Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:16]=[C:17]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14].CI.Cl>C1COCC1>[C:13]([C:15]1[CH:16]=[C:17]([CH:22]([CH3:1])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)OC(C)(C)C)c1ccc(F)c(C#N)c1
Temperature: 0 °C

Procedure:
To a stirred solution of diisopropylamine in 2 ml of THF at −78° C. was added n-butyl lithium (0.61 ml). The reaction was stirred for 30 minutes after which time a solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.300 g) in THF (2 ml) was added dropwise over 20 minutes at −78° C. The reaction was warmed to 0° C. and then transferred a flask containing 2 ml THF and MeI (0.080 ml). The reaction was acidified with 2M HCl and extracted with ethyl acetate. The combined organics were then washed with brine and dried over MgSO4. The concentrated product was purified by silica gel chromatography using a solvent system of 5% to 50% ethyl acetate/hexanes to provide tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (0.140 g).
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([CH:23]=[O:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:17]2=[N:18][CH:19]=1.S(=O)(=O)([OH:36])N.Cl([O-])=O.[Na+].OP([O-])(O)=O.[K+]>O1CCOCC1.O>[F:33][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([OH:36])=[O:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:17]2=[N:18][CH:19]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
To a solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (217 mg, 458 μmol) in dioxane (6.5 mL) and water (2 mL) at 0° C. was added sulfamic acid (267 mg, 2.75 mmol), followed by drop-wise addition of a solution of sodium chlorite (67.3 mg, 596 μmol) and KH2PO4 (748 mg, 5.5 mmol) in water (4.5 mL) via dropping funnel over 15 min. The ice bath was removed and the light yellow suspension was stirred at 25° C. for 18 h. THF (6.5 mL) added to the yellow suspension and reaction continued at 25° C. for 2 h, then sulfamic acid (267 mg, 2.75 mmol) was added followed by dropwise addition of sodium chlorite (67.3 mg, 596 μmol) and KH2PO4 (748 mg, 5.5 mmol) in 5 mL of water. After 2 h the mixture was diluted with water (20 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried (MgSO4) and evaporated. The light yellow solid residue was dissolved in dichloromethane/MeOH and dichloromethane evaporated to promote solid formation, the solid separated by filtration, rinsed with MeOH and hexanes then dried to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (127 mg, 259 μmol, 57%) as a light yellow solid. MS (M+H)+=490; 1H NMR (DMSO-d6) δ: 12.57 (br. s., 1H), 9.12 (s, 1H), 8.69 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.35 (dd, J=8.9, 2.5 Hz, 1H), 7.20 (t, J=74.8 Hz, 1H), 5.71 (s, 2H), 4.18 (s, 3H), 3.58 (t, J=7.9 Hz, 2H), 0.84 (t, J=7.9 Hz, 2H), −0.21-−0.01 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:11]1[CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ncc2c(O)cc(-c3ccccc3)nc21
Product: CCn1ncc2c(Cl)cc(-c3ccccc3)nc21

Procedure:
A mixture of 193.9 gms. of 1-ethyl-4-hydroxy-6-phenyl-1H-pyrazolo[3,4-b]pyridine (0.7 mol.) and 1000 ml. of phosphorus oxychloride is refluxed for 5 hours. The excess phosphorus oxychloride is removed in vacuo and the residue is treated with ice water. The mixture is then extracted three times with ether, the ether layer is separated, dried over sodium sulfate, treated with charcoal and concentrated in vacuo. The residue solidifies on cooling (142.4 gms = 79%; m.p. 43°-45° C.) and the product, 4-chloro-1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine is recrystallized from hexane, m.p. 46°-48° C.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(C3CCCC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.[C:70]([O:74][C:75](=[O:85])[N:76](C1C=CC=C(N)C=1)[CH3:77])([CH3:73])([CH3:72])[CH3:71].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:70]([O:74][C:75](=[O:85])[N:76]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:77])([CH3:73])([CH3:72])[CH3:71]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.07 (1H, s), 7.47 (2H, m), 7.27 (1H, m), 7.04 (2H, m), 6.92 (1H, t), 6.44 (1H, dd), 6.31 (1H, dd), 4.64 (1H, d), 4.48 (1H, d), 4.36 (1H, d), 4.13 (1H, d), 3.71 (1H, br s), 2.95 (1H, m), 2.80 (4H, m), 2.05-1.56 (13H, m), 1.27 (5H, m). The compound was further characterised as the hydrochloride salt. Found: C, 64.90; H, 7.02; N, 12.57%; C30H37N4O3.HCl requires: C, 65.26; H, 6.94; N, 12.68%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH3:27])[C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22]C)=[C:15]([CH:24]([CH3:26])[CH3:25])[CH:14]=1)=[O:12].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH3:27])[C:10]=1[C:11]([C:13]1[CH:14]=[C:15]([CH:24]([CH3:26])[CH3:25])[C:16]([OH:22])=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:18]=1)=[O:12]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3cccc(Br)c3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2cccc(Br)c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 76.2 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(3-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.34 g, 2.78 mmol) and 1M boron tribromide/CH2Cl2 (5.84 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.995 g (73%) of the title compound. 1H NMR (DMSO-d6) δ 1.14 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.32 (septet, 2H), 3.87 (s, 2H), 7.09 (d, 1H), 7.22 (t, 1H), 7.26 (s, 1H), 7.39 (d, 1H), 7.43 (s, 2H), 9.13 (s, 1H). IR (KBr) 3350, 2950, 1580, 1560 and 1325 cm−1. mass spectrum (EI) m/z 468 (M+). Anal. Calcd. for C26H29BrO3: C, 66.53; H, 6.23; N, 0.00. Found: C, 66.50; H, 6.22; N, 0.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:15][N+:16]([O-])=O)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.Cl>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:15][NH:16][C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC(c2ccc(Cl)cc2)CN1
Temperature: 0 °C
Yield: 51.3 %

