Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.CN(CCN(C)C)C.[Li]CCCC.[Sn](Cl)(C)(C)C.Br[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30].[F-].[K+]>CCOCC.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30]
Reactant: Cn1cccc1
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: C[Sn](C)(C)Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cn1cccc1-c1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
EX-602A) To solution of N-methylpyrrole (0.97 mL, 11 mmol) in Et2O (20 mL) was added neat TMEDA (1.5 mL, 10 mmol) and 1.6 M n-BuLi in hexanes (6.3 mL, 10 mmol). The solution was heated to reflux under N2 for 1h and then cooled to −78° C. A 1.0 M solution of Me3SnCl in THF was added over 15 min, and the resulting solution stirred for 30 min at −78° C. After warming to room temperature, 3-bromo-benzaldehyde (0.70 mL, 6.0 mmol), Pd(PPh3)2Cl2 (0.25 g, 0.35 mmol) and dioxane (10 mL) were added. The slurry was heated to reflux for 18 h. The cooled mixture was poured into a mixture of saturated KF and ethyl acetate and stirred 15 min. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.45 g (24%) of the desired 3-(1-methyl-1H-pyrrol-2-yl)benzaldehyde product as a yellow oil. MS: m/z=186.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])=O.O.[NH2:17][NH2:18]>CCO>[F:1][C:2]([F:15])([F:14])[C:3]1[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[NH:18][N:17]=1
Reactant: O=C(O)c1ccccc1C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(C(F)(F)F)c2ccccc12

Procedure:
A solution of 2-(2,2,2-trifluoroacetyl)benzoic acid (0.554 g, 2.54 mmol) and hydrazine hydrate (0.44 mL, 7.8 mmol) in EtOH (7.5 mL) was stirred at 80° C. overnight, concentrated, azeotroped with toluene, and dried in vacuo to give the crude title compound as a tan solid, which was used without purification). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (dd, 1H), 7.91-8.10 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:16]=2[N:17]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:16]=3[N:17]=2)=[C:4]([Cl:11])[CH:5]=1
Reactant: N#Cc1ccc2sc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)nc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc2sc(Sc3c(Cl)cc(N)cc3Cl)nc2c1
Yield: 80 %

Procedure:
The title compound was prepared using the method of example 270, starting with 2-(2,6-dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carbonitrile (262) (1.9 g, 4.97 mmol), tin chloride dihydrate (Aldrich, 5.62 g, 24.9 mmol). Compound 274 (1.40 g, 80%) was obtained as a yellowish solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(O)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-hydroxybenzoic acid (5 g, 36.2 mmol) in 50 mL of dichloromethane is treated at 0° C. with oxalyl chloride (6.3 mL, 72.4 mmol) and N,N-dimethylformamide (5.6 mL, 72.4 mmol). This solution is stirred at room temperature for 2 hours and treated with diisopropylamine (40 mL, 286 mmol) at 0° C. After stirring at room temperature for overnight, the reaction is partitioned between ethyl acetate and 1N hydrochloride solution. The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 4-hydroxy-N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH3:14])=[O:8].C(NC(C1OC=CC=1C)=O)C1C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>>[Br:34][C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[O:8])=[C:13]([CH3:14])[CH:12]=1
Reactant: Cc1ccsc1C(=O)NCc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccoc1C(=O)NCc1ccccc1
Product: Cc1cc(Br)sc1C(=O)NCc1cccc(F)c1
Yield: 89 %

Procedure:
Following the procedure as described in Preparation 19, making variations only as required to use N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide) in place of N-benzyl-3-methylfuran-2-carboxamide to react with N-bromosuccinimide, 5-bromo-N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide was obtained as a colorless solid in 89% yield: 1H NMR (300 MHz, CD3CN) δ 7.39-7.31 (m, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.08 (d, J=10.2 Hz, 1H), 7.02 (dd, J=8.5, 2.5 Hz, 1H), 6.98 (s, 1H), 4.48 (d, J=6.1 Hz, 2H), 2.42 (s, 3H); MS (ES+) m/z 328.1 (M+1), 330.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])[NH:5]C(=O)C.[ClH:20]>>[ClH:20].[CH3:16][C:15]1[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([CH3:18])[C:10]=1[CH2:9][C@@H:4]([C:3]([OH:19])=[O:2])[NH2:5]
Reactant: COC(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(C)=O
Agent: Cl
Product: Cc1cc(O)cc(C)c1C[C@H](N)C(=O)O

