Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH:36]([CH3:38])[CH3:37])[CH:35]=4)[CH2:28][CH2:27][C:26]([C:39](O)=[O:40])=[CH:25][C:24]=3[CH:42]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:47][N:48]([CH2:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=1)[CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>ClCCl.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH:36]([CH3:37])[CH3:38])[CH:35]=4)[CH2:28][CH2:27][C:26]([C:39]([NH:60][C:59]4[CH:58]=[CH:57][C:56]([CH2:55][N:48]([CH3:47])[CH:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)=[CH:62][CH:61]=4)=[O:40])=[CH:25][C:24]=3[CH:42]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(C(C)C)c2)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cnn(C(C)C)c2)cc1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (150 mg) in dichloromethane (10 ml). Then, thionyl chloride (49 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this solution was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (90 mg) and triethylamine (830 mg) in dichloromethane (20 ml) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3), which was recrystallized to give 7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 82) (119 mg) as yellow crystals.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:7][C:6]2[CH:8]=[C:9]([F:20])[CH:10]=[C:11]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:5]=2[O:4]1.[CH3:21][NH:22][CH3:23]>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:11]1[C:5]2[O:4][C@@H:3]([CH2:2][N:22]([CH3:23])[CH3:21])[CH2:7][C:6]=2[CH:8]=[C:9]([F:20])[CH:10]=1
Reactant: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)O[C@@H](CBr)C2
Reactant: CNC
Product: CN(C)C[C@H]1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Yield: 80 %

Procedure:
Treatment of (R)-2-bromomethyl-7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran (0.41 g, 1.1 mmol) and N,N-dimethylamine (2.0 M in tetrahydrofuran, 5.4 ml) generally according to the procedure described for Example 390 afforded 0.29 g (80%) of (R)-[7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl]-dimethyl-amine as a white solid, hydrochloride salt. mp 156-158° C.; [α]D25=−21.04 (c 7.71 in methanol); Anal. calcd. for C17H16Cl2FNOHCl: C, 54.21; H, 4.55; N, 3.72. Found: C, 53.98; H, 4.62; N, 3.56.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[CH2:16][CH3:17].C(N(CC)CC)C>C(#N)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH:18][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-Nitrophenyl)methanesulfonyl chloride (0.6 g, 2.55 mmol) was dissolved in acetonitrile (10 mL), then to this solution was added propylamine (0.247 ml, 3 mmol) and triethylamine (1 mL) and the reaction mixture was vigorously stirred for 3 h at room temperature. The obtained mixture was diluted with cold water (30 ml), which led to the formation of a precipitate that was filtered off, washed with water (2×10 mL) and dried. Yield of (3-nitrophenyl)-N-propylmethanesulfonamide 0.63 g (95%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][C:3]([C:5]3[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(C)OC(=O)COc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: CC(C)OC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
iso-Propyl 4-bromoacetylphenoxyacetate (6.3 g) was added to a stirred, cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., then overnight at ambient temperature when the precipitated solid was removed. The liltrate was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica, eluting firstly with 0 to 10% v/v methanol/dichloromethane and then toluene/ethyl acetate/.880 ammonium hydroxide/ethanol (60:20:10:35 v/v/v/v), gave a cream solid. Recrystallisation from iso-propanol gave the title compound, 2.1 g: m.p. 121°-122° C.; NMR (d6DMSO) δ8.14 (2H, d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.99 (1H, m), 4.85 (2H, s), 3.84 (2H, s), 3.33 (4H, t), 2.62 (4H, t), 1.22 (6H, d); m/e 398 (M+H)+ ; calculated for C22H27N304: C, 66.5; H, 6.9; N, 10.6. found: C, 65.8; H, 6.8; N, 10.4%.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:3]=1.[Na+].[Cl-].[OH-].[NH4+:18]>[OH-].[Na+].O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=1
Reactant: COc1ccccc1-c1nsc(S)n1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1-c1nsc(SN)n1
Reaction time: 0.17 h

