Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.CN(C)C1C=CC=CC=1.[CH:25]([OH:28])([CH3:27])[CH3:26]>C(OCC)(=O)C>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[N:7]=[C:6]([NH:5][C:1](=[O:2])[O:28][CH:25]([CH3:27])[CH3:26])[N:11]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C(Cl)Cl
Reactant: CC(C)O
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(NC(=O)OC(C)C)n1
Temperature: 22.5 °C
Reaction time: 0.25 h

Procedure:
Phosgene (20 g, 202 mmol) was passed at 20-25° C. in the course of 45 min into a recipient vessel of ethyl acetate (120 ml). A solution of 2-amino4,6-dimethoxypyrimidine (15.6 g, 101 mmol) and N,N-dimethyl-aniline (26 ml, 203 mmol) in ethyl acetate (90 ml) was added dropwise at 25° C. in the course of 3 h. After 15 min, the suspension was aerated with nitrogen until it was free of phosgene, ethyl acetate (120 ml) was added and isopropanol (10 ml, 130 mmol) was added dropwise in the course of 10 min with cooling (20-25° C.). The reaction was filtered after 1 h, washed with ethyl acetate (3×20 ml) and the combined filtrates were extracted with hydrochloric acid (1.0 N, 2×30 ml) and water (2×30 ml). The solution was then concentrated and the product was crystallized from the residue; yield 19.2 g (80% of theory), m.p. 51-54° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][CH:11]=[CH2:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C)cc(C)c1

Procedure:
1000 g of 3,5-dimethylphenol (A) were dissolved in 1000 ml of acetone, 980 g of allyl bromide were added dropwise, and 114.8 g of potassium carbonate were subsequently added. The mixture was refluxed for 18 hours and then cooled. The potassium carbonate was filtered off, and the filtrate was treated with 3000 ml of water. It was extracted three times using tert-butyl methyl ether, and the organic phases were combined and washed twice using in each case 300 ml of 10% strength sodium hydroxide solution. The organic phase was dried over potassium carbonate and filtered, and the filtrate was concentrated. After distillation, 837 g (64% of theory) of allyl 3,5-dimethylphenyl ether of a boiling point of 98 to 110° C. at 10 mbar were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:10]=2[N:11]=1.N1[C:35]2[C:26](=[CH:27][CH:28]=[C:29]3[C:34]=2N=CC=C3)[CH:25]=[CH:24]C=1.C([O-])([O-])=[O:37].[Cs+].[Cs+]>[Cu]I>[C:26]1([CH:25]([O:37][C:2]2[CH:3]=[CH:4][C:5]3[O:6][CH2:7][CH2:8][N:9]([S:12]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)(=[O:14])=[O:13])[C:10]=3[N:11]=2)[CH3:24])[CH:35]=[CH:34][CH:29]=[CH:28][CH:27]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(Br)nc32)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(OC(C)c4ccccc4)nc32)c1
Temperature: 130 °C