Procedure:
The solution of ethyl 3-(4-chlorophenyl)-4-nitrobutanoate (2.33 g) in acetic acid (18 ml) was stirred vigorously while iron powder (5.7 g) was added. The suspension was stirred at reflux temperature for 1.5 h. The resulting thick slurry was pored into a mixture of conc. HCl (30 ml) and ice (30 g). The aqueous layer was extracted with dichloromethane (2×50 ml) and the combined organic layers washed with water and dried (sodium sulfate). After evaporation of the solvent the oily residue was distilled with toluene to remove acetic acid whereupon crystallisation took place. The crude was washed with diethyl ether (3×2 ml) and dried in vacuo to afford 4-(4-chlorophenyl)-2-pyrrolidone (0.86 g) as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11](=[O:13])[N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])[CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CNCCOC
Reactant: Nc1ncc(-c2cccc(C(=O)O)c2)cc1C(=O)Nc1ccncc1
Product: COCCN(C)C(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with N-(methoxy-ethyl)-methyl-amine gives “A97”; method 1: HPLC/MS: 1.23 min, [M+H]=406;
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>CO>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C#CC(C)(C)C
Solvent: CO
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Methyl 2-(3,3-dimethylbutynyl)-4-nitrobenzoate (0.8 g, 3.1 phenol) was dissolved in 50 mL of methanol containing 5% potassium hydroxide solution and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was taken up in water and washed with diethyl ether. The aqueous fraction was carefully acidified with concentrated HCl to a pH of 2.0 and extracted with ethyl acetate (2×50 mLs). The organic fractions were combined, washed once with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to give the title compound (0.7 g, 91%) an off-white solid: m.p. 170-173° (C.); 1H NMR (300 MHz, methanol-d4) δ 8.16 (d, J=2.2 Hz, 1H, Aromatic), 8.12 (dd, J=8.7, 2.3 Hz, 1H, Aromatic), 7.96 (d, J=8.5 Hz, 1H, Aromatic), 1.35 (s, 9H, t-Butyl); 13C NMR (75 MHz, methanol-d4) δ 168.5, 150.7, 140.4, 132.4, 129.0, 126.6, 123.1, 107.4, 77.7, 31.2, 29.6; MS m/e calc'd for: 247.0845, found 247.0821.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:33][C:30]3[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1ncc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 140 °C
Yield: 48.7 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 2-methylpyrimidin-5-amine (57.4 mg, 526 μmol), BINAP (10.9 mg, 17.5 μmol), palladium (II) acetate (19.7 mg, 87.7 μmol) and sodium tert-butoxide (84.3 mg, 877 μmol) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 40-80% ethyl acetate in hexanes) gave N-tert-butyl-2-(2-methylpyrimidin-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 171 μmol, 49%) as a brown solid. MS (EI/CI) m/z: 456.2 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=1.CO.[BH4-].[Na+].Cl>O1CCCC1>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reaction time: 6 h
Yield: 97.2 %

