Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19](=[O:33])[C:18]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:37][C:36]=1[F:49])[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([CH:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:19](=[O:33])[C:18]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[NH:3][C:4](=[O:7])[O:5][N:48]=2)=[CH:37][C:36]=1[F:49])[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A mixture of hydroxylammonium chloride (1 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[7-butyl-2-methyl-5-oxo-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.49 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.32 g, 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([F:45])[CH:39]=3)=[O:36])[CH2:34][CH2:33]2)=[O:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]2([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:13]4[C:12]5[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)=[C:10]([O:20][CH3:21])[CH:11]=5)[N:16]=[CH:15][N:14]=4)=[C:40]([F:45])[CH:39]=3)=[O:36])[CH2:34][CH2:33]2)=[O:31])=[CH:27][CH:28]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (5 g, 16.67 mmol), cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide(4-fluoro-phenyl)-amide (8.3 g, 25 mmol), potassium carbonate (125 mmol, 17.25 g), and dimethylacetamide (125 ml) was heated 50° C. with stirring for 16 h. Reaction mixture was poured onto ice/water (600 ml) and stirred for 30 minutes, and filtered. The solid was dissolved in ethyl acetate and washed with water (1×), brine, and concentrated. The crude was purified on silica get column eluting with 30% acetone in hexanes to yield cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (7.5 g, 76%). 1H NMR (CDCl3): 8.64 (1H, br. s), 8.55 (1H, s), 8.33 (1H, br. s), 7.74-7.71 (1H, dd), 7.54 (1H, s), 7.48-7.33 (8H, m), 7.31-7.24 (2H, m), 7.06-7.02 (2H, m), 5.32 (2H, s), 4.06 (3H, s), 1.77-1.74 (2H, m), 1.63-1.61 (2H, m).
Reaction SMILES: I[CH2:2]CI.[Cl:5][C:6](=[CH2:23])[CH2:7][C:8]1([CH3:22])[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]1=[O:21].ICI.[OH-].[Na+].Cl>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:10]2[C:9]3([O:21][CH2:2]3)[C:8]([CH:7]=[C:6]([Cl:5])[CH3:23])([CH3:22])[CH2:12][CH2:11]2)=[CH:15][CH:16]=1
Reactant: ICCI
Reactant: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ICI
Product: CC(Cl)=CC1(C)CCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, anhydrous THF (9 ml) was combined with Sm (1.01 g, 6.71 mmol), and then, at room temperature, 1,2-diiodoethane (1.05 g, 3.73 mmol) was added. The reaction solution was stirred for 1 hour at room temperature, and then cooled to −7 degrees C. to −2 degrees C., and 2-(2-chloro-2-propenyl)-5-(4-chlorobenzyl)-2-methylcyclopentanone (Compound (V), (Ra)Xana=CH3, (Rb)Xbnb=CH2CCl═CH2, Ym=4-Cl) dissolved in diiodomethane (0.90 g, 0.00168×2.0 mol) and THF (5 ml) was added, and stirred for 1.5 hours at the same temperature. To this, a 2N aqueous solution of NaOH (8 ml) was added, and stirring was conducted for 1 hour while cooling with ice. A 2N aqueous solution of hydrochloric acid (8 ml) was added, and then extraction with hexane (100 ml×2) was conducted. The organic layer was washed with water (50 ml) and saturated brine (30 ml), and then dried over anhydrous sodium sulfate and concentrated to obtain a crude intended substance (0.44 g), which was used in the next reaction as it was.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[C:15]2[C:14](C)(C)CCC(C)(C)[C:10]=2[CH:9]=[C:8](B(O)O)[CH:7]=1)[CH3:2].[C:23](=O)([O-])[O-].[Cs+].[Cs+].ClC(C1C=C2C(=CC=1)C=C(C(OC)=O)C=C2)=O>C1(C)C=CC=CC=1.[Pd](Cl)Cl>[C:4]([O:3][CH2:1][CH3:2])(=[O:5])[CH3:23].[CH3:14][CH2:15][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCOCOc1cc(B(O)O)cc2c1C(C)(C)CCC2(C)C
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ccc2cc(C(=O)Cl)ccc2c1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCCCCCC
Product: CCOC(C)=O
Yield: 142.7 %

