Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]12[O:10][CH:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CC#N>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[CH2:25][N:8]1[CH2:7][CH:6]2[O:10][CH:2]([CH2:3][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CC(C)(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CC(=O)C(C)(C)C)CC(C1)O2
Temperature: 40 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (Preparation A; 0.26 g, 1.0 mmol) and K2CO3 (1.45 g, 10.5 mmol) in MeCN (8 mL) was treated with 1-chloropinacolone (0.216 g, 1.6 mmol), and the mixture stirred at 40° C. overnight. The following morning, the temperature was raised to 50° C. for 4 h before the solids were filtered off from the mixture and the filtrate concentrated in vacuo. The crude product was dissolved in DCM and the solution was added to an ion-exchange solid phase extraction plug (10 g CBA (carboxylic acid on silica support)). After 1 h, the plug was washed with DCM (15 mL), after which the product was finally eluted with dichloromethane:MeOH:TEA (90:5:5). The solvents were evaporated to give 0.276 g (85.5%) of the sub-title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[N:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[CH:5]=[N:1][N:2]([C:19]2[N:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: c1ccc(-c2cn[nH]c2)nc1
Reactant: N#Cc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-n2cc(-c3ccccn3)cn2)n1
Temperature: 140 °C

Procedure:
2-(1H-Pyrazol-4-yl)pyridine (300 mg, 2.0 mmol) was dissolved in DMF (10 mL), potassium carbonate (566 mg, 4 mmol) and 6-fluoropyridine-2-carbonitrile (250 mg, 2 mmol) was added. The reaction was heated at 140° C. for 16 h. The crude mixture was cooled to rt and diluted with EtOAc (300 mL) and washed with H2O (200 mL) and brine (200 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes:EtOAc (7:3) to afford 6-(4-pyridin-2-yl-1H-pyrazol-1-yl)pyridine-2-carbonitrile. This material was dissolved in methylene chloride (5 mL) and, upon treatment with 1M HCl in diethyl ether (0.6 mL), precipitated as the hydrochloride salt. M.P. 260-261° C. 1H-NMR (CDCl3, 300 MHz) δ 9.67 (s, 1H), 8.83 (s, 1H), 8.79-8.77 (d, J=6 Hz, 1H), 8.47-8.29 (m, 4H), 8.13-8.10 (m, 1H) 7.77-7.73 (t, 1H). MS ESI) 249 (M++H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[C:17]([O:19]CC)=[O:18])[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[C:17]([OH:19])=[O:18])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(-c2c(Cl)cncc2Cl)noc1C1CC1
Temperature: 120 °C
Yield: 82.3 %

Procedure:
To a solution of ethyl 5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (210 mg, 0.642 mmol) in 2:1 tetrahydrofuran:methanol (3 mL) was added 1 N sodium hydroxide (0.963 mL, 0.963 mmol). The solution was heated in a microwave reactor to 120° C. for 500 seconds. Then 1 N hydrochloric acid (0.963 mL, 0.963 mmol) was added and the solution was concentrated. The residue was taken up with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to afford 5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylic acid (158 mg, 82%). 1H-NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.81 (s, 2H), 2.91-2.84 (m, 1H), 1.34-1.24 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].Br[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccc(Cl)cc12

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and 4-bromomethyl-benzonitrile are processed according to the method described in Example 11 to give 4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.28 (s, 3H), 5.42 (s, 2H), 6.98 (d, J=8.3 Hz, 1H), 7.20 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.55 (dd, J=7.8, 5.1 Hz, 1H), 7.57-7.62 (m, 2H), 7.66 (d, J=2.0 Hz, 1H), 7.84 (dt, J=7.8, 1.9 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 358.1120 [(M+H)+ Calcd for C22H17ClN3: 358.1111].
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[N:6]([CH:11]=[C:12]([CH3:14])[N:13]=3)[N:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:3][CH2:2]1.[CH2:15]([CH:17]([C:20]1[C:21]2[N:22]([C:27](I)=[C:28]([CH3:30])[N:29]=2)[N:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:18][CH3:19])[CH3:16]>>[CH:1]1([C:4]2[C:5]3[N:6]([C:11]([C:27]4[N:22]5[N:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH:17]([CH2:15][CH3:16])[CH2:18][CH3:19])[C:21]5=[N:29][C:28]=4[CH3:30])=[C:12]([CH3:14])[N:13]=3)[N:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cn2nc(C)cc(C3CC3)c2n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C5CC5)cc(C)nn34)c(C)nc12
Yield: 43.9 %

Procedure:
Using a procedure analogous to Example 16B, 8-cyclopropyl-2,6-dimethyl-imidazo[1,2-b]pyridazine (76.5 mg, 0.41 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.14 g, 0.41 mmol) give the title compound (71.6 mg, 0.18 mmol, 43%). 1H NMR (CDCl3): δ 0.91 (t, J=7.1 Hz, 6H), 1.05-1.11 (m, 2H), 1.24-1.30 (m, 2H), 1.75-1.93 (m, 4H), 2.41 (s, 3H), 2.42 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H), 2.65-2.75 (m, 1H), 3.33-3.45 (m, 1H), 6.64 (s, 1H), 6.67 (s, 1H) ppm. ES-MS (m/z): calcd for C24H30N6 (M+H)+: 403.6. found: 403.3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccccc2)cc1O
Reaction time: 8 h

