Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[F:12][C:13]1[C:14]([CH2:46]O)=[C:15]([F:45])[C:16]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH:28]C(=O)C(C)(C)C)=[C:24]([F:35])[CH:23]=3)=[CH:19][C:18](=[O:36])[C:17]=2[C:37]=1[NH:38]C(=O)C(C)(C)C>>[NH2:38][C:37]1[C:17]2[C:18](=[O:36])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([F:35])[CH:23]=3)[O:21][C:16]=2[C:15]([F:45])=[C:14]([CH2:46][O:5][C:4](=[O:6])[CH2:3][CH2:2][Br:1])[C:13]=1[F:12]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: O=C(O)CCBr
Agent: O=S(=O)(O)O
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCBr)c(F)c3o2)cc1F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
7.65 g (50.0 mmol) of 3-bromopropionic acid and 1.5 mL of sulfuric acid were added to 504 mg (1.00 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in EXAMPLE 118 (4), and the mixture was stirred at 100° C. for 10 minutes. The reaction solution was poured into 100 mL of ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetonitrile=19:1), to give 163 mg of Compound 160 (yield: 35%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1
Reactant: Nc1ccc(CCO)cc1
Product: Cc1cc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c(C)n1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-chloro-2,6-dimethyl-3-nitropyridine (Tanaka, A.; et al. J. Med. Chem., 1999, 41, 4408.) and 4-aminophenylethyl alcohol.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: Cc1ccc(CO)cc1
Product: Cc1ccc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)cc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.180 mmol), intermediate 42.1, and 4-methylbenzyl alcohol (90 mg; 0.721 0 mmol), example 77 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([O:11]C)=O)[CH:7]=1.F[C:17]1[C:26]([N+:27]([O-])=O)=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2([CH3:13])[C:9](=[O:11])[NH:27][C:26]3[CH:25]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:19]([C:30]([F:33])([F:31])[F:32])=[CH:18][C:17]=3[O:14]2)[CH:7]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C(F)(F)F
Reactant: COC(=O)C(C)(O)c1cc(Br)ccc1F
Product: COC(=O)c1cc2c(cc1C(F)(F)F)OC(C)(c1cc(Br)ccc1F)C(=O)N2

Procedure:
Using methyl 2-(5-bromo-2-fluorophenyl)-2-hydroxypropanoate and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:30][CH:29]=1)[C:22](N(OC)C)=[O:23])[CH3:19]>>[CH2:18]([O:20][CH:21]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:32][CH:33]=1)[C:22]([C:15]1[O:14][C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1)=[O:23])[CH3:19]
Reactant: CCOC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(OC)c(OC)c2)o1)c1ccc(-c2nnc(C)o2)cc1

Procedure:
2-Ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone was prepared from 2-(3,4,5-trimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.060 g, 15% yield). MS: m/z 479.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]I)[CH:3]=1.[CH2:22]([NH:24][CH2:25][CH2:26][OH:27])[CH3:23].Cl>O1CCCC1.C(OCC)C.ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][OH:27])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Reactant: CCNCCO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(CCO)CCC[C@@H](Oc1cc(Cl)ccc1C#N)c1ccccc1
Yield: 65.4 %

Procedure:
A solution of the product from Example 1 step (c) (200 mg) and 2-(ethylamino)ethanol (163 mg, 0.14 ml) in tetrahydrofuran (5 ml) was stirred for 2 days. The solvent was removed in vacuo and the residue dissolved in water and aqueous potassium carbonate and extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (Na2SO4) and evaporated to give an oil. To a solution of this amine in diethyl ether-dichloromethane was added a 1M solution of hydrogen chloride in diethyl ether. The crystals that formed were collected and dried to afford the title compound as a white solid (65 mg). M.p. 141-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[C:21]([C:22]([C:24]4([CH3:32])[CH2:29][O:28]C(C)(C)[O:26][CH2:25]4)=[O:23])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl>O1CCCC1.CO>[OH:26][CH2:25][C:24]([CH2:29][OH:28])([CH3:32])[C:22]([C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:14]=2)[NH:19][CH:20]=1)=[O:23]
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)COC(C)(C)OC4)c3n2)cc(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(CO)CO)c3n2)cc(OC)c1OC
Reaction time: 1 h
Yield: 7.1 %