Procedure:
5 g (16 mmol) of 4-ethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene boronic acid are dissolved in 100 mL of toluene. 26 g (80 mmol) of caesium carbonate are added and the medium is degassed for 15 minutes with a flow of nitrogen. 14 mg (0.8 mmol) of palladium chloride are added, followed by 5.47 g (22 mmol) of methyl 6-chlorocarbonyl-2-naphthalenecarboxylate in 1 g portions. The reaction medium is refluxed for 15 hours and then hydrolysed and extracted with ethyl acetate. The residue obtained is purified by chromatography (eluent: 9/1 heptane/ethyl acetate). The product is then recrystallized from an ethyl acetate/heptane mixture (m=4.3 g; yield=59%; m.p.=96° C.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[F:25])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[F:25])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c(F)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a solution of N-tert-butyl-2-(2-fluoro-4-methylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 184 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (421 mg, 284 μL, 3.69 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(2-fluoro-4-methylphenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (58 mg, 170 μmol, 92%) as an off-white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.27 (s, 1H), 8.97 (s, 1H), 8.10 (s, 1H), 7.96 (d, J=2.3, 1 H), 7.81 (t, J=8.6, 1 H), 7.70 (s, 1H), 7.10 (d, J=12.4, 1 H), 6.95 (d, J=8.0, 1 H), 2.29 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 342.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]2=[O:21])=O)=[CH:5][CH:4]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH:13]2[C:14](=[O:21])[NH:15][C:16](=[O:20])[NH:17][C:18]2=[O:19])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)C2C(=O)NC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CCCC2C(=O)NC(=O)NC2=O)cc1
Temperature: 600 °C
Yield: 91.8 %

Procedure:
To a suspension of 10 g of 5-[3-(4-methoxyphenyl)propionyl]barbituric acid in 100 ml of acetic acid are added portionwise 4.5 g of sodium cyanoborohydride, then the mixture is heated to 600° C. After 1 hour the reaction mixture is cooled to room temperature and poured into ice. After 30 minutes a solid is recovered by filtration, which is dried under vacuum at 50° C. to give 8.74 g of the product, m.p. 195-197° C.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:34])[C@H:9]([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C@@H:8]1[C:15]([O:17][CH:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].N(CCO)(CCO)CCO.[SH2:45]>O>[CH3:6][C:7]1([CH3:34])[C@H:9]([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C@@H:8]1[C:15]([O:17][CH:18]([C:32](=[S:45])[NH2:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: S
Solvent: O
Solvent: CN(C)C=O
Solvent: OCCN(CCO)CCO
Product: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)OC(C(N)=S)c1cccc(Oc2ccccc2)c1
Yield: 98 %

Procedure:
Into 20 ml of N,N-dimethylformamide were dissolved 2.50 g of 3-phenoxy-α-cyanobenzyl cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate and 1 ml of triethanolamine, and hydrogen sulfide gas was bubbled into the solution at room temperature over a period of 15 hours. The resultant reaction mixture was poured into 500 ml of water and extracted with diethyl ether. The ethereal layer was washed with water, dried over anhydrous magnesium sulfate and distilled to remove diethyl ether. By the above procedure there were obtained 2.63 g of 3-phenoxy-α-thiocarbamoylbenzyl cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate [Compound (27)] having the NMR spectrum shown hereinbelow (yield: 98%)
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14].[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([C:4]1[C:5]2[N:6]([N:9]=[CH:10][N:11]=2)[CH:7]=[N:8][C:3]=1[CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=1)[CH2:13][CH3:14]
Reactant: N#Cc1cccc(-c2ncc[nH]2)n1
Reactant: CCCc1c(CBr)ncn2ncnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(C#N)n2)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 169 (97 mg, 0.38 mmol), 172 (64 mg, 0.38 mmol) and K2CO3 (160 mg) in DMF (4 mL) is stirred at room temperature overnight. Solvent is removed in vacuo. Water (10 mL) is added and the mixture is extracted with ethyl acetate (3×25 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% MeOH in methylene chloride) to give the title product (171) as a solid. 1H NMR 9.12 (s, 1H), 8.49 (q, 1H), 8.36 (s, 1H), 7.87 (t, 1H), 7.56 (q, 1H), 7.21 (s, 2H), 6.11 (s, 2H), 3.13–3.19 (m, 2H), 1.71–1.79 (m, 2H), 1.02 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:7]=1.C(O)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.[Pd].C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C#CCCn2ccnn2)nn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccc(CCCCn2ccnn2)nn1

