Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:24])(=O)=O)=CC=1.Cl>C1COCC1.C(OCC)C>[F:24][C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:6]([OH:8])=[O:7]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1sccc1F
Temperature: -78 °C
Yield: 40 %

Procedure:
2-Thiophene-carboxylic acid (1.7 g, 13.3 mmol) was dissolved in anhydrous THF (30 mL) and the solution was cooled to −78° C. under Ar, with stirring. n-Butyllithium (18.3 mL, 29.3 mmol) in hexanes was added to the above solution and the mixture was stirred for 30 min. A solution of N-fluorobenzenesulfonimide (5 g, 15.9 mmol) in THF (30 mL) was then added and the resulting solution was stirred at −78° C. for 4 h and allowed to warm to ambient temperature over a period of 6 h. The reaction was diluted with diethyl ether (100 mL), cooled to 0° C., and 1 N HCl (15 mL) was added to give a biphasic mixture. The aqueous layer was isolated and washed with diethyl ether (3×50 mL). The combined ethereal layers were dried over MgSO4, filtered, and concentrated in vacuo to yield an orange oil. The oil was subjected to column chromatography on silica gel using 1:1 hexanes/ethyl acetate as the eluent. (14) was obtained as a slightly brown solid (0.777 g) in 40% yield. TLC (1:1 ethyl acetate/hexanes) Rf 0.17; 1H NMR (CDCl3) δ 10.7 (s, 1H), 7.53 (dd, J=5.4, 3.6 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.2 (d, J=3.5 Hz), 161.5 (d, J=278 Hz), 132.0 (d, J=10 Hz), 118.9 (d, J=24.7 Hz), 113.6; 19FNMR (282 MHz, CDCl3, CFCl3) δ-65.2 (d, J=6 Hz); EI-MS m/e 145.9838 (M+ calcd 145.9838 for C5H3FO2S).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-].[NH4+:10].[OH-].[Na+]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:10].[NH4+:10]
Reactant: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])/C=C/C(=O)[O-]
Reaction time: 0.25 h

Procedure:
A slurry of 11.6 g (0.1 mole) fumaric acid was dissolved in 30 ml water was mixed with 26 g of 30% aqueous solution of ammonium hydroxide (0.22 mol NH3). Carefully warming the slurry to boiling gave a dear solution. This solution was boded to dryness over a period of 15 minutes to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 235°-245° C. for 1.5 hours to give a water insoluble, brown, grasslike solid weighing 9.0 g. This solid was dissolved in 100 g of an aqueous solution containing 2.0 g of sodium hydroxide to form a pale yellow solution, pH 8.5, containing 25% solids.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:25][OH:26])[CH:15]=[CH:14][C:13]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16]([CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:25]=[O:26])[CH:15]=[CH:14][C:13]1=2
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
A solution of 0.35 ml of oxalyl chloride in 20 ml of methylene chloride was treated, at −78° C., with 0.4 ml of DMSO absolute. The mixture was stirred at −78° C. for 5 minutes then 554 mg of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanol dissolved in 4 ml of methylene chloride were added dropwise. The reaction mixture was stirred at −78° C. for 15 minutes. 1.3 ml of triethylamine were added and the mixture was stirred 15 minutes at −78° C. then 2.5 hours at room temperature. The mixture was quenched with 20 ml water and extracted with 3 portions of 20 ml of methylene chloride. The combined extracts were washed with 2 portions of 5 ml of water and 1 portion of 50 ml of a saturated aqueous solution of NaCl. The organic phase was dried over MgSO4 and the solvent evaporated to yield a yellow oil. The product was purified with flash chromatography (SiO2, 5% ethyl acetate/hexanes), to yield 483 mg of a colorless oil, 1H NMR (CDCl3): 9.64 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.08 (d, J=3.0 Hz, 1H), 6.95 (dd, J=8.4, 3.0 Hz, 1H), 3.43 (td, J=7.2, 2.0 Hz, 1H), 2.05 (m, 1H), 1.70 (m, 1H), 1.68 (s, 4H), 1.22-1.40 (m, 6H), 1.27 (s, 12H), 0.86 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16]/[CH:17]=[C:18](\[CH2:21][C:22]#[N:23])/[C:19]#[N:20])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O-]CC.[K+].O>O1CCCC1.C(O)C>[NH2:23][C:22]1[N:16]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=1
Reactant: N#CC/C(C#N)=C\NC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(N)n(C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-2-({[bis(4-fluorophenyl)methyl]amino}methylene)butanedinitrile (13.9 g, 45.1 mmol) in tetrahydrofuran (48 ml) and ethanol (48 ml) was slowly added potassium ethoxide (6.67 g, 79.2 mmol), which was stirred at room temperature for 1 hour and poured into iced water. The product was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as oily matter.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:6][CH:5]=1.Cl[CH2:30][O:31][CH2:32][CH3:33].O>O1CCCC1>[CH2:32]([O:31][CH2:30][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[CH:8][CH:9]=1)[CH3:33]
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
To 50 ml dry tetrahydrofuran was added 1.0 g of sodium hydride (60% in oil) and then 5.0 g of 3-phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether in 15 ml of dry tetrahydrofuran was added dropwise to the mixture under reflux over a period of 30 minutes. The mixture was further refluxed for 10 minutes and 5.0 ml of ethyl chloromethyl ether was added dropwise to the mixture for 30 minutes. And the resulting mixture was further refluxed for 10 minutes, cooled to room temperature, poured into water, and extracted with benzene. The benzene extract was washed with water, dried over Na2SO4, and evaporated to give the oily residue which was purified by column chromatography on 150 g silica gel (20:1 mixed solvent of benzene and ether was used as eluent) to give 5.0 g of 3-phenoxybenzyl 2-(4-ethoxymethoxyphenyl)-2-methylpropyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH3:11][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH3:11]
Reactant: O=Cc1ccnc(F)c1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccnc(F)c1Cl
Temperature: 25 °C

