Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Product: Cc1cc(OCCCCSc2ccccc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:32]=[CH:31][C:7]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[OH:30])[CH2:13][CH2:12]3)=[N:9][O:10][C:6]=2[CH:5]=1.[CH3:33]I.O>CN(C)C=O>[F:3][C:4]1[CH:32]=[CH:31][C:7]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[O:30][CH3:33])[CH2:13][CH2:12]3)=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: CI
Reactant: CC(=O)c1ccc(NCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 164.5 %

Procedure:
To a stirred suspension of sodium hydride (0.37 g, 7 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) was added, dropwise, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanone (2.9 g, 7 mmol) dissolved in dimethylformamide (25 ml). The reaction was stirred at ambient temperature for 15 minutes, and then it was cooled with an ice bath to about 5° C., whereupon methyl iodide (1.0 g, 7 mmol) in dimethylformamide (1 ml) was added dropwise. The reaction was stirred at ambient temperature for 30 min, and then water was added. The resulting aqueous mixture was extracted with ethyl acetate, the extract washed with water, dried (MgSO4), and the solvent was concentrated to afford 4.9 g of a brown oil, which solidified on standing. The solid was flash chromatographed on silica gel. The appropriate fractions were concentrated to yield 2.7 g of product as a yellow solid. Recrystallization from toluene-hexane yielded 2.0 g (67%) of analytically pure 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylaminol-3-methoxyphenyl]ethanone as a yellow solid, m.p.=96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(C)C=CC=CC=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22](=[O:25])[CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc(Cl)cc1
Yield: 88.5 %

Procedure:
Into a mixture of p-chlorophenol (20.0 g, 156 mmol), pyridine (14.8 g, 187 mmol), and toluene (150 ml), propionic acid chloride (17.3 g, 187 mmol) was addeddropwise, and the resultant mixture was stirred for 1 hour at room temperature. Water (150 ml) was added and the aqueous layer was discarded. The organic layer was concentrated anddistilled under reduced pressure (bp. 73°-76° C./0.2 mmHg), thereby obtaining a propionic acid-p-chlorophenyl ester (25.6 g, 138 mmol, 89%).
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCOCC1>[CH3:27][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([N:2]2[NH:6][CH:5]=[C:4]([C:7]3[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=3)[S:3]2)[CH2:25][CH2:26]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Reactant: CN(C)CCCN1CCNCC1
Solvent: C1COCCO1
Product: CN(C)CCCN1CCN(N2NC=C(c3ncc([N+](=O)[O-])n3C)S2)CC1

Procedure:
A solution of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole in 200 ml. of dioxane is treated with 5.1 g. of 1-(3-dimethylaminopropyl)piperazine, and the mixture stirred at room temperature for 18 hours. The precipitate is collected, dissolved in 100 ml. of water, made alkaline with sodium hydroxide solution, and then extracted with 500 ml. of chloroform. The chloroform extract is dried and the solvent removed under reduced pressure. The yellow residue is recrystallized from 100 ml. of ethanol to give 2.9 g. of product, melting at 174°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6]([OH:8])=O.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:8])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Agent: CCP(=O)(C#N)CC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoic acid (12.1 g) and tert-butyl hydrazinecarboxylate (7.61 g) in DMF (100 mL) was added diethyl phosphoryl cyanide (8.55 mL) at room temperature. After stirring at room temperature for 30 min, triethylamine (21.6 mL) was added, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.00 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.N1C2C(=CC=CC=2)C(C(Cl)=O)=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]4[C:29]5[C:34]([CH:35]=[CH:36][C:21]3=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:16][CH:15]=2)=[O:12])=[CH:2]1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3c[nH]c4ccccc34)cc2)c2ccc3ccccc3c2N1
Yield: 55 %

