Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:5]([NH:8][S:35]([CH3:34])(=[O:37])=[O:36])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)c(Cl)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)c(Cl)cn1
Reaction time: 96 h
Yield: 38 %

Procedure:
To a methylene chloride solution (10.0 ml) of [5-chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]amine (114 mg, 0.276 mmol) was added pyridine (440 μl, 5.5 mmol). To the resulting mixture was added methanesulfonyl chloride (addition of 77 μl once a day for 3 days, 230 μl in total, 3.0 mmol). The resulting mixture was stirred for 4 days in total. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1), followed by crystallization in ether to give the title compound (51 mg, 38%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[Cl-].CCO>[Fe].O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2ccc(Cl)nc12
Temperature: 60 °C

Procedure:
A solution of 2-chloro-8-nitroquinoline (1.02 grams), iron powder (2.05 grams) and NH4Cl (2.6 grams) in 5:1 EtOH:Water (50 mL) was refluxed for 9 hours. After the reaction was complete, the solution was cooled to 60° C. and filtered through celite. The cake was washed with isopropyl alcohol followed by ethyl acetate. The filtrate was concentrated to dryness, dissolved in ethyl acetate and washed with water, dilute aqueous NaHCO3, brine and dried (Na2SO4) and concentrated to an oil. The desired product crystallized with the addition of pentane, brown solid (0.818 grams).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:10]([CH2:18]O)=[CH:11][C:12]2[CH2:16][O:15][CH2:14][C:13]=2[CH:17]=1.[Cl:20]CCl.CS(Cl)(=O)=O>O>[Cl:20][CH2:18][C:10]1[C:9]([CH3:8])=[CH:17][C:13]2[CH2:14][O:15][CH2:16][C:12]=2[CH:11]=1
Reactant: Cc1cc2c(cc1CO)COC2
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc2c(cc1CCl)COC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Triethylamine (1.7 mL, 12 mmol) was added under ice cooling to a mixture of (6-methyl-1,3-dihydro-2-benzofuran-5-yl)methanol described in Production Example 1-5 (1.0 g, 6.1 mmol) and dichloromethane (10 mL), followed by the addition of methanesulfonyl chloride (470 μL, 6.1 mmol) at that temperature. The reaction mixture was stirred for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:10) to give the title compound (680 mg, 61% yield).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20][CH3:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[C:18]([C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:20][CH3:21])#[N:19]
Reactant: COc1c(C#N)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C#N)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To 150 mg of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 3 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with hexane/dichloromethane. Filtration of the suspension gave 121 mg (100% yield) of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([N:17]([CH3:24])[C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ncc(-c2ccccc2)nc1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc(-c2ccccc2)nc1N(C)C(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
Methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate. A solution of methyl 3-amino-5-phenylpyrazine-2-carboxylate (360 mg, 1570 μmol) in DCM (10 mL) was treated with DIPEA (547 μl, 3141 μmol) and trifluoroacetic anhydride (275 μl, 1963 μmol). The reaction stirred under nitrogen at 23° C. After 14 hours, the reaction was diluted with DCM (50 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo affording methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate as an orange solid, which was carried forward to the next reaction. A suspension of methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate (511 mg, 1571 μmol) and potassium carbonate (651 mg, 4713 μmol) in DMF (10 mL) was treated with iodomethane (196 μl, 3142 μmol). The reaction flask was capped with a septum and heated to 65° C. After 4 hours, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 5-25% EtOAc/hexane), affording 221 mg (41%, 2 steps) of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate as an yellow solid. A solution of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate (253 mg, 746 μmol) in MeOH (2 mL) and DCM (2 mL) was treated with sodium methoxide (0.5M solution in MeOH (2983 μl, 1491 μmol)). The reaction was stirred under nitrogen at 23° C. After 90 minutes, the reaction was diluted with brine (25 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated, affording 179 mg (99%) of methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate as a yellow solid. Mass: Calculated: 243.261. Observed: 244.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (1H, s), 8.07-8.17 (2H, m), 7.95 (1H, br. s.), 7.46-7.55 (3H, m), 4.00 (3H, s), 3.18 (3H, d, J=4.7 Hz).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH:15]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[CH:15]1([CH2:20][CH2:21][C:22]([N:6]2[CH:7]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][CH:26]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(CCC1CCCC1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
3-Cyclopentyl-1-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-propan-1-one was prepared from phenanthridine, 3-cyclopentylpropionyl chloride, and indole according to GP 2. Yield, 5%. 1H-NMR (CD3OD): δ=0.80-0.99 (m, 2H), 1.27-1.70 (m, 9H), 2.60 (“t”, J≈7 Hz, 2H), 6.08 (s, 1H), 6.98-7.04 (m, 2H), 7.07 (td, J≈7 Hz, J=1.3 Hz, 1H), 7.12 (td, J=7.9 Hz, J=1.4 Hz, 1H), 7.21 (“d”, J≈7.4 Hz, 1H), 7.26 (“t”, J≈7.6 Hz, 1H), 7.36-7.42 (m, 3H), 7.45-7.52 (m, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.90 (d, J=7.7 Hz, 1H), 7.97 (d, J=7.7 Hz, 1H); (+)-ESI-MS: m/z=421 [M+H]+, 304 [M-indole+H]+, 180.
Reaction SMILES: [OH-].[K+].[SH2:3].Cl[C:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:6][N:7]=[CH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1>C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:5]2[S:3][CH:8]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:7][N:6]=2)[CH:16]=1
Reactant: S
Reactant: ClC(=NN=Cc1cccnc1)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1cncc(C2=NNC(c3cccnc3)S2)c1