Procedure:
A suspension of [2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(2,2,5-trimethyl-[1,3]dioxan-5-yl)-methanone (30 mg, 0.7 mmol) in tetrahydrofuran (5 ml) and MeOH (4 ml) was heated using a heat gun until homogeneity was achieved. The reaction mixture was treated with 1M HCl (1.0 ml, 1.0 mmol) and stirred for 1 hour. The reaction mixture was concentrated to 3 ml of solvent and then partitioned between EtOAc/saturated aqueous NaHCO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated affording 20 mg (73%) of 3-hydroxy-2-hydroxymethyl-2-methyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a pale yellow solid. MP 222-223° C., M+H=402.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)#[CH:2].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)[CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1cccc(F)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 27.5 %

Procedure:
Add 1-ethynyl-3-fluorobenzene (250 mg, 2.11 mmol) to a mixture of 3,5-dibromopyridine (500 mg, 2.11 mmol) in triethylamine (4 mL) containing bis(triphenylphosphine)palladium (II) dichloride (28 mg, 0.04 mmol) and copper (I) iodide (15 mg, 0.08 mmol) and heat at 70° C. for 2 h. Cool to room temperature, dilute with ethyl acetate and an aqueous solution of ammonium chloride and separate the resulting layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 0.5% ethanol in 50:50 dichloromethane:hexanes to give the title compound (160 mg, 28%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH3:35])[CH:29]=[CH:28][C:27]([O:30]CC(O)=O)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:30][C:27]2[CH:28]=[CH:29][C:24]([CH3:35])=[CH:25][CH:26]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Cc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(OCC(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.2 g, 0.64 mmol) and 2-(p-tolyloxy)acetic acid (106 mg, 0.64 mmol) in dry DCM (20 mL), DIPEA (495 mg, 3.86 mmol) followed by HATU (486 mg, 1.27 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM and washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.21 g, 77.5%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1.C(Cl)([Cl:14])=O>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([Cl:14])=[O:11])=[C:6]([CH3:8])[N:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1nc(C)c(C(=O)O)s1
Solvent: Clc1ccccc1
Product: COc1nc(C)c(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 10.4 g (0.06 mole) of 2-methoxy-4-methylthiazole-5-carboxylic acid were suspended in 150 ml of chlorobenzene. Under heating and reflux, phosgene was blown at a rate of 400 ml/hr for 15 hours (0.27 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.9 g of 2-methoxy-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 95.0% and 90.0%, respectively. NMR (δCDCl 3/TMS, ppm): 2.70(3H,s), 3.85(3H,s).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)(=[O:20])=[O:19].[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3cccc(OC)c3)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Yield: 77.9 %

Procedure:
Reaction of benzoate 37 (213 mg, 0.53 mmol) and 2 M NaOH (10 mL) in dioxane (10 mL) gave acid 38 (160 mg, 78%) as a white solid: mp (H2O) 280-283° C.; 1H NMR δ 13.12 (br s, 1H, CO2H), 8.05 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.93 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.53 (dd, J=8.9, 7.7 Hz, 1H, H-5′), 7.35 (dt, J=7.7, 1.2 Hz, 1H, H-6′), 7.27-7.33 (m, 2H, H-2′, H-4′), 4.70 (s, 2H, CH2SO2), 3.79 (s, 3H, OCH3), 2.18 (s, 3H, CH3); MS m/z 388.5 (MH+, 100%). Anal. calcd for C19H17NO6S.¼H2O: C, 58.23; H, 4.50; N, 3.57. Found: C, 57.89; H, 4.37; N, 3.43%.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:14])[CH:8]=1)[CH3:3].[CH:16]1([C:21](=O)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>Cl>[ClH:1].[CH2:2]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:23]([NH2:24])=[CH:22][C:21]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:14]2)[CH:8]=1)[CH3:3]
Reactant: N#CCC(=O)C1CCCC1
Reactant: CCOC(=O)Cc1cccc(NN)c1
Agent: Cl
Product: CCOC(=O)Cc1cccc(-n2nc(C3CCCC3)cc2N)c1
Yield: 34 %

