Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=O)[CH2:21][CH3:22])=[C:15]([OH:24])[CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[CH2:29]([O:31][NH2:32])[CH3:30]>C(Cl)(Cl)Cl>[CH2:29]([O:31][N:32]=[C:20]([C:16]1[C:17](=[O:19])[CH2:18][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:14][C:15]=1[OH:24])[CH2:21][CH3:22])[CH3:30]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC(=O)c3ccccc3C)cc2)CC1=O
Solvent: ClC(Cl)Cl
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC(=O)c3ccccc3C)cc2)CC1=O
Reaction time: 15 h
Yield: 56.1 %

Procedure:
Into 30 ml of chloroform was dissolved 1.6 g of 5-[4-(2-methylbenzamido)phenyl]-2-propionyl-3-hydroxy-2-cyclohexen-1-one and to the solution was added 0.4 g of ethoxyamine. The mixture was kept for 15 hours at 40° C. and the reacting solution was washed with water and a surplus amount of ethoxyamine was removed from it. After dried, the chloroform was distilled off from it and ethyl ether was added in the residue. The crystal sedimented was collected with a filtering step and 1.0 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 139°-140° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[I-:22].[Na+].O>CC(=O)CC>[I:22][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: O=C(CCCCc1ccccc1)c1ccc(CCBr)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: O=C(CCCCc1ccccc1)c1ccc(CCI)cc1
Yield: 83.2 %

Procedure:
A solution of 1-[4-(2-bromoethyl)phenyl]-5-phenylpentan-1-one (18.2 g) and sodium iodide (9.5 g) in 2-butanone (180 ml) was stirred at 60° C. for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (19.2 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=20:1) to give 1-[4-(2-iodoethyl)phenyl]-5-phenylpentan-1-one (17.2 g) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:17]([CH3:18])[C:24](=[O:25])[C:23]1[CH:22]=[C:21]([C:20]([F:35])([F:34])[F:19])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cccc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1OC

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2,3-dimethoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (72%). MS (ESI): m/z=485.127 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2[Cl:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(O)c2cc(OCc3ccccc3)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)c2cc(OCc3ccccc3)ccc2n1
Temperature: 0 °C

Procedure:
6-Benzyloxy-4-hydroxy-2-methylquinoline (2.6 g; see step (ii) above) in phosphorus oxychloride (40 mL) was heated at reflux for 3.5 hours. The mixture was then added carefully to ice/water and solid sodium carbonate added until the solution reached pH 8.0. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The resulting solid was triturated with diethyl ether to give the title compound (6.4 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)C(C)C)C>[O:1]([CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1)[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2OC1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
To solution of 4.8 g racemic-2-(2-hydroxyethyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine in dimethylformamide (100 mL) and 3.4 mL diethylisopropylamine at 0° C. was added 4.7 g tert-butyldimethylsilylchloride. The reaction mixture was stirred at 0° C. for 20 minutes, at room temperature for 3 hour, concentrated and the resulting residue was partitioned between sodium bicarbonate solution and EtOAc. The aqueous phase was extracted with EtOAc and the combined organics washed with water, brine then dried over MgSO4. The solvent was removed by in vacuo and the crude material purified by column chromatography (hexanes/EtOAc) to yield 1 g of the desired product racemic-2-(2-t-butyldimethylsiloxyethyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine MS (m/e): 353 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:25]([O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1)[CH3:26]>C(N(CC)CC)C.[Cu]I.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>[CH:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:32]3[CH:33]=[CH:34][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:36])=[CH:30][CH:31]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:15])[CH3:14]
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 151.0 mg (76%) of the title compound as an orange solid.
Reaction SMILES: C1(CBr)CC1.[CH:6]1([CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=2)[CH2:8][CH2:7]1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.N1CCCCC1>O1CCCC1.[Pd]>[CH3:21][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH:6]2[CH2:8][CH2:7]2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:22][CH:24]1[O:26][CH2:25]1
Reactant: ClCC1CO1
Reactant: Cc1cc(OCCOCC2CC2)ccc1O
Agent: [Pd]
Agent: BrCC1CC1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(OCCOCC2CC2)ccc1OCC1CO1

Procedure:
The epoxide starting material is obtained from reaction of 4-hydroxy-3-methylphenyl benzoate with benzyl bromide to give 4-benzyloxy-3-methylphenyl benzoate (M.P. 120°-121° from methanol/ether), followed by de-esterification with 2M NaOH solution to give 4-benzyloxy-3-methylphenol (M.P. 69°-70° from ether/hexane) and reaction with 2-bromoethanol (light brown oil) to form an alcohol which is reacted with cyclopropylmethyl bromide in tetrahydrofuran. Debenzylation of the cyclopropylmethoxyethoxy derivative (unpurified) with 10% Pd on activated charcoal forms 4-(2-(cyclopropylmethoxy)ethoxy)-2-methylphenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine to give 2-methyl-1-(2,3-epoxypropoxy)-4-(2-(cyclopropylmethoxy)ethoxy)benzene (light brown oil after chromatography on silica gel with toluene/ethyl-acetate (8:2)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (466 mg) described in Preparation Example 254 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (420 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[C:12]1C=CC=[CH:17][C:13]=1[C:14](Cl)=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:13]([CH3:17])([CH3:14])[CH3:12])=[O:5]
Reactant: O=C(Cl)c1ccccc1I
Reactant: O=C(O)c1ccccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1I
Reaction time: 0.33 h

