Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH2:13][NH:14][C@@H:15]([C:18]([OH:20])=[O:19])[CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:22][C:23](Cl)=[O:24].[OH-].[Na+]>O.C1COCC1>[O:24]=[C:23]1[N:14]([CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:15]([C:18]([OH:20])=[O:19])[CH2:16][O:17][CH2:22]1
Reactant: O=C(O)[C@@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
K2CO3 (10.6 g, 76.4 mmol) in H2O (30 mL) precooled to 0° C. was added to N-(phenylmethyl)-D-serine (4.91 g, 25.2 mmol) in THF (30 mL) cooled to −10° C., internal temperature. Chloroacetyl chloride (3.30 mL, 41.4 mmol) was added dropwise, keeping the internal temperature below 5° C. After stirring for 2 h NaOH (10 mL, 50% w/w in water), precooled to 0° C. was added dropwise, keeping the internal temperature below 10° C. The reaction mixture was stirred for 2 h and subsequently warmed to rt. The reaction mixture was washed twice with heptane (20 mL) and the aqueous layer was cooled to −5° C. Concentrated HCl was added until pH <2, keeping the internal temperature below 10° C. The mixture was placed in a freezer overnight and the solid was filtered, washed twice with cold H2O (20 mL) and dried at 50° C. in a vacuum oven to give the title compound of step B (3.67 g, 15.6 mmol, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (d, J=15.4 Hz, 1H), 3.84-3.92 (m, 2H), 4.05-4.15 (m, 3H), 5.21 (d, J=15.2 Hz, 1H), 7.20-7.31 (m, 5H), 13.20 (br. s., 1H). [α]D20° C.=−108.6, I=100 mm, c=1.0 in 1N NaOH.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]CC4C=CC=CC=4)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1CC=CCC=1>CCO.[Pd]>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.9 %

Procedure:
To a refluxing mixture of cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (46 g, 113 mmol), 10% Pd/C (2 g) in EtOH (400 mL) was added dropwise 1,4-cyclohexadiene (62.7 mL, 678 mmol). Stirring was continued for 2-5 h until the reaction was complete. The mixture was cooled to rt, filtered through celite, and washed with EtOH . . . . The solution was then concentrated under reduced pressure. To the flask containing the crude product was added CHCl3 (200 mL). The resulting suspension was stirred for 15 min at rt. The solid was filtered, and dried in the air to give cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide(4-hydroxy-phenyl)-amide (34.4 g, 95%, yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][S:9]([C:12]1[CH:38]=[CH:37][C:15]([O:16][C:17]2[C:31]([CH:32]3[CH2:36][CH2:35][CH2:34][NH:33]3)=[CH:30][C:20]3[NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:23][C:19]=3[CH:18]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:31]([CH:32]3[CH2:36][CH2:35][CH2:34][N:33]3[C:1](=[O:3])[CH3:2])=[CH:30][C:20]3[NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:23][C:19]=3[CH:18]=2)=[CH:37][CH:38]=1)(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.003 ml of acetic anhydride was added to a methylene chloride (1 ml) solution of 10 mg of 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole, and the reaction liquid was stirred at room temperature for 1 hour. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][CH:30]=1.CC#N.C(Cl)CCl>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:36]([NH:35][C:32]5[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)cc4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-Amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Example 253, Step E, 165 mg, 0.4 mmol, 1.0 eq.) was dissolved in CH3CN/DMF (2/1, v/v, 15 ml) and 1-chloro-4-isothiocyanato-benzene (as described in preparation III, 75 mg, 0.4 mmol, 1.0 eq.) in as a CH3CN solution was added dropwise. The reaction was stirred at RT for 16 h. EDC (85 mg, 0.4 mmol, 1.0 eq.) was added and the reaction was heated to 80° C. for 2 h. The mixture was concentrated and the crude product was purified by column chromatography (0-10% MeOH/CH2Cl2/1% NH4OH) to yield 4-[2-(4-chloro-phenylamino)-benzoxazol-5-yloxy]-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide. MS m/z=506.01 (M+H)+Calc'd for C27H28ClN5O3: 505.19.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]([N:15]([CH3:17])[CH3:16])=O.[CH3:18][C:19]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[C:33]([CH3:39])[C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1>O1CCCC1.C(O)(=O)C>[CH3:39][C:33]1[CH:34]=[C:35]([C:37]2[N:38]=[N:13][N:15]([CH3:17])[CH:16]=2)[CH:36]=[C:19]([CH3:18])[C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1
Reactant: CN(C)N=O
Reactant: Cc1cc(CCCCCOc2c(C)cc(C#N)cc2C)on1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(CCCCCOc2c(C)cc(-c3cn(C)nn3)cc2C)on1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6.6 ml diisopropylamine in 150 dry tetrahydrofuran at 0° C. under nitrogen was slowly added 18.4 ml (2.5 m) n-butyllithium. The mixture was cooled to -78° C., and 3.2 ml N-nitrosodimethylamine was then slowly added. The latter mixture was stirred for 30 min, and 6.0 g 5-[5-(2,6-dimethyl-4-cyanophenoxy)pentyl]-3-methylisoxazole in 33 ml dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -73° C. for 8.5 hours, and 3 ml glacial acetic acid in 10 ml tetrahydrofuran was then added. The reaction mixture was stirred overnight, then concentrated, and the residue dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride, dried over magnesium sulfate and concentrated to an oily residue. The latter was chromatographed on silica gel and eluted with ethyl acetate/hexane 60:40. The product was recrystallized from ethyl acetate/hexane to give 2.69 g 4-[3,5-dimethyl-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}phenyl]-1-methyl-1H-1,2,3-triazole, m.p. 117-118° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH:5]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOc1cc(N)cc(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1cc(NS(=O)(=O)CCCCl)cc(C(=O)OC)c1
Reaction time: 16 h
Yield: 97.3 %

