Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.Cl.S(Cl)(Cl)=O.[Cl:24][CH2:25]Cl>C1COCC1.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.O>[Cl:24][CH2:25][C:4]1[CH:3]=[CH:2][C:1]([CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:11][CH2:12]2)=[CH:6][CH:5]=1
Reactant: ClCCl
Reactant: CCC(=O)N1CCC(c2ccccc2)CC1
Agent: C=O
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g (23 mmol) of 1-(4-phenylpiperidin-1-yl)propan-1-one, 4.84 g (161 mmol) of paraformaldehyde and 4.7 g (34.5 mmol) of zinc chloride were initially charged in 200 ml of dichloromethane. With vigorous stirring, hydrogen chloride gas was then passed through the reaction mixture for 30 min After the introduction had ended, the reaction mixture was stirred at room temperature overnight. Water was then added to the reaction solution, the organic phase was separated off and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated to dryness on a rotary evaporator. The residue obtained was purified by preparative HPLC. During concentration, some of the product hydrolyzed to the analogous 4-(hydroxymethyl) compound. The product mixture obtained (3.68 g) was then taken up with stirring in 100 ml of THF, and 500 mg of zinc chloride and then 2 ml of thionyl chloride were added. This mixture was then stirred at room temperature for 1 hour. After addition of water and ethyl acetate to the reaction solution, the organic phase was separated off, dried over sodium sulphate, filtered and concentrated to dryness. This gave 3.4 g (12.79 mmol, 56% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].C(Cl)(=O)C(Cl)=O.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]([C:6]([C:5]3[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=3)=[O:8])[CH2:23][C:22]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
To a stirred mixture of 4-bromo-3-methyl benzoic acid (21.5 g, 100 mmol) and N,N-dimethylformamide (0.251 mL, 3.00 mmol) in anhydrous dichloromethane (200 mL) was added dropwise oxalyl chloride (9.16 mL, 105 mmol). The mixture was heated to reflux for 1.5 hours, then cooled to room temperature and the solvent evaporated. Fresh anhydrous dichloromethane (200 mL) was added and the resulting solution concentrated and the residue was dried in vacuo. The crude acid chloride thus obtained and 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (17.5 g, 95.0 mmol) were combined in anhydrous dichloromethane (200 mL), and N,N-diisopropylethylamine (19.2 mL, 110 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the crude amide which was recrystallized from ethyl acetate to provide pale orange crystals (34.8 g) of the title compound, m.p.175-176° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Cl:13])[CH:12]=1)[CH2:9][N:8]([CH3:14])[CH2:7][CH:6]2[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)Cl>[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:6]2[C:5]3[C:10](=[C:11]([Cl:13])[CH:12]=[C:3]([Cl:2])[CH:4]=3)[CH2:9][N:8]([CH3:14])[CH2:7]2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Reactant: NCCOCCOCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride hydrochloride (intermediate 10.6) (9 g, 20.02 mmol, 1.00 equiv, 95%) in DCM (200 mL) was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (15.6 g, 105.41 mmol, 5.00 equiv) and triethylamine (4.26 g, 42.18 mmol, 2.00 equiv) and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was diluted with 100 mL of DCM and then washed with 2×50 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (10:1). This resulted in 3 g (28%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].O>C(OCC)(=O)C>[Br:20][CH2:17][C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1occc1C(=O)Nc1ccc(Cl)c(CO)c1
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1occc1C(=O)Nc1ccc(Cl)c(CBr)c1

Procedure:
