Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([CH2:7][CH2:8][C:9](O)=O)[CH2:2][CH2:3][C:4](O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>O=P(Cl)(Cl)Cl>[S:1]([CH2:7][CH2:8][C:9]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:2][CH2:3][C:4]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1
Reactant: NNC(N)=S
Reactant: O=C(O)CCSCCC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(CCSCCc2nnc(N)s2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 3,3′-thiodipropanoic acid (1 equivalent) and thiosemicarbazide (2 equivalents) were taken in POCl3 (10 fold) and stirred at 90° C. for 3 h. The reaction mixture was cooled to room temperature and poured on to ice. The resulting mixture was filtered and then brought to pH 14 using KOH. The white solid that was formed was filtered, washed with water and dried to afford the desired product I-2 in 50-60% yield. This material was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([Cl:10])[N:3]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[CH:16]=[CH:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:10])[CH:5]=1)[CH3:15]
Reactant: O=Cc1cc(Cl)nc(Cl)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cc(Cl)nc(Cl)c1
Yield: 71.5 %

Procedure:
The above aldehyde (1.2 g) was dissolved in dichloromethane (40 ml) and carboethoxymethylenetriphenylphosphorane (2.4 g) was added. After 18 hours at 25° the solution was concentrated in vacuo and the residue washed with hexane. Combined hexane washings were concentrated in vacuo to give ethyl-3-(2,6-dichloro-4-pyridyl)propenoate (1.2 g). NMR 1H : 7.50(2H,d), 2.28(2H,s), 6.52(2H,d), 4 29(2H,q), 1.32(3H,t).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH2:16])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:16])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(N)=O)nn1Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C#N)nn1Cc1ccccc1
Temperature: 90 °C
Yield: 13.1 %

Procedure:
1-Benzyl-5-methyl-1H-pyrazole-3-carboxamide (28.22 g, 0.131 mol) was treated with phosphorus oxychloride (112 mL) according to the general method described in Part C of Example 8. The mixture was heated for 3 hours at 90° C. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-25% ethyl acetate in hexanes). The appropriate fractions were combined, dried over magnesium sulfate, and concentrated under reduced pressure to yield 3.38 g of 1-benzyl-5-methyl-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1cccs1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OCc4cccs4)[C@@H](COC(C)=O)O3)c2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 0.30 g of 5'-O-acetyl-2'-deoxy-5-fluoro-3'-O-(2-thienyl)methyluridine in 10 ml of dioxane were added 0.55 ml of triethylamine and 0.16 g of 4-methoxy-benzoyl chloride. The mixture was stirred at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed with water. The ethyl acetate layer was dried over sodium anhydrous sulfate and concentrated. The residue was subjected to silica gel chromatography and purified by elution with chloroform, giving 0.37 g of 5'-O-acetyl-2'-deoxy-5-fluoro-3-(4-methoxybenzoyl)-3'-O-(2-thienyl)me thyluridine in a yield of 91%.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:19]=[CH:20]2)=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:18]2[CH:19]=[CH:20][C:21]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:13])[CH:22]=3)[S:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cn(C)nc3c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3cn(C)nc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((2-methyl-2H-indazol-6-yl)methyl)sulfamoyl)benzoate (step-1 of Example 18).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([N:16]3[CH2:17][CH2:18][CH2:19][CH:15]3[CH2:14][O:13][CH3:12])[CH:21]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COCC1CCCN1c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COCC1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (170 mg, 0.83 mmol), 3-(2-(methoxymethyl)pyrrolidin-1-yl)aniline (170 mg, 0.83 mmol) and DIEA (214 g, 1.66 mmol) in 15 mL of DMSO was stirred at room temperature overnight. 100 mL of water were added, the mixture was extracted with ethyl acetate (3×30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL), concentrated under reduced pressure to give 5-chloro-N-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 64%) as a yellow solid. LC-MS: 376 [M+H]+, tR=1.75 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O>C(Cl)Cl>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:17][CH3:18])=[C:4]2[C:5]=1[CH:16]1[CH:11]([C:9]2=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1c(C)cc(C)cc1C(=O)C1=CCCCC1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1c(C)cc(C)c2c1C(=O)C1CCCCC21
Temperature: 0 °C