Procedure:
3-Chloro-2-fluoropyridine-4-carbaldehyde (56.1 mg, 0.35 mmol) in tetrahydrofuran (2 mL) was mixed with methylmagnesium bromide (0.98 M in tetrahydrofuran, 1.13 mL, 1.05 mmol) under −78° C., and the reaction mixture was warmed slowly to room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (64.7 mg).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].FC(F)(F)C(O)=O.O[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.Cl>C(#N)C.[Cu]Cl>[CH3:1][C:2]([O:6][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:3])[C:4]#[CH:5]
Reactant: Oc1ccc2ncccc2c1
Reactant: C#CC(C)(C)O
Agent: Cl[Cu]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-methyl-3-butyn-2-ol (2.45 mL, 25.1 mmol) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) in acetonitrile (15.5 mL) was stirred 0° C. for 30 minutes, and anhydrous trifluoroacetic acid (3.55 mL, 25.1 mmol) was added dropwise. The resulting mixture was added dropwise to a mixed solution of 6-hydroxyquinoline (2.43 g, 16.7 mmol), copper (I) chloride (8.3 mg, 0.0835 mmol), acetonitrile (15.5 mL) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) at 0° C., and stirred at 0° C. for 3 hours. The resulting solution was acidified with 1 mol/L HCl and extracted with ethyl acetate, and the resulting aqueous phase was neutralized with sodium hydrogencarbonate aqueous solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1 to 1/3) and the aimed product was obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>O>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)=[CH:13][C:4]1=2)[CH3:2]
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: O
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
4,4-Diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to the procedure of Example 4, as an off-white solid: mp 193-194° C.; 1H-NMR (CDCl3) δ 9.19 (s, 1H, D2O exchangeable), 8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0 Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H, J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z 325 ([M−H]−, 100%). Anal. Calcd. For C18H18N2O4.0.3 H2O: C, 65.17; H, 5.65; N, 8.44. Found: C, 65.31; H, 5.60; N, 8.10.
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([N+:15]([O-])=O)[CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[H][H]>O1CCOCC1.[Ni]>[C:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Ni]
Solvent: C1COCCO1
Product: CC(=O)Oc1cc2c(N)cccc2cn1

Procedure:
5-Nitro-3-isoquinolinyl acetate (50 mg, 0.21 mmol) in 1,4-dioxane (20 mL) was treated with Raney-nickel powder (85 mg) and exposed to a hydrogen atmosphere via a balloon for 16 hours. The mixture was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to provide the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:32]1[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][N:19]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:11])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1Br
Reactant: CCc1cnc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ncc(CC)cn2)cc1Br
Yield: 23 %