Procedure:
2,6-Dimethyl-(S)-Tyrosine hydrochloride was prepared by deprotecting N-acetyl-2,6-dimethy-(S)-tyrosine methyl ester as follows: In a 100 ml round-bottom flask was placed 3.40 g (13 mmol) of N-acetyl-2,6-dimethyl-(S)-tyrosine methyl ester and 20 mL of 6N hydrochloric acid. The reaction mixture was refluxed under argon for 41/2 hours, cooled and then concentrated under reduced pressure to afford 3.48 g of a white solid; 1H NMR analysis indicated: (δ, CD3OD) 6.35 (s, 2H), 3.90 (t, J=7 Hz, 1H), 3.3-3.0 (m, 2H) and 2.21 (s, 6H). Mass spectrum analysis indicated: (m/e) 209 (M+), 135 (100%) and 91.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)=O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: COCCCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are dissolved in 15 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, 15 ml of ethanol are added to the reaction mixture. Said mixture is neutralized with potassium carbonate under ice-cooling. Then, 150 ml of ethyl acetate are added to said mixture and insoluble materials are removed by filtration. The filtrate is washed with an aqueous sodium bicarbonate solution, dried and evaporated to remove solvent. The residue thus obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol=5:2:1). 1.2 g of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[N:23][N:24]4COCC[Si](C)(C)C)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2nn(COCC[Si](C)(C)C)c3cc(-c4ccc(NC(=O)Nc5cccc(F)c5)cc4)ccc23)cn1
Agent: Cl
Solvent: CCO
Product: Cn1cc(-c2n[nH]c3cc(-c4ccc(NC(=O)Nc5cccc(F)c5)cc4)ccc23)cn1

Procedure:
A suspension of Example 1E (45 mg, 0.081 mmol) in ethanol (6 ml) was treated with 2 ml of a 6N HCl solution, refluxed for 1 hour, then cooled and concentrated to near dryness. The residue was triturated with water and the resulting solid was collected, dissolved in methanol and CH2Cl, adsorbed onto Celite, and purified by silica gel chromatography (4% methanol in CH2Cl2) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 6.79 (dt, J=8.82 Hz, 2.37 Hz, 1 H) 7.15 (d, J=8.14 Hz, 1 H) 7.32 (q, J=8.14 Hz, 1 H) 7.45 (dd, J=8.48 Hz, 1.36 Hz, 1 H) 7.51 (dt, J=2.37 Hz, 11.87 Hz, 1 H) 7.59 (m, 2 H) 7.69 (m, 3 H) 7.99 (s, 1 H) 8.05 (d, J=8.48 Hz, 1 H) 8.37 (s, 1 H) 8.89 (s, 1 H) 8.96 (s, 1 H) 12.94 (s, 1 H). MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3](Cl)(Cl)[Cl:4].[CH2:13]([O:20][C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][CH:32]([CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[OH:33])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CCCCCC>ClCCl>[CH2:13]([O:20][C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][CH:32]([O:33][C:3]([Cl:4])=[O:2])[CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC(=O)Cl
Reaction time: 1 h
Yield: 89 %