Procedure:
To 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (50 mg, 140 mmol) in (d,l)-1-phenylethanol (400 μL) was added CuI (15 mg, 79 mmol), 1,10-phenanthroline (15 mg, 83 mmol), and Cs2CO3 (70 mg, 210 mmol). The resulting mixture was heated to 130° C. for 2 hours. Next, the reaction mixture was cooled to room temperature and quenched with a small amount of water, then extracted with ethyl acetate. The aqueous phase was discarded and the organic phase was concentrated under reduced pressure. The resulting residue was purified by HPLC to give 6-(1-phenyl-ethoxy)-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. LCMS(ESI): calc. C22H22N2O4S=410; obs. M+H=411.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@H:10]([OH:13])[C@H:9]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[S:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.[C:29](Cl)(=[O:31])[CH3:30].C1(C)C=CC=CC=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]([O:13][C@@H:10]1[C@H:9]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[S:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:28])[C:11]1=[O:12])(=[O:31])[CH3:30]
Reactant: COC(=O)c1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 127 mg (0.317 mmol) of methyl 4-((2S,3S)-5-(2-(dimethylamino)ethyl)-3-hydroxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-2-yl)benzoate in 160 μL of pyridine at 0° C. was added 25 μL (0.35 mmol) of acetyl chloride. The solution was stirred at 0° C. for 2 hours. The solvent was evaporated to leave a residue which was co-evaporated with toluene (3×). The material was then dissolved in DCM, washed with 1 N NaOH, dried (Na2SO4), and evaporated. Purification was afforded by flash chromatography on silica gel, eluting first with DCM then gradually increasing to 5% methanol/DCM to give 1m. MS found M+H=443. The observed 1H NMR coupling constants between the C2 and C3 methine protons (J=7.4 Hz) confirmed retention of the cis stereochemical relationship. The hydrochloride salt of 1m was recrystallized from isopropanol/ether; mp 214-216° C.; [α]25D+98.9° (c 0.99, CHCl3).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>ClCCl>[Br:18][C:19]([CH3:24])([CH3:23])[C:20]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:17][CH:16]=1)=[O:21]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
7.82 g of AlCl3 were added in about 30′ to a solution of 10 g (0.0587 mol) of diphenylether and 7.44 ml (0.0587 mol) of α-bromoisobutyrylbromide (97.5% w/w) in 100 ml of dichloromethane, maintaining the temperature between 0 e 5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](=O)([O-:12])[O-:11].[K+].[K+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: OCc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CO)cc1O
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A mixture of 3-hydroxybenzylalcohol (10 g, 80 mmol) and potassium carbonate (33.35 g, 240 mmol) were stirred under carbon dioxide in a sealed vessel at 1500-2000 psi and 150° C. for 18 hours. The cooled residue was dissolved in water, acidified to pH 1 using concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. The product was recrystallised from cyclohexane to afford the title compound, 740 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(OC)c1
Yield: 97.4 %

Procedure:
A mixture of methyl 4-methyl-3-(methyloxy)benzoate (1.00 g, 5.55 mmol), N-bromosuccinimide (1.09 g, 6.10 mmol) and a catalytic amount of 2,2′-azobis(isobutyronitrile) (AIBN) was refluxed in carbon tetrachloride (40 ml) for 16 h. The reaction mixture was filtered and the solution was washed with brine (25 ml), dried over sodium sulfate and concentrated to give methyl 4-(bromomethyl)-3-(methyloxy)benzoate (1.4 g, 97% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Br)[CH2:11][CH2:10]1.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([C:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=3)=[CH:28][NH:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][N:35]2[CH2:36][CH:37]=[C:32]([C:27]3[C:26]4[C:30](=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=4)[NH:29][CH:28]=3)[CH2:33][CH2:34]2)[CH2:11][CH2:10]1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: COc1ccccc1N1CCN(C(=O)CCCCBr)CC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CCCCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)CC1
Yield: 39.8 %

Procedure:
Following the same procedure reported in the Step 2 of EXAMPLE 13, the reaction of 1-(2-methoxyphenyl)-4-(5-bromovaleryl)piperazine (3.54 mmol) with 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3.54 mmol) and triethylamine (4.23 mmol) gave the alkylation product (715 mg, 40%).
Reaction SMILES: C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)CCCC1.[CH:30]1([CH2:35][NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=2[Cl:44])[CH2:34][CH2:33][CH2:32][CH2:31]1.C([O:47][C:48](=[O:57])[CH2:49][S:50]C1SC(N)=NC=1)C>>[Cl:44][C:38]1[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=1[N:36]([CH2:35][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1)[C:8](=[O:19])[NH:9][C:10]1[S:11][C:12]([S:50][CH2:49][C:48]([OH:57])=[O:47])=[CH:13][N:14]=1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: Fc1cccc(NCC2CCCC2)c1Cl
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(F)c2Cl)s1

Procedure:
The title compound was prepared via {2-[3-(2-chloro-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2-chloro-3-fluoro-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: C(OC(=O)C[C:6]([CH2:8][CH:9]([CH2:18][C:19](=[O:26])CC(OCC)=O)[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)=[O:7])C.[OH-:28].[Na+].C([OH:32])C>>[F:17][C:12]1[CH:11]=[C:10]([CH:9]([CH2:8][C:6]([OH:7])=[O:32])[CH2:18][C:19]([OH:26])=[O:28])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: CCOC(=O)CC(=O)CC(CC(=O)CC(=O)OCC)c1ccc(F)c(F)c1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CC(CC(=O)O)c1ccc(F)c(F)c1
Temperature: 0 °C

