Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].N.Br[CH2:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11]>>[CH3:11][O:10][CH:9]([O:12][CH3:13])[CH2:8][CH2:7][C:1]#[CH:2]
Reactant: COC(CCBr)OC
Reactant: [C-]#[C-]
Agent: N
Agent: [Li+]
Product: C#CCCC(OC)OC
Reaction time: 2 h

Procedure:
To an equivalent quantity of lithium acetylide in liquid NH3 55 g (0.3 mol) of 1-bromo-3,3-dimethoxypropane were added in 30 minutes. Subsequently, stirring was continued for a further 2 hours, after which the NH3 was allowed to evaporate and the residue was dissolved in a mixture of ice and water. The mixture was extracted with ether and the combined organic layers were dried and concentrated by evaporation. The residue was distilled under reduced pressure and 11.5 g of 1,1-dimethoxy-4-pentyne were obtained.
Reaction SMILES: C([O:3][C:4](=[O:12])[CH:5]([N:9]=[N+:10]=[N-:11])[CH2:6][CH2:7][CH3:8])C.[OH-].[Na+]>CO.O>[N:9]([CH:5]([CH2:6][CH2:7][CH3:8])[C:4]([OH:12])=[O:3])=[N+:10]=[N-:11]
Reactant: CCCC(N=[N+]=[N-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(N=[N+]=[N-])C(=O)O
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
A solution of ethyl-2-azidopentanoate (3.082 g, 18.0 mmol) in a mixture of methanol (10 ml) and water (5 ml) was treated dropwise with 20 ml of 1M sodium hydroxide (20 mmol, 1.1 equiv). After 1.5 h at room temperature, the methanol was evaporated under reduced pressure and the remaining aqueous phase was washed with ether (2×10 ml) and acidified with dilute HCl (3N) at 0° C. The aqueous phase was extracted with dichloromethane (3×25 ml). The compound organic phases were washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oil which was distilled (bulb to bulb) to give 2.393 g (93%) of a clear liquid: bp 80°-85° C./0.5 toor (air bath temperature; ir (firm) νmax : 2110 (N3), 1720 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.90 (1H, dd, J=6, J=7, H-2), 2.0-1.0 (4H, m, H-3, H-4) and 1.00 ppm (3H, distorted t, J=6, H-5); Anal. calcd for C5H9N3O2 : C 41.95, H 6.34, N 29.36; found: C 42.06, H 6.49, N 29.26.
Reaction SMILES: C([O:8][C@H:9]1[CH2:15][C@@H:14]([O:16][CH3:17])[C:13]2([CH2:19][CH3:20])[O:18][C@@H:10]1[CH2:11][O:12]2)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:19]([C:13]12[O:18][C@H:10]([CH2:11][O:12]1)[C@@H:9]([OH:8])[CH2:15][C@H:14]2[O:16][CH3:17])[CH3:20]
Reactant: CCC12OC[C@@H](O1)[C@@H](OCc1ccccc1)C[C@H]2OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCC12OC[C@@H](O1)[C@@H](O)C[C@H]2OC

Procedure:
A solution of (1R,2S,4R)-2-benzyloxy-5-ethyl-4-methoxy-6,8-dioxabicyclo[3.2.1]octane (see Example 15.2) (3.4 g) in absolute ethanol (150 ml) containing acetic acid (2 ml) and 5% palladium on barium sulphate (1 g) was shaken in a hydrogen atmosphere at 40 p.s.i for 24 h, and then the solution was filtered and the solvent was removed. Chromatography of the residue on silica gel gave the title alcohol; m.p. 52°-53° C.; [α]D -97.1°; 13C nmr data: 108.2 (C-5), 78.7 and 78.0 (C-1 and C-4), 66.9 (C-2), 66.3 (C-7), 57.6 (OCH3), 27.0 and 26.0 (C-3 and CH2CH3), and 6.4 (CH2CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:36])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cncc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cncc(Br)c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
(5-Bromo-pyridin-3-yl)-methanol (500 mg, 2.7 mmol) and triphenylphosphine (840 mg, 3.2 mmol) are dissolved in 12 mL of DCM and NBS (570 mg, 3.2 mmol) is added. The mixture is stirred for 4 hrs and then the reaction mixture is directly purified by flash column chromatography give 455 mg of 3-bromo-5-bromomethyl-pyridine.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2CC(O)=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[CH2:7]([O:14][C:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:1][C:2]([Cl:4])=[O:3])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Solvent: ClCCl
Product: O=C(Cl)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of N6-(benzyloxycarbonyl)-9-(carboxymethyl)adenine (16.6 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4](C)[C:5]#[CH:6].C(=O)([O-])[O-].[K+].[K+].CC(=O)[CH2:16][C:17](=[O:19])[CH3:18].CCOCC>C(O)C.O.CCCCCC>[CH3:16][C:17](=[O:19])[CH2:18][CH2:2][CH:3]=[CH:4][C:5]#[CH:6]
Reactant: C#CC(C)=CCBr
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: C#CC=CCCC(C)=O
Yield: 77.2 %

