Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][F:26]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][F:26]
Reactant: FCCCCCCCCBr
Reactant: C#CCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: FCCCCCCCCC#CCCOC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of 3-butyn-1-yl tetrahydropyranyl ether (0.4815 g, 3.05 mmol) (prepared as in Example 1 above) in dry tetrahydrofuran (15 mL) at -78° C. is added n-butyllithium (3.05 mmol, 2.80 mL of 1.09M n-BuLi in hexane). The resulting yellow mixture is stirred for 1 hour at -78° C., warmed to -5° C. for about 5 min and then a solution of 8-bromo-1-fluorooctane (0.7716 g, 3.65 mmol, 1.2 eq.) in HMPA (10 mL) is added dropwise over 45 minutes (Hendry et al., J. Chem. Ecol., 1, 317, 1975). After the addition is completed, the reaction is allowed to warm to room temperature and stirred overnight. After quenching the solution by the dropwise addition of water (about 10 mL), the aqueous solution is extracted with pentane (4×50 ml) and the combined pentane extracts are washed with saturated sodium chloride (50 mL) and dried (MgSO4). The volatiles are removed in vacuo and the crude product is flash chromatographed using hexane/ethyl acetate (9:1, v/v) to give 12-fluoro-3-dodecyn-1-yl tetrahydropyranyl ether (0.526 g, 60%) as a clear colorless oil: Rf=0.60, hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-3000 (alkane CH) and 1H-NMR (CDCl3) δ1.20-1.90 (m, 18H), 2.05-2.20 (m, 2H), 2.30-2.55 (m,2H), 3.30-3.95(m, 4, 4.42 (dt, J=48 Hz, 6 Hz, 2H), 4.60 (br s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)c1cc(Cl)nc(C)n1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc(C)n1
Yield: 21.4 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (94.7 mg, 0.29 mmol), ethyl 6-chloro-2-methylpyrimidine-4-carboxylate (56 mg, 0.28 mmol) (reference: Bioorganic and Medicinal Chemistry Letters; 14; 15; 2004; 3869-3874) and diisopropylethylamine (108 mg, 0.84 mmol), to obtain 27 mg of the title compound as a yellow brown oily substance (22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:8][CH2:9][CH:10]3[CH2:15][O:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N+:8]([O-:31])[CH2:9][CH:10]3[CH2:15][O:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)N1CCOCC1CN=C2c1ccco1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)N1CCOCC1C[N+]([O-])=C2c1ccco1
Yield: 36.4 %

Procedure:
A solution of 6 g of 1,2,4,4a-tetrahydro-10-methoxy-7-(2furyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine (for the preparation, see Example 2) in 100 ml of methylene chloride is heated under reflux with 4.2 g of 3-chloroperbenzoic acid for 3 hours. The reaction solution is then rendered alkaline with aqueous dilute sodium hydroxide solution and is worked up in the customary manner. The crude product isolated is purified by chromatography on aluminium oxide of activity level II, using methylene chloride, and is crystallised from isopropanol. 2.3 g of 1,2,4,4a-tetrahydro-10-methoxy-7-(2-furyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine 6-oxide are obtained. Melting point: 183° to 186° C.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH3:23])[N:20]([C:24]4[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=4)[C:19]=3[CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[NH2:30][C:26]1[N:27]=[CH:28][N:29]=[C:24]([N:20]2[C:19]3[CH:31]=[C:15]([C:14]#[C:13][C:8]4([CH2:7][OH:6])[CH2:9][CH2:10][CH2:11][CH2:12]4)[CH:16]=[CH:17][C:18]=3[N:22]=[C:21]2[CH3:23])[N:25]=1
Reactant: Cc1nc2ccc(C#CC3(C(C)(C)O[SiH2]C(C)(C)C)CCCC3)cc2n1-c1ncnc(N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccc(C#CC3(CO)CCCC3)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-{6-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentylethynyl]-2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine (6-e) (80 mg, 0.17 mmol) was dissolved in THF (100 mL), TBAF (113 mg, 0.43 mmol) was added. The resulting mixture was stirred at room temperature for 12 h. Water (5 mL) was added, extracted with EtOAc. The organic phase was concentrated, purified via prep-TLC separation to afford the title target (27.5 mg, 47%): 1H NMR (400 MHz, DMSO) delta 1.55-1.76 (m, 8H), 2.86 (s, 3H), 3.40 (d, J=4.8 Hz, 2H), 4.96 (t, J=4.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.90-8.10 (m, 2H), 8.30 (t, J=0.8 Hz, 1H), 8.63 (s, 1H). LCMS: m/z=+349.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:20](Br)[CH:21]=[CH2:22]>CO>[NH:1]([CH2:22][CH:21]=[CH2:20])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C=CCBr
Reactant: COC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CO
Product: C=CCN[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C)C(=O)OC

