Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1.[Cl-].[C:44]1([C:50]2[NH:51][CH:52]=[C:53]([CH:55]=O)[N:54]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][CH2:55][C:53]3[N:54]=[C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[NH:51][CH:52]=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ncc(C)n2nc(CCc3c[nH]c(-c4ccccc4)n3)nc12

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.087 mL, 0.58 mmol) was added to a stirred suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.27 g, 0.58 mmol) and 2-Phenyl-1H-imidazole-4-carbaldehyde (0.100 g, 0.581 mmol) in dry THF (8 mL) and the mixture was stirred at room temperature under an atmosphere of Argon overnight. Some solid was filtered off and the solvent was removed in vac. The remanens was dissolved in DCM, and purified by silica gel chromatography (Eluent: 0-100% EtOAc in n-heptane). Yield: 97 mg of the intermediate as a cis/trans mixture as an oil (53%).
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[Br:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>CO.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]2[NH:18][C:2](=[O:3])[NH:19][C:14]=2[CH:13]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 33.9 %

Procedure:
Add phenyl chloroformate (922 mg, 5.89 mmol) to a suspension of 4-bromo-benzene-1,2-diamine (1.00 g, 5.35 mmol) and NaHCO3 (483 mg, 5.89 mmol) in methanol (20 mL) and H2O (10 mL). Stir at room temperature for 3.5 h and add 1.00N aqueous NaOH (6 mL, 6.00 mmol). Stir overnight at room temperature and filter. Wash the filter cake with H2O and dry in-vacuo overnight to obtain 386 mg (34%) of the title compound as a brown powder. MS (ES) 213,215 (M+H), 211,213 (M−H); HPLC shows 95% purity.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:28])[CH:6]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:7][CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O>COCCOC>[CH3:3][O:4][C:5]([C:6]1([O:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:7][CH2:8]1)=[O:28]
Reactant: COC(=O)C(CCOS(=O)(=O)c1ccc(C)cc1)Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1(Oc2ccc(Cl)cc2)CC1
Temperature: 22 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
A suspension of sodium hydride in oil (55% w/w, 36.4 mg) was added to a solution of 2-(4-Chloro-phenoxy)-4-(toluene-4-sulfonyloxy)-butyric acid methyl ester (Example 473c), 145 mg) in 1,2-dimethoxyethane (2.27 mL) at room temperature. The mixture was stirred at 22° C. for 48 hr. The reaction mixture was filtered and the solid was washed with ethyl acetate. Water was added to the filtrate. The phases were separated and the aqueous layer was extracted with ethylacetate. The organic layers were washed with brine, dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (56 mg; 68%). MS (ESI): m/z=226 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.O>[F:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCCC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 33 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 2-pyrrolidinone (0.046 mL, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 6 h under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from MeOH/H2O to give the title compound (73.6 mg, 33% yield) as a pale yellow solid: mp 200-202° C.; NMR (300 MHz, CDCl3): δ ppm 2.16-2.26 (2H, m), 2.62-2.68 (2H, m), 3.82-3.87 (2H, m), 3.90 (3H, s), 6.40 (1H, t, J=9.0 Hz), 7.10 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.30 (1H, d, J=1.9 Hz), 7.35-7.45 (5H, m), 7.77-7.83 (3H, m). LC-MS (ESI) m/z 446 [M+H]+. Anal. Calcd for C24H20FN5O3.0.25H2O: C, 64.06; H, 4.59; N, 15.59. Found: C, 64.08; H, 4.57; N, 15.49.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]1([C:12]([CH3:14])=[CH2:13])[CH2:9][CH:8](CO)[O:7][C:5]1=[O:6].[OH-].[Na+].C1C[O:21]CC1.I([O-])(=O)(=O)=O.[Na+]>O>[CH3:1][CH:2]([CH3:15])[CH2:3][C@:4]1([C:12]([CH3:14])=[CH2:13])[CH2:9][C@H:8]([OH:21])[O:7][C:5]1=[O:6]
Reactant: C=C(C)C1(CC(C)C)CC(CO)OC1=O