Procedure:
3-Chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine (2.50 g, 10.7 mmol) is dissolved in ethyl acetate (450 ml) and hydrogenated for 3.5 h at r.t. in the presence of palladium on charcoal (10%, 2.50 g). The reaction mixture is filtered and concentrated in vacuo. The residue was dissolved in THF (10 ml) and added to a solution of benzyl alcohol (0.94 ml, 9.0 mmol) and sodium tert-butoxide (NaOtBu) (0.842 g, 8.76 mmol) in THF (80 ml). After stirring for 2 h ethyl acetate (100 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over Na2SO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate) 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine is obtained as a colorless solid. Yield 1.14 g (45%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH:22](=[O:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([CH:22]([OH:24])[CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 from Example 19 (0.3 mmol) dissolved in THF (3 mL) at −78° C. was added 1.6M solution of n-butyllithium (0.39 mmol). The reaction mixture was stirred for 30 mins at which point acetaldehyde (1.2 mmol) was added. The reaction was stirred for one hour and quenched with ice and allowed to warm to room temperature. The aqueous layer was extracted with methylene chloride and the organic layer was filtered through sodium sulfate. The organic phase was concentrated to yield 1-(2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-yl)ethanol (72 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[OH:20])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SCCC(O)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
By the method of Example 14, the aldehyde of Example 4 was reacted with 7.1 ml of 1.97 M cyclohexyl magnesium bromide in tetrahydrofuran to give the title alcohol.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([OH:24])=O)[N:16]=[N:15]2)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=C[C:28]2N(O)N=[N:31][C:29]=2[CH:30]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH2:1]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([NH:31][CH:29]3[CH2:30][CH2:28]3)=[O:24])[N:16]=[N:15]2)=[CH:12][CH:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
1-{4-[(Butylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (504 mg, 1.53 mmol) obtained in Example 56b), HOBt (208 mg, 1.53 mmol, 1.0 eq.) and cyclopropylamine (0.142 ml, 1.98 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (358 mg, 1.83 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (535 mg, 1.45 mmol, 94.9%).
Reaction SMILES: [CH:1]([O-:6])([O-])[O:2][CH2:3][CH3:4].[C:7]([C:15]1[CH:19]=[C:18]([CH3:20])[N:17]([CH:21]([CH3:24])C=O)[C:16]=1[CH3:25])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:26][CH2:27]OCC>S(=O)(=O)(O)O>[CH2:26]([O:6][CH:1]([O:2][CH2:3][CH3:4])[CH:21]([N:17]1[C:18]([CH3:20])=[CH:19][C:15]([C:7](=[O:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:16]1[CH3:25])[CH3:24])[CH3:27]
Reactant: CCOCC
Reactant: CCOC([O-])[O-]
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C=O
Agent: O=S(=O)(O)O
Product: CCOC(OCC)C(C)n1c(C)cc(C(=O)c2ccccc2)c1C
Reaction time: 5 h
Yield: 25 %