Procedure:
Indole-3-carboxylic acid (51 mg, 0.316 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and indole-3-carboxylic acid chloride mentioned above, the title compound (40 mg, yield 55%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13].C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12](=[O:13])[C:11]([F:18])([F:17])[F:10]
Reactant: NCc1ccccc1Br
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 2-bromobenzylamine (1.3 mL, 10.8 mmol) in methanol (5 mL) was added ethyl trifluoroacetate (1.54 mL, 21.6 mmol) and triethylamine (1.4 mL, 10.8 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated under vacuum to yield N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (3.15 g, quant.). HPLC ret. time 2.86 min, 10-99% CH3CN, 5 min run; ESI-MS 283.9 m/z (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:11][CH:12]=1)#[N:6]>C(O)CCC>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([O:19][CH2:5][CH2:7][CH2:8][CH3:9])=[O:18])=[N:11][CH:12]=1)#[N:6]
Reactant: N#Cc1ccc(NC(=O)CCC(=O)O)nc1
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOC(=O)CCC(=O)Nc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of butan-1-ol (3 mL) was added dropwise thionyl chloride (2.73 mmol, 0.200 mL 3 eq). After 5 min, 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (prepared as described before, 200 mg, 0.912 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was washed with a saturated solution of sodium hydrogenocarbonete and dried on magnesium sulfate, then concentrated under vacuum. The residue was first washed with cyclohexane and the solid obtained was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give butyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A66 (10%) and the by-product butyl 6-[(4-butoxy-4-oxo-butanoyl)amino]pyridine-3-carboxylate A67 (9%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH:4]1[C:12]([O:14]CC)=[O:13])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH:4]1[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCOC(=O)C1CC2(CC1CC)OCCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC1CC2(CC1C(=O)O)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with ethyl 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol) and aqueous sodium hydroxide (1 N, 14.0 mL, 14.0 mmol). The solution was stirred overnight at rt. To the solution was added DCM (30 mL) followed by the addition of 20% aqueous citric acid (about 20 mL) to reach pH of about 2. The layers were separated and the aqueous solution was extracted with DCM (2×30 mL) and DCM/EtOAc (1:1, 30 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid as a clear, colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c) Rt=1.20 min; MS m/z: 201 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].NC(N)=N.[CH3:13][O:14][C:15]1[CH:24]=[C:23]([CH:25]=[C:26]([CH2:29]OC)[C:27]#[N:28])[C:18]2[CH:19]=[CH:20][CH2:21][O:22][C:17]=2[C:16]=1[O:32][CH3:33]>CO>[NH2:4][C:3]1[N:5]=[C:27]([NH2:28])[C:26]([CH2:25][C:23]2[C:18]3[CH:19]=[CH:20][CH2:21][O:22][C:17]=3[C:16]([O:32][CH3:33])=[C:15]([O:14][CH3:13])[CH:24]=2)=[CH:29][N:2]=1
Reactant: N=C(N)N
Reactant: COCC(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OCC=C2
Temperature: 3 °C
Yield: 42.8 %

Procedure:
Guanidine hydrochloride (11.46 g, 0.12 mole) in methanol (25 mL) was added to sodium methoxide (6.55 g, 0.12 mole) in methanol (40 mL) and the resultant sodium chloride was filtered and washed with methanol (10 mL). The guanidine solution was added to 3-(7,8-dimethoxy-2H-1-benzopyran-5-yl)-2-methoxymethylpropenenitrile (11.5 g, 0.04 mole) and the mixture heated at reflux for 2 hr. Cooling the mixture at 3° C. provided 5.38 g of yellow solid in two crops. HPLC assayed yield of 28.6%. A sample recrystallized from alcohol/water gave mp 232°-4° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:13]([Si](C)(C)C)#[CH:14]>>[C:13]([C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)#[CH:14]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cccc2c(Br)cncc12
Product: C#Cc1cncc2c(N)cccc12

