Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[SH2:12]>N1C=CC=CC=1>[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1](=[S:12])[NH2:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: S
Solvent: c1ccncc1
Product: NC(=S)c1ccc2[nH]ccc2c1

Procedure:
A solution of 5-cyanoindole (Aldrich) (2.84 g, 20.0 mmol) in 20 mL of pyridine and 8.35 mL of TEA was purged with H2S gas for 1.5 h. Solvents were removed under vacuum. The residue was dissolved in 100 mL of EtOAc, washed with H2O, 0.3 N HCl (aq.), and H2O. The EtOAc layer was separated, dried (Na2SO4), and concentrated to yield the corresponding 5-indole-thiocarboxamide that was used directly in the next step. A solution of 5-indole-thiocarboxamide (150 mg, 0.85 mmol) and 3-(2-bromoacetyl)hydroquinolin-2-one (Example 27, 120 mg, 0.45 mmol) in 50 mL of MeOH was heated at reflux for 4 h. The mixture was then concentrated. The residue was treated with CH2Cl2 and the precipitates were collected by filtration to provide the title compound as a pale orange solid. MS m/z: 344 (M+1). Anal. Calc'd for C20H13N3OS.H2O.0.8HBr: C, 56.37; H, 3.74; N, 9.86; O, 7.51; S, 7.52. Found: C, 56.64; H, 3.80; N, 9.64; O, 7.30; S, 7.44.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[O:67]=[S:68]1(=[O:82])[CH2:73][CH2:72][N:71]([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:71]4[CH2:70][CH2:69][S:68](=[O:82])(=[O:67])[CH2:73][CH2:72]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=S1(=O)CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 31.6 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(1,1-dioxothiomorpholino)benzaldehyde (1.1 eq, 0.084 mmol, 20 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (14 mg, 32%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.61 (s, br, 4H, piperazine N(CH2)2), 3.14 (t, J=4.7 Hz, 4H, 1,1-dioxothiomorpholine N(CH2)2), 3.61 (s, 2H, NCH2), 3.65 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 3.91 (t, J=5.0 Hz, 4H, 1,1-dioxothiomorpholine S(CH2)2), 7.16 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 7.39 (dd, J=7.5, 4.8 Hz, 1H, pyridine H-5), 7.78 (dt, J=7.8, 1.9 Hz, 1H, pyridine H-4), 8.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.8 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.26 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: C(=O)([O-])O.[Na+].[NH:6]([CH:13]1[C:18]2=[N:19][CH:20]=[C:21]([C:24]([OH:26])=[O:25])[C:22](=[O:23])[N:17]2[CH:16]([CH3:27])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[NH:6]([C:13]1[C:18]2=[N:19][CH:20]=[C:21]([C:24]([OH:26])=[O:25])[C:22](=[O:23])[N:17]2[CH:16]([CH3:27])[CH2:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCC(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1CC=C(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a solution of 0.4 g. of sodium hydrogen carbonate in 20 ml. of water 1.0 g. (3.34 mmoles) of 9-anilino-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is added. The suspension is stirred at 80°-90° C., while air is bubbled through the mixture. The solids are dissolved and the solution is then stirred for half an hour and allowed to cool to room temperature. The pH-value is adjusted to 2 by the addition of a 5% by weight solution of hydrochloric acid. The precipitated crystals are filtered, washed with water and dried. 0.65 g. (65.5%) of 9-anilino-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained. Melting point: 152°-154° C. After recrystallization from methanol the product melts at 172°-174° C. The substance when admixed with the product of Example 1 does not show melting point depression.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.P([O-])([O-])(O)=O.[NH4+:18].[NH4+]>[N+](CCC)([O-])=O.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:18]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: [NH4+]
Agent: O=P([O-])([O-])O
Solvent: CCC[N+](=O)[O-]
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 5-bromo-indole-3-carboxaldehyde (5 g, 22.3 mmol), diammonium hydrogen phosphate (15.6 g, 31.8 mmol) in 1-nitropropane (66 mL) and acetic acid (22 mL) were heated at reflux for 16 h. After cooling to room temperature, the solvents were removed under reduced pressure and water added to the dark residue. After a short while, 5-bromo-1H-indole-3-carbonitrile precipitated rapidly. The solid was filtered, washed severally with water and dried for several hours to afford 4.3 g (86%) of the desired product. 1H-NMR (CD3OD) δ 7.40 (m, 2H), 7.77 (s, 1H), 7.97 (s, 1H). Mass spec.: 222.95 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.C1COCC1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[Cl:22])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NNc1ccc(Br)cn1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NNc1ccc(Br)cn1)c1ccccc1Cl
