Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]#[N:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]([CH3:23])([CH3:22])[C:7]=2[CH:24]=1>Cl.N1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]#[N:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]([CH3:22])([CH3:23])[C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 170 °C
Reaction time: 13 h
Yield: 94 %

Procedure:
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A5-2, 6.58 g, 20.8 mmol) was dissolved in pyridine hydrochloric acid salt (25.0 g), and stirred at 170° C. for 13 hr. The reaction mixture was partitioned in ethyl acetate (400 mL) and distilled water (400 mL), and the aqueous layer was extracted one more time with ethyl acetate (400 mL). The combined organic layer was washed twice with distilled water (100 mL) and once with saturated brine (100 mL) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (5.91 g, 93%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCBr
Reactant: Cc1ccc(C)c(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c(SCCC(=O)O)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
43.4 g (1.086 mol) of sodium hydroxide was added to 230 mL of water, 75.0 g (0.543 mol) of 2,5-dimethylthiophenol (purchased from Aldrich Chemical Company) was then added and the mixture was cooled to about 10° C. 91.30 g (0.597 mol) of 3-bromopropionic acid (purchased from Aldrich Chemical Company) was added in portions keeping the temperature below 25° C. The mixture was warmed to room temperature, stirred for 2 hr under nitrogen, and was then washed with diethyl ether (3×500 mL). The aqueous layer was acidified with 1N HCl and filtered to yield 112.79 g of the title compound of Step A as a solid melting at 97-98° C. 1H NMR (CDCl3): δ2.3 (s,3H), 2.34 (s,3H), 2.68 (t,2H), 3.1 (t,2H), 6.9 (d,1H), 7.06-7.14 (m,2H).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C@H:25]([OH:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:22]=[CH:23][CH:24]=2)[CH2:13][CH2:12]1)(=[O:10])[CH3:9]>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][C@H:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([C:8](=[O:10])[CH3:9])[CH2:12][CH2:13]1)[OH:36]
Reactant: CC(=O)N1CCC(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1CCC(COc2cccc([C@H](O)CCN)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4M, 2 mL) was added to a solution of (R)-tert-butyl (3-(3-((1-acetylpiperidin-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate (0.60 g, 1.40 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give after purification by triturating in diethyl ether Example 11 hydrochloride as a white solid. Yield (0.40 g, 88%); 1H NMR (400 MHz, DMSO-d6); δ 7.18 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.6 Hz, 2H), 6.75 (d, J=7.6 Hz, 1H), 4.60 (t, J=6.4 Hz, 1H), 4.38 (d, J=14.8 Hz, 1H), 4.11 (s, 2H), 3.79 (d, J=6 Hz, 3H), 3.02 (t, J=11.2, 1H), 2.64 (d, J=3.2 Hz, 2H), 2.54 (s, 1H), 1.97 (s, 4H), 1.76 (t, J=16.0 Hz, 2H), 1.66-1.61 (m, 2H), 1.26-1.04 (m, 2H); MS: m/z 307.01 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[CH:15]=CN[N:12]=1.[CH3:17][C:18]1[NH:19]C=CN=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[N:12]=[C:18]([CH3:17])[NH:19][CH:15]=1
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Reactant: Cc1ncc[nH]1
Product: Cc1nc(CC(=O)c2ccc(Cl)cc2Cl)c[nH]1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that 2-methylimidazole (3.7 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (5% MeOH/CH2Cl2) to yield a light yellow solid.
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9](S(C)(=O)=O)[S:8][N:7]=1.[CH3:17][NH:18][CH3:19].O>C(COC)OC>[I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9]([N:18]([CH3:19])[CH3:17])[S:8][N:7]=1
Reactant: CS(=O)(=O)c1snc(OCC#CI)c1C#N
Reactant: CNC
Solvent: O
Solvent: COCCOC
Product: CN(C)c1snc(OCC#CI)c1C#N

