Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]([O:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][O:18][C:17]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]=1
Reactant: C1CNCCN1
Reactant: Clc1ccccc1OCCOc1nc2ccccc2nc1Cl
Product: Clc1ccccc1OCCOc1nc2ccccc2nc1N1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
Piperazine (0.580 g, 6.65 mmol) was added to the crude material from Step 1 and the resulting mixture was stirred at room temperature for 5 h. The solvent was evaporated, and the crude mixture was dissolved in DMSO and precipitated with water T he precipitate was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (40:3:3:2) as eluent to afford 0.100 g (22%) of the title compound as a yellow oil. HRMS m/z calcd for C20H21ClN4O2 (M)+ 384.1353, found 384.1334.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:20]1([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:25][C:26]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(NC1CCCC1)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCCC3)c2)ccn1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (2.50 g, 11.1 mmol, CAS No. 417722-11-3), which was described in WO 02/32872, was dissolved in N,N-dimethylformamide (30 ml); sodium hydride (0.530 g, 13.3 mmol) was added thereto at room temperature; and the reaction mixture was stirred for 30 minutes. Phenyl N-cyclopentylcarbamate (2.50 g, 12.2 mmol) was added thereto at room temperature while stirring; and the reaction mixture was stirred for 30 minutes. Water was added to the reaction mixture; and the precipitated crystals were filtered off, and washed with water. This crystals were dissolved in methanol, and purified by silica gel column chromatography (Fuji Silysia NH; hexane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:methanol=98:2 in this order). The obtained crystals were suspended in hexane:ethanol=10:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (2.08 g, 6.18 mmol, 55.7%).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:12])[CH:9]=1)=[O:4]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Under a nitrogen atmosphere to a cold (0° C.) suspension of 2,2,2-Trichloro-1(1H-pyrrol-2-yl)ethanone (21.1 g, 99.3 mmol) and silver trifluoroacetate (23.2 g, 105 mmol) in chloroform was added iodine (25.4 g, 100 mmol) portionwise over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 2 hours. This was filtered through celite and washed with chloroform. The organic phase was washed sequentially with 5% Na2S2O5, water, brine, dried (MgSO4) and filtered. Evaporation and trituration with 80% hexane/ether (80 mL) gave the title compound as a white solid (25.5 g, 78% yield), mp 140° C., 1H NMR (400 MHZ, CDCl3) δ 7.2 (m, 2H), 7.4 (m, 1H), (9.5 (bs, 1H), MS m/e (M+H)+ 339.
Reaction SMILES: CN(C)C1NC(=O)[C:6](CCO)=[C:5]([CH3:13])N=1.[Cl:15][CH2:16][CH2:17][C:18]1[C:19](=[O:29])[N:20]([CH3:28])[C:21]([N:25]([CH3:27])C)=[N:22][C:23]=1[CH3:24].ClCCC1C(=O)N(CCC)C(N(C)C)=NC=1C.Cl.ClCCC1C(=O)N(CC)C(N(C)C)=NC=1C>>[CH2:27]([NH:25][C:21]1[N:20]([CH3:28])[C:19](=[O:29])[C:18]([CH2:17][CH2:16][Cl:15])=[C:23]([CH3:24])[N:22]=1)[CH2:6][CH2:5][CH3:13]
Reactant: Cc1nc(N(C)C)n(C)c(=O)c1CCCl
Reactant: Cc1nc(N(C)C)[nH]c(=O)c1CCO
Agent: CCCn1c(N(C)C)nc(C)c(CCCl)c1=O
Agent: CCn1c(N(C)C)nc(C)c(CCCl)c1=O
Agent: Cl
Product: CCCCNc1nc(C)c(CCCl)c(=O)n1C