Reactant: C1CCOC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Product: C=C(C)[C@@]1(CC(C)C)C[C@H](O)OC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
A mixture of [S-(R*,R*)]-α-(2-methylpropyl)-α-(propen-2-yl)-γ-hydroxymethyl-γ-butyrolactone (682 mg, 3.21 mmol), NaOH (350 mg, 8.75 mmol), THF (40 mL), and H2O (10 mL) is stirred for 19 hours at room temperature. Additional NaOH (114 mg, 2.85 mmol) is added after 16 hours. The mixture is concentrated and the residue taken up into MeOH (43 mL). A solution of sodium periodate (862 mg, 4.03 mmol) and H2O (4.3 mL) is added and the mixture stirred at room temperature for 3 hours. After concentration, the aqueous residue is acidified (HCl) and extracted with CH2Cl2 (3×40 mL). The organic layers are dried (MgSO4), filtered, and concentrated to provide 625 mg (98%) of the title compound as a semi-solid.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C:7]([N:9]([CH3:27])[C:10]1[CH:26]=[CH:25][C:13]2[N+:14](CCCS([O-])(=O)=O)=[C:15]([CH3:17])[S:16][C:12]=2[CH:11]=1)=[O:8])([OH:3])=[O:2].C1CS(=O)C1>C(#N)C>[CH3:27][N:9]([C:10]1[CH:26]=[CH:25][C:13]2[N:14]=[C:15]([CH3:17])[S:16][C:12]=2[CH:11]=1)[C:7](=[O:8])[CH2:6][O:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1sc2cc(N(C)C(=O)COCC(=O)O)ccc2[n+]1CCCS(=O)(=O)[O-]
Agent: O=S1CCC1
Solvent: CC#N
Product: Cc1nc2ccc(N(C)C(=O)COCC(=O)O)cc2s1

Procedure:
3-{5-[[(Carboxymethoxy)acetyl](methyl)amino]-2,3,3-trimethyl-3H-indolium-1-yl}propane-1-sulfonate (22) and 3-{6-[[(Carboxymethoxy) acetyl](methyl)amino]-2-methyl-1,3-benzothiazol-3-ium-3-yl}propane-1-sulfonate (23). To a solution of acid (21 or 22, 1.00 mmol) in 25 mL of dry acetonitrile was added propane sulfone (10 mmol). This mixture was stirred under reflux for 48 h. After cooling the hygroscopic salt was filtered, washed with acetone, and immediately used in the next step.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][C:3]=1[C:22]([O:24]CC)=[O:23].[OH-].[Na+].Cl>>[OH:1][C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1cnc2c(ccc3c(-c4ccccc4)ccnc32)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2c(ccc3c(-c4ccccc4)ccnc32)c1O

Procedure:
Ethyl 4-hydroxy-7-phenyl-1,10-phenanthroline-3-carboxylate (5.37 g) is boiled with 10% aqueous NaOH (32 mL) for 2 hours, acidified with 10% HCl to yield a precipitate that is collected, washed with water and dried to give the desired product.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:31][C:32]1([CH3:44])[O:36][C@@H:35]([C:37]2[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)[CH2:34][O:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[C:8]([NH:43][C:40]2[CH:39]=[N:38][C:37]([C@H:35]3[CH2:34][O:33][C:32]([CH3:44])([CH3:31])[O:36]3)=[CH:42][N:41]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@H](c2cnc(N)cn2)O1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)OC[C@H](c2cnc(NC(=O)[C@H](CC3CCCC3)N3Cc4c(cccc4C(F)(F)F)C3=O)cn2)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 125 mg, 0.37 mmol) in methylene chloride (10 mL) was treated with N,N-dimethylformamide (1 drop) and cooled to 0° C. It was then treated with a solution of oxalyl chloride (2.0 M in methylene chloride, 220 μL, 0.44 mmol) and stirred for 10 min at 0° C. and then warmed to room temperature and stirred for 30 min. After this time, the reaction mixture was concentrated in vacuo to about 1 mL and then it was added to a flask containing 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared as in WO2004052869, Example 54, 107 mg, 0.55 mmol) and 2,6-lutidine (81 μL, 0.73 mmol) in methylene chloride (10 mL) at 0° C. The reaction mixture was then allowed to warm up to room temperature and stirred overnight for 16 h. After this time, the reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (10 mL) and extracted with methylene chloride (3×10 mL). The organic layers were then combined and washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (12 g silica gel column, 15-40% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (78 mg, 41%) as a white foam: [α]27D=−18.0° (c=0.15, methylene