Procedure:
A solution of 4.6 g of 5-mercapto-3-(2-methoxyphenyl)-1,2,4-thiadiazole in 70 ml of 5% sodium hydroxide and a solution prepared by diluting 44 ml of 5.25% NaCl to 70 ml with water were added dropwise simultaneously to 190 ml of ammonium hydroxide solution while maintaining the mixture at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 minutes and the solids were collected, washed with water and dried under high vacuum (with P2O5) to give 3.0 g of solid, m.p. 136°-138° C. dec.
Reaction SMILES: [N:1]1([C:10](OC(C)(C)C)=O)CCC[CH:3]2[CH2:7][NH:8][CH2:9][CH:2]12.CC1C=CC(S(O[C:28]2[C:29]3[CH2:38][CH2:37][CH2:36][C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[C:30]=3[N:31]=[CH:32][N:33]=2)(=O)=O)=CC=1.CC1C=CC(S(OC2C3CCCC4C=CC=CC=4C=3N=C(N)N=2)(=O)=O)=CC=1>>[CH3:10][NH:1][C@@H:2]1[CH2:3][CH2:7][N:8]([C:28]2[C:29]3[CH2:38][CH2:37][CH2:36][C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Reactant: Cc1ccc(S(=O)(=O)Oc2ncnc3c2CCCc2ccccc2-3)cc1
Agent: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Product: CN[C@@H]1CCN(c2ncnc3c2CCCc2ccccc2-3)C1

Procedure:
The title compound was prepared using the procedure outlined in Example 59D substituting Example 1E for t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate, and substituting the product from Example 118C for the product from Example 59C, followed by the procedure outlined in Example 59E. 1H NMR (CD3OD) δ 1.84-1.98 (m, 1H), 2.17-2.27 (m, 1H), 2.28-2.36 (m, 2H), 2.41-2.50 (m, 5H), 2.66 (t, 2H), 3.33-3.40 (m, 1H), 3.52-3.61 (m, 1H), 3.72-3.80 (m, 1H), 3.83-3.93 (m, 2H), 7.27-7.33 (m, 1H), 7.37-7.43 (m, 2H), 7.65-7.71 (m, 1H), 8.40-8.44 (m, 1H). MS (M+H)+ m/z 295.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].CC([O-])(C)C.[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+]>[CH2:13]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](O)[C@@H](C)O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of 4.0 g (44.4 mmol) of (2R,3R)-butane-2,3-diol in 300 ml of THF was admixed at room temperature with 5.0 g (44.6 mmol) of potassium tert-butylate and the mixture was refluxed for 15 minutes. The mixture was cooled to ca. 50° C. and admixed with 5.3 ml (44.6 mmol) of benzyl bromide. The mixture was refluxed for 3 hours, then stirred overnight at room temperature. The mixture was diluted with ethyl acetate and sodium chloride solution and then washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×). The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 1:1). This gave 3.4 g (18.9 mmol; yield: 43%) of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH:33]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[C:15]([CH3:17])([CH3:16])[S:14][CH2:13][N:12]1[C:18](=[O:32])[C@@H:19]([OH:31])[C@@H:20]([NH2:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:10].C([O:38][C:39]1[C:40]([CH3:48])=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](O)=[O:43])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH:33]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[C:15]([CH3:17])([CH3:16])[S:14][CH2:13][N:12]1[C:18](=[O:32])[C@@H:19]([OH:31])[C@@H:20]([NH:30][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[C:39]([OH:38])[C:40]=1[CH3:48])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[O:10]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2cc(F)ccc2C)cc1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Product: COc1ccc(C[C@H](NC(=O)c2cccc(O)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2cc(F)ccc2C)cc1
Yield: 73.4 %

Procedure:
The reaction was carried out in the same manner as in Step 3 of Example 1 using the compound obtained in Step 2 (150 mg) and 3-acetoxy-2-methylbenzoic acid (53 mg). The resulting crude product was purified by silica gel column chromatography (CH2Cl2—MeOH) and reprecipitated from n-hexane to obtain the target compound (125 mg, 81%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-benzyloxybenzaldehyde 1.79 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.63 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1.[F:21][C:22]([F:33])([F:32])[CH:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[N:13]([C:29]([N:26]3[CH2:25][CH2:24][CH:23]([C:22]([F:32])([F:21])[F:33])[CH2:28][CH2:27]3)=[O:30])[N:12]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Reactant: CC1CCN(C(=O)Oc2n[nH]c3cc(N)ccc23)CC1
Product: CC1CCN(C(=O)Oc2nn(C(=O)N3CCC(C(F)(F)F)CC3)c3cc(N)ccc23)CC1

Procedure:
In analogy to example 12, 35.66 mg (0.13 mmol) of 6-amino-1H-indazol-3-yl 4-methylpiperidine-1-carboxylate were reacted with 33.63 mg (0.16 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 10 mg (17%), M+H+: 454.13.
Reaction SMILES: [F:1][C@H:2]1[C@H:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]1=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:16]([NH:23][CH:3]1[CH2:4][CH:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:2]1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C[C@@H](COCc2ccccc2)[C@@H]1F
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Reaction time: 0.08 h