Procedure:
and further, following the same procedures 2-dimethylamino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone (Coll. Czech. Chem. Commun., 32, 1582, 1967) was converted into 5-(2-chloroethyl)-2-(dimethylamino)-3,6-dimethyl-4(3H)-pyrimidinone (interm. 32); 5-(2-chloroethyl)-2-(dimethylamino)-6-methyl-3-propyl-4(3H)-pyrimidinone (interm. 33); and 5-(2-chloroethyl)-2-(dimethylamino)-3-ethyl-6-methyl-4(3H)-pyrimidinone monohydrochloride (interm. 34).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][OH:5].CCN(CC)CC.C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C@H:34]([CH3:38])[C:35](Cl)=[O:36])[CH:28]=[CH:27]2>CN(C1C=CN=CC=1)C.O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C@H:34]([CH3:38])[C:35]([O:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[O:36])[CH:28]=[CH:27]2
Reactant: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Reactant: COC(CO)OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCC(OC)OC)ccc2c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
2,2-Dimethoxyethanol (8.12 g), Et3N (8.99 g), DMAP (80 mg) and toluene (71 mL) are combined and stirred at room temperature. (S)-6-Methoxy-α-methyl-2-naphthaleneacetyl chloride (18.42 g) is added in portions over a period of 8 minutes. The resulting slurry is agitated (35-40° C.) until the reaction is judged to be complete. To the reaction mixture is added water (80 mL) and the phases are separated. The toluene phase is washed with saturated sodium bicarbonate (40 mL) and water (40 mL) and concentrated. Dichloromethane (20 mL) is added and the vacuum evaporation is repeated to produce 21.20 g of 2,2-dimethoxyethyl (S)-6-methoxy-α-methyl-2-naphthaleneacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[O:5][CH:6]=1
Reactant: O=Cc1cc(Br)co1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1coc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
To a solution of 4-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and morpholine (0.5 mL, 5.71 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (600 mg, 86%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:13]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]([CH2:36][C:37]([F:40])([F:39])[F:38])C(=O)OC(C)(C)C)[CH:23]=4)[O:20][CH:21]=3)=[O:16])=[CH:12][N:11]([CH3:41])[N:10]=2)[C:5]1=[O:42].Cl>C(OCC)(=O)C.CO>[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:13]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:36][C:37]([F:38])([F:40])[F:39])[CH:23]=4)[O:20][CH:21]=3)=[O:16])=[CH:12][N:11]([CH3:41])[N:10]=2)[C:5]1=[O:42]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCN(CCO)C2=O)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)c(N2CCN(CCO)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A mixture of tert-butyl (4-(4-((3-(3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (1.00 g) and 3M hydrogen chloride in a mixed solvent (10 mL) of ethyl acetate/methanol (1:1) was stirred overnight at room temperature. The precipitate was collected by filtration, and the obtained solid was washed with ethyl acetate/methanol (9:1), and dried under reduced pressure. To the obtained solid were added 1N aqueous sodium hydroxide solution (2.39 ml) and water (4 ml), and the mixture was stirred at room temperature for 30 min, and then at 0° C. for 30 min. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (531 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[C:17](=O)(OC)OC.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(CC(=O)O)ccc2c1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1
Reaction time: 8 h

Procedure:
Alternatively, the reaction for the selective methylation can be carried out by reacting a mixture of (6-methoxy-2-naphthyl)acetic acid, dimethyl carbonate and K2CO3, in the 1:20:2 molar ratio, in autoclave at a temperature of 220° C. The reaction is completed within about 8 hours. (In this case DMC acts first as a methylating agent for the carboxylic group, through an already known reaction; then the monomethylation reaction takes place on the resulting ester).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:22]=[C:21]1[CH2:33]Cl)[CH2:11][O:12][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:22]=[C:21]2[CH2:33][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)n1c(CCl)nc2cnc3ccccc3c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Temperature: -78 °C
Yield: 85.1 %

Procedure:
1-[(1S)-2-(Benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (1.61 g, 3.13 mmol) was dissolved in 250 mL of anhydrous CH2Cl2 and the solution was cooled to −78° C. under N2. A 1.0 M solution of tetrabutylammonium fluoride in THF (3.43 mL, 3.43 mmol) was added and the stirred solution was allowed to warm to ambient temperature overnight. The reaction mixture was then washed successively with 50 mL of saturated NaHCO3 solution and brine (4×50 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-3% methanol/CHCl3) gave 0.92 g of (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a colorless syrup.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[CH2:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[O:36]1[CH2:26][CH:25]1[C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:29])([F:30])[F:28])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 0.09 g, 0.220 mmol) in dichloromethane (5 mL) was added 3-chlorobenzoperoxoic acid (0.109 g, 0.441 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. Next, 3 mL of 10% sodium sulfite solution was added to the reaction mixture at room temperature and the contents were stirred for 10 min. The reaction mixture was concentrated and partitioned between ethyl acetate (10 mL) and sat. aq. sodium bicarbonate (2×10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield a pale yellow solid. LC/MS M+1=425.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:26]([NH:27][CH3:28])=[C:25](I)[N:24]=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[CH2:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]#[CH:32].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:26]3[N:27]([CH3:28])[C:31]([CH2:30][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:32][C:25]=3[N:24]=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: CNc1c(I)ncnc1Nc1ccc(Oc2cccc(OC(F)(F)F)c2)c(Cl)c1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c(CNC(=O)OC(C)(C)C)cc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65.3 %