Procedure:
A suspension of 3-amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv) in CH2Cl2 (100 ml) was treated with DMAP (400 mg, 3.2 mmol,) and pyridine (1.74 g, 22 mmol, 1.1 equiv) followed by 3-chloropropanesulfonyl chloride (3.89 g, 22 mmol, 1.1 equiv) dropwise. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with 2N aqueous HCl solution (100 ml) followed by saturated aqueous NaHCO3 solution (100 ml), then dried over MgSO4 and concentrated in vacuo to give 3-(3-chloro-propane-1-sulfonylamino)-5-ethoxy-benzoic acid methyl ester (D53) (6.7 g, 98%) as a pale orange solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11](C(O)=O)=[C:7]2[CH:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[IH:27].Br.CC([O-])=O.[Na+].ICl.[O-]S([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:27][C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:6][C:7]=12
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cc12
Reactant: I
Agent: Br
Agent: CC(=O)[O-]
Agent: ClI
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3c2)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (example C.22 step 8) (650 mg, 1.74 mmol) in acetic acid (20 mL) containing HI (57%, 200 uL) was refluxed for 2 days, but only 30% conversion. Added HBr (48%, 2 mL, 18 mmol) and continued refluxing for 2 h. Cooled to 23° C., added NaOAc (2.5 g, 30 mmol) and ICl (2M in HOAc, 6.1 mL, 12.2 mmol) and the mixture was stirred at 23° C. for 1 h. Added sat. Na2SO3-sol. to destroy excess ICl, diluted with water, filtered precipitate off, washed with water, dissolved in TBME, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light yellow solid (740 mg, 93%; LC-MS shows mixture of bromide and iodide). MS (for iodide) (ISP) 456.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[CH:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH3:44]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)CCCCN(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (520 mg) obtained in Example 23-4 was dissolved in anhydrous DMF (10 ml) and added with diisopropylethylamine (463 μl) and diethyl bromomalonate (340 μl) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added thereto and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (421 mg) as a colorless oily substance.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=1)(=[O:3])[NH2:2].[F:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[C:1]([C:4]1[N:9]=[C:8]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:40][CH:39]=3)=[CH:29][CH:28]=2)[N:7]=[C:6]([NH:11][C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C
Yield: 50.7 %

Procedure:
To a suspension of (S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (5.133 g, 19.84 mmol) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.858 g, 21.83 mmol), 2M aqueous Na2CO3 (19.9 mL, 39.8 mmol) and PdCl2(dppf) (0.809 g, 0.99 mmol). The reaction vessel was flushed with argon, sealed and heated at 100° C. overnight. After cooling, the reaction mixture was diluted with 500 mL EtOAc and washed with brine (3×100 mL). The organic layer was dried over Na2SO4, filtered and chromatographed over silica gel with 20-60% acetone in hexanes. The product fractions were isolated and evaporated in vacuo to give the product (S)-methyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoate as a yellow-orange solid (4.128 g, 10.05 mmol, 51% yield). LC/MS: m/z=411.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].SC1SC2C=CC(C#N)=CC=2N=1.[Cl:23][C:24]1[S:25]C2C=CC(Cl)=CC=2N=1>>[Cl:23][C:24]1[S:25][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: N#Cc1ccc(Cl)c(N)c1
Agent: N#Cc1ccc2sc(S)nc2c1
Product: N#Cc1ccc2sc(Cl)nc2c1
Temperature: 95 °C