chloride); HR-ES(+) m/e calcd for C26H29N4O4F3 [M+Na]+ 541.2033, observed 541.2030; 1H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.21 (d, J=1.21 Hz, 1H), 8.48 (d, J=1.21 Hz, 1H), 8.02 (t, J=8.00 Hz, 2H), 7.72-7.82 (m, 1H), 5.12-5.29 (m, 2H), 5.05 (d, J=17.81 Hz, 1H), 4.76 (d, J=18.11 Hz, 1H), 4.35 (dd, J=6.64, 8.45 Hz, 1H), 3.93 (dd, J=6.64, 8.45 Hz, 1H), 1.04-2.20 (m, 17H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:9]([NH:20][C@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[N:10][C:11](S(C)(=O)=O)=[N:12][C:13]=2[O:14][CH3:15])=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CC#N>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:9]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[N:10][C:11]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:12][C:13]=2[O:14][CH3:15])=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1ncc(F)cn1
Solvent: CC#N
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1ncc(F)cn1
Temperature: 100 °C

Procedure:
To (S)-tert-butyl 3-((5-fluoro-6′-methoxy-2′-(methylsulfonyl)-[2,5′-bipyrimidin]-4′-yl)amino)piperidine-1-carboxylate (0.05 g, 0.104 mmol) in MeCN (3.5 mL) was added morpholine (0.027 ml, 0.311 mmol) in a pressure tube. The reaction was heated to 100° C. for 18 h. Upon completion of the reaction, the solvent was removed and reaction was purified via column chromatography (0-50% EtOAc/Hex) to afford the desired product as a white solid. MS (m/z)=490 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:11](Br)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4]1)[CH3:2].[Li]C(C)(C)C.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:11]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]3[C:10]=2[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCn1nc2ccccc2c1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCn1nc2ccccc2c1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 22.5 %

Procedure:
To a solution of 2-ethyl-3-bromoindazole (3.4 g, 15.18 mmol) in THF (30 mL) was added t-BuLi (1.7 M in pentane, 10.72 mL, 18.22 mmol) dropwise at −78° C. After stirring at −78° C. for 20 min., was added tert-butyl 4-oxo-1-piperidinecarboxylate (3.03 g, 15.18 mmol) in THF (10 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min. and at rt for 18 h. After the reaction was quenched with aq. NH4Cl, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by purification by flash chromatography (hexanes ethyl acetate=4:1, then 1:1) to give 1.18 g of the title compound as a foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][N:24]=[C:25]=[O:26])[CH3:20].C(N(C(C)C)CC)(C)C>>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][NH:24][C:25]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:14][CH2:15]1)=[O:26])[CH3:20]
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine (1.5 g, 5.7 mmol), isocyanato-acetic acid-ethy ester (0.7 mL, 6.3 mmol) and diisopropylethyl amine (1.5 mL, 8.6 mmol) are reacted to give [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid-ethyl ester the product as a white solid (990 mg, 40%). A mixture of the ester (990 mg), LiOH.H2O (1 g) in THF-H2O (5:1, 45 mL) was stirred at rt for 3 h, then acidified with 1.0 N HC (aq.) to pH to 4–5. After the removal of THF in vacuo, crude product precipitated. 760 mg (76%) of the acid was obtained after drying under vacuum for 3 h. LC-MS: 363 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[OH:14]>[O-2].[O-2].[Mn+4].ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[C:3]=1[OH:14])[CH:8]=[O:9]
Reactant: OCc1cc(Cl)c(O)c(C(F)(F)F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30.0 g (345 mmol) manganese dioxide was added batchwise, with stirring, to a mixture of 5.90 g (26 mmol) 2-chloro-4-hydroxymethyl-6-trifluoromethyl-phenol and 100 ml dichloromethane and stirred for 2 hours at ambient temperature. The reaction mixture was suction filtered to remove the solid, the solution was evaporated down under reduced pressure and further reacted as the crude product.