Reaction time: 16 h
Yield: 85.5 %

Procedure:
To (5-bromo-pyridin-2-yl)-hydrazine (2.0 g, 10.6 mmol) and triethylamine (1.5 mL, 11.0 mmol) in 1:1 THF:CH2Cl2 (15 mL) was added 2-chlorobenzoyl chloride (1.34 mL, 10.6 mmol) and the resulting reaction stirred for 16 hours. The reaction was quenched with water (100 mL), the resulting solids filtered, and dried to give the title compound (2.96 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([OH:17])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([O:17][CH3:26])[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COn1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4yl)-1H-pyrrolo[3,2-b]-pyridine (0.38 g, 1.25 mmol) in chloroform (8 ml) and methanol (2 ml) was added to a solution of diazomethane at 0° C. The reaction was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (50%-100% ethyl acetate/hexanes gradient) to 3-(4-fluorophenyl)-1-methoxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine as an off white solid (210 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Yield: 80.4 %

Procedure:
A mixture of 4.7 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate in 45 ml of ethyl acetate was hydrogenated in the presence of 500 mg of 10% palladium hydroxide on barium sulfate and 6.5 ml of quinoline and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried and evaporated to dryness. The 5.1 g of oil residue were chromatographed over silica gel and eluted with a 70-30-1 mixture of hexane-ethyl acetate-acetic acid to obtain 3.8 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-hydroxy-3-oxo-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:41](=[O:42])[CH2:40][Cl:39])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Temperature: 4 °C
Reaction time: 25 h
Yield: 95.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (1.1 g, 2.5 mmol; prepared as described in Example 31-starting materials) was dissolved in a mixture methylene chloride (20 ml) and diisopropylethylamine (1.0 ml) under a nitrogen atmosphere. The solution was cooled in an ice/water bath to 4° C. and chloroacetyl chloride (0.2 ml, 2.63 mmole) was added. The reaction mixture was stirred cold for two 25 hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (1.14 g, 94.9%); Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19].CN(C)C=O>O>[CH2:17]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
4-Nitrophenol (177 g), potassium carbonate (177 g) and isobutyl bromide (190 g) were added to dimethylformamide (500 ml) and the mixture was stirred at 90° C. for 4 h. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained oily substance was distilled under reduced pressure to give 4-isobutoxynitrobenzene (203 g), boiling point: 125° C./0.15 mmHg
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH2:18][C:17]3([CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([C:14]2[CH2:18][C:17]3([CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)[O:16][N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(c3ccccc3)=NO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2=NOC3(CCCNC3)C2)cc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL, 26.0 mmol) was added dropwise to a solution of tert-butyl 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-7-carboxylate (270 mg, 0.853 mmol) in CH2Cl2 (5 mL) at room temperature. After 1 h at room temperature, the mixture was concentrated to give the expected product as TFA salt (280 mg, 99% yield). LCMS: (M+H)+=217.15. 1H NMR (400 MHz, methanol-d4) δ ppm 7.62-7.78 (2H, m), 7.36-7.51 (3H, m), 3.35-3.49 (4H, m), 3.00-3.24 (2H, m), 2.04-2.22 (2H, m), 1.85-2.07 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][C:18]([O:20]CC)=O)=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:20]=[C:18]1[CH2:17][C:4]2=[CH:5][N:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]3[C:3]2=[C:2]([CH:10]=[CH:9][CH:8]=3)[NH:1]1
Reactant: CCOC(=O)Cc1cn(CC(=O)OCC)c2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1cc2c3c(cccc31)NC(=O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl 2,2′-(4-amino-1H-indole-1,3-diyl)diacetate from Step F (83 mg, 0.273 mmol) in toluene (8 mL) was added p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) and the mixture was heated at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and the mixture was partitioned between EtOAc (40 mL) and aqueous NaHCO3 (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 92:8, to give the title compound. MS: m/z=259 (M+1).
