Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)C(N)=O
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Sc1cccc(Br)c1)C(N)=O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 98.4 %

Procedure:
To a mixture of 5.0 g 3-bromobenzenethiol and 5.96 g potassium carbonate in 50 ml DMF were added 3.86 g 2-bromopropionamide at RT. The mixture was warmed up and stirred at 70° C. for 3.5 hrs. After cooling, 200 ml water were added and the mixture extracted 3 times with dichloromethane. Drying and evaporation of the organic phases yielded 6.5 g of the title product which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:11]([C:10]1[C:9]2[CH:14]=[CH:15][C:16]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]3)=[CH:17][C:8]=2[O:7][C:6]=1[C:4]([OH:5])=[O:3])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)ccc2c1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 150.4 %

Procedure:
The above prepared 3-isopropyl-6-(1-isopropyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (0.720 g, 1.54 mmol, corrected for purity) was dissolved in 4 mL of THF/ethanol=1/1 and treated with 0.771 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 3 h at ambient temperature and was then neutralized by adding 1.16 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents and drying afforded then 0.800 g of the title compound as light yellow foam contaminated with innocouos inorganic salts.
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[CH:11]=[CH:10][N:9]=1)C1C=CC=CC=1.C([O-])(=O)C.[NH4+:26].[OH-].[Na+]>O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][N:9]=[C:8]2[NH2:26])=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1ccc2ccnc(Oc3ccccc3)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nccc2ccc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
A mixture of 1-phenoxy-7-(trifluoromethyl)isoquinoline (670 mg, 2.3 mmol), from above step D, and ammonium acetate (1.8 g, 23 mmol) was heated at 160° C. for 4 h. The mixture was cooled to room temperature and dissolved in water. Sodium hydroxide (1N solution) was added until the solution was basic and extracted with EtOAc (×4). The combined organic fractions were washed with saturated NaCl, dried over Na2SO4 and evaporated under vacuum to give the title compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=O.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:46]=[CH:45][C:19]([CH2:20][N:21]2[C@@H:29]3[C@@H:25]([CH2:26][CH2:27][CH2:28]3)[C:24]([OH:30])=[C:23]([C:31]3[NH:36][C:35]4[CH:37]=[CH:38][C:39](I)=[CH:40][C:34]=4[S:33](=[O:43])(=[O:42])[N:32]=3)[C:22]2=[O:44])=[CH:18][CH:17]=1.N1CCCCC1>[Cu](I)I>[O:42]=[S:33]1(=[O:43])[C:34]2[CH:40]=[C:39]([N:1]3[CH2:8][CH2:7][CH2:6][CH2:2][CH2:3]3)[CH:38]=[CH:37][C:35]=2[NH:36][C:31]([C:23]2[C:22](=[O:44])[N:21]([CH2:20][C:19]3[CH:45]=[CH:46][C:16]([F:15])=[CH:17][CH:18]=3)[C@@H:29]3[C@H:25]([C:24]=2[OH:30])[CH2:26][CH2:27][CH2:28]3)=[N:32]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNCC1
Product: O=C1C(C2=NS(=O)(=O)c3cc(N4CCCCC4)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 60 h
Yield: 147.6 %

Procedure:
A reaction flask was charged with L-proline (24.3 mg, 0.21 mmol), potassium carbonate (146.3 mg, 1.06 mmol), copper iodide (21 mg, 0.11 mmol) and (4aR,7aS)-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 39c, 300 mg, 0.53 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous dimethylsulfoxide (5 mL) was added followed by addition of piperidine (0.16 mL, 1.60 mmol). The resulting suspension was vigorously stirred at 90° C. for 60 h, and then allowed to cool to 25° C. The mixture was passed through a plug of Celite and rinsed with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 40%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-3-(1,1-dioxo-7-piperidin-1-yl-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (160 mg, 0.31 mmol, 58%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.63 (9H, m), 1.96 (2H, m), 2.06 (1H, m), 3.23 (4H, m), 3.32 (1H, m), 3.83 (1H, m), 4.45 (1H, d, J=15.6 Hz), 4.89 (1H, d, J=14.8 Hz), 7.14 (3H, m), 7.32-7.44 (4H, m), 13.86 (1H, s). LC-MS (ESI) calcd for C27H29FN4O4S 524.19, found 525.3 [M+H+]. e.e. >97% based on the e.e. of the commercially available (1R,2S)-2-amino-cyclopentanecarboxylic acid (Example 40a).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]([C:18]3[CH:19]=[N:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[NH:3][C:4](=[O:12])[C:5]=2[CH:10]=[CH:9]1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)nc3)nc21
Temperature: 150 °C
Yield: 6.8 %