Reaction SMILES: [Br-:1].[K+].C([O-])(=O)C.[Na+].[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:22]([F:25])([F:24])[F:23])=[N:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12])[CH3:9].BrBr.S(=O)(O)[O-].[Na+]>CO>[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:22]([F:24])([F:25])[F:23])=[N:15][C:16]2[N:17]([C:19]([Br:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn2ccnc2nc1C(F)(F)F
Reactant: [Br-]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Solvent: CO
Product: CCOC(=O)c1cn2c(Br)cnc2nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium bromide (26.4 mg) and sodium acetate (2.5 eq, 6.6 mmol, 541 mg) were added sequentially to 7-trifluoromehyl-imidazo[1,2-a]pyrimidine-6-carboxylic acid ethyl ester (0.684 g, 2.64 mmol ) in methanol (5.5 mL) and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was then cooled to −5° C. and bromine (1.02 eq, 0.138 mL) was added. Once addition was complete, the reaction was stirred for 1 hour. The mixture was then treated with a saturated aqueous solution of sodium bisulphite and, after stirring for 5 minutes, the solvents were removed under reduced pressure. Water was added to the residue and the pH adjusted with sodium hydroxide until just basic. The resulting solid was collected by filtration, washed with ether and crystallized from hot methanol to afford 3-bromo-7-trifluoromehyl-imidazo[1,2-a]pyrimidine-6-carboxylic acid ethyl ester in quantitative yield. m/z (M+H)=339.2.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([NH2:18])=O)=[CH:14][N:15]=2)[CH2:7]1.C(N(CC)CC)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]#[N:18])=[CH:14][N:15]=2)[CH2:7]1
Reactant: NC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Reaction time: 0.08 h

Procedure:
A suspension of 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboxamide (670 mg, 1.9 mmol) and triethylamine (0.92 mL, 6.6 mmol) in CH2Cl2 (25 mL) was cooled with an ice-acetone bath. Triflic anhydride (412 μL, 2.4 mmol) was added dropwise over 10 min. The mixture was stirred for 5 min and then the cooling bath was removed. After further stirring at rt for 15 min, the mixture was quenched with water and extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed twice with diluted brine, dried (Na2SO4) and concentrated. Combi-Flash chromatography (40 g, 40-80% EtOAc in hexanes in 20 min, 35 mL/min, 18 mL/fraction) gave a gum that was triturated with hexanes-Et2O (1:1) to give the title compound as a white powder. 1H NMR (400 MHz, acetone-d6): δ 7.88 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.18 (t, 1 H), 5.53 (s, 1 H), 3.99 (m, 1 H), 3.85-3.67 (m, 3 H), 2.63-2.45 (m, 2 H). MS (+ESI) m/z 340 (MH+).
