Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:49][O:50][C:51](=[O:59])[C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:49][O:50][C:51](=[O:59])[C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:54][CH:53]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(F)c(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87, 202 mg, 0.66 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (294 mg, 0.66 mmol), and 6-amino-nicotinic acid methyl ester (111 mg, 0.73 mmol) in N,N-dimethylformamide (3.32 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.24 mL, 1.39 mmol). The reaction mixture was stirred at 25° C. for 12 h. At this time, the reaction was poured into water (50 mL) and extracted into ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-nicotinic acid methyl ester (36.7 mg, 12.6%) as a white foam: EI-HRMS m/e calcd for C22H22F4N2O3 (M+) 438.1566, found 438.1568.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH3:18][C:19]1([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[OH:32])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([O:43][CH3:44])=[O:42]>>[CH3:18][C:19]1([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[O:32][CH:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:34]=2)[C:41]([O:43][CH3:44])=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)c(C2(C)CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1C1(C)CCCCC1)c1ccccc1
Yield: 91.2 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.496 g (2.4.3 mmol) of 2-(1-methylcyclohex-1-yl)-4-methylphenol was alkylated with 0.834 g (3.64 mmol) of methyl 2-bromophenylacetate to afford 0.780 g (91%) of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:20][C:21]1[N:22]=[CH:23][C:24]([CH:27]=O)=[N:25][CH:26]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Reactant: Cc1cnc(C=O)cn1
Product: Cc1cnc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C(C)C)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 5-methylpyrazine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 11.4 (brs, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 7.99 (s, 1H), 5.00-4.93 (m, 1H), 4.00-3.97 (m, 1H), 3.78-3.67 (m, 1H), 3.33 (t, J=8.3 Hz, 1H), 3.04 (d, J=9.9 Hz, 1H), 2.85-2.82 (m, 1H), 2.65-2.61 (m, 1H), 2.49 (s, 3H), 2.48-2.41 (m, 1H), 2.13 (t, J=8.5 Hz, 1H), 1.46 (dd, J=11.6,6.6 Hz, 6H), 1.17 (d, J=7.05 Hz, 3H). MS: (M+H m/z=368.1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.O[C:12]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[C:18]([OH:24])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].[NH2:25][C:26]1[C:27]([NH2:34])=[C:28]([NH2:33])[C:29]([NH2:32])=[N:30][CH:31]=1.[OH:35]C1C=C(C(O)=O)C(O)=CC=1C(O)=O>>[OH:35][C:17]1[C:18]([OH:24])=[C:19]([CH:20]=[CH:12][C:13]=1[C:14]([O-:16])=[O:15])[C:21]([O-:23])=[O:22].[NH2:10][C:3]1[CH:2]=[CH:7][N+:6]([NH2:25])=[C:5]([NH2:8])[C:4]=1[NH2:9].[NH2:34][C:27]1[CH:26]=[CH:31][N+:30]([NH2:1])=[C:29]([NH2:32])[C:28]=1[NH2:33]
Reactant: Nc1cnc(N)c(N)c1N
Reactant: O=C(O)c1cc(O)c(C(=O)O)cc1O
Product: Nc1cc[n+](N)c(N)c1N
Product: O=C([O-])c1ccc(C(=O)[O-])c(O)c1O

