O)OCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)CC1

Procedure:
The title compound was prepared starting from N-methyl piperazino acetic acid and 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloro-ethyl ester in the same manner as described for example 7 (yield: 7.9 mg, 26%). 1H-NMR (300 MHz, CDCl3): δ 2.28-2.54 (m, 4H), 2.42 (s, 3H), 2.63-2.88 (m, 4H), 2.88-3.29 (m, 10H), 3.60-3.67 (m, 1H), 5.00-5.21 (m, 2H), 6.91-7.00 (m, 2H), 7.13-7.20 (m, 2H), 7.22-7.33 (m, 4H); Mass Spectrum: M+H+ 475.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]2.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:44][CH:45]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]([CH2:55][C:56]#[N:57])[C:46]1=[O:58]>C(Cl)Cl.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:44][CH:45]1[CH2:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]([CH2:55][C:56]#[N:57])[C:46]1=[O:58])=[O:23])=[CH:15]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N#CCN1C(=O)C(N)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
HOBT (168 mg, 1.24 mmol), 5-chloroindole-2-carboxylic acid (243 mg, 1.24 mmol), DIPEA (0.22 mL, 1.24 mmol) and then EDCI (296 mg, 1.55 mmol) were added to a solution of (3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (Method 12, 250 mg, 1.24 mmol) in DCM (10 mL). The reaction was stirred for 18 h at ambient temperature, diluted with EtOAc (15 mL), washed with 1 N NaOH (15 mL), 1 N HCl (15 mL), saturated aqueous NaHCO3 solution (15 mL), dried (MgSO4) and the volatiles removed under reduced pressure to give the title compound (366 mg, 78%) as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)N1CCN(CC(=O)OC)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=CN(C)C)C(=O)OC)CC1
Reaction time: 48 h

Procedure:
To a solution of the product of step (i) (10 g) in dry DMF (80 ml) was added dimethylformamide dimethyl acetal (DMFDMA) (30 ml) and the reaction mixture was heated to reflux. After 2 days a further quantity of DMFDMA (30 ml) was added and refluxing was continued for a further 2 days. The reaction mixture was evaporated and the residue partitioned between aqueous ammonium chloride solution and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica by elution with ethyl acetate to yield 1-ethoxycarbonyl-4-(1-dimethylamino-2-methoxycarbonylethen-2-yl)-piperazine (7 g) as an orange oil: NMR (CDCl3) δ 1.28 (3H, t), 2.90 (4H, m), 3.14 (6H, s), 3.50 (4H, m), 3.64 (3H, s), 4.12 (2H, q), 7.01 (1H, s); m/Z 286 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][OH:13].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][O:13][C:16](=[O:17])[N:15]([CH3:19])[CH3:14]
Reactant: Cn1c(CO)nc([N+](=O)[O-])c1C#N
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)OCc1nc([N+](=O)[O-])c(C#N)n1C

Procedure:
1.8 G. (0.01 moles) of 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole and 2.14 g. (0.12 moles) of dimethylcarbamoyl chloride are combined in 15 ml. of pyridine and heated at 100°C. for 24 hours. The reaction mixture is evaporated to dryness, treated with 50 ml. of water and extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried, evaporated to dryness and the residue triturated with ether. The solid material is filtered and crystallized from isopropanol affording 1-methyl-2-(N,N-dimethylcarbamoyloxymethyl)-4-nitro-5-cyanoimidazole, m.p. 85° to 88°C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1[CH3:7].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[N:3]=[C:4]([CH3:16])[N:5]([C:8]3[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=3)[C:6]=2[CH3:7])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(I)c(C)n1-c1ccn(C)c(=O)c1
Reactant: C#Cc1cccc(F)c1
Product: Cc1nc(C#Cc2cccc(F)c2)c(C)n1-c1ccn(C)c(=O)c1

Procedure:
The title compound, brown waxy solid, MS: m/e=322.1 (M+H+), was prepared in accordance with the general method of example 1c from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1-methyl-1H-pyridin-2-one and 1-Ethynyl-3-fluoro-benzene.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[F:20])[CH2:5][CH2:4]1.[Cl:24][C:25]1[C:38]([N:39]=[C:40]=S)=[C:37]([Cl:42])[CH:36]=[CH:35][C:26]=1[CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CC(C)N=C=NC(C)C>>[F:23][C:2]([F:1])([F:22])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[C:12]([F:20])=[CH:13][C:14]3[N:18]([CH3:19])[C:40]([NH:39][C:38]4[C:37]([Cl:42])=[CH:36][CH:35]=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]=4[Cl:24])=[N:17][C:15]=3[CH:16]=2)=[O:21])[CH2:7][CH2:8]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(F)cc21