Procedure:
Condensation of ethyl 2-[2-bromo-4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (500 mg; 1.02 mmol) with 2-chloro-5-ethyl-pyrimidine (1 eq) as per general procedure E (conditions: 1.1 eq DIEA, toluene, 200C, 14 hr) provided the intermediate ethyl 2-[2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (134 mg; 23% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+].Cl.O1CCOCC1>C(O)CCC.C(O)C>[ClH:1].[CH3:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: C1CNCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCCCO
Product: CNC(=O)c1cc(N2CCNCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A mixture of 4-Chloro-N-methyl-pyridine-2-carboxamide (400 mg, 2.345 mmol), piperazine (808 mg, 9.38 mmol) and sodium bicarbonate (591 mg, 7.03 mmol) in 1-butanol (4 ml) was heated under reflux for 18 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica, 1-5% MeOH—basified with ammonia—in DCM) to give a colourless oil. The oil was dissolved in 2 ml ethanol and 4N HCl in dioxane (1.11 ml, 4.4 mmol) was added. The mixture was stirred for 1 hour at room temperature and filtered. The filter residue was rinsed with DCM and ethanol, dried under reduced pressure to give 200 mg of a white solid (0.779 mmol, 33%). MS (ESI) m/z=221.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18](Cl)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([N:22]([CH3:21])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CNc1ccccn1
Reactant: Nc1nccc(-n2nc(C(=O)Cl)c3ccc(I)cc32)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carbonyl chloride (330 mg, 0.83 mmol) in DCM (5 mL) was added N-methylpyridin-2-amine (0.1 ml, 0.99 mmol) followed by triethylamine (0.29 ml, 2.06 mmol). The reaction was stirred at RT overnight and then concentrated in vacuo. The residue was diluted with water (10 ml) and extracted with DCM (2×20 ml). The title intermediate was obtained as a precipitate which was collected by suction filtration. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The precipitate and organic extracts were combined to give the crude title intermediate; LC-MS purity=79%: 1H NMR (500 MHz, DMSO) delta 3.54 (3H, s), 6.28 (1H, d, J=5.5 Hz), 7.15 (2H, s), 7.25 (1H, dd, J=6.7, 5.0 Hz), 7.40 (1H, d, J=8.1 Hz), 7.74 (1H, dd, J=8.5, 1.3 Hz), 7.79-7.84 (2H, m), 8.19 (1H, d, J=5.5 Hz), 8.32 (1H, dd, J=4.6, 1.5 Hz), 9.24 (1H, s); LC-MS: m/z=+472.00 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2ccc(C3(CNc4ncccn4)CCOCC3)cc2)CC1
Product: N
Temperature: 150 °C
Yield: 100.4 %

Procedure:
A mixture of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (150 mg, 0.422 mmol), 2-chloropyrimidine (52 mg, 0.422 mmol) and N,N-diisopropylethylamine (161 μl, 0.904 mmol) in N-methylpyrrolidinone (0.5 ml) was heated at 150° C. in the microwave (Smith Personal Synthesiser) for 900 seconds. The reaction mixture was partitioned between ethyl acetate (10 ml) and saturated NaHCO3 (10 ml). The organic washings were dried over Na2SO4 and concentrated in vacuo to give an orange oil. The compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:ammonia, 100:0:0 to 96:4:0.4, to give the title compound as a solid (87 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 2H), 7.21 (d, 2H), 6.90 (d, 2H), 6.48 (t, 2H), 4.71 (m, 1H), 4.20-4.35 (broad, 1H), 3.80-3.90 (m, 2H), 3.55-3.70 (multiple peaks, 4H), 2.70-2.90 (m, 3H), 2.32-2.49 (m, 2H), 1.78-2.19 (several multiplets, 8H), 1.10 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH3:29]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:28]([CH3:29])[CH3:27])[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Reactant: CNC
Solvent: CC#N
Product: CN(C)CCn1cc(Br)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
Add 4-[4-bromo-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.2 g; 0.023 mol; 1.0 equiv), dimethyl amine (40% aqueous solution, 22 mL; 0.18 mol; 8.0 equiv) in ACN (100 mL) and stir at 100° C. for 3 h. Concentrate, quench the reaction with saturated NaHCO3 solution and extract with EA. Concentrate the organic layer; purify over a silica gel column with EA/hexane to give the title compound (7.5 g; 83.33%).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].C([O:17][C:18]([C:20]1[N:21]=[C:22]([C:29]2[CH:34]=[C:33]([O:35][C:36]3[CH:57]=[CH:56][C:39]4[N:40]([CH3:55])[C:41]([NH:43][C:44]5[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=5[F:54])=[N:42][C:38]=4[CH:37]=3)[CH:32]=[CH:31][N:30]=2)[NH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])=O)C>C1(C)C=CC=CC=1>[F:54][C:45]1[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:52])[F:51])=[CH:49][C:44]=1[NH:43][C:41]1[N:40]([CH3:55])[C:39]2[CH:56]=[CH:57][C:36]([O:35][C:33]3[CH:32]=[CH:31][N:30]=[C:29]([C:22]4[NH:23][C:24]([C:25]([F:28])([F:26])[F:27])=[C:20]([CH2:18][OH:17])[N:21]=4)[CH:34]=3)=[CH:37][C:38]=2[N:42]=1
Reactant: CCOC(=O)c1nc(-c2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)[nH]c1C(F)(F)F
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(-c4nc(CO)c(C(F)(F)F)[nH]4)c3)ccc21
Reaction time: 0.33 h
Yield: 61.3 %