12 g of the N-(4-chloro-3-hydroxymethylphenyl)-2-methyl-3-furancarboxamide prepared in Step 5 above, was dissolved in 180 mL ethyl acetate. 1.8 mL of phosphorus tribromide was then added. The resultant mixture was stirred for 90 minutes at room temperature. 100 mL of water was then added to the mixture. The resultant organic phase was separated, washed with water, aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. The solvent was evaporated off to produce 12.97 g of N-(3-bromomethyl-4-chlorophenyl)-2-methyl-3-furancarboxamide as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:35])([F:34])[C:13]1[CH:14]=[C:15]([N:23]([CH2:31][CH2:32][OH:33])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)CC)C>C1COCC1.O>[F:11][C:12]([F:34])([F:35])[C:13]1[CH:14]=[C:15]([N:23]([CH2:31][CH:32]=[O:33])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CCO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CC=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 68 %

Procedure:
A solution of oxalyl chloride (0.15 mL) in THF (5.0 mL) was cooled to −78° C., DMSO (0.17 mL) in THF (2.0 mL) was slowly added dropwise. The reaction mixture was stirred for 5 min, a solution of the compound (0.34 g) obtained in step 4 in THF (3.0 mL) was added dropwise. The reaction mixture was stirred at −78° C. to −20° C. for 1 hr, and triethylamine (0.88 mL) was added. The reaction mixture was stirred at room temperature for 30 min, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 3→20% ethyl acetate/hexane) to give the title compound (0.23 g, 69%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](O)=O)[C:17]=3[CH:24]=2)[C:3]1=[O:25].C(Cl)(=O)C(Cl)=O.Cl.Cl.[C:34](=[NH:44])([O:41][CH2:42][CH3:43])[CH2:35][C:36](=[NH:40])[O:37][CH2:38][CH3:39].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O.C(OCC)C>[CH2:38]([O:37][C:36]1[CH:35]=[C:34]([O:41][CH2:42][CH3:43])[N:44]=[C:21]([C:18]2[C:17]3[CH:24]=[C:13]([N:4]4[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[N:2]([CH3:1])[C:3]4=[O:25])[CH:14]=[CH:15][C:16]=3[S:20][N:19]=2)[N:40]=1)[CH3:39]
Reactant: CCOC(=N)CC(=N)OCC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)nc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
To a cooled mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (3.71 g, 10.0 mmol), diethyl ether and N,N-dimethylformamide (3.0 ml) is added oxalyl chloride (1.52 g, 12.0 mmol). The mixture is allowed to warm to room temperature and stirred overnight. The mixture is allowed to settle and the supernatant is decanted and concentrated in vacuo. The residue is taken up in methylene chloride and added dropwise to a stirred mixture of diethyl malonimidate dihydrochloride (2.31 g, 10.0 mmol), diisopropylethylamine (10 ml) and methylene chloride at −40° C. over one hour. The resultant mixture is allowed to warm to room temperature, diluted with methylene chloride, washed with water, 10% aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.410 g, 8.31%, mp 197-200° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:8](O)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(Cl)(=O)=O.[NH2:43][C@@H:44]1[C:73](=[O:74])[N:46]2[C:47]([C:57]([O:59][CH:60]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:58])=[C:48]([S:51][C:52]3[S:56][N:55]=[N:54][CH:53]=3)[CH2:49][S:50][C@H:45]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>CN(C)C(=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[C:8]([NH:43][C@@H:44]2[C:73](=[O:74])[N:46]3[C:47]([C:57]([O:59][CH:60]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)=[O:58])=[C:48]([S:51][C:52]4[S:56][N:55]=[N:54][CH:53]=4)[CH2:49][S:50][C@H:45]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3cnns3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Sc4cnns4)CS[C@H]23)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of 2-(2-aminothiazol-4-yl)-2-(Z)-trityloxyiminoacetic acid (2.87 g) in N,N-dimethylacetamide (28.7 ml) was added potassium carbonate (0.925 g) and methanesulfonyl chloride (1.04 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, the mixture was added dropwise to a solution of diphenylmethyl 7β-amino-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (3.23 g) and bis-trimethylsilylacetamide (9.93 ml) in N,N-dimethylacetamide (32.3 ml) under ice-cooling. After being stirred at the same temperature for 45 minutes, the mixture was poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (4.87 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH:21]12[CH2:26][CH:25]1[CH2:24][N:23]([C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=1)[CH2:22]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:25]12[CH2:26][CH:21]1[CH2:22][N:23]([C:27]1[N:32]=[C:31]([NH:33][C:2]3[C:3]4[N:4]([CH:18]=[CH:19][N:20]=4)[N:5]=[C:6]([C:8]4[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=4)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=3)[CH:30]=[CH:29][CH:28]=1)[CH2:24]2
