Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[N:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>>[CH3:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:18]2[CH:17]=[C:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=2)=[N:32][CH:33]=1
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cnc(Nc2cnc(C)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 33.3 %

Procedure:
Methyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate (90 mg, 0.23 mmol), 5-methylpyrazin-2-amine (38 mg, 0.35 mmol, as described in Itoh et al., 2002), cesium carbonate (153 mg, 0.47 mmol), 4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (11 mg, 8 mol %), and tris(dibenzylidene acetone)dipalladium chloroform complex (10 mg, 4 mol %) were added to an oven-dried microwave reactor vial (2 mL) which was capped and flushed with nitrogen. Anhydrous toluene (1.35 mL) was added and nitrogen was bubbled through the stirred solution for 10 minutes. The mixture was heated at 130° C. for 30 minutes by microwave irradiation. The solution was cooled, diluted with dichloromethane-methanol and adsorbed onto a 2 g (solute SCX-II column. The resin was washed with methanol, then with 2M ammonia in methanol. The basic fractions were concentrated and the residue was purified by preparative TLC, eluting with 10% methanol-dichloromethane) to give methyl 6-(5-methylpyrazin-2-ylamino)-4-(1-Boc-piperidin-4-ylmethylamino)nicotinate (35 mg) as a light green powder.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[C:28]2[C:7]([CH2:8][C@:9]3([CH2:27]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[C:10]3=[O:26])=[CH:6][C:5]=1[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])([O-:3])=[O:2].Cl.[OH-].[Na+].C(N)CN>CO>[N+:1]([C:4]1[CH:29]=[C:28]2[C:7]([CH2:8][C@:9]3([CH2:27]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]3=[O:26])=[CH:6][C:5]=1[CH2:30][C:31]([OH:33])=[O:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: NCCN
Product: O=C(O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
A solution of tert-butyl ((2S)-6-nitro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetate from Step C (2.01 g, 3.83 mmol) in MeOH (25 mL) was saturated with HCl (g) and stood at ambient temperature for 18 h. The mixture was concentrated to dryness in vacuo, then redissolved in MeOH (25 mL). This stirred solution was adjusted to pH 10 with 10 N NaOH and ethylene diamine (0.26 mL, 3.83 mmol) was added. The resulting mixture was stirred for 3 h, then concentrated to dryness in vacuo. The residue was dissolved in THF (25 mL) and 1 N NaOH (25 mL, 25 mmol) was added. The mixture was stirred at ambient temperature for 18 h, then the THF was removed under reduced pressure. The residual mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (100 mL). The organic layer was discarded and the aqueous layer was adjusted to pH 2 with aqueous HCl, then extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2 SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=340 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15]([OH:16])=[C:14]([OH:17])[N:13]=[C:12]([C:18]3([CH3:32])[N:23]([CH3:24])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:24][N:23]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1([C:12]1[N:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=2)=[O:9])[C:15]([OH:16])=[C:14]([OH:17])[N:13]=1)[CH3:32]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1(C)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCNCC1(C)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1

Procedure:
Crude material tert-butyl 3-(4-{[(4-fluorobenzyl)amino]carbonyl}-5,6-dihydroxypyrimidin-2-yl)-3,4-dimethylpiperazine-1-carboxylate (C-46) was stirred in DCM/TFA (1:1) for 1 hour. Evaporation of the solvent afforded the crude title compound (C-47).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(I)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoro-4-iodoaniline to yield 2-[(2-fluoro-4-iodophenyl)amino]phenylacetic acid.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:16]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:7][C:8]([N:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[N:9][CH:10]=1.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>N1C=CC=CC=1>[CH2:35]([NH:37][C:38](=[O:39])[O:14][CH2:13][CH2:12][N:11]([C:8]1[CH:7]=[C:6]([CH:16]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:5]([Cl:4])=[CH:10][N:9]=1)[CH3:15])[CH3:36]
Reactant: CN(CCO)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)OCCN(C)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 19 h
Yield: 74 %

Procedure:
To a methylene chloride (1.0 ml) solution of 2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethanol (73 mg, 0.15 mmol) was added pyridine (0.5 ml), followed by further addition of ethyl isocyanate (100 μl). The resulting mixture was stirred for 19 hours. After the reaction mixture was concentrated under reduced pressure, the residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to yield the title compound (65 mg, 74%) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[N:9][C:5]2=[N:6][C:7]=1[Cl:8].[C:13]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:7]1[N:6]=[C:5]2[N:9]=[CH:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: Clc1nc2cccnc2nc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nc2cccnc2nc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 17.1 %