Procedure:
In a 25 mL flask with trans-2-fluoro-3-(benzyloxymethyl)cyclobutanone (0.20 g, 0.96 mmol) inside, dry 1,2-DCE 3.4 mL was added under argon to give a colorless solution. To this, benzylamine (0.11 mL, 1.01 mmol) was added to give still a colorless solution. After stirring for 5 min, sodium triacetoxyborohydride (0.29 g, 1.37 mmol) was added all at once to give a white emulsion. Then AcOH (0.06 mL, 1.05 mmol) was added drop by drop. After 5 min, it gave a yellow solution and this was left stirring for 2 hr and then the reaction was quenched by sat. NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc twice. The combined organic phase was dried over MgSO4 and the crude product was purified by silica gel flash chromatography (Hexane:EtOAc=3:1) to give 0.19 g (65%, Rf=0.18) of the product. 1H NMR (CDCl3, 600 MHz): δ 1.81-1.95 (m, 3H), 2.80-2.89 (m, 1H), 3.46-3.56 (m, 3H), 3.76-3.84 (m, 3H), 4.51-4.55 (m, 2H), 4.89-5.00 (td, 1H, J=54.6, 4.8), 7.25-7.37 (m, 10H).
Reaction SMILES: Cl.[Cl:2][C:3]1([CH:15]([Cl:17])[Cl:16])[O:7]C(C(F)(F)F)=[N:5][C:4]1([CH2:13][CH3:14])[CH3:12].O.Cl>CO>[ClH:2].[NH2:5][C:4]([CH3:12])([CH2:13][CH3:14])[C:3](=[O:7])[CH:15]([Cl:17])[Cl:16]
Reactant: CCC1(C)N=C(C(F)(F)F)OC1(Cl)C(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: CCC(C)(N)C(=O)C(Cl)Cl
Reaction time: 8 h

Procedure:
The 5-chloro-5-(dichloromethyl)-4-ethyl-4-methyl-2-trifluoromethyloxazoline hydrochloride prepared in the preceding step was dissolved in 1800 mL of methanol, 72 mL of water, and 190 mL of concentrated hydrochloric acid, warmed to 50° C., and stirred at that temperature overnight. The crude reaction mixture was cooled and poured into an ice/water/ethyl ether mixture. The phases were separated and the ether layer was extracted once with water. The ether was saved (organic I). The combined aqueous layers were washed once with ethyl ether, and the organic layer was combined with organic I (organic II). The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted twice with ethyl ether. The combined ether layers were washed with water, brine, dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered through Celite™. To the resulting colorless solution was bubbled in anhydrous hydrogen chloride keeping the temperature below 20° C. The resulting white solid was filtered and dried yielding 124.8 g of the expected 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride as a white solid. The ethyl ether filtrate was combined with organic II and concentrated in vacuo; the resulting residue (150 g) was taken in a mixture of methanol/water/concentrated hydrochloric acid and heated at 50° C. over the weekend. The previously described workup yielded another 51 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride. The total amount obtained was 175.8 g (61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[C:16]([S:28][CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=[O:40])CCC1=O>ClCCCl.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:23])([F:25])[F:24])=[O:19])=[C:16]([S:28]([CH3:29])=[O:40])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: CS(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 43.4 %

Procedure:
In a solution of 0.38 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylthio-N-(2,2,2-trifluoroethyl)benzoic acid amide (Compound of the present invention No. 5-322) synthesized similarly to Synthetic Example 13 in 6 ml of 1,2-dichloroethane, 0.10 g of N-chlorosuccinic acid imide was added with stirring at room temperature, and stirred at the same temperature for 11 hours. After the completion of the reaction, the reaction mixture was poured in 30 ml of water, and extracted with ethyl acetate (20 ml×3). The organic phase was washed with 30 ml of saturated sodium hydrogen carbonate, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2), and 0.17 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:13]1[O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2](=[O:1])[CH2:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12]1
Reactant: O=C(O)c1cnc2cc3c(cc2c1O)OCO3
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1CC=Nc2cc3c(cc21)OCO3
Reaction time: 1.5 h

