Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])[N:11]=1)=[O:6].[I-].[Na+].[CH3:37][NH:38][CH3:39]>C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][C:10]2[N:11]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][N:38]([CH3:39])[CH3:37])=[O:6])[N:8]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=3)[CH:9]=2)=[O:14])=[C:17]([CH3:23])[CH:18]=1
Reactant: CNC
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCCl)n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCN(C)C)n1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
25.7 mg (0.05 mmol) of N-(2-chloroethyl)-4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxamide (Example 21A) are dissolved in 200 μl of a 2 molar solution of dimethylamine in THF, and 7.5 mg (0.05 mmol) of sodium iodide are added. The reaction mixture is stirred in a tightly closed reaction vessel at 55° C. for 16 h. The reaction solution is then evaporated in vacuo, and the residue from evaporation is dissolved in DMSO, filtered and purified by preparative HPLC (Method 10).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([OH:24])=O)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([NH2:39])[C:33]=1[NH2:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([NH:39][C:22]([C:17]2[C:18]([F:21])=[C:19]([F:20])[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([CH3:28])([CH3:27])[O:6][SiH2:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:13][CH:12]=3)=[C:15]([F:26])[C:16]=2[F:25])=[O:24])[C:33]=1[NH2:40]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(-c2c(F)c(F)c(C(=O)O)c(F)c2F)cc1
Reactant: COC(=O)c1cc(C)cc(N)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)cc(NC(=O)c2c(F)c(F)c(-c3ccc(C(C)(C)O[SiH2]C(C)(C)C)cc3)c(F)c2F)c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.5 %

Procedure:
To a solution of 4′-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,6-tetrafluoro-biphenyl-4-carboxylic acid (2.2 g, 5.3 mmol) in dry DMF (50 mL) was added 2,3-diamino-5-methyl-benzoic acid methyl ester (0.95 g, 5.3 mmol) and HATU (3.03 g, 7.9 mmol) followed by N,N-diisopropylethylamine (1 mL). The reaction mixture was stirred for 14 h at room temperature under nitrogen atmosphere. TLC shows completion of the reaction. The reaction mixture was quenched to crushed ice and the precipitate was filtered, washed with water and dried to get an off white solid (2.4 g, 80.80%) which was directly taken to the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:3]=1.[C:16]([S:20]([NH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=O)[CH2:26][CH2:25]1)(=[O:22])=[O:21])([CH3:19])([CH3:18])[CH3:17].N[C@@H]1CC[C@H](C(O)=O)CC1.FC(F)(F)C1C=CC(N)=C(N)C=1>>[C:16]([S:20]([NH:23][C@@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]2[NH:8][C:7]3[C:2](=[N:3][C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[F:15])=[N:5][CH:6]=3)[N:1]=2)[CH2:28][CH2:29]1)(=[O:22])=[O:21])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1cnc(-c2ccccc2F)nc1N
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](c2nc3nc(-c4ccccc4F)ncc3[nH]2)CC1

Procedure:
By following the same procedure as described in Example 1 except that use was made of 4,5-diamino-2-(2-florophenyl)-pyrimidine and cis-4-tert-butylsulfonylaminocyclohexane-carboxylic acid as prepared from cis-4-aminocyclohexane-carboxylic acid in accordance with the 1st, 2nd and 4th steps of Example 4 described in WO0137826 in place of 4-trifluoromethyl-1,2-phenylenediamine, the title compound was prepared.
Reaction SMILES: [C:1]([N:6]=C=O)(=[O:5])C(C)=C.[C:9]([O:14][CH3:15])(=[O:13])[C:10]([CH3:12])=[CH2:11].[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])[CH:25]=[CH2:26].N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>C(OCCCC)(=O)C>[N-:6]=[C:1]=[O:5].[C:9]([O:14][CH3:15])(=[O:13])[C:10]([CH3:12])=[CH2:11].[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=C(C)C(=O)N=C=O
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCCCC
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: CCCCOC(C)=O
Solvent: C=Cc1ccccc1
Product: [N-]=C=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a reaction vessel, butyl acetate (40 g) was charged, and heating was made to 100° C. A mixture of methacryloyl isocyanate (7.5 g), methyl methacrylate (17.5 g), styrene (15.0 g), n-butyl acrylate (10.0 g) and 2,2'-azobis(2,4-dimethylvaleronitrile) (0.5 g) was dropwise added thereto in 2 hours. After stirring at 100° C. for 30 minutes, a solution of 2,2'-azobis(2,4-dimethylvalernoitrile) (0.25 g) in butyl acetate (10 g) was dropwise added thereto at 100° C. in 30 minutes, followed by stirring at 100° C. in 1.5 hours to give a copolymer of methcaryloyl isocyanate with methyl methacrylate, styrene and n-butyl acrylate. Number average molecular weight, 10,500. Non-volatile content, 42.3%. Viscosity (determined by Gardner bubble viscometer), K<<L.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:9][CH2:8]1)(=O)=O.Cl.[CH3:31][O:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25]([CH:27]1[CH2:28][CH2:29]1)=[O:26])=[C:14]2[NH:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][N:35]2[CH2:36][CH2:37][CH:33]([O:32][CH3:31])[CH2:34]2)[CH2:12][CH2:11]1
Reactant: COC1CCNC1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Temperature: 80 °C

