Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>>[CH2:11]([C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[C:3]=2[CH:10]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)Cc1cc2c(Cl)ncnc2s1
Product: CC(C)Cc1cc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)ncnc2s1

Procedure:
The title compound was prepared (337 mg, 65%) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (300 mg, 1.32 m. mol) and tert-butyl 4-aminopiperidine-1-carboxylate (400 mg, 1.99 m. mol) by following the general procedure described for Preparation 9. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (m, 1H), 4.35 (m, 1H), 4.15 (m, 2H), 2.95 (m, 2H), 2.75 9d, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.45 (s, 9H), 1.40–1.50 (m, 2H), 0.95 (d, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49]C(=O)OC(C)(C)C)[CH2:44]2)=[C:34]2[CH2:40][CH2:39][C:38]([OH:42])([CH3:41])[C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl.CO.[NH4+].[OH-]>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH2:49])[CH2:44]2)=[C:34]2[CH2:40][CH2:39][C:38]([OH:42])([CH3:41])[C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2(C)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1N)c2N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (0.02 mL, 0.2 mmol) was added to a solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (4.0 mg, 0.0044 mmol) in DCM (0.01 mL). The reaction mixture was stirred at room temperature for 30 min., and then diluted with MeOH and neutralized with NH4OH. After filtration, the crude was purified by preparative LC-MS (Waters SunFire™ preparative C18 5 μm 30×10 mm column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.1% TFA) to give the title compound tris-trifluoroacetate salt as two diastereoisomers.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[C:15]([O:25][CH:26]([CH3:30])[C:27]([OH:29])=O)=[N:16][C:17]([CH3:24])=[N:18][C:19]=1[C:20]([F:23])([F:22])[F:21].[NH2:31][C:32]([CH3:39])([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]#[N:34].O>O1CCCC1>[Cl:13][C:14]1[C:15]([O:25][CH:26]([CH3:30])[C:27]([NH:31][C:32]([C:33]#[N:34])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])=[N:16][C:17]([CH3:24])=[N:18][C:19]=1[C:20]([F:21])([F:22])[F:23]
Reactant: CC(C)(C)C(C)(N)C#N
Reactant: Cc1nc(OC(C)C(=O)O)c(Cl)c(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(OC(C)C(=O)NC(C)(C#N)C(C)(C)C)c(Cl)c(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (0.8 g) was added to a solution containing 2-(5-chloro-2-methyl-6-trifluoromethylpyrimidin-4-yloxy)propionic acid (1.0 g) dissolved in tetrahydrofuran (30 ml), at room temperature, and the mixture was stirred for 30 min. Subsequently, 2-amino-2,3,3-trimethylbutyronitrile (0.5 g) was added to the mixture, and the reaction mixture was stirred for 10 hours at room temperature. After completion of the reaction, water was added to the resulting mixture and the organic layer was extracted with ethyl acetate, and subsequently dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 0.3 g of the A-configurational diastereomer having a melting point of 1 33° C. to 1 34° C. and 0.2 g of the B-configurational diastereomer having a melting point of 137° C. to 139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[C:11]([CH:13]=[CH:14]C3C=CC=CC=3)[NH:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.CC[O:23]C(C)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:9]=[N:10][C:11]([C:13](=[O:23])[CH3:14])=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2N=C(C=Cc3ccccc3)NN2)c1
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1nnn(-c2cccc(Cl)c2)n1
Yield: 79.4 %