Procedure:
To a mixture of (3-aminophenyl)acetic acid ethyl ester (15 g, 84 mmol) in conc. HCl (20 mL) was added sodium nitrite (6 g, 87 mmol) aqueous solution dropwise under ice-salt bath. The resulting mixture was stirred at 0° C. for 30 min and then added a solution of SnCl2.2H2O (38 g, 168 mmol) in conc. HCl dropwise also at such a rate that the reaction mixture never rose above 5° C. After the addition was completed, the mixture was stirred for another 2 h at room temperature. The precipitate was collected by suction and washed with ethyl ether to afford (3-Hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 88%) as a brown solid. MS (ESI) m/z: 195 (M+H+). A solution of (3-hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 74 mmol) and 3-cyclopentyl-3-oxopropionitrile (12.2 g, 88.8 mol) in alcohol (150 mL) containing conc. HCl (10 mL) was heated to reflux overnight. After removed of the solvent, the precipitate was collected by suction and washed with ethyl ether to afford the crude product, which was purified by column chromatography to afford [3-(5-amino-3-cyclopentylpyrazol-1-yl)phenyl]acetic acid ethyl ester hydrochloride (8.8 g, 34% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.40-7.66 (m, 4H), 5.68 (s, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 3.00-3.08 (m, 1H), 1.98-2.00 (m, 2H), 1.58-1.70 (m, 6H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 314 (M+H+).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1CC[CH2:12][CH2:11][CH2:10]1.C#CC>[Cu]I.O>[C:10]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)#[C:11][CH3:12]
Reactant: C1CCNCC1
Reactant: Nc1ccc(I)cc1
Agent: [Cu]I
Agent: C#CC
Solvent: O
Product: CC#Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.47 g (25 mmol) of 4-iodoaniline, 0.878 g (1.25 mmol) of bis-triphenylphosphine palladium dichloride, 0.47 g (2.5 mmol) of copper (I) iodide, and 20 mL of piperidine are placed in a pressure apparatus. Then 6.1 bar gaseous propyne are piped into the pressure apparatus, while the temperature rises to 39° C. It is therefore cooled with water. The mixture is stirred for 2 hours at ambient temperature and the reaction mixture is then extracted with ethyl acetate and water. The organic phase is dried over sodium sulfate, evaporated down, and the residue purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (4:1)). Yield: 2.1 g (64% of theory); C9H9N (M=131.17); calc.: molecular ion peak (M+H)+: 132; found: molecular ion peak (M+H)+: 132.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][B-](F)(F)F.F[B-](F)(F)F.F[N+]12CC[N+](O)(CC1)CC2>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][C:16]([F:26])=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: F[B-](F)(F)F
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(Br)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(Br)cc3)c(F)[nH]2)N(C(=O)OC(C)(C)C)C1
Yield: 34.5 %

Procedure:
A solution of (2S,4S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.23 mmol) and 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (436 mg, 1.36 mmol) in DMF (20 mL) was stirred at RT for 1 h, concentrated by rotary evaporation, and purified by silica gel chromatography (0-100% EtOAc/hexanes with 1% Et3N). Desired fractions were collected and concentrated to provide the title intermediate (180 mg, 35% yield). (m/z): [M+H]+ calcd for C19H24BrFN3O2 424.10, 426.09 found 424.1.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3]([F:5])=[O:4].[Cl-:7].[Ca+2].[Cl-]>>[F:1][CH:2]([F:6])[C:3]([Cl:7])=[O:4].[F:1][CH:2]([F:6])[C:3]([F:5])=[O:4]
Reactant: [Cl-]
Agent: O=C(F)C(F)F
Agent: [Ca+2]
Product: O=C(Cl)C(F)F
Temperature: 160 °C

