Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[NH2:23])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>CCN(CC)CC>[C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[NH:23][C:38]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:39])=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(N)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)N4CCOCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 96 h
Yield: 19.2 %

Procedure:
A mixture of 7-amino-1-methylindole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (64 mg, 0.14 mmol), morpholinecarbonyl chloride (0.13 mL, 1.1 mmol), diisopropylethylamine (0.2 mL) and Et3N (0.5 mL) was stirred for 4 days. The reaction mixture was extracted and purified by reverse phase HPLC on a C18 column eluting with an acetonitrile-water gradient to provide 15 mg (19%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.I[CH:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH:35]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH:11]=[C:10]([NH:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)=[CH:19][CH:20]=4)=[O:14])[CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:30]1)([CH3:37])[CH3:36]
Reactant: CC(C)I
Reactant: CN(CC1CCNC1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1CCC(CN(C)c2nc3ccc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)cc3s2)C1
Yield: 90.9 %

Procedure:
Place 4′-fluoro-biphenyl-4-carboxylic acid [2-(methyl-pyrrolidin-3-ylmethyl-amino)-benzothiazol-6-yl]-amide (16 mg, 0.035 mmol), 2-iodopropane (0.007 mL, 0.070 mmol), and potassium carbonate (15 mg, 0.108 mmol) in DMF (2 mL) and stir at rt for 3 d. Dilute the reaction with ethyl acetate and wash the organic layer with water (5 times). Chromatograph (silica gel, eluting with 10% 2M NH3 in MeOH:DCM) to yield 16 mg (91%) of the title compound: mass spectrum (ion-spray): (m/z)=503.3 (M+1).
Reaction SMILES: C(O[K])(C)(C)C.CN(C)C=O.[OH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2c(OCc3ccccc3)cccc21
Reaction time: 2 h

Procedure:
3.1 g of t-butoxypotassium was added under ice cooling and nitrogen replacement to a 50 mL dimethylformamide solution of 4.0 g of 5-hydroxytetralone, and the system was stirred for 15 minutes at the same temperature, after which 3.2 mL of benzyl bromide was added, and the system was stirred for 2 hours at the same temperature. After the reaction, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate, then subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (20% ethyl acetate/hexane) to obtain 6.3 g of 5-benzyloxytetralone (compound 2-7 in Table 3-1) in the form of a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Yield: 55.9 %

Procedure:
A mixture composed of 15 g of 4-benzyloxybenzyl chloride and 15 g of 4-aminophenol was refluxed in 200 ml of N,N-dimethylformamide for 30 minutes. After water was added to the reaction mixture, the product was extracted with ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 50:1 mixture of chloroform and acetone as the eluent) to obtain 11 g of 4[-N-(4-benzyloxybenzyl)-amino]phenol.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([NH:19]C(OC(C)(C)C)=O)=[CH:17][CH:18]=1)[CH:6]([S:8]C(=O)C)[CH3:7])C>Cl>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][CH:5]([CH:6]([SH:8])[CH3:7])[C:4]([OH:27])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(C)SC(C)=O
Agent: Cl
Product: CC(S)C(Cc1ccc(N)nc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester/B (55 mg; 0.14 mmol) in concentrated HCl (2 mL) was refluxed under argon for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford 39.4 mg of the title compound as the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([O:14]CC)=[O:13])[C:8]=2[OH:11])[CH:3]=1.C(O)(=O)C>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]=2[OH:11])[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)sc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cnc2cc(Br)sc2c1O
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of ethyl 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (1.3 g, 4.3 mmol) [Elliott, R.; O'Hanlon, P. J.; Rodgers, N. B. Tetrahedron, 43(14), 3295 (1987)] in 20 mL of ethanol and 6 mL of 2.5 N sodium hydroxide is heated at reflux for 4 hours. The mixture is poured into ice water and the pH is adjusted to 5-6 by the addition of acetic acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration washing with water to provide 840 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylic acid. A mixture of 2-bromo-7-hydroxythieno[2,3-b]pyridine-6-carboxylic acid (810 mg, 2.95 mmol) and N,N-carbonyldiimidazole (1.0 g, 6.17 mmol) in 15 mL of N,N′-dimethylformamide is heated at 65° C. for 2 hours. The mixture is poured into 50 mL of ice cold aqueous ammonium hydroxide and stirred for 14 hours. The resultant solids are collected by filtration washing with water to provide 800 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide. A mixture of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide (273 mg, 1.0 mmol) and 3 mL of phosphorous oxychloride is heated at reflux for 1 hour. The solvent is removed in vacuo and the residue is poured into ice water and treated with sodium bicarbonate. The resultant solids are collected by filtration washing with water. The solids are purified by flash column chromatography eluting with chloroform to provide 240 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 198-199° C.; 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 9.11 (s, 1H); MS 273.1, 275.1, 277.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:10]1[CH2:9][C@H:8]([NH2:7])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tert-butyl(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (intermediate 10, 720 mg, 2.262 mmol) was dissolved in dichloromethane (30 mL) and treated with trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 15 minutes then evaporated to dryness under reduced pressure and further dried under high vacuum. The crude amine salt was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:31]([NH:35][CH3:36])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CNC(C)(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 44E and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21](=O)[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[NH2:37][NH2:38].CC(O)=O>CCO>[Cl:1][C:2]1[C:3]([C:21](=[N:37][NH2:38])[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cnc21
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CC(=NN)c2c(Cl)cnc3[nH]ccc23)CC1
Yield: 44.2 %