Reactant: Nc1cccc(N2CC3CC3C2)n1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CC5CC5C4)n3)c3nccn3n2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (250 mg, 0.75 mmol), 6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridin-2-amine (198 mg, 1.13 mmol), Pd2(dba)3 (43 mg, 0.075 mmol), BINAP (187 mg, 0.3 mmol), Cs2CO3 (734 mg, 2.25 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give crude product which was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 30% acetonitrile/70% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give methyl 3-(8-(6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (70 mg, 22%) as a light yellow solid. [M+H]+, 427.1, tR=1.926 min.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1I)=O.C([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)#C.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(#N)C>[CH3:13][O:12][C:10]1[CH:11]=[C:6]2[C:7]([CH:2]=[C:3]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:5]2)=[CH:8][CH:9]=1
Reactant: C#Cc1cccnc1
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COc1ccc2cc(-c3cccnc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A mixture of 2,2,2-trifluoro-N-(2-iodo-5-methoxyphenyl)acetamide (1.00 g), 3-ethynylpyridine (359 mg), bis(triphenylphosphine) palladium(II) dichloride (61.3 mg), copper(I) iodide (33.1 mg), triethylamine (0.81 mL), and acetonitrile (15 mL) was stirred at 50° C. for 1 hour. Then, potassium carbonate (801 mg) was added thereto, followed by stirring at 50° C. overnight. To the reaction mixture was added saturated brine, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (353 mg). 1H-NMR (CDCl3) δ ppm: 3.87 (3H, s), 6.78-6.86 (2H, m), 6.89-6.94 (1H, m), 7.29-7.43 (1H, m), 7.52 (1H, d, J=8.5 Hz), 7.85-7.94 (1H, m), 8.20-9.10 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]=[C:10]1[CH2:15][C:14](=O)[CH2:13][CH2:12][NH:11]1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCNC(=O)C1
Product: O=C1C=C(Nc2ccc(F)cc2)CCN1
Yield: 94.2 %

Procedure:
A mixture of 4-fluoroaniline (978 mg) and 2,4-dioxopiperidine (1.0 g) was heated at 120° for 1 h, and then cooled. The solid was triturated with ether (30 ml) and the solvent was decanted to leave the title compound (1.71 g), m.p. 195°-198°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10].ClC1C=C(Cl)[CH:17]=[C:16]([O:21]CC2C=CC=CC=2)[C:13]=1[CH:14]=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C@@H:9]1[O:10][C:14](=[O:15])[CH2:13][C@@H:16]([OH:21])[CH2:17]1
Reactant: O=CCc1ccccc1Cl
Reactant: O=Cc1c(Cl)cc(Cl)cc1OCc1ccccc1
Product: O=C1C[C@@H](O)C[C@H](Cc2ccccc2Cl)O1

Procedure:
By substituting an equimolar amount of o-chlorophenylacetaldehyde for 2,4-dichloro-6-phenylmethoxybenzaldehyde in step C of Example 1 and following Steps C through F there is obtained a corresponding amount of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH2:14])=[C:12]([C:15]2[C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:19]=2)[O:11][N:10]=1.[C:31](O)(=[O:33])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH:14][CH:31]=[O:33])=[C:12]([C:15]2[C:16]([C:27]([F:29])([F:30])[F:28])=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:19]=2)[O:11][N:10]=1
Reactant: CC(=O)O
Reactant: Nc1c(-c2c(F)cccc2Cl)noc1-c1cn(-c2cccc(F)c2)nc1C(F)(F)F
Product: O=CNc1c(-c2c(F)cccc2Cl)noc1-c1cn(-c2cccc(F)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 130 mg (0.295 mmol) 3-(2-chloro-6-fluorophenyl)-5-[1-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]isoxazol-4-amine (example I-117) in a mixture of 1847 mg (17.4 mmol) trimethylorthoether and 1660 mg (27.7 mmol) acetic acid was stirred at r.t. for 1 h. The suspension was filtered, and the obtained white solid salts were washed on the filter with hexane. Filtrates were combined and evaporated to dryness. The residue was treated by hexane, and the extract was purified by CC on silica gel, (eluent EtOAc/hexane 1/1). The obtained fraction of the pure product (example I-141) was evaporated to give 50 mg of a light greenish oil (yield 36%). Result of LC/MS MH+: 469.04; 1H NMR (400 MHz, methanol-d4): 7.29-7.35 (m, 1H) 7.44 (s, 3H) 7.46-7.50 (m, 1H) 7.57-7.67 (m, 2H) 7.72 (s, 1H) 8.26 (s, 1H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.O.[B-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCc2ccc(C(=O)O)cc21
