Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:33]([C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39](B(O)O)[CH:40]=1)=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(O)C.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:37]3[C:38]([O:44][CH3:45])=[CH:39][CH:40]=[C:35]([CH:33]=[O:34])[CH:36]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cc(C(F)(F)F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(C=O)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1=O

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Example 66, 50 mg; 0.0858 mmol), 5-formyl-2-methoxyphenyl boronic acid (46 mg; 0.257 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg; 0.0103 mmol), and sodium carbonate (74 mg) in benzene/ethanol/water (2.8/0.4/1.2 mL) was heated at reflux for 60 h. The reaction was diluted with EtOAc (30 mL) and washed successively with H2O (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 2′-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-carbaldehyde as a yellow oil. LCMS=592.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 9.98 (s, 1H), 7.99-7.96 (m, 1H), 7.90 (s, 1H), 7.75 (s, 2H), 7.69-7.64 (m, 2 Hz), 7.53 (s, 1H), 7.41-7.38 (m, 1H), 7.17-7.14 (m, 1H), 5.37 (t, J=8.2 Hz, 1H), 4.59 (d, J=15.3 Hz, 1H), 4.37 (d, J=15.6 Hz, 1H), 3.92 (s, 3H), 3.67-3.64 (m, 1 Hz), 3.19-3.16 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1ccccc1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccccc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 62.7 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.38 g of potassium carbonate, and 0.1 g of phenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of 4-(2-butynyloxy)-6-phenoxypyrimidine (the present compound (9)).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[NH:11][N:10]=1.CSC.B.N>O1CCCC1.O.CO.C(O)=O>[CH3:1][NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[NH:11][N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: B
Agent: N
Solvent: O=CO
Solvent: O
Solvent: CSC
Product: CNc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: -20 °C
Reaction time: 1 h

Procedure:
3-Methylamino-5-nitro-1H-indazole can be obtained in the following way: 2.4 ml of formic acid are added dropwise to a solution, cooled to 0° C., of 5 ml of acetic anhydride. The solution is then brought to 50° C. for one hour and then again cooled to −20° C. 3.5 g of 3-amino-5-nitro-1H-indazole in solution in 150 ml of tetrahydrofuran are then added and stirring is maintained at −20° C. for one hour. The reaction medium is concentrated by evaporation under reduced pressure and the residue thus obtained is dissolved in 50 ml of tetrahydrofuran. The solution thus obtained is cooled to 0° C. and 25 ml of borane-dimethyl sulfide complex (2M solution in tetrahydrofuran) are added dropwise. The reaction medium is brought slowly to a temperature in the region of 25° C. and then brought to reflux for 3 hours and again brought to a temperature in the region of 0° C. After addition of 100 ml of methanol, 50 ml of 3M hydrochloric methanol are added dropwise and the mixture is brought to reflux for one hour. The medium is brought to a temperature in the region of 25° C. and concentrated under reduced pressure by evaporation. The residue thus obtained is taken up with 100 ml of water and neutralized to pH 11 by addition of aqueous ammonia, and then extracted with 3 times 100 ml of ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. 1.1 g of 3-methylamino-5-nitro-1H-indazole are thus obtained in the form of an orange solid melting at 252° C.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCCl>[CH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCC(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of commercially available sec-butylbenzene (1.34 g; 10 mmol) in 1,2-dichloroethane (50 mL) was added phosphorus pentachloride (2.5 g; 12 mmol) followed by chlorosulfonic acid (1.3 mL; 20 mmol) slowly. The mixture was heated at 80° C. overnight, then cooled to room temperature and mixed with ice water (150 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (2×10 mL). The organic phases were combined and dried over magnesium sulfate and concentrated under reduced pressure to give an orange oil which was used without further purification (2.3 g).
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+:32].C(O)(C)C>O>[C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][K:32])=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCN(CCCCCC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCN(CCCCCC(=O)O[K])S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A round bottom flask fitted with an overhead stirrer was charged with C4F9SO2N(C3H7)(CH2)5COOC2H5 (63.0 g; 0.143 mole), KOH (13.1 g; 0.234 mole; pellets) isopropanol (26 mL) and deionized water (21 mL). The ensuing mixture was refluxed overnight, cooled to room temperature, yielding a solution of C4F9SO2N(C3H7)(CH2)5COOK (61.3% solids).
Reaction SMILES: [C:1]1([C@@H:7]2[O:9][C@H:8]2[C:10]([O-:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36]>C1COCC1>[OH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:10]([C@H:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:9]1)=[O:12]
Reactant: Nc1ccccc1O
Reactant: O=C([O-])[C@@H]1O[C@H]1c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Nc1ccccc1O)[C@@H]1O[C@H]1c1ccccc1
Temperature: 10 °C
Yield: 77 %