Procedure:
In accordance with a procedure suggested by L. Miginiac, et al., Org. Prep. Proced. Int., 10, 261 (1978), a mixture containing 2.81 g (17.7 mmoles) of 5-bromo-3-methyl-3-penten-1-yne (produced in accordance with Example I), 3.27 g (23.6 mmoles) of anhydrous potassium carbonate, and 2.00 mL (19.5 mmoles) of 2,4-pentanedione (purchased from Aldrich Chemical Co., Milwaukee, Wis.) in 12.0 mL of absolute ethanol was heated, protected from atmospheric moisture, at reflux for 19 hours. The cooled mixture was diluted with 60 mL of water to dissolve the inorganic solids and the product was isolated by extraction (3×60 mL) with 1:1 (v/v) ether:hexane. After subsequent washing of the combined organic extracts with 10% aqueous sodium chloride (3×80 mL), the organic layer was dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure, followed by evaporative distillation, afforded 1.67 g (69% yield) of the named ketone: boiling point 82°-91° C. (bath temperature, 2.5 mm). The identity and purity of this known ketone were ascertained by IR and proton NMR analysis. An alternate synthesis of this ketone has been described by P. I. Zakharova, et al., Chem. Abstracts. 75, 109784h (1971).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][CH:14]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][CH:14]=2)[N:5]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2nc(Cl)cc(Cl)n2)cn1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2nc(Cl)cc(N3CCOCC3)n2)cn1

Procedure:
N-(5-(4,6-dichloropyrimidin-2-yl)pyridine-2-yl)pivalamide (975 mg, 3.0 mmol), morpholine (0.262 mL, 3.0 mmol) and triethylamine (502 mL, 3.6 mmol) are stirred in NMP (10 mL) for 2 hours at 85° C. At this time the reaction mixture is partitioned between EtOAc (200 mL) and NaHCO3(sat.) (50 mL). The organic layer is separated, washed with water (30 mL), then brine (30 mL), dried over Na2SO4, filtered, concentrated, obtaining the desired product.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH2:19]1[O:21][C@H:20]1[CH2:22]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.O>CN(C)C=O>[S:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH:20]3[CH2:19][O:21]3)=[CH:12][CH:13]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2
Reactant: Oc1ccc(-c2csc3ccccc23)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Cool a mixture of sodium hydride (585 mg, 60% dispersion in mineral oil, 14.6 mmol) in dimethylformamide (20 mL, anhydrous), with an ice bath, under a nitrogen atmosphere. Add a solution of 4-benzo[b]thiophen-3-yl-phenol (3.0 g, 13.3 mmol) in dimethylformamide (20 mL) over a period of 5 minutes. Reaction mixture has noticeable gas evolution and is a yellow mixture. Stir at room temperature for 0.5 hours and cool via an ice bath to give a yellow solution. Rapidly, add a solution of (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (3.78 g, 14.6 mmol) in dimethylformamide (20 mL) and stir at 0° C. for 35 minutes. The reaction mixture is a red-orange color. Stir reaction mixture at room temperature overnight. Pour the reaction mixture into cold (0° C.) water (300 mL) and extract with ethyl acetate (3×100 mL). Combine the organic layers, wash with water (100 mL), saturated sodium chloride (100 mL), dry (MgSO4) and concentrate (in vacuo) to give a brown oil. The brown oil is purified by column chromatography (dichloromethane) to give a light green/clear, viscous oil. The oil is dried (0.5 mm Hg) at room temperature for 3 hours to give the title compound as a solid (3.19 g, 85% Yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[OH:18][NH2:19].C([O-])(=O)C.[Na+].C(OCC)(=O)C.CCCCCC>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[N:19][OH:18])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NO
Reactant: CCCCC(=O)c1ccc(OC)c(OC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: CCCCC(=NO)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
To a stirred solution of 3′,4′-dimethoxyvalerophenone (0.08 grams, 3.60 mmol) in a mixture of ethanol (25 milliliters) and water (5 milliliters) was added hydroxyamine hydrochloride (0.40 grams, 5.76 mmol) and sodium acetate (0.59 grams, 7.20 mmol) in water (5 milliliters). The solution was refluxed for two days. Reaction progress was monitored by TLC (20%, ethyl acetate/hexane, UV) and was complete after 2 days. The reaction was allowed to cool to ambient temperature and the ethanol was removed in vacuo to afford an oil/aqueous mixture. The mixture was extracted with methylene chloride. The dried extracts were concentrated in vacuo to afford 0.93 grams of crude product as a yellow oil. The crude product was purified by flash chromatography (silica gel, 20%, ethyl acetate/hexane) to afford 0.56 grams of product as a yellow oil: 1H NMR (CDCl3) δ8.23-8.01(br s, 1H), 7.30-7.05(m, 2H), 6.93-6.81(m, 1H), 3.91(s, 3H), 3.90(s, 3H), 2.84-2.70(m, 2H), 1.74-1.31(m, 4H), 0.93(t, J=7.2 Hz, 3H);13 C NMR (CDCl3) δ159.6, 150.1, 148.9, 128.5, 119.3, 110.6, 108.9, 55.9, 28.7, 25.6, 22.9, 13.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.N>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Yield: 50.8 %