Procedure:
Diethyl-3,4-difluorobenzal-bis-acetoacetate (11 g) in ethanol (150 mL) was treated with 50% NaOH (150 mL) and heated at reflux for 4 hours. Approximately 100 mL of solvent was removed by distillation. The remaining solution was cooled to 0° C. and sufficient HCl was added dropwise to adjust the pH to 1. The resulting solution was extracted with EtOAc (3×300 mL) and the combined extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a white solid (7.4 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].O>C(OCC)C.C1CCCCC1>[C:5]1([C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:4])[CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: O
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a well-stirred solution of propiophenone (20.1 g, 0.15 mol) in dry diethyl ether (125 ml) kept under nitrogen at room temperature was added a solution of phenylmagnesium bromide (55 ml, 3 M in diethyl ether) in dry diethyl ether (25 ml). The reaction mixture was stirred for 1 h and a mixture of a saturated ammonium chloride solution (100 ml) and water (50 ml) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic phases was washed with a 0.5 N hydrochloric acid solution and dried over sodium sulphate. The solvent was evaporated in vacuo to give a solid residue which was trituated with cyclohexane (100 ml). The solid was collected by filtration and dried to give 26.4 g (83%) of 1,1-diphenyl-1-propanol.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]([NH2:34])=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14].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>C1COCC1.O>[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:23]([NH:34][C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:12])=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cc(NCc2ccccc2)c(N)cn1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C(=O)Nc2cnc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (3.589 g; 21.47 mmol) and (5-amino-4-benzylamino-pyridin-2-yl)-carbamic acid tert-butyl ester E-2.11 (4.500 g; 14.31 mmol) are dissolved in THF and and cooled to 0° C. DIPEA (5.539 g; 42.94 mmol) and HATU (10.878 g; 28.63 mmol) are added. The mixture is stirred at room temperature for 1 hr. Water is then added to the reaction mixture, precipitation of the product occurs. The precipitate is filtered off and dried under vacuum. The residue is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH:6]=[CH:5]2.[N-:20]=[N+:21]=[N-:22].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.[OH-].[Na+].[C:40](Cl)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]1[N:20]=[N:21][N:22]([C:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:15]=1)[CH:6]=[CH:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2nc(-c3ccccc3C#N)ccc2c1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc2nc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2c1
Yield: 377.6 %

Procedure:
3.5 ml of toluene were added to 855 mg (3.5 mmol) of 2-(6-methyl-quinolin-2-yl)benzonitrile obtained in Reference Example 8. To the mixture were further added 0.24 g (0.68 mmol) of sodium azide and 1 ml (3.83 mmol) of tributyltin chloride. After heating under reflux for 45 hours, the mixture was allowed to cool and diluted with 7 ml of toluene. To the mixture were added 0.4 ml (4 mmol) of a 10 N sodium hydroxide aqueous solution and 1.01 g (3.61 mmol) of tritylchloride with stirring. After stirring at room temperature for 1.5 hours, 15 ml of hexane were added to the mixture and the solid material was collected by filtration. The thus obtained solid material was washed with 10 ml of water twice and then 5 mls of methanol three times. The filter cake was dried under vacuum to obtain 1.36 g of 5-[2-(6-methylquinolin-2-yl)phenyl]-2-triphenylmethyl-2H-tetrazole.
Reaction SMILES: C([Mg]Br)C.[O:5]1CCC[CH2:6]1.[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.C=O.CN(C)P(N(C)C)(N(C)C)=O>C(OCC)C.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[C:14](=[CH:15][CH:16]=1)[CH:6]=[O:5]
Reactant: C1CCOC1
Reactant: Oc1cccc(Cl)c1
Agent: C=O
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1ccc(Cl)cc1O
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A 2M solution of ethylmagnesium bromide in tetrahydrofuran (50 ml, 0.10 mole) was placed in a flask, and a solution of 12.85 g (0.10 mole) of 3-chlorophenol in 50 mL of diethyl ether was added slowly with stirring. The addition required two hours, after which the solvents were removed by evaporation under reduced pressure. Toluene (200 ml), 7.50 g (0.25 mole) of paraformaldehyde, and 17.92 g (0.10 mole) of hexamethylphosphoramide were added to the residue, and this mixture was heated at 80° C. for approximately 16 hours. The solvent was evaporated under reduced pressure, leaving a residue. This residue was washed successively with 50 mL of hydrochloric acid and 300 mL of water. Vacuum distillation of the washed residue yielded 11.50 g of 4-chlorosalicylaldehyde, b.p. 112° C. at 9 mm of Hg. This reaction was repeated several times.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][SH:7])=[O:5].[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[N:18][N:19]=2)[N:16]=1.O>C(O)C>[CH2:2]([O:3][C:4]([CH2:6][S:7][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[N:18][N:19]=2)[N:16]=1)=[O:5])[CH3:1]
Reactant: Clc1ccc2nncn2n1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSc1ccc2nncn2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl thioglycollate, 1.2 g, is dissolved in 30 ml of dry ethanol, to which 400 mg of sodium hydride (60% in an oil) is added under cooling with ice water and the mixture stirred for 10 minutes. Then 1.55 g of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine is added and stirred at room temperature for 67 hours. The reaction mixture is treated with water and extracted twice with chloroform. The combined extract is washed with saline and dried over anhydrous potassium carbonate. The solvent is evaporated under reduced pressure, and the residue is purified by column chromatogaraphy (on 40 g of silica gel, developed and eluted with ethyl acetate), to give 1.93 g of the desired compound as colorless crystals of m.p. 130°-133° C.
Reaction SMILES: O1CCCC1.[OH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1.[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C(OCC)(=O)C.O>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:6][CH:7]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C1
Yield: 48.7 %