Procedure:
To a solution of (trans-4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (362 mg, 0.75 mmol) and 3-methoxypyrrolidine hydrochloride (410 mg, 2.98 mmol) in acetonitrile (15 mL) was added K2CO3 (1.24 g, 9 mmol) and KI (300 mg, 1.81 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol) and the reaction mixture was heated at 50° C. for 16 h and 80° C. for 24 h. The solution was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purification by column chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (155 mg, 42%) as an off-white solid. ESI MS m/z 486 [C25H32BrN3O2+H]+
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:26]([OH:28])=O)[CH3:25])([O:18]C(C)(C)C)=O.[CH2:29]([NH:36][CH2:37]C(OCC)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:29]([N:36]1[CH2:37][C:16](=[O:18])[NH:23][C@@H:24]([CH3:25])[C:26]1=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
The title compound was prepared according to the procedure described by John S. Kiely and Stephen R. Priebe in Organic Preparations and Procedures Int., 22 (6), 761-768 (1990). Thus 100 mL of a stock solution of dicyclohexylcarbodiimide in methylene chloride (0.5M) was added to methylene chloride (250 mL). This solution was cooled to 0° C. under nitrogen and Boc-L-alanine (9.46 g, 50.00 mmol) was added. The resulting slurry was stirred for 5 min, and then ethyl N-benzylglycinate (9.37 mL, 50.00 mmol) was added. The reaction was stirred for 2 h at 0° C., then at 20° C. overnight. The precipitate was removed by filtration, and hydrogen chloride gas bubbled through the methylene chloride solution for 2-4 h, until the reaction was shown to be complete by tlc. The solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (42 mL). The organic phase was washed with saturated sodium chloride, dryed over magnesium sulfate, filtered and evaporated. The crude product was recrystallized from toluene to give the title compound as white crystals (5.88 g). NMR (300 MHz, CDCl3) δ 7.30-7.38 (3H, m), 7.22-7.30 (2H, m), 6.94 (1H, br s), 4.59 (2H, s), 4.14 (1H, q, J=7 Hz), 3.84 (2H, s), 1.52 (3H, d, J=7 Hz).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[OH:20])[O:16][C:15]([CH3:21])=[C:14]([C:22]1[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=1)[C:13]2=[O:30].O.CCCCCC>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([Cl:1])[C:19]=1[OH:20])[O:16][C:15]([CH3:21])=[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:13]2=[O:30]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2c(C)oc3cc(O)c(Cl)cc3c2=O)cc1
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1oc2c(Cl)c(O)c(Cl)cc2c(=O)c1-c1ccccc1
Reaction time: 3 h

Procedure:
N-Chlorosuccinimide (0.27 g, 2 mmol) was added to a solution of 6-chloro-7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one (0.29 g, 1 mmol) in DMF (4 ml) and the solution stirred for 3 hrs. and at 50° C. for ˜3 hrs. The resulting solution was poured into water (50 ml) and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with water (5×50 ml) and saturated aqueous sodium chloride solution (30 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a dark yellow oil. Trituration with hexane gave 6,8-dichloro-7-hydroxy-2-methyl-3-phenyl-chromen-4-one as a pale orange powder, dried in vacuo, (0.19 g)
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.N(C([C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1)=O)=[N+]=[N-].C[N:26](C)[CH:27]=[O:28]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:27]([NH:26][C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[O:28])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Cn1nccc1C(=O)N=[N+]=[N-]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CN(C)C=O
Product: Cn1nccc1NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 7.7 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (100 mg, 0.45 mmol) and 5-(azidocarbonyl)-1-methylpyrazol (280 mg, 1.85 mmol) in 2 mL of N,N-dimethyl-formamide was stirred at room temperature for 3 days. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (12 mg, 7.7%). LC-MS (m/z) 346.0 (M+).
Reaction SMILES: B(O)(O)O.[NH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:15].[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](O)=O.O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19]1[O:15][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc2oc(-c3c(F)cccc3F)nc12