Procedure:
A stainless steel reaction tube having an inner diameter of 23 mm and a length of 400 mm was packed with granular anhydrous calcium chloride (63 g, 120 cc; available from Junsei Chemical Co., Ltd. (particle size: about 2.5 to 3.5 mm)). While flowing nitrogen at 50 cc/min into the reaction tube, the reaction tube was heated at a setting temperature of 160° C. The flow of the nitrogen was stopped simultaneously with feeding the difluoroacetyl fluoride, which had been obtained in Raw Material Preparation Example 1, into the reaction tube at a rate of 0.3 g/min (retention time: 66 seconds). It was observed that a heat spot of 10 to 20° C. was generated in the vicinity of the inlet of the reaction tube and shifted toward the outlet of the reaction tube with the passage of time. The outlet gas was sampled and analyzed over time by the gas chromatograph. It was confirmed by the experimental results that difluoroacetyl chloride (DFAC) and difluoroacetyl fluoride (DFAF) were contained in the gas sample. The experimental results are graphed in FIG. 1.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 117.5 mg (43%) of the desired product as a creme solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:24]=[CH:23][C:5]3[N:6]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:8][C:4]=3[CH:3]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: COc1ccc(-n2c(-c3ccccc3)nc3cc(N)ccc32)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COc1ccc(-n2c(-c3ccccc3)nc3cc(NS(=O)(=O)c4ccc(Cl)cc4)ccc32)cc1

Procedure:
5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazole was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C1(C)C=CC=CC=1.[CH2:15]=[CH:16][C:17]([Cl:19])=[CH2:18]>C1(C)C(C)=CC=CC=1>[Cl:19][CH:17]1[CH:16]=[CH:15][CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:18]1)=[O:7]
Reactant: C=CC(=C)Cl
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)C2CC(Cl)C=CC12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
156.9 g (1.6 mole) of maleic anhydride and 250 ml toluene were added to a flask. 25 ml of toluene was removed by distillation to dry the solution. 150 g (1.69 mole) of chloroprene dissolved in 250 ml of xylene was slowly added to the flask. The entire addition took 30 minutes. The resulting solution was then heated at 55° C. for three hours. The solution was then distilled to remove solvents. The remaining material was distilled at 160-165° C. (1 to 2 mm pressure) to afford 4-chlorotetrahydrophthalic anhydride in 85% yield (253 grams).
Reaction SMILES: [CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][OH:4].[Li+].[Br-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[CH3:24][O:25][CH2:26]OC>>[CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][O:4][CH2:24][O:25][CH3:26]
Reactant: COCOC
Reactant: CC(C)(CO)[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Product: COCOCC(C)(C)[N+](=O)[O-]
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of 2-methyl-2-nitro-1-propanol (366.8 mg, 3.08 mmol) and LiBr (60.8 mg, 0.700 mmol) in dimethoxymethane (5 ml) was added p-toluenesulfonic acid hydrate (56.3 mg, 0.296 mmol) and stirred for 24 hours. The mixture was added to water and extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=4/1) to give the title compound (382.7 mg; 76%).
Reaction SMILES: C=C.[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[C:4](C)=[CH2:5].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>>[CH2:3]=[CH2:4].[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[CH:4]=[CH2:5].[C:14]1(=[O:15])[O:16][C:11](=[O:17])[CH:12]=[CH:13]1
Reactant: C=C(C)C(=O)OCC
Agent: C=C
Agent: O=C1C=CC(=O)O1
Product: C=CC(=O)OCC

Procedure:
(MFR=7.4 g/10 min, ethylene content=90.2% by weight, ethyl methacrylate content=6.2% by weight and maleic anhydride content=3.6% by weight)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)no1

Procedure:
The title compound was prepared from 1-bromo-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzene [EP 0533268A1] (0.58 g) and 4-boronobenzoic acid (0.4 g) as described in Description 11 as a white solid (0.64 g, 97%).