Procedure:
A high pressure microwave reaction vial was charged with 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate A) (55 mg, 0.3 mmol), 6-(trifluoromethyl)pyridin-3-ylboronic acid (68.6 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (21.9 mg, 0.03 mmol), a 2M aqueous sodium carbonate solution (0.45 mL, 0.9 mmol), and ethanol (2 mL). The vessel was sealed, degassed and flushed with nitrogen three times. The reaction was then heated at 150° C. for 10 min in a Biotage microwave reactor. At this time, the resulting black mixture was concentrated in vacuo. The residue was treated with ethyl acetate (20 mL), stirred and filtered. The filtrate was concentrated in vacuo. Reverse phase chromatography (10-100% acetonitrile/water) and lyophilization afforded 7-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (6 mg, 6.81%) as a white solid. LC-MS calcd. for C13H10F3N4O [(M+H)+] 295, obsd. 294.8.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:18][C:19]([O-:21])=[O:20].[Na+].Cl>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C([O-])CCl
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
16.50 g of sodium hydride with 64% purity and 350 ml of dry dimethyl sulfoxide were supplied to a well dried 1-litre 4-necked flask. Then 101.30 g of ethyl 3,4-dichlorophenylacetate obtained in Example 6 was added dropwise, the solution being stirred at room temperature even after the end of the dropwise addition. Thereafter, 48.61 g of sodium chloroacetate was added and the solution was further stirred at room temperature. At this point, the reaction solution changed from a yellow to a red suspension. The reaction solution was stirred overnight at room temperature, then poured into a mixture of 500 ml of 1N hydrochloric acid and 300 ml of ice water, and stirred vigorously. The reaction mixture was extracted with 800 ml of ether and the organic layer was washed with 500 ml of water (three times) and 500 ml of a saturated saline solution (once). This organic layer was then dried over approximately 50 g of anhydrous sodium sulfate, concentrated to approximately 50 ml solvent and crystallized by treating it with approximately 300 ml of an ether/hexane mixed solvent. The precipitated crystals were filtered out and dried to give 106.07 g of primary crystals of the title substance. Meanwhile, the filtrate was concentrated to produce an oily substance, and it was crystallized by adding 20 ml of ether and 60 ml of hexane. Further, after additional supply of hexane, the precipitated crystals were filtered out and dried to obtain 3.09 g of the secondary crystals (109.16 g when combined with the primary crystals, yield 84.0%) of the title substance.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and t-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][Br:15]
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Br)c(CBr)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (4.7 g, 18 mmol) in methylene chloride (50 mL) at −10° C. was added carbon tetrabromide (CBr4) (7.17 g, 21.6 mmol). The resulting mixture was stirred at −10° C. for 15 minutes. Triphenylphosphine (5.61 g, 21.4 mmol) was then slowly added portion-wise. This mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated ammonium chloride (NH4Cl) (50 ml) and methylene chloride (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate) to yield the title compound as a white solid (4.01 g), 1H NMR (400 MHz, CDCl3) δ4.6 (s, 2 H) 7.5 (dd, J=8.3, 1.6 Hz, 1 H) 7.8 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][OH:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][NH:28][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Yield: 71.2 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (87 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-(2-aminoethoxy)-ethanol (30 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 480.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.48 (bs, 1H), 8.48 (t, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 3.68 (s, 3H), 3.57 (t, 2H), 3.52 (t, 2H), 3.49-3.41 (m, 4H), —OH proton signal was not observed.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.NN>C(O)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 105.9 %

Procedure:
N-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}phthalimide (4 g, 9.92 mmol) prepared in Reference Example 153 was suspended in ethanol (30 ml), to which hydrazine monohydrate (0.53 ml, 10.91 mmol) was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was allowed to return to room temperature, and the resulting precipitates were collected by filtration. This was purified by silica gel column chromatography (methylene chloride/ethyl acetate=100/1) to afford 2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethylamine (2.87 g, yield 100%) as a colorless crystalline powder.
Reaction SMILES: Cl[S:2]([C:5]1[N:14]=[C:8]2[N:9]=[C:10]([CH3:13])[CH:11]=[CH:12][N:7]2[N:6]=1)(=[O:4])=[O:3].C[Si](C)(C)[NH:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].CS(C)=O.Cl>CC#N>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[NH:17][S:2]([C:5]1[N:14]=[C:8]2[N:9]=[C:10]([CH3:13])[CH:11]=[CH:12][N:7]2[N:6]=1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)Nc1c(F)cccc1F
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A solution consisting of 91.4 mg of about 77 percent pure 2-chlorosulfonyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (0.30 mmole), 0.5 ml of CH3CN, 0.5 ml of N-trimethylsilyl-2,6-difluoroaniline, and 10 μl (0.141 mmole) of dimethyl sulfoxide was stirred at room temperature for 4 hours. The solution was treated with 2 ml of 1.0N HCl and the resultant mixture filtered. The precipitate was dried in vacuo, washed with CH2Cl2 and again dried to afford 68.7 mg (0.211 mmole, 70.0 percent yield) of N-(2,6-difluorophenyl)-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide product as a white powder, m.p. 250°-251° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9]>O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: CNC
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCl
Yield: 99 %