Procedure:
197.0 Grams of 1-cyclohexenyl 3,5-dimethyl-2-methoxyphenyl ketone was gradually added to polyphosphoric acid prepared from 900 g of phosphorus pentoxide and 900 g of phosphoric acid at 100° C. with stirring and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into 3 liters of ice water and extraction was carried out with 3 liters of methylene chloride. The extract was washed with water and then saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Methylene chloride was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane =99:1) and then recrystallized from n-hexane to obtain 46.0 g of 5,7-dimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[N:2]1.[S:21]1[CH:25]=[N:24][N:23]=[C:22]1[NH2:26].C(Cl)CCl.O>C1COCC1.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:26][C:22]2[S:21][CH:25]=[N:24][N:23]=2)=[O:15])=[N:2]1
Reactant: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: Nc1nncs1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(Nc1nncs1)c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.7 %

Procedure:
To a solution of (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.13 g, 0.49 mmol) obtained in Step 1 of Example 47 in THF (2.6 mL), [1,3,4]thiadiazol-2-ylamine (0.075 g, 0.74 mmol) and EDC (0.18 g, 0.94 mmol) were added, followed by stirring at room temperature for 4.5 hours. The reaction mixture was added with water and ethyl acetate to separate the mixture into organic layer and aqueous layer and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol=100/0 to 90/10) and the obtained compound was crystallized from ethyl acetate/methanol (1/1, 2.0 mL) to obtain Compound 145 (0.020 g, 12%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].C1C=C2[N:25]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:25][C:16](=[O:18])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
A solution of Boc-D-phenylglycine (500 mg, 1.99 mmol), HOBt hydrate (370 mg, 2.41 mmol) and EDC (500 mg, 2.60 mmol) in DMF (8 mL) was stirred at room temperature for 30 min. Conc. NH4OH (1.00 mL) was added. The mixture was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 2-amino-2-oxo-1-phenylethylcarbamate as a solid (446 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=3)=[O:9])[CH:3]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Examples 73-87 using (5-aminopyridin-3-yl)(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 103) and 4-chlorophenylacetic acid to afford the title compound as a white solid in 66% yield, 223 mg.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.CCOCC.[C:43]([CH:48]([CH:50]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[OH:51])[OH:49])([O:45][CH2:46][CH3:47])=[O:44]>C(=O)([O-])[O-].[K+].[K+]>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:51][CH:50]([CH:48]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[OH:49])[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC(C(=O)OCC)C(O)C(=O)OCC)cc1

Procedure:
N-trifluoroacetyl-4-(4-tetradecenylamino)benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent evaporated from the combined filtrate and washings to yield a solid residue. After dissolving in aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the diethyl tartrate as a white, crystalline solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C@H:14]3[N:17]([Si](C(C)(C)C)(C)C)[C:16](=[O:25])[C@@H:15]3[CH3:26])[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C@H:14]3[NH:17][C:16](=[O:25])[C@@H:15]3[CH3:26])[N:13]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1c1cn2cc(C(C)(C)C)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N[C@@H]1c1cn2cc(C(C)(C)C)ccc2n1
Reaction time: 2 h

Procedure:
(3R,4S)-4-(6-(tert-butyl)imidazo[1,2-a]pyridin-2-yl)-1-(tert-butyldimethylsilyl)-3-methylazetidin-2-one (Preparation 40) was dissolved in THF and 1 M tetrabutylammonium fluoride in THF (3 mL, 10 mmol) was added. The reaction mixture was stirred for 2 hours then the solvent was removed in vacuo. The intermediate was purified by silica gel column chromatography eluting with 0-100% CMA80 in dichloromethane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:17](I)([CH3:19])[CH3:18]>CC(C)=O.[Ag]=O>[CH:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: COc1ccc(C2CCCNC2)cc1OC
Agent: O=[Ag]
Solvent: CC(C)=O
Product: COc1ccc(C2CCCN(C(C)C)C2)cc1OC
Temperature: 20 °C
Reaction time: 24 h