Procedure:
To a solution of 6.7 g (0.1 mole) of 85% potassium hydroxide in 190 ml of ethanol which has been freshly saturated with hydrogen sulfide are added 24.3 g (0.1 mole) of 1-chloro-1,4-bis(pyrid-3-yl)-2,3-diazabutadiene at low temperature. After 2 hours the solvent is removed by evaporation under vacuum and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and with a saturated solution of sodium chloride, then dried over sodium sulfate, filtered, and the filtrate is concentrated by evaporation. The residue is stirred in hexane/ether, filtered, washed and dried, affording 2,5-bis(pyrid-3-yl)-4,5-dihydro-1,3,4-thiadiazole of formula ##STR11## with a melting point of 77°-78° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24]([OH:26])=O)[CH2:9]1)=O)(C)(C)C.[CH:46]1([NH:49][CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:53][C:52]=2[CH3:62])[CH2:48][CH2:47]1>>[CH:46]1([N:49]([CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:53][C:52]=2[CH3:62])[C:24]([C:13]2[C@@H:14]3[NH:16][C@H:10]([CH2:11][C:12]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=2)[CH2:9][NH:8][CH2:15]3)=[O:26])[CH2:47][CH2:48]1
Reactant: COCCCc1ccc(C)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Product: COCCCc1ccc(C)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and cyclopropyl-[5-(3-methoxy-propyl)-2-methyl-benzyl]-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 678.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]([OH:14])=O)[C:6]=2[N:7]=1.CN(C(ON1N=N[C:25]2C=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH2:39]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]([N:29]3[CH2:24][CH2:25][O:39][CH2:27][CH2:28]3)=[O:14])[C:6]=2[N:7]=1
Reactant: O
Reactant: O=C(O)Cn1ccc2cnc(Cl)nc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(Cn1ccc2cnc(Cl)nc21)N1CCOCC1
Yield: 80 %