Agent: [B-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2ccc(CO)cc21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of 1-methylindoline-6-carboxylic acid (321 mg, 1.80 mmol) in tetrahydrofuran (6 mL) was added N,N′-carbodiimidazole (309 mg, 1.89 mmol) at room temperature. The mixture was stirred at 50° C. for 15 minutes, and then cooled to 0° C. Then, thereto were added water (1 mL) and sodium hydroborate (204 mg, 5.40 mmol), and the mixture was stirred at the same temperature for 1 hour. The reaction solution was cooled to room temperature, and then thereto was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→1:1) to give (1-methyl-2,3-dihydro-1H-indol-6-yl)methanol (245 mg, 83%) as a pale yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22.5 g (149 mmol) 2,3-dihydro-benzo[1,4]dioxin-6-ylamine and 25 ml (179 mmol) triethylamine in 1 l diethyl ether is added at 12° C. within 10 minutes 20 ml (164 mmol) pivaloyl chloride dissolved in 250 ml diethyl ether. The temperature is kept between 12-16° C. The reaction mixture is stirred at room temperature for 1 hour. Then it is washed with 2× with 300 ml water, 2× with 150 ml 1N HCl and 2× with brine, dried with Na2SO4 and partially evaporated to a volume of 80 ml. This leads to a suspension. Hexane is added and the solid is filtered to give N-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2,2-dimethyl-propionamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[Cl:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30]B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>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]>[Cl:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:2]3[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=4)[N:3]=3)=[CH:26][CH:25]=2)[CH:22]=1
Reactant: CC1(C)OB(Cc2ccc(Cn3cc(Cl)cn3)cc2)OC1(C)C
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Cc2ccc(Cn3cc(Cl)cn3)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 25.4 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.100 g, 0.40 mmol), 4-chloro-1-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)-1H-pyrazole (0.197 g, 0.59 mmol), Pd(dppf)Cl2 (0.032 g, 0.04 mmol), and powdered Na2CO3 (0.126 g, 1.19 mmol) in dioxane (2.4 mL) and water (1.6 mL) was stirred under an argon atmosphere at 90° C. for 6 h, cooled, and filtered through celite with ethyl acetate washing. The filtrate was washed with saturated sodium chloride (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, hexane/dichloromethane) to afford the title compound (0.043 g, 43%) as a yellow oil. MW=423.34. 1H NMR (DMSO-d6, 500 MHz) δ 8.38-8.32 (m, 2H), 8.05 (s, 1H), 7.62-7.50 (m, 3H), 7.35 (d, J=8.1 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J=8.1 Hz, 2H), 5.25 (s, 2H), 4.11 (s, 2H), 2.77 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); APCI MS m/z 423 [M+H]+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3]C(C)(C)C)=O.[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=C=O)[CH:13]=1>C(#N)C>[CH3:21][C:12]1[CH:13]=[C:14]([NH:18][C:1]([NH:8][CH2:9][CH2:10][NH2:11])=[O:3])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCCN)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
N-Boc-Ethylene diamine (800 mg, 5 mmol) and m-tolyl isocyanate (665 mg, 5 mmol) were dissolved in acetonitrile and the mixture stirred at room temperature for 4 hrs. Solvent was removed under reduced pressure and the residue absorbed onto silica gel; prior to purification by flash column chromatography (silica, hexane:EtOAc 1:1) to yield the desired compound as a white solid (300 mg, 21%) (MS(+ESI, m/e) 294 (M+H)+). The N-Boc protected compound (300 mg, 1.02 mmol) was dissolved in formic acid (10 ml) and the mixture stirred at room temperature overnight. Excess acid was removed to yield the formate salt of the title compound as a white foam (210 mg).