Procedure:
The title compound was prepared from 3-amino-4-chlorobenzonitrile via 2-mercapto-1,3-benzothiazole-5-carbonitrile as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 95° C. for 10 h.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25]([OH:27])=O)=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.C(Cl)(=O)OCC.Cl.[NH2:46][CH2:47][CH2:48]Cl>O.O1CCCC1.C(N(CC)CC)C>[O:27]1[CH2:48][CH2:47][N:46]=[C:25]1[CH2:24][C:23]1[C:19]([O:18][CH2:17][C:16]2[CH:34]=[CH:35][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:38])=[C:14]([O:36][CH3:37])[CH:15]=2)=[N:20][N:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: NCCCl
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC2=NCCO2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 0.67 h
Yield: 19.1 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}acetic acid (0.70 g), triethylamine (0.17 g) and tetrahydrofuran (30 mL) was added ethyl chlorocarbonate (0.18 g) at −30° C., and the mixture was stirred at the same temperature for 40 min. The reaction mixture was added to a mixture of 1-amino-2-chloroethane hydrochloride (0.81 g), triethylamine (0.71 g) and tetrahydrofuran (20 mL) at −30° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, potassium carbonate (0.24 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-{[4-({[4-(4,5-dihydro-1,3-oxazol-2-ylmethyl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)-2-methoxyphenoxy]methyl}-2-(2-furyl)-5-methyl-1,3-oxazole as colorless crystals (0.14 g, yield 18%) from a fraction eluted with ethyl acetate-methanol (50:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: C([C:3]1([C:13]([O-])=[O:14])[CH2:8][CH2:7][C:6]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:5][CH2:4]1)C.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:11]1[CH2:10][O:9][C:6]2([CH2:5][CH2:4][CH:3]([CH:13]=[O:14])[CH2:8][CH2:7]2)[O:12]1
Reactant: CCC1(C(=O)[O-])CCC2(CC1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1CCC2(CC1)OCCO2
Reaction time: 0.25 h
Yield: 87 %

Procedure:
214 mg (1 mmol) of ethyl-4,4-(ethylenedioxy)cyclohexanecarboxylate is cooled in 15 ml of toluene under argon and in a moisture-free environment to −78° C., and it is mixed drop by drop with 0.85 ml of a 1.2 molar solution of diisobutyl aluminum hydride (DIBAH) in toluene. After 15 minutes of stirring at this temperature, it is mixed with about 10 ml of a saturated ammonium chloride solution. The organic phase is separated, washed with saturated common salt solution, dried, filtered and concentrated by evaporation. 148 mg (85% of theory) of 4,4-(ethylenedioxy)cyclohexane carbaldehyde is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(N2CCCC2=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-oxopyrrolidin-1-yl)benzoic acid (19.94 mg, 0.097 mmol) in DCM (5 ml) was added oxalyl chloride (2M solution in DCM, 0.058 ml, 0.117 mmol) and 2 drops of DMF. The resulting mixture was stirred at r.t for 1 hr., then concentrated in vacuo. The residue (off white solid) was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][NH2:33])=[N:26][CH:27]=1.[Cl-].[NH+]1C=CC=CC=1.Cl>N1C=CC=CC=1>[F:34][C:21]([F:20])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][N:33]=[C:6]([CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:12][C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:10][C:9]=2[Cl:19])[CH3:7])=[N:26][CH:27]=1
Reactant: NOCCCOc1ccc(C(F)(F)F)cn1
Reactant: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CC(COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of 0.34 g of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone, 0.24 g of O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)hydroxylamine, 0.14 g of pyridinium chloride, and 10 ml of pyridine was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.40 g (yield, 71%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)oxime, nD23.0 1.5310.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16]C)=[O:15])=O)=[CH:5][CH:4]=1.[NH2:22]N>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:12]3[C:13](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:15])[NH:16][N:22]=2)=[CH:5][CH:4]=1
Reactant: CNC(=O)c1ccccc1C(=O)Cc1ccc(OC)cc1
Reactant: NN
Solvent: CCO
Product: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1

Procedure:
To 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide (1.76 g, 6.20 mmol) in EtOH (20 mL) was added hydrazine (3.50 ml, 112 mmol). A water condenser was attached and the mixture was heated to reflux under a nitrogen atmosphere for 5 days. After concentration, the reaction was diluted with EtOAc and extracted with water. The organics were dried over sodium sulfate, filtered and concentrated. The crude was purified by washing the resulting solid with diethyl ether and filtering to yield 4-(4-methoxybenzyl)phthalazin-1(2H)-one as a white solid. MS m/z=267[M+1]+. Calc'd for C16H14N2O2: 266.30.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].CN(C=O)C.OOS([O-])=O.[K+].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>O>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:3][C:2]=2[N:1]=[C:26]1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CNc1ccc(NS(C)(=O)=O)cc1N
Reactant: O=Cc1cccnc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)nc2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(3-amino-4-(methyl amino) phenyl) methane sulfonamide (0.3 g, 0.0013 mol) in the mixture of DMF (10 ml) and water (2 ml) was added OXONE® (1.02 g, 0.0016 mol) and followed by nicotinaldehyde (0.16 g, 0.0015 mol) was added portion wise with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated on a high vacuo pump and diluted with cold water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product N-[1-methyl-2-(pyridin-3-yl)-1H-benzimidazol-5-yl]methanesulfonamide (363) as a brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.53 (bs, 1H), 9.04 (s, 1H), 8.75-8.77 (d, J=4.0 Hz, 1H), 8.28-8.26 (d, J=8.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.24-7.21 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 2.91 (s, 3H). LCMS (ES) m/e MS (M+1=244), Purity 95.64%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[NH:40]1[C:41]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C

Procedure:
A mixture of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine 31 from Example 4 (2.00 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 7 (2.26 g), toluene (24 mL), ethanol (12 mL), water (6 mL), sodium carbonate (1.72 g) and PdCl2(PPh3)2 (325 mg) was heated to 130° C. in the microwave for 90 minutes (US 2008/0076768; WO 2006/046031, incorporated by reference herein).