Procedure:
3.6 Grams of 3-(3-iodo-2-propynyloxy)-4-cyano-5-methylsulfonylisothiazole was dissolved in 30 ml of dimethoxyethane, 1.5 g of dimethylamine (as 50% aqueous solution) was added at room temperature with stirring, and then the reaction solution was stirred at 50° C. for 2 hours. Water was added to precipitate crystals, which were then collected by filtration, washed with water, dried and recrystallized from ethyl acetate. Thus, 2.2 g of white crystals having a melting point of 171° to 172° C. was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N:21]([O-])=O.[Na+]>O>[CH3:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[N:21]2)[N:14]=1
Reactant: Cc1cccc(Nc2ncccc2N)n1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cccc(-n2nnc3cccnc32)n1

Procedure:
A mixture of 1.0 g. of the crude amine from Step B, 20 ml. of water and 3 ml. of concentrated sulfuric acid was stirred, cooled to 0°-5° C. and treated dropwise with a solution of 0.345 g. of sodium nitrite in 2 ml. of water. After an additional hour at 0°-5° C. and storage at room temperature over the weekend, the precipitate was collected and recrystallized from 6 ml. of ethanol to give 3-(2-methyl-6-pyridyl)-3H-1,2,3-triazolo[4,5-b]pyridine, m.p. 144°-145° C.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.Cl.Cl.[C:14]([C:16]1([NH:25][C:26](=[O:34])[CH:27](N)[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)#[N:15]>>[C:14]([C:16]1([NH:25][C:26](=[O:34])[CH:27]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]=2)[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)#[N:15]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Reactant: N=C1NC(=O)c2ccccc21
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC2=NC(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared from 3-imino-2,3-dihydro-isoindol-1-one and 2-amino-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 86. MS, m/z 424.5=M+1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:17](=[NH:20])[NH:18][OH:19])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:17]2[NH:20][C:27](=[O:28])[O:19][N:18]=2)[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=N)NO)CC12CCCCC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(c2noc(=O)[nH]2)CC12CCCCC2
Yield: 69.8 %

Procedure:
To a solution of [1-(N-hydroxycarbamimidoyl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester (5.8 g, 19.5 mmol) in THF (250 mL) was added CDI (4.74 g, 29.3 mmol). After 3 hours at reflux another portion of CDI (1 g) was added. The solution was heated to reflux for an additional 4 hours and then the solvent was removed under reduced pressure. The residue was partitioned between ether (200 mL) and 1N NaOH (75 mL). The organic layer was extracted with 1N NaOH (2×75 mL). The combined aqueous layers were washed with ether (100 mL). The aqueous layer was acidified to pH=3 by the addition of potassium hydrogen sulfate with ice bath cooling while layered over methylene chloride (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (2×200 mL). The combined organic layers were washed with water (75 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give an off white foam. The residue was chromatographed on a wet-packed silica gel column (6.5×28 cm) eluting with 3-4% methanol in methylene chloride. The appropriate fractions were combined and evaporated to give 4.4 g (70%) of [1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester as a white foam: 1H NMR (300 MHz, CDCl3) δ0.78 (d, J=5.3 Hz, 1H), 1.44 (s, 9H), 1.3-1.7 (m, 11H), 3.24 (dd, J=5.0, 13.9 Hz, 1H), 3.84 (dd, J=5.0, 13.9 Hz, 1H), 4.97 (s, 1H); MS (APCI) m/z 324 [M+H]+.
Reaction SMILES: Br[CH:2]([CH:9]=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:11]([NH2:14])(=[S:13])[CH3:12]>ClC(Cl)C>[CH3:12][C:11]1[S:13][C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][N:14]=1
Reactant: CCOC(=O)CC(Br)C=O
Reactant: CC(N)=S
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cc1cnc(C)s1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
A mixture of 28.7 g of ethyl 3-bromo-4-oxo-butyrate, 300 ml of dichloroethane and 11.2 g of thioacetamide was refluxed for 10 hours with stirring while replacing the dichloroethane that distilled to keep the volume constant and then the mixture was cooled to room temperature. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was extracted with 2N hydrochloric acid and the pH of the aqueous extracts was made alkaline by addition of ammonium hydroxide. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to dryness to obtain 8.3 g of ethyl 2-methyl-5-thiazole acetate. The IR spectrum in CHCl3 showed ester C=O at 1737cm-1 and C=C and C=N at 1535cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: OC1CCC(NCc2ccc(Cl)cc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(Cc1ccc(Cl)cc1)C1CCC(O)CC1