Procedure:
A suspension of 4-hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid (30 g, 0.129 mol) in diphenyl ether (320 mL) was heated to reflux with vigorous stirring. The reaction was carefully monitored until it became clear, about 1.5 h, and then immediately removed from heat. By this time all of the starting material had dissolved but a black tarry residue remained. The solution was decanted and cooled, allowing the product to precipitate. This material was filtered and washed with ethyl ether to remove all traces of phenyl ether. A second crop was obtained by vigorously washing the tarry residue with ethanol (16×250 mL), filtering and evaporating the ethanol, and rinsing the material with ethyl ether. The total yield was 14.9 g as a pale yellow solid, in 61%; mp 285-289° C. (lit.221 mp 276° C.); 1H NMR (DMSO-d6) δ 5.95 (d, 1H, J=7.3), 6.13 (s, 2H), 6.97 (s, 1H), 7.38 (s, 1H), 7.77 (d, 1H, J=7.3); 13C NMR (DMSO-d6) δ 97.5, 102.1, 102.6, 108.7, 119.4, 122.0, 130.8, 138.7, 145.8, 151.7.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[CH3:23][CH:24]1[CH2:29][CH2:28][C:27]2[S:30][C:31]([NH2:33])=[N:32][C:26]=2[NH:25]1>>[CH3:12][O:11][C@H:9]1[CH2:10][N:6]([CH2:5][C:4](=[O:22])[NH:33][C:31]2[S:30][C:27]3[CH2:28][CH2:29][CH:24]([CH3:23])[NH:25][C:26]=3[N:32]=2)[CH2:7][C@@H:8]1[NH:13][C:14]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:15]
Reactant: CC1CCc2sc(N)nc2N1
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(C)N3)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 25.3 {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylamine (CAS 17899-48-8) to give 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-4-methoxy-1-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-pyrrolidin-3-yl}-amide as yellow solid. MS 470.5 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:14]Cl>>[Cl:14][NH:11][C:9](=[O:10])[C:8]1[C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=[N:6][CH:7]=1
Reactant: NC(=O)c1cnccc1C(F)(F)F
Reactant: ClCl
Product: O=C(NCl)c1cnccc1C(F)(F)F

Procedure:
in which A is a non-oxidizable organic or inorganic anion can be prepared by chlorinating 4-trifluoromethylnicotinamide with Cl2 in aqueous acid and, if desired, subsequent anion exchange and/or, if desired, reaction with a base to give N-chloro-4-trifluoromethylnicotinamide.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl.[OH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][CH2:19][C@H:14]([OH:13])[CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: O[C@H]1CCCNC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1
Temperature: 175 °C
Yield: 37.5 %

Procedure:
A mixture of Intermediate 24b (394 mg, 2.30 mmol), (S)-3-hydroxypiperidine hydrochloride (1.00 g, 7.27 mmol) and DIPEA (1.27 mL, 7.30 mmol) in DMA (8 mL) was heated in the microwave at 170-180° C. for 9.5 h. The cooled mixture was concentrated in vacuo and applied to an SCX-2 cartridge (70 g), washing with methanol then eluting basic components with 0.4-2 M ammonia in methanol. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the title compound as a pale brown solid (204 mg, 38%). LCMS (Method 3): Rt 2.02 min, m/z 237 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.[CH2:19](O)[C:20]#[C:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:19][C:20]#[C:21][CH3:22])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: CC#CCO
Reactant: CCCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC#CCOc1cc(-n2nnn(CCC)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 20.7 %

Procedure:
To a stirred solution of 0.5 g (0.0017 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (Example 10, Step A) and 0.15 g (0.0021 mole) of 2-butyn-1-ol in 5 mL of acetonitrile was added 0.33 g (0.0016 mole) of dicyclohexylcarbodiimide. The reaction mixture was heated at reflux temperature for 4 days, cooled to room temperature, and filtered. The filtrate was washed with 10 mL of a 10% aqueous sodium hydroxide solution, diluted with methylene chloride, and washed with 10 mL of 6N hydrochloric acid. The washed organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to leave an oil. The oil was purified by column chromatography on silica gel, eluting with ethyl acetate: heptane (20:80), to yield 0.12 g of 1-[2,4-dichloro-5-(2-butynyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 58°-60° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: Cc1coc2cccc(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2occ(C)c12

Procedure:
A solution of 3-methyl-4-hydroxybenzofuran (5.0 gm, 34.7 mmoles), acetic anhydride (50 mL) and triethylamine (25 mL) in tetrahydrofuran (150 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel. Elution with 15% ethylacetate in hexane yielded 3-methyl-4-acetoxybenzofuran.