Reaction SMILES: C[O-].[Na+].CO.CO.C([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:36])[NH:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][C:21]=2[C:32]([O:34][CH3:35])=[O:33])=[C:14]([O:37]C(=O)C)[CH:13]=1)(=O)C.Cl>C(OCC)(=O)C>[OH:37][C:14]1[CH:13]=[C:12]([OH:11])[CH:17]=[CH:16][C:15]=1[C:18]([NH:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][C:21]=1[C:32]([O:34][CH3:35])=[O:33])=[O:36]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC(C)=O)cc1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Under ice-cooling, a 28% sodium methoxide-methanol solution (0.34 g) was added to a methanol (3.1 mL) suspension of 4-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)-1,3-phenylene diacetate (0.31 g), followed by stirring at room temperature for 1 hour. The reaction mixture was added to 0.5 mol/L hydrochloric acid (20 mL) under ice-cooling, and then ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue to obtain 0.24 g of methyl 2-(2,4-dihydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12]I)[C:5]2=[CH:4][CH:3]=1.[NH2:14][C@H:15](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.CN>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][NH:14][CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(CCI)c[nH]c2n1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CN
Solvent: CCO
Product: CNCCc1c[nH]c2nc(Cl)ccc12
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A mixture of 1 g (3.26 mM) of 6-Chloro-3-(2-iodo-ethyl)-1H-pyrrolo[2,3-b]pyridine and 0.49 g (3.26 mM) Nal were mixed together in 100 mL of an ethanol solution saturated with methyl amine gas. This solution was heated to 100° C. in a steel bomb for 12 hours. The reaction mixture was cooled to room temperature and the solvent evaporated. The residue was chromatographed on silica using a mixture of 10:1 CH2Cl6 : CH3OH as the elutant. The appropriate fractions were combined and evaporated. The residue was crystallized from isopropyl ether-methanol to yield 140 mg of [2-(6-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-methyl-amine. MP=214-215° C. NMR (D6DMSO) δ11.75 (s, 1H), 8.08 (d, 1H), 7.41 (s, 1H), 7.15 (d, 1H), 3.20 (t, 2H), 3.02 (t, 2H), 2.60 (s, 3H). 13C NMR (D6DMSO) 147.5, 143.2, 129.9, 124.8, 118.2, 114.8, 108.7, 48.4, 32.6, 21.6. Mass spectrum: m/e=210, 212(P+1, P+3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([O:23][CH2:22][CH2:21][C:5]2[CH:6]=[C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1cccc(Cl)c1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][C:2]1CC=C[CH:3]=1.[CH3:7][C:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[CH:9]=1>>[CH3:13][C:10]1[C:11](=[C:2]([CH3:3])[CH3:1])[CH:12]=[C:8]([CH3:7])[CH:9]=1
Reactant: CC1=CCC(C)=C1
Reactant: CC1=CC=CC1
Product: CC1=CC(=C(C)C)C(C)=C1

Procedure:
The synthetic procedure according to Example 1 step A, is followed but the methylcyclopentadiene is replaced by 1,3-dimethylcyclopentadiene.
Reaction SMILES: N[C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([I:21])[N:10]=[C:11]([CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([O-:20])=[O:19])[CH2:14][CH2:13]3)[N:4]2[N:3]=1.[CH3:22]N(C=O)C.N(OC(C)(C)C)=O>C1COCC1>[I:21][C:9]1[N:10]=[C:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:22])=[O:19])[CH2:16][CH2:17]2)[N:4]2[C:5]=1[C:6](=[O:8])[NH:7][CH:2]=[N:3]2
Reactant: Nc1nn2c(C3CCC(C(=O)[O-])CC3)nc(I)c2c(=O)[nH]1
Reactant: CN(C)C=O
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl ir ans-4-(2-amino-5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.880 g, 0.00211 mol) in anhydrous THF (74 mL) and DMF (13.2 mL) was charged with tert-butyl nitrite (1.2 mL, 0.010 mol) and stirred at rt for 2 h. The reaction was concentrated in vacuo and was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 570 mg, (67% yield) of the title compound as a pale orange solid. (1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.54 (m, 2H), 1.56-1.69 (m, 2H), 1.92-2.06 (m, 4H), 2.36-2.46 (m, 1H), 3.02-3.14 (m, 1H), 3.61 (s, 3H), 7.89 (d, J=3.28 Hz, 1 H) and 11.79 (br. s., 1H); MS (ES+): m/z 402.86 [MH+].