Procedure:
2 g (32.4 mmol; 1 eq.) of boric acid is added to a solution of 5 g (32.4 mmol) of 2-amino-3-nitrophenol and 5.12 g (32.4 mmol; 1 eq.) of 2,6-difluorobenzoic acid in 50 ml of xylene. The mixture is heated under reflux of the xylene for 8 hours with elimination of the water formed by a Dean-Stark apparatus. After returning to ambient temperature, the reaction medium is diluted by 100 ml of ethyl acetate and neutralized by a 10% aqueous solution of soda. The organic phase is washed 3 times with 50 ml of water then with a saturated solution of NaCl before being dried over sodium sulphate, filtered and concentrated under reduced pressure. The 2-(2,6-difluorophenyl)-4-nitro-1,3-benzoxazole is used without other purification in the following stage.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH3:19])=[C:5]2[CH2:20][C:21]([NH2:23])=[O:22].[H-].[Na+].[CH3:26][O:27][P:28]([CH2:32][CH2:33][CH2:34]Br)(=[O:31])[O:29][CH3:30].CO.CCOC(C)=O>O>[CH3:26][O:27][P:28]([CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH3:19])=[C:5]2[CH2:20][C:21]([NH2:23])=[O:22])(=[O:31])[O:29][CH3:30]
Reactant: CCc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: COP(=O)(CCCBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
5-Hydroxy-2-ethyl-1-(phenylmethyl)-1H-indole-3-acetamide (308 mg, 1.0 mmol) was added to 40 mg (1.0 mmol) of NaH/mineral oil washed with hexanes) in 4 mL of DMF, stirred 0.5 hours, 196 mg (0.85 mmol) of (3-bromopropyl)phosphonic acid dimethyl ester added and stirring maintained for 6.5 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel eluting with EtOAc, 5% MeOH/EtOAc, then 10% MeOH/EtOAc to give 269 mg (59% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH:15]=C)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].C[N+]1([O-])CC[O:21]CC1.I([O-])(=O)(=O)=O.[Na+]>O.C1COCC1.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH:15]=[O:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2]
Reactant: C=CCc1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Methyl 5-nitro-2-(prop-2-en-1-yl)benzoate (0.20 g, 0.90 mmol) in water (2 mL) and THF (5 mL) was added osmium tetroxide (0.57 mL 2.5% solution, 0.045 mmol) and NMO (0.16 g, 1.4 mmol). The mixture was allowed to stir at RT for 16 hours and monitored by TLC. The reaction was diluted with EtOAc, washed with NH4Cl and brine, and concentrated. The residue was redissolved in MeOH and water. After cooling the solution to 0° C., an aqueous solution of sodium periodate (0.39 g, 1.8 mmol) was dropped into the reaction and allowed to stir for 2 hours. The reaction was diluted with water, extracted with EtOAc, dried over sodium sulfate, and concentrated. The crude residue was purified by silica gel chromatography to provide Methyl 5-nitro-2-(2-oxoethyl)benzoate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.48 (S, 1H), 8.97 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 4.31 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[CH3:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.O>[CH3:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)COc1cccc(C)c1