Procedure:
To a suspension of tert-butyl 4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate (1.00 g, 1.87 mmol) in EtOH (6.4 mL) were added anhydrous hydrazine (2.94 mL, 94.0 mmol) and AcOH (0.536 mL, 9.36 mmol). The reaction mixture was stirred at reflux for about 16 h. The solvent was removed under reduced pressure and the crude material was taken up in DCM and dried over anhydrous MgSO4. The solvent was removed and DCM (3 mL) was added. The solid was removed by filtration and the filtrate was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford tert-butyl 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-1-carboxylate (0.324 g, 44%) as a white solid consisting of a 1/1 mixture of E/Z isomers: LC/MS (Table 1, Method r) Rt=1.46 and 1.53 min; MS m/z: 392/394 and 392/394 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([CH3:11])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:15][CH:16]1OC(C)OC(C)O1>>[C:1]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([CH3:11])[C:10]=1[CH2:15][CH3:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCc1[nH]c(C(=O)OCC)cc1C
Reactant: CC1OC(C)OC(C)O1
Product: CCCc1[nH]c(C(=O)OCC)c(CC)c1C

Procedure:
The crude product, obtained in Example 68 but using 2-carbethoxy-4-methyl-5-n-propylpyrrole and paraldehyde, was crystallized from aqueous ethanol, sublimed, recrystallized and resublimed, m.p. 58°-59.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:31]([CH3:32])[C:27]1[CH:26]=[C:25]([O:24][C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH2:23][CH:14]([C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)=[O:13])[CH2:15]3)=[CH:20][CH:19]=2)[CH:30]=[CH:29][N:28]=1)(=[O:35])[CH3:34]
Reactant: CNc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-{[2-(methylamino)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (337 mg, 0.78 mmol) in THF (8 mL) was added TEA (0.219 mL, 1.57 mmol). The reaction mixture was cooled to 0° C. and acetyl chloride (0.062 mL, 0.86 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 hr. during which time further portions of TEA (0.219 mL, 1.57 mmol) and acetyl chloride (0.62 mL, 0.86 mmol) were added. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography. The product was further purified by HPLC (250 mm C18 column) eluting with 40% A/60% B to 100%/0% B (25 min gradient) (A=99/1 H2O in AcCN, 0.1% FA, B=95/5 AcCN/H2O, 0.1% FA). The product was dissolved in DCM and MeOH and 2M HCl-Et2O solution was added. The solvents were evaporated to provide 7-({2-[acetyl(methyl)amino]pyridin-4-yl}oxy)-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-395 as the HCl salt (22 mg, 5.4%). 1H NMR (300 MHz, d6-DMSO, HCOOH Salt) δ: 9.94 (s, 1H), 8.31 (d, 1H), 7.63 (t, 1H), 7.50 (d, 1H), 7.24-7.18 (m, 2H), 7.10-7.05 (m, 2H), 6.76 (dd, 3H), 3.24 (s, 3H), 2.95-2.71 (m, 5H), 2.13-1.99 (m, 4H), 1.85-1.72 (m, 1H), and 1.26 (s, 9H). LCMS: (FA) ES+470.2, ES−472.9
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([CH3:16])=[C:11]([NH:15][S:26]([N:25]([CH3:30])[CH3:24])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccccc1
Product: Cc1c(NS(=O)(=O)N(C)C)cccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product from Example 2B and N,N-dimethylsulfamoylchloride were processed as described in Example 3 to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ2.25 (s, 3H), 2.33 (m, 6H), 3.88 (s, 4H), 6.72 (dd, 1H), J=7.7, 1.5 Hz), 6.82 (m, 2H), 7.03 (m, 2H), 7.10 (m, 8H), 8.73 (s, 1H); MS (APCI+) m/z 410 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](O)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O.C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:14])[C:4]=2[CH:3]=1
Reactant: Oc1ncnc2sc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2sc(Br)cc12
Temperature: 80 °C
Yield: 83 %