Procedure:
To a stirred suspension of potassium (2R,3S)-3-phenyloxirane-2-carboxylate (64a) (4.040 g, 20.00 mmol) in dry THF (100 mL) under nitrogen cooled in an ice-water bath was added isobutyl chloroformate (2.730 g, 20.00 mmol) slowly via syringe. NMM (0.460 mg, 4.55 mmol) was added and the mixture stirred while gradually warming to 10° C. over 75 min. The mixture was cooled to 0° C. and 2-aminophenol was added, then the cooling bath was removed and the reaction stirred at ambient temperature for 24 h. The reaction was diluted with diethyl ether (100 mL) then filtered through diatomaceous earth to remove suspended solids. Rotary evaporation of the solution afforded a yellow solid that was triturated with diethyl ether and collected by filtration. The solid was rinsed on the filter with additional diethyl ether to afford pure title compound (3.920 g, 77%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ4.00 (d, 1H, J=1.8 Hz), 4.22 (d, 1H, J=1.8 Hz), 6.80 (m, 1H), 6.87-7.00 (m, 2H), 7.40 (s, 5H), 7.95 (d, 1H, J=7.9 Hz), 9.27 (s, 1H), 9.97 (s, 1H). 13C-DEPT NMR (75 MHz, DMSO-d6) δ57.7 (CH), 58.4 (CH), 115.5 (CH), 119.4 (CH), 121.6 (CH), 125.1 (CH), 125.8 (C), 126.5 (CH), 128.9 (CH), 129.1 (CH), 135.9 (C), 147.7 (C), 165.4 (C). MS APCI, m/z=256 (M+1). LC/MS: 2.12 min.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH3:12])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1
Reactant: CCCCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 179.6 %

Procedure:
In a 250 milliliter round bottom flask there was added 2,7-dibromofluorene (6.45 grams), n-hexyl bromide (16.5 grams), tetra-n-butylammonium chloride (0.5 grams), and a 50 weight % aqueous sodium hydroxide solution. The resulting mixture was stirred at 80° C. for 3 hours. After cooling to ambient temperature, about 23° C., the product mixture was transferred to a separatory funnel and extracted with toluene. The toluene extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the organic solvent by evaporation afforded an oily residue, which was crystallized from ethanol to provide 8.8 grams of 2,7-dibromo-9,9-di-n-hexylfluorene as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39](C=O)=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:39]4[CH:42]=[CH:43][C:36]([C:35]([F:45])([F:44])[F:34])=[CH:37][CH:38]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(COc2ccc(N3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
Tert-butyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 131 (88 mg, 0.19 mmol) was dissolved in trifluoroacetic acid (5 ml), and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (2 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in dichloroethane and added 4-trifluoromethylbenzaldehyde (40 μl, 0.29 mmol) and sodium triacetoxyborohydride (82 mg, 0.38 mmol) with cooling on ice-bath followed by stirring at room temperature overnight. To the solution, a saturated sodium hydrogencarbonate solution and methylene chloride were added. The mixture was extracted with methylene chloride, and the organic phase was dried over magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-ethyl acetate to afford 2-methyl-6-nitro-2-{4-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (53 mg, yield 53%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([N:14]2[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]2)[N:3]=1.C(Cl)Cl.[C:23](Cl)(Cl)=[O:24].[OH-].[Na+]>C1(C)C=CC=CC=1.O.C(N(CC)CC)C>[N:14]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[N:7]3[O:8][C:23](=[O:24])[N:1]=[C:2]3[N:3]=2)[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Nc1cc(N2CC=CCC2)nc2nc(=O)on12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
53 Mg. of methyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide are dissolved in 5 ml. of methylene chloride. The solution is cooled to 0° C. and treated with 0.2 ml. of triethylamine and 0.12 ml. of 20% phosgene in toluene. The mixture is stirred for 30 minutes and then treated with 0.5 ml. of concentrated sodium hydroxide and 10 ml. of water. After stirring for 15 minutes, the two phases are separated, and the organic phase is again washed with water. The combined aqueous phases are acidified with hydrochloric acid, there being obtained pure methyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate having a melting point of 213°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:21]1[CH:26]=[N:25][C:24]([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)=[CH:23][N:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Clc1cnc(-n2cncn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3cnc(-n4cncn4)cn3)CC2)nc1
Temperature: 90 °C