Procedure:
533 Mg. (2 meq.) of H-Tyr-D-Ala-OMe in 80 ml. of methanol with 400 mg. (4 meq.) of powdered KHCl3 and 484 mg. (4 meq.) of allyl bromide were refluxed 2.5 hours under nitrogen. The solution was evaporated to dryness and dried in vacuo over KOH. The desired product was purified by high performance liquid chromatography using reverse phase C-18 column and eluting with 0.1 molar NH4OAc ph 4.2 containing 23% acetonitrile. The mass spectrometric analysis of the isolated product confirms the presence of an N-allyl group on the dipeptide. TLC (S. C., BAW peptidechlorine spray) indicated the presence of one major component RF 0.65.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][CH2:17][S:18]([CH2:21][CH2:22]Br)(=[O:20])=[O:19]>CS(C)=O.C1COCC1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:22][CH2:21][S:18](=[O:20])(=[O:19])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 98.3 %

Procedure:
A slurry of NaH (71.4 mg, 1.79 mmol, 60% dispersion) in DMSO (3 mL) and THF (1 mL) was treated with solid (4-nitro-phenyl)-acetonitrile (121 mg, 0.744 mmol) and stirred at RT for 3 min. A solution of 1-bromo-2-(2-bromoethanesulfonyl)-ethane (250 mg, 0.893 mmol) in THF (3 mL) was added, and the mixture was heated to 70° C. for 1.5 h. The mixture was partitioned between EtOAc (100 mL) and water (75 mL), and brine (25 mL) was added. The aqueous layer was extracted with EtOAc (1×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column with 10-50% EtOAc-hexane afforded the title compound (205 mg, 98%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 8.33 (d, 2H, J=8.8 Hz), 7.75 (d, 2H, J=8.8 Hz), 3.64-3.52 (m, 2H), 3.29-3.19 (m, 2H), 2.88-2.76 (m, 2H), 2.54-2.44 (m, 2H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH:19]([C@H:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[N:22]1[CH2:28][C:29]#[C:30][CH2:31][O:32][CH2:33][C:34]#[N:35])=O>C1COCC1>[O:27]=[C:23]1[CH2:24][CH2:25][CH2:26][C@H:21](/[CH:19]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:22]1[CH2:28][C:29]#[C:30][CH2:31][O:32][CH2:33][C:34]#[N:35]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: N#CCOCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 18 mg, 0.45 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (110 mg, 0.45 mmol) in THF (1.5 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile (0.50 mmol, crude from step 5) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 10 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10%→40% EtOAc/CH2Cl2, gradient) afforded 75 mg (48%) of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])C(C)C.[C:25]([O-])(=O)[CH3:26]>>[NH2:11][C:14]1[CH:16]=[C:17]([CH:18]=[CH:25][CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7]
Reactant: CC(C)COC(=O)N1CCN(C(=O)c2ccc(C(=N)N)cc2)CC1
Reactant: CC(=O)[O-]
Product: N=C(N)c1ccc(C(=O)N2CCN(C(=O)c3cccc(N)c3)CC2)cc1