Reaction SMILES: [Cl:1][CH2:2][S:3]([N:6]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:5])=[O:4].[F:19][CH:20]([F:50])[C:21]1[N:25]([C:26]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:29]=[C:28](N3CCNCC3)[N:27]=2)[C:24]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:23]=2[N:22]=1.CCN(C(C)C)C(C)C.C(Cl)Cl.CO>C1COCC1>[Cl:1][CH2:2][S:3]([N:6]([CH:7]1[CH2:12][CH2:11][N:10]([C:28]2[N:27]=[C:26]([N:25]3[C:24]4[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:23]=4[N:22]=[C:21]3[CH:20]([F:50])[F:19])[N:31]=[C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:29]=2)[CH2:9][CH2:8]1)[CH2:13][CH2:14][CH2:15][N:16]([CH3:17])[CH3:18])(=[O:4])=[O:5]
Reactant: CN(C)CCCN(C1CCNCC1)S(=O)(=O)CCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(CCCN(C)C)S(=O)(=O)CCl)CC2)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
A mixture of the above amine (82 mg, 0.28 mmol), 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (98 mg, 0.25 mmol), and DIPEA (0.3 mL) in THF (5 mL) was stirred at 20° C. for 4 hrs. Most of the THF was removed under vacuum and the residue was diluted with water (20 mL). The resulting precipitate was collected by filtration, washed with water, and chromatographed on silica eluting initially with CH2Cl2/EtOAc (4:1), then with CH2Cl2/MeOH/aqueous NH3 (95:4:1) to give chloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide (120 mg 74% yield), which treated with 1.25 M HCl in MeOH to give the hydrochloride salt: mp (MeOH/EtOAc) 260-263° C.; 1H NMR (DMSO-d6) δ10.0 (br s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.70 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 5.10 (s, 2H), 4.86-4.74 (m, 2H), 3.98-3.90 (m, 1H), 3.98 (s, 3H), 3.81 (m, 4H), 3.79 (m, 4H), 3.24-3.25 (m, 2H), 3.11-2.96 (m, 4H), 2.70 (s, 6H), 1.93-1.75 (m, 6H); Calcd. for C27H39Cl2F2N9O4S.0.5H2O: C, 46.1; H, 5.7; N, 17.9; Cl, 10.1. Found: C, 46.1; H, 5.8; N, 17.9; Cl, 9.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid (86.0 g, 0.283 mmol) in DMF (1 mL) were added potassium carbonate (59.0 mg, 0.424 mmol) and methyl iodide (0.0260 mL, 0.424 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 76.9 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](OCCCCl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35].[I-].[Na+]>COCCO.ClCCl>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:3][CH2:4][CH2:5][O:6][C:19]2[N:18]=[C:17]([NH:16][C:3]3[C:4]4[O:8][CH2:7][O:6][C:5]=4[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])=[CH:10][C:2]=3[Cl:1])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=2)[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: CC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2nc(OCCCN3CCN(C(C)=O)CC3)nc3ccc(OC)cc23)c2c1OCO2
Temperature: 105 °C
Yield: 145 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.158 g) was dissolved in 2-methoxyethanol (5 ml) and then N-acetylpiperazine (0.600 g) was added and the mixture heated to 105° C. A small amount of sodium iodide was added to the reaction mixture, and heating continued for a total of 2½ hours. The reaction mixture was cooled to room temperature and then diluted with dichloromethane. The mixture was washed with a water/brine (5/1) mixture followed by brine and then dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. There was thus obtained the title compound (0.136 g) as a pale yellow foam. NMR Spectrum: (CDCl3) 2.10 (quin, 2H), 2.43 (m, 2H), 2.47 (m, 2H), 2.57 (t, 2H), 3.46 (s, 3H), 3.47 (m, 2H), 3.49 (s, 3H), 3.62 (t, 3H), 3.98 (s, 3H), 4.25 (t, 2H), 4.35 (s, 2H), 6.08 (s, 2H), 7.06 (s, 1H), 7.20 (s, 1H), 7.28 (s, 2H), 8.62 (s, 1H); Mass Spectrum: M+H+ 582/584.