Procedure:
To a solution of N4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N5-methylpyrimidine-4,5-diamine (1.53 g), tert-butyl prop-2-ynylcarbamate (0.67 g) and triethylamine (1.19 mL) in acetonitrile (28 mL) were added bis(triphenylphosphine)palladium(II) dichloride (100 mg) and copper(I) iodide (32.5 mg) at room temperature. Under an argon atmosphere, the mixture was stirred at room temperature for 4.5 hrs, heated at 50° C., and the mixture was stirred for 6 hrs. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=7:3→3:7→basic silica gel, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (1.05 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:31]([N:34](COC)[C:35]2[N:36]=[N:37][CH:38]=[CH:39][CH:40]=2)(=[O:33])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1.ClC1C=C(S(/N=C2/N(COC)N=CC=C/2)(=O)=O)C=CC=1OC1C=CC(C2C=CC(C(F)(F)F)=CC=2)=CC=1C1C=CN=NC=1.Cl>ClCCl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:31]([NH:34][C:35]2[N:36]=[N:37][CH:38]=[CH:39][CH:40]=2)(=[O:32])=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1
Reactant: COCN(c1cccnn1)S(=O)(=O)c1ccc(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnnc2)c(Cl)c1
Agent: COCn1nccc/c1=N\S(=O)(=O)c1ccc(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnnc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccnn1)c1ccc(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnnc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A mixture of 3-Chloro-N-(methoxymethyl)-N-pyridazin-3-yl-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide and 3-chloro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide (Preparation 49, 85 mg, 0.13 mmol) were dissolved in dichloromethane (1 mL) and a 4M solution of hydrogen chloride in 1,4-dioxane (0.34 mL) added. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo and the resulting residue purified by reverse phase preparative HPLC (Trilution method) to afford the title compound as a white solid (26 mg, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:12][C:11]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7][C:8]([C:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH:20]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nc(Br)ccc1N
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nc(C2=CCC3(CC2)OCCO3)ccc1N

Procedure:
A mixture of 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester- (Compound 232G, 0.31 g, 1.3 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester (0.406 g, 1.52 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.10 g, 0.12 mmol) in a 35 mL sealable microwave tube was taken up in 1,4-Dioxane (4.9 mL). This mixture was treated with a solution of Potassium carbonate (0.52 g, 3.8 mmol) in H2O (1 mL), flushed with nitrogen, sealed and irradiated in a microwave reactor for 30 minutes at 100° C. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 filtered and concentrated to a brown residue. This was taken up in DCM, treated with silica and concentrated. The resulting silica plug was loaded on to a sample cartridge and purified on an ISCO Combiflash system (0-50% EtOAc/Heptane) to isolate the desired product as 247 mg of an oil which crystallized upon standing. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.20 Hz, 3H), 1.77 (t, J=6.44 Hz, 2H), 2.32-2.40 (m, 2H), 2.60 (td, J=6.44, 1.52 Hz, 2H), 3.91 (s, 4H), 4.28 (q, J=7.07 Hz, 2H), 6.25 (t, J=4.04 Hz, 1H), 6.65 (s, 2H), 7.17 (d, J=8.84 Hz, 1H), 7.52 (d, J=8.84 Hz, 1H). MS (ES+): m/z=305.12 (100) [M+1]. HPLC: tR=3.50 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][OH:12])=[CH:6][CH:5]=1.ClN1C(=O)CCC1=O.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:31][C:30]([C:25]3[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([Cl:22])[CH:24]=3)([C:32]([F:33])([F:35])[F:34])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C=NO)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 68.7 %