Procedure:
To a tetrahydrofuran solution (2.0 mL) of tert-butyl 3-hydroxyazetidine-1-carboxylate (87 mg, 0.50 mmol), sodium hydride (33 mg, 0.75 mmol, purity 55%) was added at 0° C. and the resultant solution was stirred for 30 minutes. Subsequently, 4-fluorobenzyl bromide (62.3 μL, 0.50 mmol) was added to the reaction solution and the resultant mixture was stirred at room temperature for 19 hours. After completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (68.5 mg, yield 49%).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]=2[CH3:21])[CH2:6][CH2:5]1.[CH3:22][S-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:21][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][S:23][CH3:22])[CH2:5][CH2:6]1
Reactant: C[S-]
Reactant: COc1cc(N2CCC(CCI)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(CCSC)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To 4-(2-iodoethyl)-1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperidine (40.6 g, 100 mmol) was added sodium thiomethoxide (7.75 g, 111 mmol) and diluted with DMF (201 mL). The reaction was stirred at 50° C. overnight. The solution was diluted with EtOAc and washed with H2O. The organic layer was dried (MgSO4), filtered, and rotovapped down to provide the title compound of step H (33.5 g) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.23 (d, J=12.1 Hz, 2H), 2.60-2.72 (m, 2H), 2.46-2.52 (m, 2H), 2.14 (s, 3H), 2.01 (s, 3H), 1.75 (d, J=12.1 Hz, 2H), 1.50 (t, J=5.7 Hz, 3H), 1.16-1.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]([CH2:14][C:15](=O)[CH2:16][CH3:17])[C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl.[NH2:23][OH:24].N1C=CC=CC=1.O>C(O)C>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]([CH2:14][C:15](=[N:23][OH:24])[CH2:16][CH3:17])[C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1
Reactant: CCC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)=NO

Procedure:
1-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-butan-2-one (339 mg, 1 mmol), hydroxylamine hydrochloride (227.5 mg, 3.25 mmol) and pyridine (3 mL) in ethanol (3 mL) were heated to 70° C. for 5 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with 15% NaCl, brine, then dried over anhydrous MgSO4. The solvent was distilled out under reduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0% to 60%) yielded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:14])[CH:3]=1.[BH4-].[Na+].Cl.O>O1CCOCC1.CO>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:14])[CH:3]=1
Reactant: CC(C)Oc1cc(C=O)c(F)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(CO)c(F)cc1Cl
Reaction time: 0.67 h
Yield: 88.5 %

Procedure:
Then, 7.5 g of 4-chloro-2-fluoro-5-isopropoxybenzaldehyde was dissolved in 70 ml of 1,4-dioxane and 5 ml of methanol, to which 0.92 g of sodium borohydride was added at 5° C., and the mixture was stirred for 40 minutes. After completion of the reaction, a small amount of diluted hydrochloric acid was added, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 6.7 g of 4-chloro-2-fluoro-5-isopropoxybenzyl alcohol.