Procedure:
The title compound of Example 10.1 (1.50 g, 5.06 mmol) was dissolved in dichloromethane (79 mL) and ozone was bubbled through the solution for a period of 15 minutes. The solution turned from orange to a darker orange colour. The reaction completeness was checked using a 10% EtOAc:hexanes TLC solvent system. Oxygen was bubbled through the solution for an additional 5 minutes to remove any excess ozone remaining. Dimethyl sulfide (5 mL) was added to the solution and the mixture was allowed to equilibrate to room temperature. The solvent was removed under vacuum and an oily brown substance remained. A 3 cm flash column was prepared containing 15 cm silica and ˜3 cm sand. The column was run using a 5% EtOAc:hexanes solvent system. The eluted fractions containing the product were collected and concentrated under low pressure. Flash column chromatography (silica, 5% EtOAc:hexanes) yielded 893 mg (79.4% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1Br
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To a solution of (4-bromo-3-methylphenyl)methanol (420 mg, 2.09 mmol) in DCM (6 mL) at rt was added MnO2 (1.82 g, 20.9 mmol). The reaction mixture was stirred for 12 h, filtered and concentrated under reduced pressure to give 4-bromo-3-methylbenzaldehyde (372 mg; yield 89%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][O:21][C@@H:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17]2)=[CH:4][CH:3]=1
Reactant: c1ccc([C@H]2CNCCO2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
1.417 g of 4-Bromobenzyl bromide and 0.617 g of (S)-2-Phenyl-morpholine in 11 mL of acetonitrile were stirred at room temperature and 1.567 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification by flash chromatography afforded 0.851 g of product. 68% yield ES MS m/z 331.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.O[Li].O.Cl>C1COCC1.CO.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([S:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][CH:6]=3)[N:17]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CSc2nccc(-c3ccc(OC)cc3)n2)cc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(SCc3ccc(C(=O)O)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To a stirred solution of 226a (4.58 mmol) in THF (20 ml) and MeOH (20 ml) at room temperature was added a solution of LiOH—H2O (960 mg, 22.9 mmol) in water (50 ml). The reaction mixture was stirred 18 h at room temperature, diluted in water and acidified with 1N HCl (pH 5-6) to form a precipitate which was collected by filtration, washed with water and dried to afford the title compound 227a (1.64 g, 99% yield). LRMS (calc.): 352.4, (found): 353.4.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].C1COCC1>CO>[F:1][C:2]([F:16])([F:17])[CH2:3][O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(COCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(COCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Methyl 4-[(2,2,2-trifluoroethoxy)methyl]benzoate (Intermediate 249, 1.05 g, 4.23 mmol) was dissolved in MeOH (10 mL), 2M aq. sodium hydroxide (6.4 mL, 12.69 mmol) was added and the mixture was stirred at room temperature for 3 h. THF (2 mL) was then added and the mixture stirred at room temperature over the weekend. The mixture was then concentrated under vacuum and the residue acidified by adding 2M hydrochloric acid. The mixture was diluted with a little water and extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a white solid (0.974 g, 98%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.14 (2H, d), 7.49 (2H, d), 4.79 (2H, s) and 3.91 (2H, q).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)CCCCc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 74.2 %

Procedure:
Ethyl 5-(6-cyano-2-pyridyl)valerate (0.34 g, 1.5 mmol) and methyl thiosalicylate (0.40 g, 2.4 mmol) were dissolved in toluene (2 ml), and triethylamine (0.43 ml, 3.1 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs and subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethanol-hexane to give the titled compound (0.41 g, 76%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]=[C:13]=[S:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)N=C=S
Reaction time: 1.5 h

Procedure:
4-Fluorophenylacetylchloride (Aldrich, 0.072 mL, 0.525 mmol, 2.5 eq) was added to a solution of sodium thiocyanate (0.056 g, 0.695 mmol, 3.3 eq) in ethyl acetate (2.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to afford a solution of 2-(4-fluorophenyl)ethanoyl isothiocyanate (0.263 M). A solution of 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (0.050 g, 0.21 mmol, 1.0 eq) in CH2Cl2 (1.0 mL) was added dropwise to the 2-(4-fluorophenyl)ethanoyl isothiocyanate solution and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 3/1 hexane/ethyl acetate) to afford the title compound (0.058 g, 64%) as a solid. 1H NMR (DMSO-d6) δ 12.46 (s, 1H), 11.84 (s, 1H), 8.35-8.33 (m, 1H), 8.02-8.33 (m, 1H), 6.99-7.52 (m, 8H), 3.84 (s, 2H); MS(ESI+) m/z 434 (M+H)+; HRMS(ESI+) calcd.: 434.0542, found: 434.0547.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:20][C:21]#[CH:22]>>[CH:23]1([CH2:19][CH2:20][C:21]#[C:22][C:2]2[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C#CCCC1CCCC1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CCCC2CCCC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with but-3-ynyl-cyclopentane yielded N-(3-(3-(4-cyclopentylbut-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a dark brown oil. Yield (690 mg, 69%): 1H NMR (400 MHz, CDCl3) δ 7.22-7.57 (m, 4H),
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C@:5]2(NC(N)=O)C(O)=O.[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:20]
Reactant: NC(=O)N[C@]1(C(=O)O)CCOc2ccc(F)cc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C1CCOc2ccc(F)cc21