Procedure:
Red-A1 (sodium bis(2-methoxyethoxy)aluminium hydride, 65% wt in toluene, 0.1 mL) was added dropwise to a solution of 2-{4-[2-(2-fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-5-trifluoromethyl-1H-imidazole-4-carboxylic acid ethyl ester (0.0104 g, 0.017 mmol) in toluene. Effervescence was observed and after 20 min, the reaction was quenched with H2O, NaOH and extracted with EtOAc. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated to give 5.9 mg of crude (2-{4-[2-(2-fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-5-trifluoromethyl-1H-imidazol-4-yl)-methanol which was further purified by RP HPLC (reverse phase HPLC) to give 1.1 mg of the pure compound (98% purity). LC/MS m/z 567.1 (MH+), Rt 2.40 min.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C2C(=CC(C(NC(C(O)=O)CO)=O)=CC=2)C(NC(N)=N)=NC=1.Cl.[NH2:33][C:34]([NH2:36])=[NH:35].[C:37]([O:41][C:42](=[O:65])[CH:43]([CH2:59][O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH:44][C:45]([C:47]1[CH:56]=[C:55]2[C:50]([C:51]([Cl:58])=[CH:52][N:53]=[C:54]2Cl)=[CH:49][CH:48]=1)=[O:46])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[C:37]([O:41][C:42](=[O:65])[CH:43]([CH2:59][O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH:44][C:45]([C:47]1[CH:56]=[C:55]2[C:50]([C:51]([Cl:58])=[CH:52][N:53]=[C:54]2[NH:35][C:34]([NH2:36])=[NH:33])=[CH:49][CH:48]=1)=[O:46])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OCC(NC(=O)c1ccc2c(Cl)cnc(Cl)c2c1)C(=O)OC(C)(C)C
Reactant: N=C(N)N
Agent: Cl
Agent: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CO)C(=O)O)cc12
Solvent: O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OCC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 42.9 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine trifluoroacetate ##STR72## NaH (54 mg, 80% dispersion in mineral oil, 1.80 mmol) was added to a solution of guanidine hydrochloride (173 mg, 1.81 mmol) in DMSO (6 mL) and the solution was heated to 80° C. for 30 min. O-t-Butyl-N-[(1,4-dichloro-7-isoquinolinyl)carbonyl]-DL-serine t-butyl ester (330 mg, 0.70 mmol) was added and the mixture heated at 80° C. for 3 h. The cooled mixture was poured into water (50 mL) and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (Na2SO4) and evaporated in vacuo. The residue was crystallised with i-Pr2O to give O-t-butyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine t-butyl ester (138 mg, 0.30 mmol) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1ccccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(Nc2ccccn2)n1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
To a N2 purged sealed tube, 2,4-dichloropyrimidine (1.0 g, 6.7 mmol, 1.2 eq.) and 2-aminopyridine (0.53 g, 5.6 mmol, 1.0 eq.) were added followed by 7 mL of anhydrous IPA. To the resulting suspension DIEA (0.98 mL, 5.6 mmol, 1.0 eq.) was added. The reaction was heated to 90-100° C. and stirred for 12 h. The reaction mixture was cooled to RT and the solvent was removed. The crude mixture was further purified by column chromatography (0-20% EtOAc in hexanes) providing pure (2-chloro-pyrimidin-4-yl)-pyridin-2-yl-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N1C2C(=CC=CC=2)C=C1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1Cl
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Yield: 88.1 %

Procedure:
To a one liter round bottom flask equipped with a reflux condenser was added 26.3 grams (0.135 mol) of 7-chloro-1H-indole-6-carboxylic acid and 200 mL of dry methanol. Three equivalents (41.8 mL, 0.404 mol) of cyclohexanone was added in one portion. The heterogeneous mixture was heated to 60° C. at which point all of the indole went into solution. 6.1 equivalents of a methanolic sodium methoxide solution (0.820 mol, 187 mL) was then added in two portions. The solution was heated at reflux overnight. In the morning, the reaction mixture was cooled and evaporated to dryness. The crude mixture was diluted with 75 mL of ethyl acetate and acidified with 1M HCl. The resulting solid was filtered, washed with cold ethyl acetate and dried overnight in a vacuum desiccator to yield 32.8 grams (88%) of a powder. 1H NMR (300 MHz, CD3OD) δ 7.73 (d, J=8.42 Hz, 1H), 7.61 (d, J=8.42 Hz, 1H), 7.37 (s, 1H), 6.16 (br s, 1H), 2.42 (m, 2H), 2.24 (m, 2H), 1.79 (m, 2H), 1.68 (m, 2H), MS m/z 276.01 (M+H).