Procedure:
With vigorous stirring and without the introduction of any air b) was added to a), producing a rich yellow precipitate. After further adiabatic stirring for 5 minutes, the slurry was cooled, with stirring, to about 10° C. and filtered, washed three times with about 250 ml of degassed water and twice with degassed ethanol, all this without the introduction of air, flushed with nitrogen for 45 minutes, and dried at 1 mbar, 50° C. for 18 hours to produce 16.56 grams (which corresponds to a yield of 98.2%) salt of tetraaminopyridine and 2,5-dihydroxyterephthalic acid. This salt showed a 1:1 tetraaminopyridine/2,5-dihydroxyterephthalic acid composition in NMR. It was found possible to polymerise it to very high DP polymer under standard conditions. Storing the salt of tetraaminopyridine and 2,5-dihydroxyterephthalic acid samples under air instead of under nitrogen showed only slow deterioration of its colour.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[CH:3]=1.ClC1C=C(C(F)(F)F)C=[C:16]([O:24]C)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH:16]=[O:24]
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)c1
Reactant: COc1cc(Cl)cc(C(F)(F)F)c1
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared as described in Example 159 substituting 1,3-dichloro-5-(trifluoromethyl)benzene for 1-chloro-3-methoxy-5-(trifluoromethyl)benzene.
Reaction SMILES: O1CCOC1[C:6]1[CH:7]=[C:8]([N:14]2[CH:18]=[N:17]N=N2)C=[CH:10][C:11]=1[O:12][CH3:13].C([Li])CCC.C(=O)(O)[O-].[Na+].[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O1CCCC1.CCCCCC>[O:32]1[CH2:33][CH2:34][O:31][CH:29]1[C:30]1[CH:10]=[C:11]([O:12][CH3:13])[CH:6]=[CH:7][C:8]=1[NH:14][C:18]#[N:17]
Reactant: CCOC(C)=O
Reactant: COc1ccc(-n2cnnn2)cc1C1OCCO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(NC#N)c(C2OCCO2)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1-(3-[1,3]dioxolan-2-yl-4-methoxy-phenyl)-1H-tetrazole (9.09 g) in dry tetrahydrofuran (200 ml) at -78° under nitrogen, n-butyl lithium solution in hexane (30 ml of 1.6 mol dm-3) was added. Nitrogen gas was evolved. After stirring under nitrogen for 5 min the mixture was allowed to warm to 0° over 10 min and 8% aqueous sodium bicarbonate (200 ml) was then added. After stirring for 10 min ethyl acetate (150 ml) was added and the layers separated. The aqueous layer was then extracted with dichloromethene (2×200 ml) and the organic layers combined, dried (Na2SO4) and evaporated in vacuo to yield the title compound as an oil (8.0 g). T.l.c. (5% Methanol/methyl tert-butyl ether), Rf 0.7.
Reaction SMILES: CS(C)=O.[I-].[CH3:6][S+](C)(C)=O.[H-].[Na+].[CH3:13][CH:14]([CH3:23])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]>O1CCCC1>[CH:14]([C:15]1([C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[CH2:6][O:16]1)([CH3:23])[CH3:13]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)C(=O)c1cncnc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)C1(c2cncnc2)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 50 ml of dimethyl sulphoxide were slowly added dropwise to 8.06 g (37 mmol) of trimethylsulphoxonium iodide and 1.47 g of sodium hydride (60%, 37 mmol). The reaction mixture was then stirred at room temperature for 15 min, and 5.00 g (33 mmol) of 2-methyl-1-(5-pyrimidinyl)-1-propanone, dissolved in 10 ml of tetrahydrofuran, were added. The reaction mixture was stirred at 50° C. for 90 min. The reaction mixture was then concentrated under reduced pressure, and saturated aqueous sodium chloride solution and ethyl acetate were added to the residue. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated. This gave 1.36 g (25%) of the desired product, which was reacted without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]1=[O:23].[CH3:24]I.Cl>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:24])[C:13]1=[O:23]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)c1
Yield: 72.1 %

Procedure:
A mixture of 0.7 gram (0.017 mole) of sodium hydride (60% in mineral oil) in 30 mL of N,N-dimethylformamide was stirred, and a solution of 5.1 grams (0.017 mole) of 3-(2-fluoro-4-methoxyphenyl)-6-trifluoromethyluracil in 35 mL of N,N-dimethylformamide was added dropwise. The reaction mixture was then stirred for about 30 minutes, and a solution of 3.8 grams (0.017 mole) of methyl iodide in 35 mL of N,N-dimethylformamide was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into an aqueous solution of 0.25N hydrochloric acid, and the mixture was extracted with diethyl ether. The ether extract was washed with an aqueous solution of 0.25N hydrochloric acid, water, and then with an aqueous solution saturated with sodium chloride. The organic layer was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 ethyl acetate in heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.9 grams of 3-(2-fluoro-4-methoxyphenyl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH2:35][CH:36]1[CH:40]([CH3:41])[O:39][C:38](=[O:42])[O:37]1.C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:35][CH:36]4[CH:40]([CH3:41])[O:39][C:38](=[O:42])[O:37]4)=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC1OC(=O)OC1CBr
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1OC(=O)OC1COC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 4-bromomethyl-5-methyl-1,3-dioxolan-2-one (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (15 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]1([CH3:26])[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21](B(O)O)[CH:20]=[N:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:21]3[CH:20]=[N:19][N:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:26])=[CH:13][CH:14]=4)[CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: Cc1ccc(-n2cc(B(O)O)cn2)cc1
Product: Cc1ccc(-n2cc(-c3cccn4nc(Cl)nc34)cn2)cc1