Procedure:
4-[4-(isobutyloxycarbonyl)piperazine-1-carbonyl]benzamidine, acetate, FAB 333.
Reaction SMILES: C(OC([N:8]([CH2:42][CH3:43])[C:9]1[C:10]([CH2:37][O:38]C(=O)C)=[N:11][CH:12]=[C:13]([C:15]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][C:19]4[N:25]([CH3:36])[C:26](=[O:35])[N:27]([C:28]5[C:29]([CH3:34])=[N:30][N:31]([CH3:33])[CH:32]=5)[C:18]=4[C:17]=3[CH:16]=2)[CH:14]=1)=O)(C)(C)C.[Li+].[OH-]>O1CCOCC1.CCOC(C)=O>[CH3:33][N:31]1[CH:32]=[C:28]([N:27]2[C:18]3[C:17]4[CH:16]=[C:15]([C:13]5[CH:12]=[N:11][C:10]([CH2:37][OH:38])=[C:9]([NH:8][CH2:42][CH3:43])[CH:14]=5)[CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][C:19]=3[N:25]([CH3:36])[C:26]2=[O:35])[C:29]([CH3:34])=[N:30]1
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-2-ylmethyl ester 155.1.1, 0.041 mmol) in dioxane (0.33 ml) was treated with 1 M aqueous LiOH (0.082 ml) for 1.5 h at rt then was added 1 M aqueous LiOH (0.082 ml) and the RM was stirred for 2 h at rt. The RM was diluted with EtOAc and washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The pure fraction was basified with NaHCO3, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a film. (HPLC: tR 2.10 min (Method A); M+H=444 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.12-8.08 (m, 2H), 7.97-7.90 (m, 2H), 7.63-7.60 (m, 1H), 6.87 (s, 1H), 5.49 (t, 1H), 5.31 (t, 1H), 4.57 (d, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.19 (qt, 2H), 1.96 (s, 3H), 1.25 (t, 3H))
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1
Reactant: Cn1c(C2CCN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c(C2CCNC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 165.8 %

Procedure:
tert-Butyl 3-(1-methyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (93 mg) was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL) was added. The mixture was stirred at rt for 3 h and concentrated to leave 1-methyl-2-(pyrrolidin-3-yl)-1H-benzo[d]imidazole (103 mg) as a red solid. LC-MS Method 1 tR=0.40 min, m/z=202.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[CH3:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(OCc2cccc(C)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(COc2cccc(C(=O)O)c2C(=O)O)c1

Procedure:
A solution of 3-(3-methyl-benzyloxy)-phthalic acid dimethyl ester (2.0 g crude, 6.4 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(3-methyl-benzyloxy)-phthalic acid as an off-white solid (3.0 g, 130% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][N:17]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Clc1ccc(Br)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(Cl)nc2)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
A flask was charged with 4-methoxyphenylboronic acid (1.0 g, 6.8 mmol), 5-bromo-2-chloropyridine (1.0 g, 5.2 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol), potassium carbonate (1.08 g, 7.8 mmol), 1,4-dioxane (40 mL) and water (4 mL). The mixture was stirred at 100° C. under Argon for 20 h, and evaporated to afford a crude product. The crude product was purified by chromatography on silica gel (petroleum ether:ethyl acetate=40:1) to give the title compound (1.0 g, 88% yield) as white solids. MS: m/z 220.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[N+:30]([O-])=O)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[C:11]=2[NH2:30])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C(=O)Nc3ccc(Cl)cn3)c2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C(=O)Nc3ccc(Cl)cn3)c2N)CC1
Yield: 58.6 %