Procedure:
The title compound can be prepared by oxidation of (R)-6-fluoro-4-ureidochroman-4-carboxylic acid with potassium permanganate, using the procedure of Example 1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C@@H:19]3[CH2:23][O:22]C(C)(C)[O:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])=[CH:15][CH:14]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCOc3ccc(CCCBr)cc3)cc2)O1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H](O)COc1ccc(CCCOc2ccc(CCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-(4-{3-[4-(3-bromo-propyl)-phenoxy]-propyl}-phenoxymethyl)-2,2-dimethyl-[1,3]dioxolane (5.0 g, 10.8 mmol) in DCM (50 mL) is added TFA (2.0 mL, 26.9 mmol) dropwise followed by water (2.0 mL) and the reaction mixture is stirred at RT overnight. The solvent is removed in vacuo and the residue is treated with aqueous sodium hydrogen carbonate solution. The mixture is extracted with EtOAc (3×200 mL) and the combined organic portions are washed with water, brine, dried over Na2SO4 and concentrated in vacuo. Recrystallizisation of the residue from diethyl ether-hexane affords the title compound as white solid.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[C:6]([NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([CH3:8])[CH3:7].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]([OH:26])=[O:4])=[O:25])=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
LiOH (38.5 mg, 0.9 mmol) was added to a stirred solution of 2-(4-benzyloxy-benzoylamino)-2-methyl-propionic acid methyl ester (200 mg, 0.6 mmol) in THF:MeOH:H2O (3:1:1, 3.5 mL), and the resulting mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added, acidified it with aqueous citric acid solution and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 170 mg (90% yield) of 2-(4-benzyloxy-benzoylamino)-2-methyl-propionic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(O)(=O)C>O1CCOCC1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:9]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCc1ccc(C(=CCCCC(=O)O)c2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)CCCC=C(c1ccc(CCNS(=O)(=O)c2ccc(F)cc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.1 g of 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acid (prepared analogously to Example 10d) are stirred into 150 ml of dioxan with 5 ml of saturated potassium carbonate solution. Then 2.9 g of 4-fluorobenzenesulphonic acid chloride in 20 ml of dioxan are added and the resulting mixture is stirred overnight at ambient temperature. Acetic acid is added and a precipitate is formed. This is separated off and taken up in ethyl acetate, then dried and evaporated down. Finally, the residue is chromatographed over a silica gel column using chloroform/methanol 20:1 as eluant.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:33])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:20]=[CH:19]2)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.CO>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:9]3[C:8]4=[C:7]([CH3:33])[C:6]([C:4]([OH:5])=[O:3])=[CH:14][N:13]4[N:12]=[CH:11][N:10]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A flask equipped with mechanical stirrer was charged with 4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (19) (1 equiv), THF (4 volumes) and MeOH (2.5 volumes). The suspension was cooled to 5 C and 50% NaOH (5.3 equiv.) solution was slowly added maintaining the temperature below 15° C. The resulting solution was warmed to 60° C. for 4 h, and then cooled to 25° C. THF (7 volumes) was charged to the reaction and concentrated HCl (9.95 equiv.) was slowly added maintaining the temperature below 35° C. to pH 3. The resulting slurry was stirred at ambient temperature overnight, and then filtered. The filter cake was washed with H2O (3×5 volumes) and dried on the filter for 1 h. The filter cake was washed with heptane (1×1 volume) and dried under vacuum at 50° C. to afford the product in 88% yield as an off-white solid.
Reaction SMILES: [B-](F)(F)(F)F.CC[O+](CC)CC.[CH3:13][NH:14][C:15](=O)[C:16]([O:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17].[B-](F)(F)(F)F.[Br:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].Cl>C(O)C.C(Cl)Cl>[CH3:13][NH:14][C:15](=[N:34][C:33]1[CH:35]=[CH:36][C:30]([Br:29])=[C:31]([C:37]([F:40])([F:38])[F:39])[CH:32]=1)[C:16]([O:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17]
Reactant: CNC(=O)C(C)(C)OC(C)=O
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CNC(=Nc1ccc(Br)c(C(F)(F)F)c1)C(C)(C)OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Over a five minute period, add a solution of 17.5 g. (0.10 moles) of triethyloxonium fluoborate in 50 ml. of methylene chloride to a mixture of 15.9 g. (0.10 moles) of N-methyl-2-acetoxyisobutyramide in 200 ml. of dry methylene chloride at 0°-5°C. Allow to warm to room temperature and stir for sixteen hours. Remove the solvent in vacuo and obtain the crude product of this reaction as its fluoborate salt. Dissolve the crude fluoborate salt in 150 ml. of anhydrous ethanol, add 24.0 g. (0.10 moles) of 4-bromo-3-trifluoromethylaniline and stir for three days. Remove the solvent in vacuo and partition the residue between ether and saturated aqueous sodium bicarbonate solution. Retain the ether solution, dry it over sodium sulfate and precipitate the product of this reaction as its hydrochloride salt, by adding 0.10 moles of ethereal hydrogen chloride (25 ml. of a 4.0N solution).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=O.Cl.[CH3:12][O:13][NH2:14].Cl>C(O)C>[CH3:12][O:13][N:14]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=C(C)c1ccc(N)cc1
Yield: 88.8 %