Procedure:
2-Chloro-8-(1-p-tolyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 1-p-tolyl-pyrazole-4-boronic acid in a manner analogous to Example 2c (0.40 g, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Reactant: Fc1cncc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2cncc(F)n2)cc1
Yield: 94.7 %

Procedure:
7.99 g (60.0 mmol) of 2-chloro-6-fluoropyrazine, 15.08 g (60.0 mmol) of 4-octyloxyphenylboronic acid, 12.78 g (120.0 mmol) of sodium carbonate and 0.72 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 2 hours in 400 ml of benzene, 300 ml of ethanol and 150 ml of water. The reaction mixture is partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from the solvents, and the residue is purified by chromatography (silica gel/hexane: ethyl acetate = 8:2). 17.18 g of 2-fluoro-6-(4-octyloxyphenyl)pyrazine are obtained. ##STR15## 1c
Reaction SMILES: [Na].[N+]([CH:5]([C@@H:7]1[C@@H:14]2[C@@H:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][C@H:8]1[CH3:16])[CH3:6])([O-])=O.[N+](=C)([O-])[O-:18].S(=O)(=O)(O)O>CO.O.C(O)(=O)C>[C:5]([C@@H:7]1[C@@H:14]2[C@@H:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][C@H:8]1[CH3:16])(=[O:18])[CH3:6]
Reactant: C=[N+]([O-])[O-]
Reactant: CC([C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1C)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=O)[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1C

Procedure:
Sodium (1.3 g) was dissolved in methanol (30 mL) and the solution added at 0° to a methanol (40 mL) solution of the crude, optically active (3aR,4S,5R,6aS)-4-(1-nitroethyl)hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one (10.0 g). This nitronate anion solution was added, 30 minutes later and at -30°, to a cold (-30°) solution of concentrated sulfuric acid (6 mL) in methanol (40 mL). The resulting mixture was processed as in Example III, including hydrolysis with acetic acid (8 mL) in water (30 mL) while stripping, to give 8.47 g (99%) of the crude, optically active (3aR,4S,-5R,6aS)-4-acetylhexahydro-5-methyl-2H-cyclopenta[b]furan-2-one as a yellow oil. This material was used directly in Example XIV.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]1([N:22]2[C:26]([NH2:27])=[C:25]([C:28]#[N:29])[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([N:22]2[C:26]([NH:27][C:14]([NH:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:15])=[C:25]([C:28]#[N:29])[CH:24]=[N:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cnn(-c2ccccc2)c1NC(=O)Nc1ccccc1
Temperature: 80 °C
Yield: 96 %

Procedure:
9.0 g (80 mmol) of potassium tert-butylate and 8.7 ml (80 mmol) of phenyl isocyanate were added to a solution of 5.52 g (30 mmol) of 1-phenyl-4-cyano-5-aminopyrazole in 100 ml of toluene. The mixture was heated for 15 hours at 80° C. and then cooled, the insoluble constituents were separated off and the resulting solution was acidified with acetic acid, the product crystallizing out. Yield: 96%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>FC(C1C=CC=CC=1)(F)F>[Br:25][CH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Temperature: 75 °C
Yield: 8.3 %

Procedure:
tert-Butyl 3-methyl-1H-pyrazolo[3,4-b]pyridin-1-carboxylate (6.6 g, 28.3 mmol) was added into trifluoromethylbenzene (300 mL), and heated to 75° C. Then NBS (5.04 g, 28.3 mmol) was added, and after 15 minutes AIBN (465 mg, 2.8 mmol) was added, and heated to 80° C. and reacted for 1 hour. It was cooled slowly to room temperature and reacted for 12 hours. It was filtered to remove solid. The filtrate was rotate evaporated to dryness, and chromatographed on a column (PE:EA=25:1) to obtain a white solid 730 mg, at a yield of 8.3%.
Reaction SMILES: [CH2:1]([S:13][CH:14]([CH3:27])[CH2:15][C:16]([CH:18]1[C:23]([CH3:25])([CH3:24])[CH2:22][CH:21]=[CH:20][CH:19]1[CH3:26])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC[OH:30]>CO.O>[CH2:1]([S:13]([CH:14]([CH3:27])[CH2:15][C:16]([CH:18]1[C:23]([CH3:24])([CH3:25])[CH2:22][CH:21]=[CH:20][CH:19]1[CH3:26])=[O:17])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSC(C)CC(=O)C1C(C)C=CCC1(C)C
Reactant: CCO
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCS(=O)C(C)CC(=O)C1C(C)C=CCC1(C)C
Reaction time: 15 h
Yield: 38 %