Procedure:
2.5 g of silver oxide were added to a solution of 5 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 25 ml of acetone and then 2.5 ml of isopropyl iodide were added dropwise. The mixture was stirred at 20° C for 24 hours and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 6-3-1 cyclohexane-chloroform-triethylamine mixture yielded 4.8 g of N-isopropyl-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:31]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: C1COCCO1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A suspension of compound 5 (400 mg, 0.99 mmol) and Lawesson's Reagent (402 mg, 0.99 mmol) in anhydrous 1,4-dioxane (15 mL) was stirred at 150° C. for 30 min in a CEM microware reactor. The mixture was concentrated in vacuo, and the residue was purified by prep-TLC to give compound 6 (140 mg, 34%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)c(F)c1)N1CCCC1
Yield: 95.6 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and pyrrolidine (0.30 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 1-[(4-bromo-3-fluorophenyl)sulfonyl]pyrrolidine (0.43 g, 96%) was provided after purification. HRMS: calcd for C10H11BrFNO2S, 306.96779; found (EI, M+.), 306.968. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH:17]([C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([O:32]CC)=O)=[N:24][C:23]=2[S:22][CH:21]=1)([CH3:19])[CH3:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:78]2[CH:82]=[N:81][C:80]([O:83][CH2:84][CH2:85][O:86][C:87]3[CH:88]=[C:89]([CH2:93][NH2:94])[CH:90]=[CH:91][CH:92]=3)=[N:79]2)C=CC=CC=1>>[CH:17]([C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([NH:94][CH2:93][C:89]3[CH:90]=[CH:91][CH:92]=[C:87]([O:86][CH2:85][CH2:84][O:83][C:80]4[N:81]=[CH:82][NH:78][N:79]=4)[CH:88]=3)=[O:32])=[N:24][C:23]=2[S:22][CH:21]=1)([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1nc2scc(C(C)C)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: CC(C)c1csc2nc(C(=O)NCc3cccc(OCCOc4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-isopropyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 68 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (161.3 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of the product of Example 353E (16.1 mg, 0.036 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and ethanesulfonyl chloride was added (0.0036 mL, 0.038 mmol). The mixture was warmed to 23° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile in 0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (7.7 mg, 40%). The sodium salt of the title compound was prepared by adding 1 N sodium hydroxide (0.029 mL, 0.0029 mmol) to a solution of the title compound (7.7 mg, 0.014 mmol) in water (0.4 mL) and stirring for thirty minutes. The reaction mixture was concentrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (bs, 2 H) 0.46 (d, 2 H) 0.99 (m, 1 H) 1.19 (t, 3 H) 3.01 (q, 2 H) 4.23 (s, 2 H) 5.85 (t, J=6.62 Hz, 1 H) 6.79 (s, 1 H) 6.93 (t, J=7.54 Hz, 1 H) 7.35 (t, J=6.99 Hz, 2 H) 7.59 (d, J=8.09 Hz, 1 H) 7.95 (d, J=6.62 Hz, 1 H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC>>[CH3:16][O:15][N:14]([CH3:13])[C:9]([C:6]1[CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[O:8][N:7]=1)=[O:11]
Reactant: CNOC
Reactant: O=C(O)c1cc(C2CC2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CON(C)C(=O)c1cc(C2CC2)on1
Yield: 96 %

Procedure:
In a manner analogous to that described in Example 1 d), the condensation of 5-cyclopropyl-isoxazole-3-carboxylic acid and N,O-dimethylhydroxylamine hydrochloride by N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride yielded the title compound (96% yield) as a pale yellow oil. MS (ISP): m/z=197.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=4)[C:22]([OH:24])=[O:23])[N:14]([CH3:28])[C:13]=3[CH:29]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][OH:33]>C(O)C.O>[CH3:32][O:33][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=4)[C:22]([OH:24])=[O:23])[N:14]([CH3:28])[C:13]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cn1c(COc2cccc(C(=O)O)c2)nc2ccc(Oc3ccc(Cl)nc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ccc3nc(COc4cccc(C(=O)O)c4)n(C)c3c2)cn1
Yield: 79 %

Procedure:
A solution of 3-({6-[(6-chloropyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid produced in Example (18e) (0.40 g, 0.98 mmol) and sodium hydride (63%, 0.372 g, 9.76 mmol) in methanol (9.8 mL) was heated under reflux under microwave irradiation for two hours. After leaving to cool, water was added to the reaction mixture. This aqueous solution was washed with hexane five times and neutralized by adding 1 M hydrochloric acid. The precipitated solid was collected by filtration to obtain the crude title compound. A suspension of the crude title compound in ethanol (5 mL) and water (5 mL) was heated under reflux for two hours and left to cool. Then, the precipitated solid was collected by filtration to obtain the title compound (0.312 g, 79%) as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.[Cl-].[NH4+]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: c1cc(C2OCCO2)cs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1sccc1C1OCCO1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
5.00 g (32.0 mmol) of 3-(1,3-dioxolan-2-yl)thiophene was dissolved in 100 ml of THF. 24.5 ml (1.5 mol/l) of n-butyllithium was added dropwise thereinto. After stirring for 0.5 hour, the mixture was cooled to −70° C., 3.10 ml (40.0 mmol) of DMF was added, and then the mixture was transferred to an ice bath. After stirring for about 2 hours, an aqueous saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to silica gel (ethyl acetate:hexane=1:2), to give 3.68 g (20.0 mmol, 62.4%) of the title compound as a yellow oil.