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-fluoro-4-methylamino-5-amino-benzoic acid amide and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to example 1g.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1.[OH-].[K+]>CO.[Cu].O.CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 190 °C
Yield: 21 %

Procedure:
Potassium t-butoxide (20 g) was added to a solution of 4-chloro-4'-hydroxybiphenyl (mp 142° C., prepared as in J.A.C.S, 2219, 1964) (33 g) in methanol (200 ml). The resulting mixture was evaporated to dryness under reduced pressure and the solid residue obtained was mixed with p-bromotoluene (83 g), copper powder (1 g) and dimethylsulphoxide (80 ml). The resulting mixture was refluxed (190° C.) for 16 hours, potassium hydroxide (9 g) was added and the mixture was refluxed for a further 6 hours. After cooling, the mixture was poured into water and extracted with methylene chloride. The methylene chloride extract was washed with water, dried (MgSO4) and evaporated to give a crude product in the form of an oil which solidified on standing. This crude product was triturated with 60/80 petroleum ether to give 1-(4'-chlorobiphenyl-4-yloxy)-4-methylbenzene (10 g, 29%) mp 130° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:21][C:22]([CH3:24])=[O:23]>C1COCC1.CCOCC>[OH:23][C:22]([C:13]1([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:24])[CH3:21]
Reactant: CC(C)=O
Reactant: N#CC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C1(C#N)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of diisopropylamine (4.2 mL) in THF (30 mL) at 0° C. was added n-BuLi in hexanes (1.6 M, 19 mL). After stirring for 30 min., the reaction mixture was cooled to −78° C. and cyclohexanecarbonitrile (1.09 g, 10 mmol) in THF (10 mL) was added drop wise. After 2 h, acetone (1.16 g, 20 mmol) was added. The reaction mixture was stirred from −78° C. to rt overnight, diluted with Et2O (100 mL), washed with 1N HCl, H2O, brine and dried over anhydrous sodium sulfate. Purification by flash chromatography (1:1, hexanes-Et2O) gave 1-(1-hydroxy-1-methyl-ethyl)-cyclohexanecarbonitrile (1.27 g, 76%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ (ppm) 0.86–1.91 (8H, m), 1.35 (6H, s), 2.01 (2H, d, J=12.8 Hz), 3.65 (1H, t, J=6.4 Hz). Mass Spec [M+H]+=168.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([OH:26])[CH2:4][C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:65][CH3:66])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=3)[S:56][CH:57]=2)[C:48]1=[O:64])[C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][C@H:3]([OH:26])[C@@H:2]([NH:1][C:44](=[O:45])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=3)[S:56][CH:57]=2)[C:48]1=[O:64])[CH:42]([CH3:41])[CH2:65][CH3:66])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2csc(-c3ccccn3)n2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2csc(-c3ccccn3)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution containing the product from Example 3D (0.025 g, 0.055 mmol) in DMF (0.5 mL) was treated with the product from Example 3L (0.021 g, 0.056 mmol), EDAC (0.020 g, 0.104 mmol), HOBT (0.015 g, 0.111 mmol), and NMM (0.020 mL, 0.182 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, diluted sodium bicarbonate, 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 (0.028 g, 63% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.79 (m, 15 H), 0.95 (m, 1 H), 1.29 (m, 1 H), 1.49 (m, 2 H), 1.80 (m, 1 H), 2.68 (m, 4 H), 3.03 (m, 1 H), 3.17(m, 2 H), 3.55 (s, 3 H), 3.63 (m, 3 H), 3.94 (d, J=11.03 Hz, 2 H), 4.12 (m, 2 H), 4.47 (m, 2 H), 6.62 (d, J=9.93 Hz, 1 H), 7.07 (m, 10 H), 7.25 (d, J=9.56 Hz, 1 H), 7.48 (m, 1 H), 7.57 (s, 1 H), 7.75 (d, J=8.46 Hz, 1 H), 7.93 (m, 1 H), 8.10 (d, J=8.09 Hz, 1 H), 8.62 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Br)(Br)([Br:17])=O.[OH-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2ccccc12
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)nc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
4-Nitroquinoline 1-oxide (940 mg, 4.9 mmol) in chloroform (12 mL) was cooled to 0° C. To this solution, POBr3 (1.77 g, 6.2 mmol) was added in small portions. The mixture was stirred at 0° C. for 2 h and diluted with DCM (50 mL), and poured on ice (50 g). To this suspension, 1 M NaOH was added to adjust pH to about 9. Layers were separated and the organic layer was washed with water (2×50 mL) and dried over MgSO4 and concentrated. The crude product was purified by silica chromatography to afford 2-bromo-4-nitroquinoline as a yellow solid (620 mg, 50%). 1H NMR (400 MHz, CDCl3): δ 7.63-7.94 (m, 2H), 8.06 (s, 1H), 8.17 (t, J=7.16, 6.84 Hz, 1H), 8.38 (d, J=8.76 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])[O:13][C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>CCO.[Pd]>[CH3:18][C:12]1([CH3:19])[CH2:11][CH:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:15][C:14]([CH3:17])([CH3:16])[O:13]1
Reactant: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccc(N)cn2)CC(C)(C)O1
Yield: 95 %