Procedure:
A mixture of chloroacetone (43.75 g.) and finely-powdered potassium iodide (1 g.) in ethyl methyl ketone (50 ml.) was added dropwise, over 25 minutes, to a stirred, refluxing mixture of 3-methylphenol (54 g.) and dry potassium carbonate (82 g.) in ethyl methyl ketone (100 ml). Stirring and refluxing were continued for a total of 5 hours and the mixture was cooled, poured into water (cs. 500 ml.) and extracted with ether. The ether extract was washed exhaustively with 5N-sodium hydroxide, dried over anhydrous sodium sulphate and evaporated. The residue was distilled to give a fraction b.p. 126°-134°/13 mm. Redistillation gave 1-(3-methylphenoxy)-propan-2-one, b.p. 124°-126°/13 mm.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][CH:22]([OH:38])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].[I:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1>>[I:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][O:38][CH:22]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:3]([O:4][C:5]([CH3:13])([CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:2]([Cl:1])[C:18]=2[Cl:19])=[CH:44][CH:43]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(OCc2ccc(I)cc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(4-(3-(4-iodobenzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,3-dichlorophenoxy)-2-methylpropanoate is prepared from tert-butyl 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate using 1.1 equivalents of sodium hydride and 1.1 equivalents of 4-iodobenzyl bromide according to general procedure H.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH:36][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)NCCN(C)C)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (83 mg, 0.2 mmol), N1,N1-dimethylethane-1,2-diamine (19 mg, 0.22 mmol), 1-methyl-1H-imidazole (66 mg, 0.8 mmol) and EDCI (153 mg, 0.8 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 h then concentrated. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:20) and further purified by Prep-TLC (silica gel, methanol:dichloromethane=1:10) to afford N-(2-(dimethylamino)ethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (41 mg, 42%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.89 (s, 1H), 8.48 (s, 1H), 8.13 (dd, 1H, J1=6.9 Hz, J2=1.8 Hz), 8.02-7.97 (m, 2H), 7.65-7.60 (m, 2H), 7.45 (t, 1H, J=8.1 Hz), 6.31 (d, 1H, J=7.5 Hz), 6.10 (d, 1H, J=8.1 Hz), 4.29-4.25 (m, 1H), 3.76-3.72 (m, 2H), 3.66-3.60 (m, 1H), 3.54-3.40 (m, 1H), 3.19-3.15 (m, 2H), 2.81 (s, 6H), 2.25-2.00 (m, 3H), 1.75-1.73 (m, 1H), 1.17 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 485, tR=1.062 min, HPLC: 99.08% at 214 nm, 99.16% at 254 nm, tR=4.868 min.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6](#[N:8])[CH3:7].C(C1CCC1)C.C(#N)C.[C:18](=O)=[O:19]>C1COCC1>[CH:5]1([C:18](=[O:19])[CH2:7][C:6]#[N:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C=O
Reactant: CC#N
Reactant: [Li]CCCC
Agent: CCC1CCC1
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCC1
Reaction time: 1 h

Procedure:
To 390 mL of THF at −78° C. was added n-BuLi (312 mL, 780 mmol, 2.5 M in hexanes). After the reaction temperature equilibrated (˜15 min), a solution of acetonitrile (40.7 mL, 780.0 mmol in 200 mL of THF) was added dropwise via an addition funnel over a 20 min period. The resulting milky-white slurry was allowed to stir for 1 hr before a solution of ethyl cyclobutane carboxalate (50.0 g, 390.1 mmol in 100 mL of THF) was added down the inside of the flask over a 15 min period. After 1 hr, the reaction was warmed to −45° C. (acetonitrile/CO2) and allowed to stir for 2 hr. The reaction was quenched cold by the dropwise addition of 2 N HCl (pH=7) and then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (quantitative yield) as a colorless oil that was used without further purification. LRMS m/z (APCl) 121 (M−1).
Reaction SMILES: O=[C:2]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=2[CH:12]=1)[C:3]([O:5]SC)=[O:4].Cl.[NH2:19][OH:20].[OH-].[Na+].[CH3:23]O>C(OCC)(=O)C.O>[CH3:23][O:20][N:19]=[C:2]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=2[CH:12]=1)[C:3]([OH:5])=[O:4]
Reactant: NO
Reactant: CO
Reactant: CSOC(=O)C(=O)c1cc2cc(Cl)ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)O)c1cc2cc(Cl)ccc2s1

Procedure:
A solution of 2.6 g of methylthio α-oxo-α-(5-chloro-2-benzothienyl)acetate in 180 ml of methanol containing 840 mg of hydroxylamine hydrochloride and 10 ml of 1N sodium hydroxide was stirred at 25° C. for sixteen hours. The reaction solvent was removed by evaporation under reduced pressure to give an oil. The oil was dissolved in 100 ml of ethyl acetate and 100 ml of water, and the mixture was made alkaline to pH 10.4 by addition of 1N sodium hydroxide. The aqueous layer was separated, washed with fresh ethyl acetate, and then made acidic to pH 2 by addition of 1N hydrochloric acid. The aqueous acid mixture was extracted with fresh ethyl acetate, which was then washed with water, dried and the solvent was removed to provide 2.5 g of α-methoxyimino-α-(5-chloro-2-benzothienyl)acetic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1)=[O:3].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[NH2:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: CC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(N)c(N)c1
Temperature: 25 °C

Procedure:
To a solution of 4-methylcarbonyl-2-nitro-benzenamine (500 mg, 2.775 mmol) in EtOAc (16 mL) was added SnCl2.2H2O (3.130 g, 13.88 mmol). The reaction mixture was refluxed for 2.5 h, cooled to rt, and diluted with H2O (130 mL). The pH of the mixture was adjusted to 7-8 by addition of saturated NaHCO3 solution and the aqueous phase was extracted with EtOAc (2×120 mL). The combined organic extracts were washed with brine (2×60 mL) and dried over MgSO4. After the removal of the solvent under vacuum, 142a was obtained as a red orange solid (418 mg).