Procedure:
(S)-2-(1-((5-(6-Methoxypyridin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (17 mg, 0.02 mmol) was treated with trifluoroacetic acid (340 μl, 4.41 mmol), a solution of ammonia (7N in methanol, 340 μl, 2.38 mmol) in 370 μl methanol according to the method described in Example 27 to give 5 mg (59% yield) of the title compound. Purity 100%.
Reaction SMILES: C(OC([O:6][CH2:7][C@@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)C)C.[I-].[K+].[H-].[Na+].Cl[CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.CO>[OH:6][CH2:7][C@@H:8]1[N:12]([CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:11](=[O:13])[CH2:10][CH2:9]1
Reactant: COC(=O)CCCSCCCl
Reactant: CCOC(C)OC[C@H]1CCC(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCSCCN1C(=O)CC[C@@H]1CO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5R)-5-(1-ethoxyethoxymethyl)pyrrolidin-2-one (3.31 g, 17.7 mmol) in 50 mL of anhydrous dimethylformamide at 0° C. under an argon atmosphere was added potassium iodide (3.22 g, 19.4 mmol) and sodium hydride (95%, 0.44 g, 17.7 mmol). The cooling bath was removed and the reaction was stirred for 30 minutes. A solution of methyl 4-[(2-chloroethyl)thio]butanoate (3.46 g, 17.7 mmol) in 5 mL anhydrous dimethylformamide was added and the reaction solution was warmed to 50° C. and stirred for 40 hours. The volatiles were removed via simple distillation under vacuum. Ethyl acetate (150 mL) and aqueous ammonium chloride solution (50 mL) were then added to the crude residue. Upon separation between the two phases, the ethyl acetate solution was dried (anhydrous. Na2SO4) and evaporated under reduced pressure. To a solution of the protected ester (17.7 mmol) in 70 mL of anhydrous methanol at room temperature under an argon atmosphere was added p-toluenesulfonic acid monohydrate (0.34 g, 1.8 mmol). After stirring for 5 hours, aqueous sodium bicarbonate solution (50 mL) was added and the reaction mixture was evaporated under reduced pressure. Ethanol (50 mL) was added and the solution was again evaporated. The resultant material was purified via column chromatography to yield methyl 4-({2-[(5R)-5-(hydroxymethyl)-2-oxo pyrrolidin-1-yl]ethyl}thio)butanoate as a tan oil (0.17 g, mass spec. M+=275).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:54][O:55][CH2:56][CH2:57][NH2:58]>O.CN(C)C=O>[CH3:54][O:55][CH2:56][CH2:57][NH:58][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COCCN
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.3 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), 2-methoxyethylamine (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 20 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (200 mg, 59%) as pale yellow prisms. MS 519 (MH+). mp 175-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH2Cl2, DIEA (6.6 g) was added to the mixture, followed by DMAP (100 mg). The mixture was cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mL CH2Cl2) was added dropwise to the reaction mixture. After the mixture was stirred at RT over 3 h, extracted once with saturated NaHCO3 solution and once with brine, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:Hexane to 100% EtOAc to afford N-(2-bromo-5-nitrophenyl)acetamide as a white solid. MS:258 (M−1). Calc'd. for C8H7BrN2O3—259.06.
Reaction SMILES: C(ON=O)CC(C)C.[Cl:9][C:10]1[N:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13](N)=[N:14][C:15]=1[Cl:16].C(Br)(Br)[Br:22]>>[Br:22][C:13]1[C:12]([N+:18]([O-:20])=[O:19])=[N:11][C:10]([Cl:9])=[C:15]([Cl:16])[N:14]=1
Reactant: BrC(Br)Br
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Agent: CC(C)CCON=O
Product: O=[N+]([O-])c1nc(Cl)c(Cl)nc1Br

