Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([NH:26][C:27](=[O:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:25]=1)[C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=1)=[O:11])=[O:5].[OH-].[Li+]>O.C1COCC1>[CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([NH:26][C:27](=[O:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:25]=1)[C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)=[O:11])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(NC(=O)c3ccccc3C)cc(NC(=O)c3ccccc3C)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1cc(NC(=O)c2ccccc2C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 12.6 %

Procedure:
Methyl 6-{[3,5-di-(2-methylbenzoylamino)benzoyl]amino}-3-pyridinecarboxylate (130 mg 0.25 mM) was stirred at room temperature overnight with lithium hydroxide (52.5 mg 1.25 mM) in water (2 ml) and THF (10 ml). The mixture was then evaporated to remove the THF and acidified with 1.0N hydrochloric acid to pH=3. The precipitated solid was filtered, washed with water and vacuum dried at room temperature (70 mg 72.1%). Recrystallisation from ethyl acetate/methanol gave the title compound (16 mg 16.5%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)N(C)C)C2=O)CC1
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-chloro-N,N-dimethylacetamide, to give the desired product as a white solid (71%).
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CN(C=O)C>[Si:8]([O:16][CH2:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1nc2ccccc2[nH]1
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
At room temperature, triethylamine (2.27 ml, 163 mmol) and TBDMS chloride (1.65 g, 10.95 mmol) were added to a solution of 2-hydroxymethylbenzimidazole (1.4 g, 9.95 mmol) in DMF (30 ml). After 3.5 h, the reaction was terminated by addition of water, the mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate. Chromatography (silica gel, cyclohexane:ethyl acetate 2:1, Rf=0.35) gave 2.52 g of 2-tert-butyldimethylsilyloxymethylbenzimidazole (97% of theory) as a brownish powder. MS (DCl, NH3)=263 (M+H+). 1H-NMR (DMSO-d6): 0.00 (6H, s); 0.80 (9H, s); 4.75 (2H, s); 7.0-7.1 (2H, m); 7.4-7.5 (2H, m); 12.15 (1H, br s).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][C@H:35]5[CH2:37][O:36]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][C@H:35]([OH:36])[CH2:37][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC[C@H]1CO1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC[C@H](O)CN1CCN(C)CC1
Yield: 17 %

Procedure:
A stirred solution of (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea from the previous step (25 mg, 0.0495 mmol) and N-methylpiperazine (10 mg, 0.0998 mmol) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 15 h. Concentration under reduced pressure gave a residue that was triturated with diethyl ether and further purified via silica gel chromatography eluting with 10% methanol in dichloromethane to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (5 mg, 17%). 1H NMR (300 MHz, CDCl3) δ 9.40 (brs, 1H), 8.62 (s, 1H), 8.30 (brs, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.27-7.39 (m, 3H), 7.00 (m, 1H), 5.96 (s, 1H), 4.20-4.28 (m, 3H), 4.02 (s, 3H), 2.00-2.80 (m, 14H), 1.29 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:40]([Cl:41])=[C:39]([O:42][CH3:43])[CH:38]=[C:37]([O:44][CH3:45])[C:36]=3[Cl:46])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1)=O.[CH3:47][N:48]([CH3:53])[CH2:49][CH2:50][NH:51][CH3:52]>C(Cl)Cl.C(Cl)Cl.O>[CH3:47][N:48]([CH3:53])[CH2:49][CH2:50][N:51]([CH2:15][C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:36]([Cl:46])=[C:37]([O:44][CH3:45])[CH:38]=[C:39]([O:42][CH3:43])[C:40]=3[Cl:41])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1)[CH3:52]
Reactant: CNCCN(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN(C)CCN(C)C)c[nH]3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
Sodium triacetoxyborohydride (168 mg, 0.794 mmol, 3 equiv) was added to a suspension of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (125 mg, 0.265 mmol) (Example 179) and N,N,N′-trimethylethylenediamine (81 mg, 0.792 mmol, 3 equiv) in DCM (4 mL) at rt, under an argon atmosphere. The reaction mixture was stirred for 18 h at rt, diluted in DCM/H2O and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by trituration in Et2O to afford 88 mg of the title compound as a yellow solid: ES-MS: 558 [M+H]+; tR=3.14 min (System 1); TLC: Rf=0.05 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Br[CH:2](C)[C:3]([C:8]1[CH:9]=[CH:10][C:11]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[CH:13]=1)(OC)OC.[C:27](=O)([O-:29])[O-:28].[K+].[K+].CO>O>[C:27]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([S:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:13]=1)[CH3:2])([OH:29])=[O:28]
Reactant: COC(=O)Cc1cc(C(OC)(OC)C(C)Br)ccc1Sc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A mixture of 4.39 g (10 mmol.) of methyl 5-(2-bromo-1,1-dimethoxypropyl)-2-phenylthiophenylacetate obtained in Example 1-(2), 3.45 g (10 mmol.) of anhydrous potassium carbonate, 26 ml of methanol and 13 ml of water was heated under reflux and stirring for 2 hours. The reaction mixture was distilled to remove distillates having boiling points of below 100° C. To the residue was added 10 ml of water, and the mixture was heated under reflux and stirring for 12 hrs. The reaction mixture was treated in the same manner as in Example 6-(1) to obtain 2.46 g of the desired product as white crystals (yield 78%), m.p. 145°-146° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11](=[O:23])[N:12]2[C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH:6]=1)=[O:4].[CH:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:42])[CH3:41]>C(Cl)Cl>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:46]2[CH2:47][CH2:48][N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45]2)[CH:14]=[C:13]2[C:8]=1[CH2:9][N:10]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:11](=[O:23])[N:12]2[C:15]1[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CBr)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CN4CCN(C(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 7-(bromoacetyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (38 mg, 0.059 mmol) in CH2Cl2 (1 mL) was 1-isopropylpiperazine (15 mg, 0.118 mmol) at rt. The reaction mixture was stirred for 1.5 h, then the solvent was removed in vacuo. The resulting crude material was purified by preparative thin layer chromatography using 10% MeOH in CH2Cl2 as an eluent to give the title compound. Mass spectrum (ESI): 691.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])/[CH:21]=[CH:22]/[C:23]([O-])=[O:24].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:28]([O:27][C:20](=[O:26])[CH:21]=[CH:22][C:23](=[O:24])[NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH3:29]
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
To an ice cold solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline and 0.216 g of monoethyl fumarate in 3 mL of dry dimethylformamide was added 0.288 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (EDAC). 7-Amino-4-(3-bromoanilino)-quinazoline can be made by methods well-known to those skilled in the art. See, for example, J Med Chem, 1995:3482, which is hereby incorporated by reference. After stirring at 50° C. for 5 minutes, the ice bath was removed, and the reaction was permitted to warm to room temperature where it stirred for 15 hours. The reaction was poured into cold water, and the suspension was made basic with the addition of a saturated sodium bicarbonate solution. The resulting solid was collected by filtration, washed with water, and then recrystallized from 50 mL of ethanol to afford 0.052 g of the desired product, mp >260° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=1>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:23])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: COc1cccc(CC(=O)NCCc2c[nH]c3ccccc23)c1
Temperature: 200 °C
Yield: 84.8 %