Procedure:
In a solution of 2.70 g of 4-(hydroxyiminomethyl) benzoic acid methyl ester in 15 ml of N,N-dimethylformamide, 2.04 g of N-chlorosuccinic acid imide was added, and stirred at 40° C. for 40 minutes. Then, the reaction mixture was cooled to 0° C., 3.40 g of 3,5-dichloro-1-(1-trifluoromethylethenyl) benzene and 1.72 g of triethylamine were added, continued to stir at room temperature for 18 hours. After the completion of the reaction, the reaction mixture was poured into 100 ml of ice water, extracted with ethyl acetate (50 ml×2), the organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:1 to 1:3 gradient), and 4.05 g of the aimed product was obtained as white crystal.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[Br:9]Br>[OH-].[Na+]>[Br:9][N:5]1[CH2:4][CH:3]([CH2:2][Cl:1])[O:7][C:6]1=[O:8]
Reactant: O=C1NCC(CCl)O1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Product: O=C1OC(CCl)CN1Br
Temperature: 0 °C

Procedure:
13.55 grams (0.1 mole) 5-chloromethyl-2-oxazolidinone, prepared in Example 1, were dissolved in 90 mL of a 1 M NaOH solution and then cooled to 0° C. 17.6 grams (0.11 moles) bromine were added dropwise, with stirring over a period of fifteen minutes. The product was extracted with methylene chloride. The extracts were then combined, dried and the solvent removed using a rotary evaporator to yield an orange solid. Proton NMR Data: δ3.15 (m, 1 proton), 3.48 (m, 1 proton), 3.7 (m, 2 protons), 4.7 (m, 1 proton) Elemental Analysis: Found (theory), C 24.05 (22.40), H 2.71 (2.35), N 6.98 (6.53), Cl 18.12 (16.53), Br 31.18 (37.26).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([P:13]([CH3:18])(=[O:17])[O:14][CH2:15][CH3:16])[CH2:10][CH2:11][CH3:12].C[O:20][C:21](=O)[CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(O)(=O)C>O1CCCC1.ClCCl>[C:27]([O:26][C:24]([NH:23][CH2:22][C:21](=[O:20])[CH2:18][P:13]([CH2:9][CH2:10][CH2:11][CH3:12])(=[O:17])[O:14][CH2:15][CH3:16])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCCCP(C)(=O)OCC
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCP(=O)(CC(=O)CNC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5.82 g of lithium diisopropylamide in 30 ml of anhydrous tetrahydrofuran is cooled to -78° C. under an inert atmosphere. Under constant stirring at -78° a solution of 9.84 g of ethyl n-butyl(methyl)phosphinate in 20 ml of anhydrous tetrahydrofuran is added over 15 minutes under a positive pressure of an inert atmosphere via a canula. The resulting pale yellow solution is stirred for 1 hour at -78° and a pre-cooled (-78° C.) solution of 1.89 g of N-tert.-butoxycarbonylglycine methyl ester in 10 ml of anhydrous tetrahydrofuran is added over 5 minutes via a canula. Thin layer chromatography indicates complete reaction after circa 10 minutes. At -78° 4.0 g of glacial acetic acid is added and the mixture is allowed to warm to room temperature. The reaction mixture is diluted with dichloromethane and washed with water. Drying over magnesium sulphate and removal of the solvent in vacuo affords a pale yellow oil. Removal of the excess starting material by distillation and chromatography of the resulting yellow oil on silica gel yields ethyl 3-(N-tert.-butoxycarbonylamino)-2-oxo-propyl(n-butyl)phosphinate as a colourless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:15])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cl)Cc1cc(F)cc(F)c1

Procedure:
A mixture 3,5-difluorophenylacetic acid (100 g, 0.58 mmol) and thionyl chloride (13.7M, 100 mL, 1.37 mol) was stirred for 15 hours at room temperature. Evaporation gave 3,5-difluorophenylacetyl chloride as an oily residue. A stirred suspension of aluminum chloride (154 g, 1.16 mmol) in 1 L of methylene chloride was cooled to -65° C. and the acid chloride in 200 mL of methylene chloride was added dropwise such that the reaction temperature did not exceed -60° C. Ethylene gas was bubbled through the suspension at a rapid rate for 10 minutes at -65° C. The reaction mixture was allowed to warm to 0° C. over 2 hours, then cooled to -10° C. and treated with 500 mL of water. The organic layer was separated, washed with 100 mL of aqueous sodium chloride, and then dried over magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Distillation of the residue in vacuo (bp 90°-110° C. [1.0 to 0.7 mm]) gave a clear distillate. Redistillation (bp 100°-105° C. [0.3 mm]) gave 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-one (73.56 g, 0.342 mol) as a white solid, m.p. 46° C.