Procedure:
A solution of 50.0 g (1.11 mole) of dimethylamine in 100 ml of tetrahydrofuran was added dropwise to a solution of 28.2 (0.20 mole) of 4-chlorobutyryl chloride in 50 ml of tetrahydrofuran. The reaction mixture was stirred mechanically while the temperature was maintained between 5° C. and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate concentrated under reduced pressure to yield 29.6 g (99%) of a yellow liquid. An analytical sample was prepared by filtering the liquid through a small bed of silica gel and eluting with ethyl acetate-hexane (1:1). The fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a light-yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]1[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=1.S(Cl)([Cl:23])(=O)=O>>[Cl:23][C:14]1[C:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[N:11][N:12]([CH3:19])[C:13]=1[O:15][CH:16]([F:17])[F:18]
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl

Procedure:
Analogously to Example 8, 35 g (114 mmol) of 3-(2,4-dichloro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were reacted with 16.9 g (125 mmol) of sulfuryl chloride. Yield: 30.8 g; 1H-NMR (270 MHz, in CDCl3): δ [ppm]=7.49 (s,1H), 7.30 (s,1H), 6.74 (t,1H), 3.85 (s,3H), 2.39 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.[F:18][C:19]([F:23])([F:22])[S:20]Cl>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([S:20][C:19]([F:23])([F:22])[F:18])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Clc1cn2ccnc2cn1
Reactant: FC(F)(F)SCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)Sc1cnc2cnc(Cl)cn12

Procedure:
A solution of 6-chloroimidazo[1,2-a]pyrazine (3.07 g, 0.020 mol) in acetonitrile (50 ml) containing 1.01 g (0.010 mol) of triethylamine is treated with a stream of trifluoromethanesulfenyl chloride gas at 25° C. under nitrogen. After 1 hour the solution is flushed with nitrogen, concentrated under vacuum, and the residue partitioned between water-chloroform. The chloroform extract is dried over sodium sulfate, filtered and concentrated under vacuum to give crude 6-chloro-3-trifluoromethylthioimidazo[1,2-a]pyrazine which is purified by fractional sublimation.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH:38]([CH3:42])[C:37]1=[O:43]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[C:37](=[O:43])[CH:38]4[CH3:42])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC1NCCN(C)C1=O
Product: CC1C(=O)N(C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3-dimethyl-piperazin-2-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,3-Dimethyl-piperazin-2-one following General Procedure B.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:10][NH2:11])[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>O.O1CCCC1>[CH2:18]([NH:20][C:21](=[O:22])[N:10]([CH2:7][CH2:8][CH3:9])[NH2:11])[CH3:19]
Reactant: CCCNN
Reactant: CCN=C=O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(N)C(=O)NCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred slurry of 3.35 g (20 mmol) of n-propylhydrazine oxalate and 2.24 g (20 mmol) of sodium carbonate in 50 mL of water and 10 mL of tetrahydrofuran (THF) was added 1.7 mL (21.5 mmol) of ethyl isocyanate. The mixture was stirred at room temperature for 16 h and evaporated in vacuo to leave crude 4-ethyl-2-propyl semicarbazide as a white solid.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].C([Sn](CCCC)(CCCC)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)CCC>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:25][C:11]2[C:12]3[C:13]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:31][CH:30]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(-c3nnn(C)n3)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Product: Cn1nnc(-c2cc(-c3ccccc3)c3c(Sc4ccc(Cl)cc4)c4n(c3c2)CCC4CC(=O)O)n1

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate and tributyl(phenyl)stannane, the title compound was synthesized by following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:40]=[CH:39][NH:38][N:37]=2)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:38]4[CH:39]=[CH:40][C:36]([C:33]5[CH:32]=[CH:31][C:30]([Br:29])=[CH:35][CH:34]=5)=[N:37]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4ccc(-c5ccc(Br)cc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(4-bromo-phenyl)-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)ccc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-4-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-4-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16](=N)N)[CH:9]=1)[CH3:6].ClC[CH2:21][CH2:22][C:23]#[N:24].[OH-].[Na+]>O.C(O)C>[CH3:6][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:21][CH2:22][C:23]#[N:24])[CH:9]=1)[CH3:4]
Reactant: N#CCCCCl
Reactant: CN(C)Cc1ccnc(CSC(=N)N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCCC#N)c1
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a solution of S-(4-dimethylaminomethyl-2-pyridylmethyl)isothiourea trihydrochloride (11.88 g) and 4-chlorobutyronitrile (5.21 g) in water (50 ml) and ethanol (35 ml) at 0° C. (ice-salt bath) under nitrogen, was added dropwise over 20 minutes a solution of sodium hydroxide (6.4 g) in water (65 ml), keeping the temperature below 5° C. After having been stirred for 5 hours and allowed to stand for 20 hours, the solution was extracted with 3:1 chloroform:ethanol (3×100 ml) and the combined extracts washed with water and dried (MgSO4). Solvent was evaporated at reduced pressure and the residue vacuum-distilled to give 4-(4-dimethylaminomethyl-2-pyridylmethylthio)butyronitrile (7.16 g) as a pale yellow liquid, b.p.0.01 mm 170° C.