Procedure:
A mixture of 29 g of tryptamine and 30 g of 3-methoxy-phenylacetic acid was heated at 200° C. for one hour and after cooling the mixture to 50° C., the mixture was dissolved in 200 ml of ethyl acetate. The organic phase was washed successively with N hydrochloric acid, with water, with 2 N sodium hydroxide and with water and was dried and evaporated to dryness. The 59 g of red oil were crystallized from ether and the mixture was vacuum filtered. The product was dried to obtain 47.2 g of 3-methoxy-N-[2-(1H-indol-3-yl)-ethyl]-benzeneacetamide in the form of a beige solid melting at 78° C. which was used as is for the next step. A sample recrystallized from ether melted at 82° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:27]1[CH:28]=[C:23]([C:20](=[O:22])[CH3:21])[CH:24]=[CH:25][CH:26]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(C(C)=O)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-acetyl-phenylboronic acid to give 1-{3-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 359(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][O:15][C:13]2=[O:14])[N:4]=1.[OH-:20].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([CH3:19])([CH3:18])[CH2:16][OH:15])[C:13]([OH:20])=[O:14])[N:4]=1
Reactant: COc1cc(OC)nc(OC2C(=O)OCC2(C)C)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(C)CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To 150 ml of an ethanol solution of 5.4 g of 2-(4,6-dimethoxypyrimidin-2yl)oxy-3,3-dimethyl-γ-butyrolactone, 20 ml of an aqueous solution of 1.2 g of sodium hydroxide was added, and then, the mixture was stirred at room temperature for one hour. Ethanol was evaporated under reduced pressure, and the reaction solution was adjusted to pH 2 to 3 with 5% hydrochloric acid. The reaction solution was extracted twice with ethyl acetate, washed twice with a sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain 4.7 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:8]([C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(CN[C@H](CC(C)C)C(N)=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 39.5 %