Procedure:
2,3-dichloro-pyrido(2,3-b)pyrazine (300 mg; 1.5 mmol; 1 eq.), benzenesulfonamide (235.8 mg, 1.5 mmol, 1 eq.) and K2CO3 (207.3 mg, 1.5 mmol, 1 eq.) are taken up in anhydrous DMA (10 ml) under argon. The reaction mixture is stirred at room temperature for 7 days. The solvent is evaporated and the residue obtained is purified by prep HPLC using a gradient of H2O, TFA 0.1%/ACN, TFA 0.1%, to afford 82.1 mg (17%) of the title compound. 1H NMR (DMSO-d6) δ 8.67 (dd, J=5.7, 1.5 Hz, 1H), 8.57 (dd, J=7.9, 1.5 Hz, 1H), 8.08 (dd, J=8.0 Hz, 1.8 Hz, 2H), 7.57 (dd, J=7.9, 5.7 Hz, 1H), 7.54-7.46 (m, 4H). HPLC (max plot) 94%; Rt 1.96 min. LC/MS: (ES+): 321.0, (ES−): 319.0.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[C:29]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)=[C:28]([O:39][CH2:40][CH2:41][OH:42])[N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].CN(C1C=CC=CN=1)C>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]2[N:25]=[CH:26][N:27]=[C:28]([O:39][CH2:40][CH2:41][O:42][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:29]=2[O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)(=[O:22])=[O:21])=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCO)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccccn1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOC(=O)N2CCOCC2)c1

Procedure:
In analogy to Example 1, part a), from 0.15 ml of morpholine-4-carbonyl chloride and 200 mg of p-tert-butyl-N-[6-(2-hydroxy-ethoxy) -5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide with the addition of 154 mg of dimethylaminopyridine at a reaction period of 12 hours there was obtained morpholine-4-carboxylic acid 2-[6-(4-tert -butyl-phenylsulfonylamino)-5-(3-methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl ester. MS: 587.4 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:25][C:26]1([CH3:42])[O:31][CH:30]([C:32]([NH:34][CH2:35][CH2:36][C:37](O)=[O:38])=[O:33])[C:29]([CH3:41])([CH3:40])[CH2:28][O:27]1>>[CH3:25][C:26]1([CH3:42])[O:31][CH:30]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:38])=[O:33])[C:29]([CH3:41])([CH3:40])[CH2:28][O:27]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 87 %

Procedure:
N-(3-Hydroxypropyl)oleamide (3.54 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 5.05 g of the title compound (yield: 85%)
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])([OH:3])=O.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:1]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3]
Reactant: COC(=O)c1cc(O)cc(OCC(=O)O)c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCC(=O)NCCN(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl 3-carboxymethoxy-5-hydroxybenzoate (2 g), N,N-dimethylethylenediamine (1.07 ml) and 1-hydroxybenzotriazole (1.31 g) in N,N-dimethylformamide (40 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.86 g) under ice cooling. After stirring at room temperature for 5 hours, the solvent of the reaction mixture was removed under reduced pressure. The residue was purified by column chromatography on aluminum eluting with a mixture of chloroform and methanol (20:1 to 5:1). The fractions containing the desired product were collected and evaporated in vacuo. Then the residue was triturated with diethyl ether, collected by filtration and washed with diethyl ether to give methyl 3-[(2-dimethylaminoethyl)carbamoylmethoxy]-5-hydroxybenzoate (1.94 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([CH2:24]Cl)=[CH:18][C:19](=[O:23])[O:20]2)=[CH:15][CH:14]=1.BrC1C(C)=CC([O:31]CCC(C)(O)C)=CC=1C.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH2:18][C:19]([OH:31])=[O:23])=[CH:24][O:20][C:21]=2[CH:22]=1
Reactant: O=c1cc(CCl)c2ccc(O[C@@H]3CCc4c(Br)ccc(F)c43)cc2o1
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1coc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc12
Temperature: 25 °C