Procedure:
7.2 g (30 mMol) of 4-[N-(4-chloro-benzyl)-amino]-cyclohexanol are dissolved in 30 ml of dimethyl-formamide, and after the addition of 2.2 g (16 mMol) of potassium carbonate, 4.26 g (30 mMol) of methyliodide are added dropwise. When the slightly exothermic reaction has ended, the mixture is concentrated by evaporation, mixed with water and extracted with chloroform. The concentrated extracts are chromatographed on silica gel to purify them (eluant; methylene chloride/methanol=20/1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12]C)[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([OH:31])([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)[C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Product: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-ethoxy-phenyl)-2-methoxy-quinoline (2 g, 5.59 mmol) and (6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (1.48 g, 6.70 mmol) generated the title compound of 26A (1.458 g, 52% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.[O-:25][C:26]#[N:27].[Na+]>C(O)(=O)C.O>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][C:6]2[C:7](=[O:8])[C:2]([NH:1][C:26]([NH2:27])=[O:25])=[CH:3][O:4][C:5]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2occ(NC(N)=O)c(=O)c2cc1Oc1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 20 ml of acetic acid and 10 ml of water. The solution was heated to 35° C. Thereto was dropwise added a solution of 190 mg of sodium cyanate dissolved in 5 ml of water, in 5 minutes. The mixture was stirred for 30 minutes at the same temperature. 20 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 350 mg (yield: 62.3%) of 7-methylsulfonylamino-6-phenoxy-3-ureido-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][O:126]C(=O)C3C=CC=CC=3)[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][O:114]C(=O)C4C=CC=CC=4)[C@@H:101]([O:102]C(=O)C4C=CC=CC=4)[C@H:91]([O:92]C(=O)C4C=CC=CC=4)[C@H:81]3[O:82]C(=O)C3C=CC=CC=3)[C@H:68]([O:69]C(=O)C3C=CC=CC=3)[C@H:58]2[O:59]C(=O)C2C=CC=CC=2)[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:143]=[CH:142][CH:141]=[CH:140][CH:139]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][OH:126])[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][OH:114])[C@@H:101]([OH:102])[C@H:91]([OH:92])[C@H:81]3[OH:82])[C@H:68]([OH:69])[C@H:58]2[OH:59])[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:139]=[CH:140][CH:141]=[CH:142][CH:143]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](O[C@@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H](O[C@@H]4[C@@H](COCc5ccccc5)N(C(=O)OCc5ccccc5)C[C@H]4OCc4ccccc4)O[C@@H]3COCc3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O[C@@H]3O[C@H](CO)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.8 %

Procedure:
The compound (390.8 mg, 0.20 mmol) synthesized in Example 20 (20c) was dissolved in methanol (8 mL) and potassium carbonate (27.6 mg, 0.20 mmol) was added thereto, followed by stirring of the mixture at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). The mixture was neutralized with methanol-hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (methylene chloride:methanol, 30:1-20:1-10:1, V/V) to obtain the desired title compound (146.5 mg, 61%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]([OH:41])[CH:29]5[CH2:34][CH2:33][N:32](C(=O)C(F)(F)F)[CH2:31][CH2:30]5)=[CH:24][CH:23]=4)[CH3:21])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]([OH:41])[CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:24][CH:23]=4)[CH3:21])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(Cl)cccn23)n1)c1ccc(C(O)C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(Cl)cccn23)n1)c1ccc(C(O)C2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
237 mg of the compound [37-3] was dissolved in a mixed solvent of 3 mL of tetrahydrofuran and 1 mL of methanol, then 163 μL of 5N aqueous solution of sodium hydroxide was added thereto, and the mixture was stirred for 5 hours at 50° C. After standing to cool, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5-93/7), to obtain 156 mg of 4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(piperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [374] (hereinafter, referred to as the compound [374]).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:4][CH2:3][CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: Clc1ccc(CBr)cc1
Product: OCCNCc1ccc(Cl)cc1