Procedure:
A solution of 2-nitro 5-phenylphenol(1.2 g, 5.5 mmol) in methanol was treated with 10% Pd/C(1.2 g). The reaction mixture was flushed with hydrogen and allowed to stir overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford desired (1.01 g, 98%). EI-MS m/z 186(M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH:12](OC)(OC)OC.S(=O)(=O)(O)O>CO>[CH3:12][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=1)[OH:11]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cc(I)ccc1O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)ccc1O

Procedure:
5-Iodosalicylic acid (Aldrich Chemical Company, Milwaukee, Wis.) is converted to the methyl ester by reaction with methanol, trimethyl orthoformate and sulfuric acid. The 5-iodosalicylic acid methyl ester thus obtained is reacted with (trimethylsilyl)acetylene (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium. The trimethylsilyl group is removed and two equivalents of the resultant 5-acetylenylsalicylic acid methyl ester is reacted with 4,4′-dibromobiphenyl (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium as above. The resultant alkynyl analogue of Chrysamine G, 4,4′-bis(3-methoxycarbonyl-4-hydroxyphenylacetylenyl)-biphenyl is prepared by hydrolysis of the ester as described above. This alkynyl analogue is reduced by conventional methods to form the vinyl analogue of Chrysamine G.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([F:13])=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[F:14])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([C:8]2[O:10][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:11][C:12]=1[F:13])[CH3:2]
Reactant: CCOc1c(F)cc(C(=O)O)cc1F
Reactant: N=C(NO)c1cccc2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(F)cc(-c2nc(-c3cccc4cnccc34)no2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 5.8 %

Procedure:
A mixture of 4-(ethyloxy)-3,5-difluorobenzoic acid (JRD Fluorochemicals Ltd; 130 mg, 0.641 mmol), HATU (244 mg, 0.641 mmol), Hunig's base (0.3 mL, 1.718 mmol) in N,N-dimethylformamide (DMF) (1 ml) was stirred at room temperature for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 100 mg, 0.534 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction mixture was stirred at room temperature for 2-3 hrs and then heated in a microwave at 140° C. for 1.5 hr. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Waters Atlantis column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN+0.1% Formic acid)) to give the title compound (11 mg)
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(=O)(O)[O-].[Na+]>CCO>[Cl:13][C:14]1[N:19]=[C:18]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc(C2CCCCN2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1nccc(N2CCCCC2c2ccccc2)n1
Yield: 66 %

Procedure:
2-Phenylpiperidine, Intermediate 15, (0.5 g, 2.52 mmol), 2,4-dichloropyrimidine (0.41 g, 2.77 mmol) and sodium bicarbonate (0.59 g, 5.55 mmol) in dry EtOH (10 mL) were refluxed for 2 hours, under an atmosphere of nitrogen. The mixture was filtered and the filtrate evaporated in vacuo to give a yellow oil. The oil was purified by flash chromatography (EtOAc and isohexane (1:3)/silica) to give the title compound as a colourless oil (46 g, 66%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[CH2:12]([OH:14])[CH3:13]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6](=[NH:7])[O:14][CH2:12][CH3:13]
Reactant: COc1ccccc1C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccccc1OC
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-methoxy-benzonitrile (760 mg, 5.708 mmol) in anhydrous ethanol (125 mL) cooled to 0° C. After 3.5 h, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 2-methoxy-benzimidate hydrochloride (865 mg, 70%). It was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].IC.[Cl-].[NH4+].[C:14](OCC)(=O)C>C1COCC1>[CH3:14][NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9]
Reactant: CCOC(C)=O
Reactant: Nc1c(Cl)cccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CNc1c(Cl)cccc1Cl
Temperature: -40 °C
Yield: 96 %