Procedure:
In a manner similar to that described in Paragraph A above, N-(5-chloropyridin-2-yl)-2-nitro-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide (13 g, 26 mmol) was reacted with tin(II) chloride dihydrate (29 g, 130 mmol) in pyridine (100 mL) to afford 7.1 g (60% yield) of N-(5-chloropyridin-2-yl)-2-amino-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide, as a yellow solid; NMR (DMSO-d6) 10.8 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.6 (d, 1), 7.1 (d, 1), 6.2 (d, 2), 3.3 (m, 4), 2.7 (br, 4), 1.4 (s, 9) ppm.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.C(N(CC)CC)C>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]([Cl:27])=[O:30])[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCN(c2ccc(N3CCN(C(=O)Cl)c4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.430 g of 1-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is put in 12.23 ml of dichloromethane and 0.51 ml of triethylamine, then 0.181 g of triphosgene is added at 0° C. The reaction mixture is stirred at room temperature under nitrogen atmosphere for 15 minutes to form 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carbonyl chloride. 0.378 g of trans N-(4-amino-adamantan-1-yl)-methanesulfonamide is prepared in 10 ml of dimethyl formamide and 0.51 ml of triethylamine under nitrogen atmosphere which is heated to dissolve it. The hot mixture is added to the reaction mixture containing 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carbonyl chloride and it is stirred for two hours. Water and sodium chloride are added, and it is extracted three times with dichloromethane; the organic phases are combined and then dried over magnesium sulfate, then concentrated under reduced pressure. The 0.829 g of raw product is chromatographed on silica gel, eluting with a gradient of a dichloromethane/(dichloromethane-methanol 90:10) mixture from 0 to 100%. 0.4184 g of trans (5-methanesulfonylamino-adamantan-2-yl)amide of 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[CH2:22][CH3:23].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][CH3:23])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)CBr
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 96.8 %

Procedure:
Following the procedure of Example 2, Step C, 1-(3-(benzyloxy)pyridin-2-yl)thiourea (525 mg, 2.02 mmol), 1-bromobutan-2-one (428 mg, 2.83 mmol), and triethylamine (0.480 mL, 3.44 mmol) were reacted in ethanol (20 mL) to provide N-(3-(benzyloxy)pyridin-2-yl)-4-ethylthiazol-2-amine (609 mg) as a yellow oil. The HCl salt was prepared according to Example 3, Step C, to provide N-(3-(benzyloxy)pyridin-2-yl)-4-ethylthiazol-2-amine hydrochloride (585 mg, 83%) as a white powder. 1H NMR (d6-DMSO) δ 7.97 (d, 1H), 7.59-7.61 (m, 3H), 7.35-7.42 (m, 3H), 7.12 (m, 1H), 6.86 (s, 1H), 5.34 (s, 2H), 2.67 (q, 2H), 1.23 (t, 3H). Mass spectrum (apci) m/z=312 (100) (M+H-HCl).
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:8][C:7]=2O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH3:35]>C(#N)C>[CH:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:8][C:7]=2[NH2:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C1CCCC1
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
730 mg (1.870 mmol) of 6-cyclopentyl-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol were admixed with 9 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 130 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the acetonitrile was removed on a rotary evaporator, the precipitate was filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 508 mg (70% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCCl>[C:19]([C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: CS(=O)(=O)Cl
Reactant: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: C#Cc1cccc(Nc2ncnc3ccc(NS(C)(=O)=O)cc23)c1

Procedure:
The title product of Example 8 (100 mg, 0.384 mmol), pyridine (140 μL, 1.68 mmol) and methanesulfonyl chloride (99 μL, 1.26 mmol) were refluxed in 10 mL of 1,2-dichloroethane for 7 hours. The reaction mixture was cooled and evaporated in a vacuo to a residue which was triturated in 10 mL of 1N HCl, filtered and dried in vacuo to yield (3-ethynylphenyl)-(6-methanesulfonylaminoquinazoline-4-yl)amine; 102 mg (78%) mp 248° C. dec.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl>CO.[OH-].[Na+]>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
A suspension of methyl 5-nitrobenzo[b]thiophene-2-carboxylate (32.49 g, 0.137) in methanol (400 mL) and 1 N aqueous sodium hydroxide (150 mL) was heated to reflux for 1 h after which time everything had gone into solution. After cooling to r.t. the solution was acidified with concentrated hydrochloric acid. The resulting solid was filtered off, washed with water (3×50 mL), air dried, and then placed in a vacuum oven at 60° C. for 20 h to yield 5-nitrobenzo[b]thiophene-2-carboxylic acid (29.87 g, 98%) as a cream amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 8.30 (dd, J=9, 2 Hz, 1H), 8.35 (d, J=9 Hz, 1H), 8.36 (s, 1H), 8.98 (s, 1H), 13.89 (br. s., 1H).