Procedure:
2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[OH:13])=[O:5].I[CH2:20]I>>[Cl:18][C:15]1[CH:16]=[CH:17][C:2]2[O:1][CH2:20][O:13][C:7]3[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=3[C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: ICI
Reactant: O=C(c1cc(Cl)ccc1O)c1cc(Cl)ccc1O
Product: O=C1c2cc(Cl)ccc2OCOc2ccc(Cl)cc21
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0.042 mol, prepared similarly as described in Journal of the American Chemical Society 77, 543 (1955)) and diiodomethane (11.9 g, 0.044 mol) were dissolved in dry N,N-dimethylformamnide (226 ml). Dried and powdered potassium carbonate (8.3 g) was added and the mixture was heated at 105° C. for 5 h and left overnight at room temperature. The reaction mixture was poured on ice (220 g). The precipitate was collected by filtration after 0.5 h and dissolved in diethyl ether (500 ml). The organic layer was washed with 5% sodium hydroxide (50 ml), dried over MgSO4 and evaporated in vacuo, affording 12 g (96%) of 2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(C)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c(Cl)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
Heat a solution of 2-chloro-4-methoxy-1-methyl-benzene (2.0 g, 13 mmol), N-bromosuccinimide (2.7 g, 15 mmol), and benzoyl peroxide (50 mg) in CCl4 (50 mL) to reflux and stir for 3 hr. Cool the reaction to room temperature and quench with water. Extract the aqueous with CH2Cl2, dry over MgSO4, and filter. Remove the solvent to afford 3.0 g (98%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=1.C(=O)([O-])[OH:22].[Na+]>Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]([NH2:17])=[O:22])[N:12]=1
Reactant: O=C([O-])O
Reactant: Cc1ccncc1-c1nc(-c2cccc(C#N)c2)cs1
Agent: Cl
Agent: [Na+]
Product: Cc1ccncc1-c1nc(-c2cccc(C(N)=O)c2)cs1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
3-{2-[4-Methylpyridin-3-yl]-1,3-thiazol-4-yl}benzonitrile (100 mg) was dissolved in conc. hydrochloric acid (4 ml) and the mixture was stirred at 40° C. for 16 hrs. The reaction mixture was added to aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was recrystallized from ethyl acetate-methanol to give the title compound (72 mg) as pale-yellow powder crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[O:24][C:25]([CH3:31])=[CH:26][C:27]=1[C:28](Cl)=[O:29]>>[CH3:22][C:23]1[O:24][C:25]([CH3:31])=[CH:26][C:27]=1[C:28]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:29]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Product: Cc1cc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c(C)o1

Procedure:
Compound 41 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2,5-dimethyl-3-furoyl chloride and conditions outlined in procedure N. M.p.=234-235° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.15 (d, 1H), 7.81 (d, 1H), 7.63 (t, 1H), 7.54 (t, 1H), 5.92 (s, 1H), 3.40 (m, 2H), 3.05 (s, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 2.18 (m, 2H), 1.90 (m 2H), 1.60 (s, 2H); LCMS: 424 [M+H].
Reaction SMILES: Br[CH:2]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[OH-].[K+]>O1CCCC1.O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:3]([S:4]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])=[CH:2][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C=C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a solution of 4.44 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one in 50 ml of tetrahydrofuran, a solution of 0.56 g of potassium hydroxide in 30 ml of water was added dropwise and vigorously stirred for 3 hours. The reaction mixture was combined with 100 ml of ice water, and extracted with 100 ml of chloroform. The organic solvent layer was washed twice with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 3.61 g of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonyl-1-penten-3-one.