Procedure:
A solution of 3-(dodecylthio)-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (2.00 g; 5.10 mmol) in MeOH (20 ml) was added at 0° C. to a solution of NaIO4 (1.14 g, 5.30 mmol) in H2O (11 ml). The temperature was brought to room temperature and EtOH (30 ml) was added. The suspension was stirred for 15 h and title compound extracted (ether/brine). The organic phase was washed with aqueous NaHSO3, H2O, saturated aqueous NaHCO3, then brine, dried over Na2SO4, and concentrated. (16.2 g). Flash chromatography (cyclohexane/ethyl acetate=7:3, then 1:1) on SiO2 (40 g) afforded 803 mg of the title compound (38%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)OCC[O:27]1.[Mg].Cl>O.CCOCC.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:26](=[O:27])[CH3:25])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC1(CCCCCCBr)OCCO1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)CCCCCCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
To a mixture of 12.7 g of 3,4-dibenzyloxybenzaldehyde and 150 ml of tetrahydrofuran was added dropwise an ether solution of Grignard reagent prepared from 10.4 g of 2-methyl-2-(6-bromohexyl)-1,3-dioxolane and 1.1 g of magnesium at a temperature below 5° C. After stirring the mixture for 2 hours at room temperature, water was added to the mixture and acidifying the mixture by the addition of diluted hydrochloric acid, the reaction mixture thus obtained was extracted with toluene. The extract was washed with water, dried by anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added 300 ml of acetone and 0.1 g of p-toluenesulfonic acid, the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was extracted with toluene and the extract was washed with an aqueous 5% sodium hydrogencarbonate solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide an oily product. The product was applied to silica gel (500 ml) column chromatography and eluted with a mixture of toluene and ethyl acetate (19:1) to provide 4.4 g of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanedione. Melting point 64°-66° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)C(Cl)=O>C1COCC1.N1C=CC=CC=1C1C=CC=CN=1>[Br:15][C:16]1[CH:24]=[CH:20][C:19]([F:25])=[C:18]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:17]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(Cl)c1cc(Br)ccc1F
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Br)ccc1F
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
3-Ethoxy-3-oxopropanoic acid (B) (2.16 mL, 18.3 mmol, 2.00 eq) was dissolved in THF (91 mL) in an oven dried round-bottom flask and 2,2′-bipyridyl (8.00 mg, 0.0512 mmol, 0.0056 eq) was added as an indicator. The reaction was cooled to −30° C. and n-butyllithium (1.6 M in hexanes) (29.0 mL, 45.6 mmol, 4.00 eq) was added dropwise over 20 minutes. Upon final addition the reaction turned red at which point it was allowed to warm to −5° C. The reaction was allowed to stir at −5° C. for 15 minutes, during which time the red color began to dissipate. Enough n-butyllithium was added to cause the red color to persist. The reaction was then cooled to −78° C. and 5-bromo-2-fluoro-benzoyl chloride (A) (2.17 g, 9.14 mmol, 1.00 eq) was added dropwise as a solution in THF (6.9 mL). The reaction was allowed to stir at −78° C. for 30 minutes and then allowed to warm to −30° C. and stirred for an additional 30 minutes. The reaction was poured onto ice-cold 1N HCl (92 mL) and the mixture was extracted with ethyl acetate (lx) and DCM (2×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using 0-10% hexanes/ethyl acetate afforded 1.78 g (67%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J=6.5, 2.6 Hz, 1H), 7.91-7.86 (m, 1H), 7.40-7.34 (m, 1H), 4.13-4.07 (m, 4H), 1.15 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 289.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:7]=[CH:6][CH:5]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 1 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-amino-phenyl)-5-(2-benzyl-2H-Indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and methanesulfonyl chloride as starting materials, 19 mg (1%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1 H), 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.10 (s, 3H); ES-MS m/z 510.27 [M+H]+, HPLC RT (min) 2.85.