Procedure:
A solution of 2-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (100 mg, 0.474 mmol), amine (15.4 mg, 0.496 mmol), HATU (79 mg, 0.59 mmol) and TEA (95.8 mg, 0.0.948 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, water was added to the mixture and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated, producing a the desired product which used directly in the next step without further purification (100 mg, Yield 80%). LCMS (m/z): 281.1 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.022 g of product in 70% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][CH2:24][C:25]([OH:27])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[CH3:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1N.O.C[N:40](C)C=O>C(N(CC)CC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][CH2:24][C:25]([NH:40][C:33]3[CH:34]=[CH:35][C:30]([N:29]([CH3:37])[CH3:28])=[CH:31][CH:32]=3)=[O:27])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: CN(C)c1ccccc1N
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)c1ccc(NC(=O)CCn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.75 g, 0.0138 mole) was added dropwise, slowly, to a stirred and chilled (10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (4.0 g, 0.0133 mole) in anhydrous dimethylformamide (20 ml). A yellow solid formed. The suspension was stirred at room temperature for a few minutes and then a solution of N,N-dimethylphenylenediamine (2.0 g, 0.0147 mole) in dimethylformamide (25 ml) was added. The resulting purple solution was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was poured into 150 ml of water and stirred at room temperature. Triethylamine (2.0 ml) was added to pH 8 and a solid precipitated. The solid was collected by filtration, dissolved in hot isopropyl alcohol, treated with charcoal, and filtered. Addition of water and cooling to room temperature caused a solid to form. The solid was collected by filtration and rinsed with water to give 1.1 g of solid (20% yield). Drying under high vacuum at room temperature and then at 80° C. gave a grayish solid, mp 216°-218° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1>>[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Agent: BrCC1CCCCO1
Agent: Cl
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ncccc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 137-139° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=4.6 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.57-7.50 (m, 1H), 7.02-6.94 (m, 2H), 6.72 (d, J=7.9 Hz, 1H), 6.47 (s, 1H), 6.40 (s, 1H), 5.29-5.03 (ABq, 2H), 4.76-4.64 (ABq, 2H), 4.18-4.06 (m, 4H), 2.18 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 153.0, 152.9, 144.5, 140.9, 138.2, 135.5 (q, 4J=5.31 Hz), 132.5, 132.5, 129.3, 124.5, 124.4 (q, 1J=273.6 Hz), 123.5 (q, 2J=32.3 Hz), 123.5, 122.2, 112.3, 109.3, 99.1, 79.7, 64.7, 64.1, 57.8, 42.4 (q, J=3.1 Hz), 21.0; MS (ES+) m/z 469.0 (M+1).
Reaction SMILES: ClCC(Cl)CCl.C1C(Cl)=C(Cl)C=C(Cl)C=1OCCO.[Cl:20][CH:21]([Cl:27])[C:22](Cl)([Cl:25])[CH2:23][Cl:24].[Cl:28][C:29]([Cl:35])([Cl:34])[CH:30]([Cl:33])[CH2:31]Cl.ClC(Cl)(Cl)C(Cl)(Cl)C>>[Cl:33][C:30]([C:29]([Cl:35])([Cl:34])[Cl:28])=[CH2:31].[Cl:20][C:21]([Cl:27])=[C:22]([Cl:25])[CH2:23][Cl:24]
Reactant: ClCC(Cl)(Cl)C(Cl)Cl
Reactant: ClCC(Cl)C(Cl)(Cl)Cl
Agent: CC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: OCCOc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCC(Cl)CCl
Product: C=C(Cl)C(Cl)(Cl)Cl
Product: ClCC(Cl)=C(Cl)Cl