Procedure:
A solution of 2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (2.66 g, 7.68 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (20 mL) was ice-cooled, sodium borohydride (90%, 0.323 g, 7.68 mmol) was added, and the mixture was stirred for 6 hr under nitrogen atmosphere. The reaction mixture was treated with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.60 g, yield 97%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][S:28][CH3:29]>>[CH3:29][S:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CSCCCl
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Product: CSCCOc1ccc(CCc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1
Yield: 50 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (150 mg, 0.464 mmol) obtained in Example 165 and 2-chloroethylmethylsulfide (0.182 mL, 1.86 mmol) and in the same manner as in Example 158, the title compound was obtained (91.9 mg, yield 50%) as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:38][C@@H:39]([C@H:44]([OH:46])[CH3:45])[C:40]([O:42][CH3:43])=[O:41].CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([NH:38][CH:39]([CH:44]([OH:46])[CH3:45])[C:40]([O:42][CH3:43])=[O:41])=[O:36])=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)C(NC(=O)CNC(=O)OC(C)(C)C)C(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
HATU (46.9 g, 123.30 mmol) was added to a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (18 g, 102.75 mmol) DMA (230 mL) at ambient temperature. After 5 minutes a solution of (2S,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride (17.43 g, 102.75 mmol) and DIPEA (71.8 mL, 411.00 mmol) in DMA (230 mL) was added and the resulting solution was stirred at ambient temperature for 20 hours, The reaction mixture was diluted with EtOAc (300 mL), and washed with 1N citric acid (300 mL), salt was added to the aqueous layer which was re extracted with EtOAc (4×400 mL). The organic extracts were combined, washed with saturated NaHCO3 (200 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (12.97 g, 43.5%) as a yellow glass which formed a solid on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.S(Cl)([Cl:30])=O>>[Cl:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Temperature: 85 °C
Yield: 98 %

Procedure:
A solution of 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3,4-dihydroquinazolin-4-one (2.8 g, 9.24 mmol) in thionyl chloride (28 ml) containing DMF (280 μl) was heated at reflux at 85° C. for 1 hour. After cooling, the volatiles were removed by evaporation. The precipitate was triturated with ether, filtered, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated to give 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (2.9 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:24]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(Br)c1
Yield: 73 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-bromo-benzoyl chloride to afford the title compound as a light brown solid (50 mg, 73%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.92 (d, 1H, Harom, J=8.0 Hz), 7.43 (ps t, 1H, Harom, J=8.0 Hz), 7.48 (m, 1H, Harom), 7.62 (s, 1H, Harom), 7.66 (d, 1H, Harom, J=8.0 Hz), 7.78-7.84 (m, 2H, Harom+Py,6), 7.93 (d, 1H, Harom, J=8.0 Hz), 8.12 (s, 1H, Harom), 10.45 (s, 1H, NHamide), 11.23 (s, 1H, NHPy3), 11.44 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.58, 110.82, 113.83, 114.62, 116.32, 121.66, 126.87, 128.24, 130.65, 130.87, 131.71, 136.80, 140.56, 141.08, 144.67, 147.00, 154.17, 154.68, 164.13. HRMS (EI): m/z [M+H] calcd for C19H14BrN4O3: 425.0249; found: 425.0248.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23]N=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.Cl.[CH3:33]N(C1C=NC(C(F)(F)F)=CN=1)[C@H]1CCC[C@@H]1N.N1N(C2C=CC=CC=2C(O)=O)N=CC=1>>[CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:20])[C:21]2[CH:33]=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]2[N:28]=[CH:29][CH:30]=[N:31]2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: Cl
Agent: O=C(O)c1ccccc1-n1nccn1
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 76) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 60 mg, 0.20 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 40 mg, 0.21 mmol) except this was purified only by column chromatography (silica, 0 to 100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:15]C=O)([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.Cl.[OH-].[Na+]>C(O)C>[CH3:14][C:2]([NH2:15])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1
Reactant: CC(C)(Cc1cccc(C(F)(F)F)c1)NC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(N)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
9.8 g (40 mmol) N-[1,1-dimethyl-2-(3-trifluoromethyl-phenyl)-ethyl]-formamide are dissolved in 110 mL ethanol, combined with 200 ml of conc. hydrochloric acid and refluxed overnight. The reaction mixture is added to ice water, made alkaline with sodium hydroxide and extracted with tert.-butylmethylether. The organic phases are washed with water, dried and evaporated down. Then the residue is purified by chromatography.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.CN.[NH2:49][CH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([NH:49][CH:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:26])=[CH:28][CH:29]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCOCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml) HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and methylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min, 4-Aminotetrahydropyran (0.106 g, 1.04 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.050 g, 20%.). M.P.: 202-205° C., 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.99 (m, 4H), 7.85 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 4.04 (m, 1H), 3.89 (d, J=9.7 Hz, 2H), 3.39 (t, J=10.0 Hz. 2H), 1.78 (d, J=10.5 Hz, 2H), 1.63 (m, 2H).