Procedure:
Ethyl orthoformate (2 ml) and one drop of conc. sulfuric acid were added to 257 mg (1.0 mmole) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)propionaldehyde, and the reaction was performed at room temperature for 5 hours. Ether was added, and the organic layer was washed with water, dried, concentrated and chromatographed on a column of silica gel to afford compound (904) (82 mg, 0.25 mmole, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]I)[CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>O1CCCC1.C(O)(C)C.CO>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Reactant: C1CCNC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCN1CCCC1)c1ccccc1

Procedure:
A solution of the product from Example 1 step (c) (200 mg) and pyrrolidine (0.15 ml) in tetrahydrofuran (5 ml) was stirred for 2 days. The solvent was removed in vacuo and the residue dissolved in water and aqueous potassium carbonate and extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (Na2SO4) and evaporated to give an oil. To a solution of this amine in isopropanol (3 ml) was added a solution of oxalic acid (44 mg) in methanol (0.3 ml). The crystals that formed on cooling were collected and dried to afford the title compound as a white solid (163 mg). M.p. 157-158° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:19])C(=O)C1.[O:20]1CCO[CH2:22][CH2:21]1>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>[Br:19][CH2:22][C:21]([C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: C1COCCO1
Reactant: Cc1c(Br)ccc(F)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1c(C(=O)CBr)ccc(F)c1C#N
Temperature: 100 °C
Reaction time: 22 h

Procedure:
Degassed Reactant Sn reagent (200 ml, 591 mmol) was added to a stirred mixture of 3-Bromo-6-fluoro-2-methylbenzonitrile (115 g, 537 mmol) and PdCl2(PPh3)2 (18.86 g, 26.9 mmol) in dioxane (1149 ml) at RT, then degassed with N2 and the mixture was stirred at 100° C. for 22 hours. The reaction was cooled to 0° C. and THF (575 mL) and water (230 mL) were added followed by NBS (110 g, 618 mmol) added portionwise over 15 min. After 30 minutes, HPLC showed full consumption of the intermediate ketone. The solution was diluted with MTBE (1000 mL) and washed with 0.5% aqueous HBr (3×500 mL), then washed with water. The organic layers were dried over Na2SO4, filtered and concentrated. A precipitate generated. The solid was filtered and washed several times with hexanes to give the title product.
Reaction SMILES: N1(O[C:11]2[C:12]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)C2C=CC=CC=2N=N1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C@@H:35]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:47][C:46]=2[S:55]([C:58]([F:61])([F:60])[F:59])(=[O:57])=[O:56])[CH2:36][S:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.CCOCC>[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C@@H:35]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([NH:54][C:11]3[C:12]4[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)(=[O:52])=[O:53])=[CH:47][C:46]=2[S:55]([C:58]([F:61])([F:59])[F:60])(=[O:57])=[O:56])[CH2:36][S:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:29][CH2:28]1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(On3nnc4ccccc43)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ncnc(NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)c2C1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 20.4 %

Procedure:
tert-Butyl 4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (448 mg, 1.264 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3(trifluoromethylsulfonyl)benzenesulfonamide (910 mg, 1.643 mmol), and potassium carbonate (524 mg, 3.79 mmol) were combined in N,N-dimethylformamide (6.3 mL) and stirred for 1.5 hours at 85° C. and then for 2.5 hours at 95° C. The reaction was then cooled to room temperature and stirred for 16 hours. The reaction was treated with water (˜30 mL) and sonicated. A dark brown solid stuck to the flask. The solid was washed several times with water and then several times with diethyl ether. This residue was then treated with methanol (˜15 mL), and the off-white precipitate formed was removed by filtration. The dark brown filtrate was concentrated in vacuo to afford a brown solid. The water and ether washes were combined and diluted with more water and ether. The layers were separated, and the organic layer was dried over sodium sulfate, filtered and concentrated down. This residue was combined with the brown solid and purified by flash chromatography on silica gel (0 to 10% methanol/ethyl acetate followed by 0 to 30% methanol/dichloromethane) to afford the title compound (199 mg, 13% yield). MS (ESI) m/e (M+H)+=773.5.