Procedure:
The overhead stream comprising 1,2,3-trichloropropane, TCPE, tetrachloropropanes, 1,1,2,2,3-pentachloropropane, 1,1,1,2,3-pentachloropropane, and 1,1,1,2,2-pentachloropropane is then provided to a reactor where it is dehydrochlorinated to provide dichloropropenes, trichloropropenes, 2,3,3,3-tetrachloropropene, and 1,1,2,3-tetrachloropropene. More specifically, dehydrochlorination reactor may typically be a batch or a continuous stirred tank reactor. The mixing can be done, e.g., by mechanical or jet mixing of feed streams. Those of ordinary skill in the art are readily able to determine the appropriate conditions at which to run a dehydrochlorination reactor in order to conduct the aforementioned dehydrochlorination.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=N1.[CH:25]1(CN)CCCCC1>CN(C=O)C>[CH:19]1([N:18]([CH3:25])[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: On1nnc2ccccc21
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1ccc2cnccc2n1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2cnccc2n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), cyclohexanemethylamine (57.2 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) afforded the desired product as a white solid (74.9 mg, 97%): m.p. 62-63° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:20])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].Cl.C(N(CC)CC)C.Cl[C:30]1C=[CH:33][S:32][C:31]=1C(OCC)=O.C1C[O:43]CC1>C(Cl)Cl>[CH3:20][CH:2]([NH:1][C:33](=[O:43])[S:32][CH2:31][CH3:30])[C:3](=[O:4])[C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1
Reactant: CCOC(=O)c1sccc1Cl
Reactant: CC(N)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSC(=O)NC(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100.0 mg (330 μmol) 2-amino-1-(2-phenyl-benzoxazol-6-yl)-propan-1-one as the hydrochloride are cooled to 0° C. together with 183.1 μl (1321 μmol) triethylamine and 3 ml THF, then 34.7 μl (333 μmol) ethyl chlorothiolformate are added dropwise. The mixture is stirred for 2 h at 0° C., then the reaction mixture is combined with DCM and extracted with water, the org. phase is dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i. V.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]([CH2:12][CH:13]=[CH:14][CH2:15][CH3:16])[C:7](=[O:11])[CH:8](Cl)[Cl:9].C(NCCCC)CCC.[ClH:29]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:12][CH:13]([CH:14]([Cl:29])[CH2:15][CH3:16])[CH:8]([Cl:9])[C:7]1=[O:11]
Reactant: Cl
Reactant: CCC=CCN(Cc1cccc(Cl)c1)C(=O)C(Cl)Cl
Solvent: CCCCNCCCC
Solvent: Cc1ccccc1C
Product: CCC(Cl)C1CN(Cc2cccc(Cl)c2)C(=O)C1Cl
Temperature: 90 °C

Procedure:
N-(3-chlorobenzyl)-N-(2-pentenyl)-2,2-dichloroacetamide was added by 1 g into 15 ml of xylene, to which 2 g of di-normal-butylamine and 0.5 g of cuprous chloride were added under stirring at 90° C. After continuing stirring for one hour, 40 ml of 20% hydrochloric acid was added and extracted with toluene. The extract was dried with anhydrous magnesium sulfate, concentrated by an evaporator and then purified on silica gel chromatography (hexane/ethyl acetate=3/1, v/v) to obtain 0.6 g of an oily product. This was a mixture of four isomers.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[C:21](=[O:24])([O-:23])[O-].[Na+].[Na+]>>[CH2:14]([O:13][C:11]([N:1]1[CH2:9][CH2:8][N:7]([C:21]([O:23][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:24])[CH2:6][CH2:5][N:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:3][CH2:2]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CNCCNCCN1
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), benzyl chloroformate and sodium carbonate.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:17]([F:18])=[CH:16][C:15]([C:19]4[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:14][C:13]=3[F:26])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:17]([F:18])=[CH:16][C:15]([C:19]4[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:14][C:13]=3[F:26])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCC(c2cc(F)c(OC3CCN(C4CCC4)CC3)c(F)c2)=NN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=c1ccc(-c2cc(F)c(OC3CCN(C4CCC4)CC3)c(F)c2)n[nH]1
Temperature: 130 °C
Yield: 29.9 %

Procedure:
A mixture of 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (137 mg, 0.37 mmol) and cesium carbonate (232 mg, 0.71 mmol) in dimethyl sulfoxide (5 mL) was heated at 130° C. 45 min. The mixture was cooled to rt and partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (40 g silica gel column) chromatography using 2% to 8% methanol in methylene chloride to 10% methanol containing 0.2% ammonium hydroxide in methylene chloride. The recovered product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated. The product was crystallized using a mixture of ethanol, ethyl acetate, ether and hexane to give 6-[4-(1-cyclobutyl-piperidin-4yloxy)-3,5-difluoro-phenyl]-2H-pyridazin-3-one (40 mg, 29%); Mp 195-197° C.; MS m/z 362 (M+H).