Procedure:
To a solution of 4-amino acetophenone (650 mg, 4.8 mmol) and O-methyl-hydroxylamine hydrochloride (800 mg, 9.6 mmol) in ethanol (10 ml) was added a drop of conc. hydrochloric acid and the reaction was heated to reflux for 2 hr. The solvent was evaporated under reduced pressure and ethyl acetate was added, washed with water, dried over anhydrous sodium sulphate, and then filtered. Evaporation yielded 1-(4-aminophenyl)-ethanone-O-methyl-oxime (700 mg, 89%) as a solid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[OH-].[Na+].Br[CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1.O>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]#[N:9])[CH2:15][CH2:14]2)[CH:2]=1
Reactant: Cc1cccc(CC#N)c1
Reactant: ClCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C2(C#N)CC2)c1
Temperature: 60 °C

Procedure:
To a stirred solution of 2-(m-tolyl)acetonitrile (4.2 g, 32 mmol) in toluene (15 mL) was added sodium hydroxide (30 mL, 50% w/w in water, 375 mmol), 1-bromo-2-chloroethane (9.3 mL, 112 mmol) and (n-Bu)4Br (0.5 g, 1.55 mmol). The mixture was heated at 60° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:4]=1.[H-].[Na+].[CH3:16]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[N:13]([CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:4]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccnc(-c2ncc[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccnc(-c2nccn2C)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To crude 4-methoxy-2-(1H-imidazol-2-yl)pyridine (0.40 g, 2.28 mmol) in 7.5 mL anhydrous DMF with magnetic stirring under Ar at 0° C., NaH (60% in oil, 91 mg, 2.28 mmol) was added portionwise. Stirred at 0-5° C. for 1 h, then added a solution of methyl-p-toluenesulfonate (0.344 mL, 2.28 mmol) in 0.75 mL anh. DMF dropwise with stirring. After 15 min, the ice bath was removed and the reaction mixture stirred for 2 h at room temp. Cooled back to 0° C. and quenched by very carefully adding 10% aq. Na2CO3 dropwise (about 10 mL total). Extracted 2×30 mL chloroform. Combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated to give 0.73 g as a dual-phase oil. Chromatographed on 18 g silica gel in 0-2% MeOH/CHCl3+0.5% TEA to yield 0.20 g (45%) of 4-methoxy-2-(1-methyl-1H-imidazol-2-yl)pyridine.