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (50 mg, 0.18 mmol) from step 3, Example 5 and 2-chloro-5-(1H-1,2,4-triazol-1-yl)pyrazine (35.6 mg, 0.20 mmol) were added in NMP (0.89 mL), then potassium carbonate (73.8 mg, 0.53 mmol) was added and the reaction was heated to 90° C. overnight. The reaction was cooled to room temperature, water (10 mL) was added and drops of acetic acid were added to adjust pH value to ˜4, extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The water phase was back extracted with ethyl acetate (10 mL×2). The organic phase were combined and dried by magnesium sulfate, filtered and concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 30% ethyl acetate/hexane to give the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:11][CH3:12])(=[O:10])[CH3:9].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:31])=[C:18](/[C:20](=[N:24]\[S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])/[CH:21]([F:23])[F:22])[CH:19]=1>O1CCCC1.CCCCCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:31])=[C:18]([C:20]([NH:24][S@:25]([C:27]([CH3:29])([CH3:28])[CH3:30])=[O:26])([CH:21]([F:23])[F:22])[CH2:9][C:8]([O:11][CH3:12])=[O:10])[CH:19]=1
Reactant: COC(C)=O
Reactant: CC(C)(C)[S@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
A solution of diisopropylamine (6.52 g, 9.19 ml, 64.5 mmol) in tetrahydrofuran (115 ml) was treated dropwise at −70° C. with n-butylithium (1.6 M in hexane) (40.3 ml, 64.5 mmol) and stirring was continued for 15 minutes at −70° C. The solution was treated with methyl acetate (4.77 g, 5.13 ml, 64.5 mmol) and after 30 minutes chlorotitanium triisopropoxide (0.85 M in tetrahydrofuran) (85.7 ml, 72.85 mmol) was added dropwise After stirring at −70° C. for 30 min., the mixture was treated with a solution of (S,E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (intermediate A2.9) (8.2 g, 23.0 mmol) in tetrahydrofuran (76.4 ml) and stirring was continued at −70° C. for 2 hours. For the workup, the mixture was quenched with a saturated aqueous solution of ammonium chloride (100 ml), diluted with ethyl acetate (200 ml). After filtration over Dicalite®, the organic layer was separated and washed with water and brine. The aqueous layers were re-extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and evaporated to give a yellow oil (11.5 g; 116%). The residue was purified by chromatography on 50 g silica gel using a gradient of ethyl acetate/heptane=0:100 to 50:50 as the eluent to give a 1:1 diastereomeric mixture of methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (7 g, 16.3 mmol, 70.7% yield) as a colorless oil. MS (ISP): m/z=430.2 [M+H]+ and 432.1 [M+2+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1OC
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1OC

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methoxy-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: C[C@H](CCl)COc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-bromophenyl(2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [C-]#N.[K+].[C:4]([O:12]C)(=O)[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[NH2:14][OH:15].O>O1CCCC1.CO>[OH:15][NH:14][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: COC(=O)c1ccncc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Positively charged bi-functional precursor molecules for self-assembly. Potassium cyanide (50 mg) was added to a solution of methyl isonicotinate (1.17 g, 0.01 mole) and 50% hydroxylamine in water (1.3 g, 0.02 mole) in 10 mL tetrahydrofuran and 5 mL methanol. After stirring the mixture at room temperature for 18 hours, the precipitate was filtered and washed with diethyl ether and dried to give analytically pure N-hydroxy isonicotinamide. The latter was added to 5% methyl iodide in methanol and stirred at room temperature for two days. Methanol was evaporated under reduced pressure and the solid residue was crystallized from ethanol resulting in pure 4-hydroxamido-N-methylpyridinium iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].C(Cl)Cl.IC.[CH2:25]([OH:27])[CH3:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:17]([NH:18][CH2:19][CH2:10][N:9]2[CH2:3][CH2:2][O:27][CH2:25][CH2:26]2)=[N:15][N:14]=1
Reactant: CCO
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: ClCCl
Solvent: CI
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnc(NCCN2CCOCC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (500 mg; 1.34 mmol; 1 eq) in DCM (5 mL) 4-(3-Isothiocyanato-ethyll)-morpholine (255 mg; 1.61 mmol; 1.2 eq) was added. The reaction mixture was refluxed for 4 hrs under argon. A yellow solid precipitated out, which was filtered to afford an intermediate that was suspended in ethanol (5 mL). Iodomethane (190 mg; 1.34 mmol; 1.0 eq) was then added and the reaction mixture was stirred overnight at RT. It was then heated to 80° C. and stirred for another 2 hr. Filtration afforded the yellow solid product 153 mg. LC/MS (Method A) [0.41 min; 511(M+1)]
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]([C:9]1[C:10]([Cl:20])=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1)[CH2:7][CH3:8])=[O:5].CO.[OH-].[K+].[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28][SH:29]>O.C(OCC)(=O)C>[Cl:20][C:10]1[C:9]([N:6]([CH2:7][CH3:8])[C:4](=[O:5])[CH2:3][CH2:2][S:29][CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])=[CH:13][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1
Reactant: CCN(C(=O)CCCl)c1cn(-c2cccnc2)nc1Cl
Reactant: FC(F)(F)CCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C

Procedure:
A 100 mL, 3-neck round bottom flask was charged with 3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide (500 mg, 1.60 mmol) and methanol (10 mL), potassium hydroxide (107 mg, 1.92 mmol) was added, followed by 3,3,3-trifluoro-propane-1-thiol (249 mg, 1.92 mmol) The mixture was heated at 50° C. for 4 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated the reaction was complete to give exclusively a new product. The reaction mixture was cooled to 20° C. and diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organics were dried over sodium sulfate (Na2SO4) and concentrated to dryness to afford a light yellow oil, which solidified upon standing to give a light yellow solid (650 mg, quantitative).