Procedure:
Bis(trichloromethyl) carbonate (160 mg; 0.54 mmol) was added with stirring to a solution of 1-(N-benzyloxycarbonyl-L-valyl)-3-stearoylglycerol; 1-(N-benzyloxycarbonyl-L-valyloxy)-3-stearoyloxy-2-propanol; preparative example 4; (660 mg; 1.12 mmol) and triethylamine (200 mg; 2.0 mmol) in dichloromethane (5 ml) at room temperature. After 1 h, n-hexane (10 ml) was added and the precipitated triethylamine hydrochloride was filtered off through a short column of silica gel, the product eluted with a further amount of n-hexane, and the solvent evaporated in vacuum to yield 650 mg (89%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([O:26]CC)=[O:25].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.95 g (4.73 mmol) of ethyl 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]pyridine-3-carboxylate Example 90A were initially charged in 30 ml of methanol, 3.28 g (10.4 mmol) of barium hydroxide octahydrate were added and the mixture was stirred at RT for 3 days. The suspension was diluted with 30 ml of water and adjusted to pH 6 using 1 M aqueous hydrochloric acid. The solid was filtered off, washed with 50 ml of water and dried under reduced pressure at 70° C. for 2 h. This gave 1.64 g of the target compound (90% pure, 81% of theory).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:20])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:10][C:9]([Br:21])=[CH:8][CH:7]=2)[CH3:3].C(N(CC)C(C)C)(C)C.Br[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[NH:34][CH:35]=[N:36]2>C(O)(C)(C)C>[N:40]1[C:32]([NH:1][C@H:2]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]([Br:21])=[CH:8][CH:7]=3)[CH3:3])=[C:33]2[C:37]([NH:36][CH:35]=[N:34]2)=[N:38][CH:39]=1
Reactant: Brc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1