Procedure:
2-Iodobenzoic acid (10.06 g, 40.56 mmol) was converted to 2-iodobenzoic chloride by reacting with oxalyl chloride (5.34 mL, 60.84 mmol) in methylene chloride (100 mL), initiated by a drop DMF. The solvent and excess oxalyl chloride were removed by rotary evaporation. To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) and then cooled to −78 C. A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added, followed by the solution of 2-iodobenzoic chloride in THF (50 mL). The resulting reaction mixture was stirred at −78 C for 20 min and then at rt for 2 hours. The reaction was quenched by water and worked up. The product was purified by flash chromatography to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reaction time: 6 h
Yield: 96.6 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (2.0 g, 6.1 mmol) in DCE (10 ml) under a nitrogen atmosphere was added acetaldehyde (1.0 ml, 18 mmol) followed by acetic acid (2.1 ml, 37 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (6.6 g, 31 mmol). The reaction was stirred for 16 h at room temperature after which time additional acetaldehyde (1.0 ml, 22 mmol) and sodium triacetoxyborohydride (3.0 g, 14 mmol) were added and the reaction was stirred for a further 6 h whereupon distilled water (100 ml) was added and the phases were separated. The aqueous phase was washed with EtOAc (3×100 ml), the combined organics were then dried using Na2SO4, filtered and evaporated to afford the title compound as a colourless oil (2.10 g, 93%) which was suitable for use without any further purification. LC-MS 96%, 2.38 min (3.5 minute LC-MS method), m/z=356.1/357.9, 1H NMR (500 MHz, Chloroform-d) δ 7.70 (d, J=2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 3.95 (d, J=11.3 Hz, 2H), 3.88 (d, J=9.1 Hz, 3H), 3.32 (td, J=11.5, 2.5 Hz, 2H), 3.04 (q, J=7.1 Hz, 2H), 2.98-2.87 (m, 1H), 2.44 (s, 3H), 1.77-1.55 (m, 4H), 0.86 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])/[C:6](/[NH:15][C:16](=[O:35])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:19][C:18]=1[Cl:34])=[CH:7]/[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14]>CO.O1CCCC1>[Cl:34][C:18]1[CH:19]=[C:20]([CH:23]([OH:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14])/[C:5]([OH:36])=[O:4])=[O:35]
Reactant: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c(/C=C(\NC(=O)c2ccc(C(O)CCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.5 mL, 0.5 mmol) was added to a solution of rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (Example 229; 70 mg, 0.14 mmol) in methanol/tetrahydrofuran (1:1; 2 mL). After the solution was stirred at room temperature for 5 h and the solvents were removed under reduced pressure. Water (5 mL) was added and the mixture was filtered through Celite®. The filter pad was washed with water (2 mL) and the combined filtrates were acidified with 1N hydrochloric acid solution (0.5 mL). The mixture was stirred for 1 h, then the solids were filtered off, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to give rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid (39.3 mg, 58% yield) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[H-].[Na+].FC(F)(F)S(O[CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:6]([C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1cc2cc(Br)ccc2n1CC(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a mixture of (5-bromo-1H-indol-2-yl)-morpholin-4-yl-methanone (6.64 g, 20 mmol) in tetrahydrofuran (60 mL) was added sodium hydride (60% dispersion in oil, 979 mg, 24 mmol) in several portions. The mixture was stirred 15 min at room temperature then 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.16 g, 27 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was washed with hydrochloric acid (1N) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel with dichloromethane:ethyl acetate (98:2 to 94:6 v/v) as eluant, to give 4.65 g (58%) of the desired compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[S:15][C:14]([NH:16]C(C(F)(F)F)=O)=[C:13]([C:23]([OH:25])=[O:24])[C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[C:13]([C:23]([OH:25])=[O:24])[C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)C(F)(F)F)c1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(C(=O)OCc2ccccc2)sc(N)c1C(=O)O
Reaction time: 24 h
Yield: 96 %

Procedure:
The compound prepared in Example 6 was dissolved in THF (1 ml) and Et2O (1 ml). 10% Na2CO3 (2 ml) was added and the reaction was stirred vigorously. After 24 h, the reaction was acidified with 1M HCl and extracted with CHC13 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated to yield 40 mg of a white solid (96%). 1H-NMR (CDCl3) 2.83 (s, 3H), 5.34 (s, 2H), 7.40 (m, 5H); 13C-NMR. (d6-DMSO) 15.7 (CH3), 65.1 (CH2), 105.3 (C), 107.0 (C), 127.7 (CH), 128.0 (CH), 128.6 (CH), 136.6 (C), 148.7 (C), 161.9 (C), 166.7 (C), 167.2 (C);
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH2:15][CH2:16]O)[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:6][N:7]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[ClH:14].[NH2:2][C:3]1[N:4]([CH2:15][CH2:16][Cl:20])[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:6][N:7]=1
Reactant: NC1=NCC(c2ccccc2Cl)N1CCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NC1=NCC(c2ccccc2Cl)N1CCCl