Procedure:
The title compound can be synthesized from 4-ethynylisoquinolin-8-amine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 1. 4-ethynylisoquinolin-8-amine is prepared from 4-bromoisoquinolin-8-amine and ethynyltrimethylsilane according to the 2 steps procedure described in example 1.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.CS(C)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 62.5 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (3 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (5.1 g), dimethyl sulfoxide (30 mL) and sodium bicarbonate (6.3 g). The mixture was heated to about 60-65° C. and maintained at the same temperature for about 10 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 25-30° C. followed by addition of water (30 mL) and toluene (30 mL). The mixture was stirred for about 10 minutes and layers were separated. The organic layer was with water (30 mL). The organic layer was separated and subjected to complete distillation under vacuum at 55-60° C. followed by cooling to room temperature and subsequent addition of n-hexane (45 mL). The mixture was stirred for about 3 hours at room temperature followed by isolation of solid by filtration and washing with n-hexane (15 mL). The solid isolated was subjected to drying under vacuum at 55-60° C. for about 4 hours to afford the title compound in about 78% yield having HPLC purity of about 98%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:25])[CH:3]=1.C(N(CC)CC)C>CCO.[Pd]>[O:25]=[C:9]1[N:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]1[C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2cc(Cl)ncn2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccncn2)c2ccccc21
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [3-(6-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (260 mg, 0.72 mmol), 10% Pd—C (23 mg) and triethylamine (0.15 mL, 1.08 mmol) in EtOH (5 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 2 h. The mixture was filtered through a pad of celite, washing with EtOH, and the filtrate was concentrated to give the title compound as a white solid. MS: m/Z=327 (M+1).
Reaction SMILES: FC1C=C(F)C=CC=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=[C:12]([CH3:33])[CH:11]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.CC1C=C(N)C=CC=1C>>[CH3:33][C:12]1[CH:11]=[C:10]([NH:9][C:35]2[CH:40]=[CH:39][C:38]([C:41]([C:43]3[CH:48]=[C:47]([N:49]4[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]4)[CH:46]=[CH:45][C:44]=3[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1ccc(N)cc1C
Product: Cc1ccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(C)c2)cc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3,4-dimethyl-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.0, 148.9, 145.7, 142.7, 142.3, 138.4, 137.1, 135.5, 135.1, 134.4, 132.0, 130.5, 130.2, 125.4, 121.9, 120.7, 120.2, 118.2, 118.0, 117.0, 110.4, 60.2, 29.2, 22.2, 19.5, 18.8, 18.7
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[N+:33]=[N-:34])(=[O:8])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 34 %

Procedure:
The cyclohexylsulfonyl(4-acetyloxyphenylsulfonyl)methane in Synthesis Example 12, 5 g (0.014 mol), was dispersed in 100 g of dichloromethane. To the dispersion was added 2.3 g (0.015 mol) of p-toluenesulfonylazide. With stirring under ice cooling, 2.9 g (0.015 mol) of DBU was added to the dispersion, and after 10 minutes, 55 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 50 g of water. The organic layer was concentrated and 6 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 20 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 2 g (yield 34%) of fine yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](=[O:35])[NH:28][CH2:29][C:30]([O:32]CC)=[O:31])[NH:12][C:11]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[N:10]1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[NH:12][C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CNC(=O)C1COCCN1CC1=C(C(=O)OCC)C(c2ccc(F)cc2Br)N=C(c2nccs2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NCC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-((2-ethoxy-2-oxoethyl)carbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.2 g, 0.31 mmol) and sodium hydroxide (0.13 g, 3.1 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25° C. for 20 minutes. The reaction solution was adjusted to pH 6-7 with con. HCl, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (0.14 g, 74%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N1CCOCC1)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[CH:48]([C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]([CH3:59])[C:56](O)=[O:57])([CH3:50])[CH3:49]>CN(C=O)C.O>[CH:48]([C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]([CH3:59])[C:56]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:57])([CH3:49])[CH3:50]
Reactant: CC#CC(CC(=O)OCC)c1ccc(N)cc1
Reactant: CC(Oc1cccc(C(C)C)c1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(CC(=O)OCC)c1ccc(NC(=O)C(C)Oc2cccc(C(C)C)c2)cc1
Reaction time: 72 h

Procedure:
To a solution of 200 mg (0.75 mmol) of ethyl 3-(4-aminophenyl)hex-4-ynoate, 258 mg (2.24 mmol) of N-ethylmorpholine, 126 mg (0.82 mmol) of HOBt hydrate and 128 mg (0.82 mmol) of EDAC in 3 ml of DMF was added a solution of 202 mg (0.74 mmol) of 2-(3-isopropylphenoxy)propionic acid in 2.5 ml of DMF. After 72 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. This gave 156 mg of ethyl 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[Cl:14][C:15]1[C:16]([F:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[C:16]=2[F:23])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: Fc1c(Cl)cccc1CBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncccc1OCc1cccc(Cl)c1F
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxypyridine (2.42 g, 0.022 mol), dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20 ml) was stirred for five minutes, then 3-chloro-2-fluorobenzyl bromide (5.0 g, 0.022 mol) and Adogen 464 (3 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 3.22 g (58%), m.p. 98°-100 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[C:22]([F:31])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CO.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:31])[CH:21]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetate (1.50 g, 3.25 mmol) in 21 ml of tetrahydrofuran was added 14 ml of methanol and 14 ml of water. Lithium hydroxide (0.401 g, 16.7 mmol) was added to the reaction mixture, and the reaction mixture was stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed under reduced pressure, and the remaining aqueous solution was extracted with dichloromethane (3×20 ml). The organic fractions were combined, dried over magnesium sulphate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage 100 g) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 434.1 (M+H)+.