Procedure:
To 6-bromothieno[2,3-d]pyrimidin-4-ol (3.0 g, 19.7 mmol) was added phosphorus oxychloride (5 mL). After heating to 80° C. for 1.5 hours, the reaction mixture was poured into saturated NaHCO3 and ice. The solid was filtered, washed with water and dried to provide the product (4.06 g, 83%) as brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=O)[O:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G17) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light brown solid (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=O)[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccccc1
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Product: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CCNc1ccccc1)c1ccc(Cl)c(Cl)c1

Procedure:
N-[(S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methyl-2-methoxy-3-cyano-1-naphthamide was reacted with aniline under standard reductive amination conditions to give the title compound which was converted to the citrate salt. 1H NMR (300 MHz, DMSO-d6) δ 8.64-8.61 (m), 8.07-7.98 (m), 7.79-7.55 (m), 7.51-7.47 (m), 7.37-7.32 (t), 7.08-7.00 (m), 6.53-6.49 (m), 6.31-6.28 (d), 4.60-4.50 (t), 4.07-3.96 (m), 3.92 (s), 3.90-3.78 (m), 3.86 (s), 3.45-3.11 (m), 3.00-2.88 (m), 2.79 (s), 2.73 (s), 2.68 (s), 2.56-2.44 (m), 2.03-1.88 (m); MS APCI, m/z=532 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.CCOCC>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][C:16]=1[C:21]1[N:25]([CH3:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[N:22]=1
Reactant: Cn1c(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2F)nc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(-c2cc(N3CCNCC3)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-Fluoro-3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.86 g, 1.71 mmol) in DCM (2.0 mL) 2.0 M HCl in Et2O (10 mL) was added and the resulting suspension was stirred at room temperature overnight. The precipitate was filtered off and tritured with Et2O (3×15 mL) to afford the title compound (quantitative yield).
Reaction SMILES: [OH2:1].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32])(C(C)(C)C)(C)C>O1CCCC1>[OH:1][CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32]
Reactant: O
Reactant: CC(C)(C#N)[C@@H](O)CC[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C#N)[C@@H](O)CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate is added to a solution that consists of 3 g (11.65 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentane-nitrile of the title compound of Example 8b, dissolved in 40 ml of tetrahydrofuran, and it is stirred for 16 hours at room temperature. Then, it is evaporated to the dry state in a vacuum. The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][SH:10])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C(O)C>[CH:1]([O:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][S:10][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=1)([CH3:3])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)OCCC=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)OCCC=CCSCc1ccc(Cl)cc1

Procedure:
A solution of 8.0 g (0.05 mol) of 5-isopropoxy-2-penten-1-thiol and 2 g (0.05 mol) of sodium hydroxide in 30 cc of ethanol are added dropwise at 50° during the course of 45 minutes to a solution of 8.05 g (0.05 mol) of p-chloro-benzylchloride in 25 cc of ethanol, the temperature not exceeding 55°. After the addition is complete the mixture is heated to 60° during 10 minutes. The reaction mixture is filtered, the ethanol is distilled off and the residue is chromatographed on silica gel with chloroform, whereby 4-[(5-isopropoxy-2-pentenylthio)-methyl]-chlorobenzol is obtained which is identical with the compound produced in accordance with Example 40.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][N:14]3[C:15](=[O:23])[C:16]([C:19](OC)=[O:20])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[NH3:26]>CO>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][N:14]3[C:15](=[O:23])[C:16]([C:19]([NH2:26])=[O:20])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Solvent: CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(C(N)=O)cnc3c2)n1
Reaction time: 8 h

Procedure:
A mixture of methyl 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido-[1,2-a]pyrimidine-3-carboxylate (400 mg), concentrated aqueous ammonia (6 ml) and methanol (9 ml) was stirred overnight. Insoluble solids were collected by filtration to obtain the title compound (117 mg). The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to further obtain the title compound (69 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)C[C:13]2(CC2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[S:57]1CCNC1>>[CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH2:12][CH2:13][S:57][CH:17]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][CH2:43][CH2:42][N:41]5[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C1CSCN1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC6(CC6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5SCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
was prepared in a similar fashion to (1-{6-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DW), replacing the cyclopropyl proline carboxylic acid with the corresponding thiazolidine derivative.