Procedure:
A mixture of 4.15 parts of 2-amino-5-(o-chlorophenyl)-2-imidazoline-1-ethanol hydrochloride in 22.5 parts of chloroform is treated with 3.6 parts of thionyl chloride and the whole is stirred at reflux temperature for 30 minutes. The solvent is evaporated and the residue is taken up in 15 parts of chloroform. The latter is evaporated again, yielding 2-amino-1-(2-chloroethyl)-5 (o-chlorophenyl)-2-imidazoline hydrochloride as a residue.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=O)=[CH:5][C:4]([CH3:12])=[N:3]1.Cl.[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C.O.[Rh](Cl)(Cl)Cl>[CH2:14]([NH:22][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=1)=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1cc(C)nn1C
Agent: Cl[Rh](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NCCc2ccccc2)n(C)n1
Reaction time: 21 h

Procedure:
A solution of 1.68 g of ethyl 2,5-dimethyl-2H-pyrazole-3-carboxylate in 3.8 ml of phenethylamine was treated with 0.10 g of rhodium(III) trichloride.trihydrate and heated to 140° C. while stirring for 21 h. Subsequently, the mixture was taken up in ethyl acetate/water, adjusted to pH 2-3 with 2N HCl and extracted three times with ethyl acetate. The combined organic phases were washed neutral with sat. aqueous sodium chloride solution, dried over sodium sulfate and evaporated. Chromatographic purification on silica gel with hexane/ethyl acetate 50:50 yielded 1.92 g (79%) of cryst. product of m.p. 97°-98° C. Recrystallization of a sample from tBuOMe gave 2,5-dimethyl-2H-pyrazole-3-carboxylic acid phenethyl-amide as colorless crystals of m.p. 97.5°-98.5° C.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Product: COC(=O)CON1C(=O)c2ccccc2C1=O
Yield: 56 %

Procedure:
The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and methyl 2-bromoacetate in 56% yield using the same procedure as described in the synthesis of intermediate G. LCMS (method B): [MH]+=236, tR=1.82 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22]C)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.CC(O)=O.Br>O.[OH-].[Na+]>[NH2:21][C:19]1[CH2:18][O:17][CH2:16][C@:15]2([C:14]3[CH:13]=[C:12]([OH:22])[N:11]=[CH:10][C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[N:20]=1
Reactant: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(O)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
(S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.611 g, 1.624 mmol) was dissolved in HOAc (6.14 mL, 107 mmol). Hydrobromic acid (48% aq.; 6.06 mL, 53.6 mmol) was added and the reaction was stirred at 100° C. for two hours. The reaction was diluted with water, slowly neutralized to pH 7 with 6N NaOH, and stirred overnight, during which a light pink solid crashed out of solution. The solution was filtered, and the solid was air dried to afford (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.554 g, 1.530 mmol, 94% yield) as an off-white solid. [M+H]+=363.9 Step 2: A flask was charged with (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.250 g, 0.690 mmol), cesium fluoride (9.17 mg, 0.069 mmol), and acetonitrile (6.90 mL). Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.272 mL, 1.381 mmol) was added slowly and the reaction was stirred for 15 minutes. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM), to afford (S)-7-bromo-3-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol, 19.68% yield) as a light yellow solid. [M+H]+=411.9 Step 3: A microwave vial was charged with (S)-7-bromo-3-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol). 2-fluoropyridin-3-ylboronic acid (0.038 g, 0.272 mmol), potassium phosphate (0.087 g, 0.408 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.81 mg, 6.79 μmol) were added. The vial was flushed with Ar (g), then dioxane (0.509 mL) and water (0.170 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM) to afford (S)-3-(difluoromethoxy)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.042 g, 0.098 mmol) as a light yellow solid. [M+H]+=429.0
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32]O)=[N:24]1>C(#N)C>[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][Br:20])=[N:24]1
Reactant: BrBr
Reactant: Cn1nc(CO)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cn1nc(CBr)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
To a stirring solution of 692 mg (2.64 mmol, 1.3 equiv) of triphenylphosphine in 10 mL of acetonitrile at 0° C. is added 125 μL (2.44 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 330 mg (2.03 mmol) of (1-Methyl-1H-indazol-3-yl) methanol, prepared as in Intermediate 24, in 5 mL of acetonitrile is added over 2 min. The resulting solution is stirred 1.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 185 mg of the title compound as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ7.82 (d, 1H), 7.40 (m, 2H), 7.22 (m, 1H), 4.82 (s, 2H), 4.03 (s, 3H); Rf =0.87 in hexane/EtOAc 1/1.