Procedure:
To a solution of 5-nitro-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-pyridine (as prepared in the previous step, 15.0 g, 57.1 mmol) in EtOH (60 mL) was added 10% Pd/C (7.00 g). The resulting mixture was hydrogenated at 50 psi of hydrogen pressure for 2 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to obtain a beige solid (12.7 g, 95%) which was directly used in next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 8.05 (br s, 1H), 6.98 (m, 2H), 3.59 (br s, 2H), 3.16 (m, 1H), 1.79 (m, 2H), 1.52 (m, 2H), 1.35 (s, 6H), 1.26 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C14H22N2O, 235.2 (M+H), found 235.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:12][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[C:8]([CH3:11])[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c(C)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,5-dimethylbenzoic acid (20 g, 133 mmol) in 100 mL of conc. sulfuric acid was cooled to 0° C., and then N-bromosuccinimide (24 g, 139 mmol) was added. The reaction was stirred at 0° C. for 1.5 hours. The mixture was poured onto ice/water, extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to afford 3-bromo-2,5-dimethylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr

Procedure:
To a 2-L round-bottom flask equipped with an mechanical overhead stirrer, a reflux condenser and a N2inlet was added ethyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (85g, 0.27moles, 1.0eq) and dry carbon tetrachloride (750ml, 0.38M). Freshly recrystallized N-bromo succinimide (52.72g, 1.1eq) was added as a solid, Benzoyl peroxide (6.5g, 10mol %) was added at room temperature all at once as a solid, and the reaction mixture was refluxed for 5hrs. The reaction was monitored by 1H NMR and was determined to be composed of a 9:1mixture of mono-bromination product (i.e. desired product) and di-bromination product with a 90% conversion. After cooling to 0° C. (to precipitate out the succinimide) the reaction was filtered through Celite and the solvent was removed under reduced pressure to yield a brown oil. The oil was crystallized using hexanes to yield 100g (94%) of an off-white product of 90% purity.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:4]([Cl:22])=[C:5]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:6]([F:11])=[C:7]([CH2:9]Br)[CH:8]=1>C(Cl)Cl>[NH2:1][CH2:9][C:7]1[C:6]([F:11])=[C:5]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:4]([Cl:22])=[C:3]([Br:2])[CH:8]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)c(CBr)cc(Br)c2Cl)c1
Reactant: N
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(CN)cc(Br)c2Cl)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To an ammonia (7.0 M solution in MeOH) (60.0 ml, 2771 mmol) solution was added 3-{[3-bromo-5-(bromomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile in DCM (40 ml) dropwise at 0° C. and the reaction mixture was allowed to warm to rt overnight. The solvent was removed, the residue dissolved in EtOAc and the mixture was neutralized with saturated sodium bicarbonate. The solvent was removed and the crude material was purified via silica gel chromatography to give the title compound 3-{[3-(aminomethyl)-5-bromo-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (801 mg, 2.054 mmol, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (d, 1H), 7.77 (s, 1H), 7.25-7.60 (m, 2H), 3.72 (s, 2H), 1.98 (br. s., 2H)