Procedure:
(2R)-2-[N-(4-Methoxybenzyl)amino]-4-methylpentanoic acid amide (3.57 g, 14.3 mmol) was dissolved in CH2Cl2 (100 mL) and treated with Et3N (4.2 mL, 29 mmol) and 4-chlorobenzenesulfonyl chloride (3.6 g, 17 mmol) at rt for 18 h. The solvents were removed and the residue was taken into EtOAc (500 mL). The organic solution was washed with H2O, brine, dried over MgSO4, and concentrated. The resulting material was then further purified by flash chromatography (SiO2, 1% MeOH/CH2Cl2) to afford the title compound (2.4 g) as a slightly colored solid in 40% yield. MS (ESI), (M−H)−422.9; 1H NMR (CDCl3) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J=5.0, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm−1.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[CH:8])=[CH:3][CH:2]=1.CO>Cl[Cu].N1C=CC=CC=1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:8]#[C:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Cu]
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(C#CC#Cc2ccc(C)cc2)cc1
Yield: 69 %

Procedure:
In a 100 mL round bottom flask equipped with a gas inlet tube, was placed a Teflon covered magnetic stirring bar, p-tolylacetylene (5.0 g, 43 mmol), methanol 5 mL, pyridine 1.25 mL, and CuCl (0.2 g, 2 mmol). The reaction mixture was vigorously stirred while air was bubbled through it (A. Vogel, Vogel's Textbook of Practical Organic Chemistry, 4th Ed. Longman, London, England, 1978, p 351) Concentrated HCl (2 mL) and saturated sodium chloride (10 mL) was added. The precipitate was isolated by filtration. It was washed with water, dried, and recrystallized from toluene to give 3.45 g, 69% yield, mp 181-183° C. (Lit, 183° C. (Kunckell, Chem. Zentralblatt, 1913, I,1768)). 1H NMR δ: 7.40(d, 4H, J=8.25 Hz), 7.12(d, 4K J=8.25 Hz), 2.35(s, 6H)
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:23])([CH3:22])[C@@H:9](OS(C)(=O)=O)[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2].C1C=CC=CC=1>C(OCC)(=O)C>[C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:22])([CH3:23])[CH:9]=[C:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=NC#N)NC1=CC(C)(C)Oc2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
To 15 g of 6-cyano-3,4-dihydro-3-methanesulfonyloxy-2,2-dimethyl-trans-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran obtained in Step (1) of Example 34, 300 ml of benzene and then 18 g of 1,8-diazabicyclo(5,4,0]-7-undecene were added, and the mixture was reacted under reflux for 3 hours. The reaction mixture was cooled to room temperature, then diluted by addition of 200 ml of ethyl acetate and then washed three times with water. The benzene/ethyl acetate extract solution was dried over anhydrous sodium sulfate. Then, benzene and ethyl acetate were distilled off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 9.3 g of the above identified compound in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.CN.ClCCl.[CH2:20]([N:22](CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH3:20])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-5-nitro-benzoyl chloride (502 mg, 2.3 mmol), methylamine hydrochloride (213 mg, 3.1 mmol), dichloromethane (10 ml), and triethylamine (0.84 ml, 6.0 mmol) was stirred for 60 hours. The mixture was treated with ethyl acetate (25 ml). The solution was washed with a mixture of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×20 ml), washed with aqueous sodium carbonate solution (1 M, 20 ml), dried over sodium sulfate, and concentrated under reduced pressure to provide 2-chloro-N-methyl-5-nitro-benzamide.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[Cl:13].[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:13][C:4]1[C:5]([F:12])=[C:6]([O:9][CH2:10][CH3:11])[CH:7]=[CH:8][C:3]=1[C:28]1([OH:31])[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C@H:20]2[CH2:19][CH2:18][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:22][CH2:21]2)[CH2:30][CH2:29]1
Reactant: CCOc1ccc(Br)c(Cl)c1F
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CCC2CCC(O)(c3ccc(OCC)c(F)c3Cl)CC2)CC1
Temperature: 43 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
1.0 g of well dried magnesium and 30 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 10.0 g of 1-bromo-2-chloro-4-ethoxy-3-fluorobenzene (6) dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 43 to 51° C., followed by stirring for 30 minutes. Thereafter, 21.2 g of 4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanone (7) dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 55° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 16.4 g of 1-(2-chloro-4-ethoxy-3-fluorophenyl)-4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanol (8). The resulting compound (8) was a yellow solid matter.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirred solution of 145 mg (0.38 mmol) (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester in 6 ml dichloroethane and 2 ml tetrahydrofuran at room temperature was added 0.16 ml (1.88 mmol) morpholine and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 48 mg (34%) morpholine-4-carboxylic acid (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-amide as a white crystalline solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[N:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([C:26]3[N:25]=[C:24]([CH3:23])[O:28][N:27]=3)=[CH:37][CH:36]=2)[CH2:7][CH2:6]1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)no1
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: Cc1nc(-c2ccc(C(=O)NC3CCN(CCn4c(=O)ccc5c(F)cc(F)cc54)CC3)cc2)no1
Yield: 44.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (80 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol). Solvent removed and the obtained solids were suspended in ethyl acetate and then filtered to give title compound (71.9 mg).