Procedure:
This example is also described in Example 24 of WO 2011/055215. To a solution of (S)-2-(1-aminoethyl)-6-bromo-3-phenyl-4H-chromen-4-one (0.20 g, 0.581 mmoles) in tert-butanol (6 ml), N,N-diisopropylethyl amine (0.2 ml, 1.162 mmoles) and 6-bromopurine (0.087 g, 0.435 mmoles) are added and refluxed for 24 h. The reaction mixture is concentrated, diluted with water, extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:ethyl acetate to afford the title compound as yellow solid. MP: 151-154° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 12.94 (s, 1H), 8.09 (br s, 3H), 7.94 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.42 (m, 6H), 5.22 (br t, 1H), 1.82 (d, J=6.4 Hz, 3H). Mass: 463.99 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:25][CH2:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCc1ccc(Br)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CC(C)(C)OC(=O)CCOCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
2-(4-Bromophenyl)ethanol (5 g) was treated with benzyltrimethylammonium hydroxide (Triton B®) (0.3 mL) and the resultant mixture was stirred in vacuo for 30 minutes. The mixture was then cooled to 0° C. and treated with t-butyl acrylate (3.5 g). The reaction was warmed to room temperature and stirred for 5 hours. The mixture was filtered through aluminium oxide (15 g) eluting with ether (75 mL). The collected filtrate was concentrated and purified by flash chromatography eluting with ethylacetate:iso-hexane (1:8) to give the sub-titled compound (5.42 g) as an oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:36][CH2:37][CH:38]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:36][CH2:37][CH:38]4[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:39]4)[N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CCI)C1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75 mg, 155 mmol), tert-butyl 3-(2-iodoethyl)azetidine-1-carboxylate (68 mg, 219 μmol.41) and Cs2CO3 (203 mg, 622 μmol) in DMF (2.00 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (40 g column, 50 μm silica-gel from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate (103 mg, 155 μmol, 99.5%) as a white solid. MS (M+Na)+=688; 1H NMR (CDCl3) δ: 9.24 (s, 1H), 8.56 (dd, J=8.7, 5.3 Hz, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 6.98-7.16 (m, 2H), 5.75 (s, 2H), 4.46 (t, J=6.4 Hz, 2H), 4.02 (t, J=8.3 Hz, 2H), 3.49-3.72 (m, 5H), 2.49-2.69 (m, 1H), 2.33 (q, J=6.8 Hz, 2H), 1.65 (s, 9H), 1.48 (s, 2H), 1.45 (s, 9H), 0.92-1.03 (m, 2H), 0.00 (s, 9H); LCMS ESI+ TIC MS showed 100% purity, [M+Na]+=688.0.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:12]3[N:13]([C:15]([CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:12]3[N:13]([C:15](/[CH:18]=[CH:19]/[C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C=Cc4ccncc4)cnc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(Nc2cc(Nc3ccccc3)c3ncc(/C=C/c4ccncc4)n3n2)CC1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To N6-(trans-4-aminocyclohexyl)-N8-(4-methoxybenzyl)-N8-phenyl-3-(2-(pyridin-4-yl)vinyl)imidazo[1,2-b]pyridazine-6,8-diamine (30 mg) from step (1c) in dichloromethane at room temperature was added excess TFA. The mixture was stirred for 30 min, concentrated, and the resulting residue was purified by reverse phase preparative HPLC to provide the titled compound as a yellow solid (21 mg). NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1H, s), 8.66 (2H, m), 7.78-7.90 (8H, m), 7.39-7.44 (4H, m), 7.16 (1H, m), 6.68 (1H, m), 6.26 (1H, s), 3.62 (1H, m), 3.08 (1H, m), 2.20 (2H, m), 2.02 (2H, m), 1.51-1.54 (2H, m), 1.25-1.29 (2H, m). LC/MS, m/e 426 (M+1). HPLC Rt, 1.89 min. YMC S5 ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4)—Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([CH:15]=1)[C:12](O)=[O:13])=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:58]1([NH:64][C:65]2[N:70]=[CH:69][C:68]([NH2:71])=[CH:67][N:66]=2)[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C=O)C.CO.CS(C)=O>[F:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([C:12]([NH:71][C:68]2[CH:67]=[N:66][C:65]([NH:64][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:70][CH:69]=2)=[O:13])[CH:15]=1)=[O:5]
Reactant: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1C(=O)O
Reactant: Nc1cnc(Nc2ccccc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CO
Product: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1C(=O)Nc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(2-fluoro-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid 32 (0.25 g, 0.73 mmol), HATU (0.28 g, 0.73 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.20 mL, 1.1 mmol) were taken up in DMF (6 mL). The solution was stirred at rt for 30 min then N2-phenylpyrimidine-2,5-diamine (0.105 g, 0.56 mmol) was added and the mixture was allowed to stir at rt overnight. The crude reaction mixture was taken up in minimal MeOH/DMSO and purified by preparative HPLC (acidic Gilson: 10-90% (0.1% TFA in CH3CN) in H2O over 15 min). Clean fractions were combined and allowed to stand for 2 h. Some product.TFA salt crashed out and was collected and neutralized with saturated NaHCO3 then extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated to afford 2-fluoro-N-(4-methyl-3-(((2-(phenylamino)-5-pyrimidinyl)amino)carbonyl)phenyl)-5-(trifluoromethyl)benzamide 33 as a white solid. MS m/z found 510.1 [MH+]; calc. for C26H19F4N5O2=509.15.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCN1CCNCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 2-(piperazin-1-yl)ethanamine (32.3 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 66.6 mg, (70% yield) MS (ES+): 379.2, (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[OH:38][C@H:39]1[CH2:43][CH2:42][N:41]([C:44]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][CH:47]=2)=[O:45])[CH2:40]1.CC1(C)C(C)(C)OB(C2C=CC(C(O)=O)=CC=2)O1.N1CC[C@H](O)C1>>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[C:12]([C:10]1=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:49]3[CH:48]=[CH:47][C:46]([C:44]([N:41]4[CH2:42][CH2:43][C@H:39]([OH:38])[CH2:40]4)=[O:45])=[CH:51][CH:50]=3)=[CH:37][C:6]=2[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:9]1)=[O:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC1(C)OB(c2ccc(C(=O)N3CC[C@H](O)C3)cc2)OC1(C)C
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: O[C@H]1CCNC1
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@H](O)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and (S)-(3-hydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone that was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (S)-pyrrolidin-3-ol. MS APCI (+) m/z 705 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25](O)=O)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C:17]([CH3:19])([CH3:18])[OH:20])[C:22]([CH2:21][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Cl)ccc12
Reactant: CCOCC(=O)O
Product: CCOCc1nc2cnc3cc(Cl)ccc3c2n1CC(C)(C)O

Procedure:
Using the general method of Example 42, 7-chloro-4-(2-hydroxy-2-methylpropylamino)-3nitroquinoline (18.5 g, 63 mmol, Example 82) was reduced and the resulting diamine reacted with ethoxyacetic acid to provide the desired product as a thick, green oil.