Procedure:
2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17]C)[CH:16]=[C:11]2[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([CH3:26])=[CH2:25].Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]([CH2:25][C:24]([CH3:26])=[CH2:23])[C:15](=[O:17])[CH:16]=[C:11]2[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=C(C)CBr
Reactant: COc1cc2c(cn1)N(C(=O)OC(C)(C)C)C(=O)C2(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C=C(C)Cn1cc2c(cc1=O)C(C)(C)C(=O)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Methoxy-3,3-dimethyl-2-oxo-2,3-dihydro-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester was heated with 3-bromo-2-methylpropene (4 eq.) at 100° C. for 4 h in a reactivial and then allowed to cool. Saturated HCl in EtOAc ˜10 vol) was added and the reaction was stirred for 30 minutes at room temperature. The reaction was then concentrated in vacuo to give the title compound, used without further purification. MS: [M+H]+=333.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.C([Mg]Cl)(C)C.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](=[O:34])[C:21]2=[O:35].[Cl-].[NH4+]>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](=[O:34])[C:21]2([OH:35])[C:9]1[C:8]([OH:11])=[CH:7][C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1C(=O)N(Cc2ccccn2)c2ccc(Br)cc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C1N(Cc2ccccn2)c2ccc(Br)cc2C1(O)c1cc2c(cc1O)OCCO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.55 g, 16.8 mmol) in anhydrous dichloromethane (100 mL) at 0° C. added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 10.0 mL, 19.9 mmol). The solution was stirred at 0° C. for 20 min and 5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione (4.85 g, 15.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 h, saturated aqueous ammonium chloride (25 mL) was added and the mixture was concentrated in vacuo. The residue was triturated with ethyl acetate (250 mL) and the solid collected by filtration to afford 5-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (7.26 g, 98%) as a beige solid: 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.06 (dd, J=7.80 Hz, 1H), 7.63-7.55 (m, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.35 (dd, J=8.3, 2.0 Hz, 1H), 7.20 (s, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.16 (s, 2H), 5.09 (ABq, 2H), 4.20-4.10 (m, 4H).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1([NH:2][C:24]2[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:17]=[CH:18][CH:19]=[N:20]1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2cnc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-amino-2-methylcyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 26; 287 mg, 1.01 mmol) in dry DMSO (3.4 ml) was added 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 202 mg, 1.11 mmol) and DIPEA (527 μl, 3.02 mmol). The reaction was stirred at 140° C. for 1 hour and was then partitioned between ethyl acetate and water. The organics were washed with water, brine, filtered through a hydrophobic frit and concentrated in vacuo. This was purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-20% methanol/ethyl acetate) and was then recrystallised from ethyl acetate to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])=[CH:29][CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (91 mg) and commercially available 4-hydroxybenzophenone (243 mg) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was purified in the same manner as described in Example 31 to obtain 38 mg of the title compound (yield: 24%).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[NH2-].[Na+].[C:10]1([CH2:16][O:17][CH2:18][C:19](OC)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:10]1([CH2:16][O:17][CH2:18][C:19](=[O:20])[CH2:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC(C)=O
Reactant: COC(=O)COCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCC(=O)CC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.22 h
Yield: 108.2 %

Procedure:
2-Hexanone (26.7 g) was added dropwise over 5 min at room temperature to a stirred suspension of sodium amide (10.4 g) in dry ether (290 ml) under nitrogen. The reaction mixture was stirred for 13 min. and a solution of methyl phenylmethoxyacetate (24.0 g) in dry ether (40 ml) was added dropwise over 12 min. The mixture was then heated at reflux for 3 h, cooled, and then poured into ice (400 g) and 2N HC1 (200 ml). The aqueous phase was extracted with ether (2×350 ml) and the combined etheral solution washed with 8% sodium bicarbonate solution (2×250 ml), water (200 ml) and brine (200 ml), then dried and evaporated to leave a yellow liquid (35.8 g). This was purified by column chromatography on silica gel eluting with System A (2:98) to give the title compound as a yellow oil (10.95 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[CH:5]=1.[OH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([C:14]([OH:15])=[O:13])=[CH:17][CH:18]=2)[C:7]([CH3:10])=[CH:8][CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Yield: 96.1 %

Procedure:
A mixture of 3-bromo-4-methyl-benzoic acid methyl ester (3 g), 4-hydroxycarbonyl-phenyl boronic acid (2.21 g), cesium carbonate (4.26 g) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (75 ml) was heated to reflux for 18 h. The cooled reaction was then evaporated to dryness and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 800:8:1 to 100:8:1 gave a yellow crystalline solid (3.4 g)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 110 °C

Procedure:
A solution of methyl 4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoate (1.2698 g, 3.38 mmol) in tetrahydrofuran (THF) (8 mL) and water (2 mL), was prepared and treated with sodium hydroxide (1.015 mL, 10.15 mmol). The reaction was then heated by microwaves to 110° C., for 30 minutes. After cooling, the solution was neutralised with 2M HCl and concentrated in vacuo. The product was extracted into the organic phase of an aqueous work up between water and ethyl acetate. The organic phase was then separated (hydrophobic frit) and concentrated in vacuo to give the desired product, 1.063 g. LCMS (M+1) 362, RT 1.27 mins.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[NH:13][CH:14]=[C:15]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:16](=[O:18])[N:17]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]3[NH:13][CH:14]=[C:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[C:16](=[O:18])[N:17]=3)=[CH:6][C:3]=2[C:4]#[N:5])=[CH:29][C:28]=1[C:34]([F:35])([F:36])[F:37]
Reactant: N#Cc1cc(CCc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(CCc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 150 °C
Yield: 15.3 %

Procedure:
A mixture of 2-fluoro-5-(2-(4-oxo-5-(pyrimidin-5-ylmethyl)-1,4-dihydropyrimidin-2-yl)ethyl)benzonitrile (1.0 g, 2.68 mmol), 4-chloro-3-(trifluoromethyl)phenol (0.633 g, 3.22 mmol) and K2CO3 (0.556 g, 4.03 mmol) in NMP (5 mL) was heated with a microwave reactor at 150° C. for 1.5 h. Purification via MDAP then afforded the title compound as a white solid (210 mg, 15% yield). LCMS: rt=1.65 min, [M+H+]=512