Procedure:
To 4.8 g isoamylnitrite in 150 ml bromoform heated to 95°-100° is added portionwise 5.0 g 5,6-dichloro-3-nitro-pyrazinamine. The reaction mixture is heated at reflux for 18 hours. After cooling, the bromoform is removed in vacuo to give an oil which is chromatographed on silica gel. The initial component to elute is 5,6-dichloro-2-bromonitropyrazine, which is obtained (2.6 g) as a viscous oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:34]=2[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:32]=[CH:31]3)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:8]1[C:6]2=[N:7][C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:34]=3[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:32]=[CH:31]4)=[CH:3][N:4]=[C:5]2[NH:10][CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1(C)OB(c2cccc3cnn(COCC[Si](C)(C)C)c23)OC1(C)C
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3cccc4cnn(COCC[Si](C)(C)C)c34)nc12
Temperature: 90 °C
Yield: 76.6 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.1 g, 0.337 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (121 mg, 0.37 mmol), Pd2(dba)3 (39 mg, 0.067 mmol), X-Phos (64 mg, 0.135 mmol) and Na2CO3 (107 mg, 1.01 mmol) in dioxane (20 mL) and water (5 mL) was heated to 90° C. for 16 hours under N2 atmosphere. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate (20 mL) and water (10 mL), organic phase was washed with brine (10 mL) then dried over Na2SO4 and concentrated to afford N-tert-butyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (120 mg, crude) as yellow oil. LCMS: (M+H)+=465.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[Cu][C:17]#[N:18].CCOC(C)=O>CN1C(=O)CCC1>[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:18]
Reactant: N#C[Cu]
Reactant: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c[nH]c2ccc(C#N)cc12
Yield: 46.7 %

Procedure:
Step H (2): To a solution of methyl 2-(5-bromo-1H-indol-3-yl)acetate (134 mg, 0.5 mmol) in NMP (1.0 mL) was added copper(I) cyanide (54 mg, 0.6 mmol). The reaction mixture was microwaved at 180° C. for 1.5 h. More copper (I) cyanide (54 mg, 0.6 mmol) was added, and the mixture was microwaved again at 180° C. for 2 h. 100 mL of EtOAc was added, and the reaction mixture was washed with 1.0 N HCl and H2O. The organic layer was dried and the residue was purified by flash chromatography to give 50 mg of the methyl 2-(5-cyano-1H-indol-3-yl)acetate (yield 47%). MS (ESI) (M+H)+=215.16. 1H NMR (500 MHz, CDCl3) δ ppm 3.73 (s, 3 H) 3.77 (s, 2 H) 7.26 (d, J=2.14 Hz, 1 H) 7.37 (d, J=8.24 Hz, 1 H) 7.40 (dd, J=8.24, 1.22 Hz, 1 H) 7.95 (s, 1 H) 8.54 (s, 1 H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCOCC1
Temperature: 60 °C
Yield: 20.6 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added morpholine (114.86 mg, 1.318 mmol) followed by diisopropylethylamine (0.229 mL, 1.318 mmol) and tetrabutylammonium iodide (162.3 mg, 0.439 mmol). The reaction mixture was heated at 60° C. for 3 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea (51 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.60-7.35 (m, 4H), 7.25 (m, 1H), 6.95 (m, 1H), 6.45 (s, 1H), 4.32 (m, 2H), 3.95 (s, 3H), 3.62 (m, 4H), 2.85 (m, 2H), 2.65-2.45 (m, 4H), 1.28 (s, 9H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][C:16](=[N:19][OH:20])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][CH:16]([NH:19][OH:20])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: ON=C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: ONC1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reaction time: 2.5 h
Yield: 22.3 %

Procedure:
To a stirred solution of 3-[5-(4-fluorophenylthio)-2-furyl]-2-cyclopentenone oxime (6 g; 20.8 mM) in acetic acid (40 ml) was added NaBH3CN (1.57 g; 24.9 mM) at room temperature. After stirring for 2.5 hr, acetic acid was removed. The residue was dissolved in ethyl acetate (150 ml), and the whole was washed with saturated aqueous NaHCO3 (80 ml). The aqueous layer was extracted with ethyl acetate (80 ml), and the combined organic layer washed with water (80 ml), brine (80 ml), dried over MgSO4, and concentrated in vacuo. Chromatographic purification of the residue during with CH2Cl2 -EtOH (50: 1) provided 1.35 g (yield 22%) of the subtitle compound as a yellow oil.