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[F:23][C:24]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:23][C:24]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCCCNCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added N-(2,4-difluorobenzyl)-N-octylamine hydrochloride (0.165 g, 0.57 mmol), DMAP (0.054 g, 0.45 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.082 g (38%) of a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:36])=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[C:21]([F:31])[CH:22]=[CH:23][C:24]=4[O:26][C:27]([F:30])([F:29])[F:28])[N:19]([CH2:32][CH2:33][O:34][CH3:35])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].C([OH:48])(C)C>>[OH2:16].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:36])=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[C:21]([F:31])[CH:22]=[CH:23][C:24]=4[O:26][C:27]([F:30])([F:28])[F:29])[N:19]([CH2:32][CH2:33][O:34][CH3:35])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:36])=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[C:21]([F:31])[CH:22]=[CH:23][C:24]=4[O:26][C:27]([F:30])([F:28])[F:29])[N:19]([CH2:32][CH2:33][O:34][CH3:35])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=1.[OH2:48]
Reactant: CC(C)O
Agent: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Agent: O=C(O)/C=C/C(=O)O
Product: O
Temperature: 25 °C

Procedure:
A round-bottom flask was charged with [4-(5-aminomethyl-2-fluorophenyl)-piperidine-1-yl][7-fluoro-1-(2-methoxyethyl)-4-trifluoromethoxy-1H-indol-3-yl]methanone (10.4 g, 20.4 mmol) and fumaric acid (4.74 g, 40.7 mmol). Isopropanol (IPA, 62 mL) was added and the resulting mixture was heated on a steam bath. Most of the material dissolved, before crystallization of the salt occurred. While being heated on a steam bath, additional IPA was added in 30 mL portions. Complete solution was attained after the addition of a total of 152 mL of IPA. The resulting solution was filtered and the filtrate was allowed to cool to rt. The filtrate was cooled further in an ice bath for 1.5 h, before the product was collected by filtration. The collected product was washed with cold IPA (50 mL), dried partially by suction and transferred to a drying oven where it was dried at 45° C. After drying overnight, the desired product was isolated as colorless solid: 11.8 g (84%). IR (cm−1): 3122-2700, 2920, 2824, 1698, 1584, 1512, 1443, 1397-1368, 1293-1217, 822, 794, 639. 1H NMR (300 MHz, DMSO-d6): δ 10.07 (br, 3H), 7.71 (s, 1H), 7.43 (dd, J=2.4, 7.1, 1H), 7.36 (ddd, J=2.4, 4.9, 8.4, 1H), 7.19 (d, J=8.4, 10.7, 1H), 7.10 (d, J=8.7, 11.7, 1H), 7.05 (ddd, J=1.4, 3.3, 8.7, 1H), 6.50 (s, 3H), 4.69 (br, 1H), 4.48 (t, J=5.3, 2H), 3.97 (s, 2H), 3.69 (t, J=5.4, 2H), 3.24 (s, 3H), 3.08 (dddd, J=3.5, 3.5, 12.1, 12.1, 1H), 2.91 (br, 2H), 1.75 (br, 2H), 1.63 (br, 2H). Anal. Calcd for C25H26F5N3O3-1.5C4H4O4: C, 54.31; H, 4.70; N, 6.13. Found: C, 54.30; H, 4.62; N, 6.04. MS (ESI) m/z 512.2 (M+H).