Procedure:
To 15.0 g (35.4 mmol) 7-((R)-4-bromo-7-fluoroindan-1-yloxy)-4-chloromethyl-chromen-2-one (product from step 2) in 45 ml EtOH, 9.29 ml (177 mmol) aq. NaOH (50%) is added. The funnel is rinsed with 50 ml water and the mixture is heated to reflux for approx. 0.5 h. Then, over a time period of 30 min a mixture of 30 ml water and 14.7 ml (177 mmol) conc. HCl (37%) is added. The suspension is cooled to r.t., the product is filtered off, washed with EtOH/water (1:1, 2×30 ml) and dried. Yield: 14.0 g; Rf=0.38 (silica gel, PE/EtOAc/AcOH=6/4/0.1); Mass spectrum (ESI): m/z=405 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH:17](SC)[C:18]([NH2:20])=[O:19]>[Ni].C(O)C.CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([NH2:20])=[O:19]
Reactant: CSC(C(N)=O)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCO
Product: NC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 21.34 g (0.0639 mole) of 2-amino-3-benzoyl-5-chloro-α-(methylthio)-phenylacetamide and excess Raney nickel in a mixture of 900 ml of absolute ethanol and 200 ml of dimethylformamide was stirred at room temperature for 45 min. The mixture was filtered through celite to remove the Raney nickel. The solvent was removed in vacuo to give a yellow solid which when recrystallized melted at 213.5°-215.0° C.(d).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:26])[CH:6]=1)[CH3:2].Br[C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)[C:17]=2[CH3:26])[CH:6]=1)[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc(C(F)(F)F)c1
Product: CCOC(=O)c1cc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)cc(C(F)(F)F)c1

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)-5-trifluoromethyl-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH3:19])[O:9][C:8]=1[CH3:20])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:9][C:8]([CH3:20])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:11]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1cc(F)ccc1-c1cc(C(Cl)CC(C)C)c(C)o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)c(C)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-5-(4-fluoro-2-methylphenyl)-2-methylfuran (442 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (188 mg, 26%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:28])[C:13]([CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50].C(=O)([O-])O.[Na+]>ClCCCl>[Br:50][CH2:26][CH2:25][CH2:24][CH2:23][C:13]1[C:12](=[O:28])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([F:29])[CH:10]=2)[N:15]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:14]=1
Reactant: CCC(CC)n1cc(CCCCO)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCC(CC)n1cc(CCCCBr)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
199 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-3-(4-hydroxybutyl)quinolin-4(1H)-one was dissolved in 11 ml of 1,2-dichloroethane, and 257 mg of triphenylphosphine and 405 mg of carbon tetrabromide were added at room temperature, followed by stirring for 15 minutes. Aqueous saturated sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with chloroform, washing with aqueous saturated sodium chloride, drying over anhydrous sodium sulfate and then concentration under a reduced pressure. The resulting residue was purified by a chromatography to obtain 78 mg of 3-(4-bromobutyl)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro quinolin-4(1H)-one.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[F:16])[CH2:5][N:4]([CH2:17][CH3:18])[C:3]1=[O:19].C(N(CC)C(C)C)(C)C.[CH:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](OC2C=CC=CC=2)=[N:37][C:38]#[N:39])=[CH:31][CH:30]=1>ClCCl>[C:38]([N:37]=[C:36]([O:35][C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1)[NH:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[F:16])[CH2:5][N:4]([CH2:17][CH3:18])[C:3]1=[O:19])#[N:39]
Reactant: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)Oc2ccccc2)C1=O
Reaction time: 5 h
Yield: 80 %

Procedure:
A solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-ethylazepan-2-one (135 mg, 0.503 mmol) in dichloromethane was treated N,N-diisopropylethylamine (65 mg, 0.503 mmol) and diphenyl N-cyanocarbonimidate (204 mg, 0.855 mmol). After 5 h, the reaction was quenched with 0.5N NaOH and the organic layer washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organics were dried, filtered and concentrated. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound (166 mg). MS 413.3 (M+1).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:39][CH2:40][C:41]([N:43](C)[C:44]1C=CC(N)=CC=1)=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][CH2:40][C:41]([N:43]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]2[N:11]=[C:6]([NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=2)=[CH:14][CH:15]=1)[CH3:44])=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(N)cc1
Product: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 2-benzoxy-N-methyl-N-(4-aminophenyl)acetamide and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave 2-benzyloxy N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (MS calcd for C26H28N6O2 456.2, found [MH] 457.0).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:17]1[O:19][CH2:18]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:21]([O:20][CH2:16][CH:17]([OH:19])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH:17]([OH:19])[CH2:16][O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOCC1CO1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)COc1ccc(Cc2ccc(OCC(O)COCCCC)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Bis(p-hydroxyphenyl)methane (303 g; 1.5 moles), butyl glycidyl ether of epoxide content 7.45 equiv./kg (402.7 g; 6 equiv.), and benzyltrimethylammonium chloride (3 g) were stirred together and heated to 100° C., at which temperature an exothermic reaction commenced. The mixture was kept at 120° C. by moderate cooling and then, when the temperature of the mixture began to fall, heating was resumed, keeping the temperature at 120° C. for 1 hour and 150° C. for 4 hours. The mixture was cooled, and its epoxide content was found to be 0.1 equiv./kg, indicating that the reaction was virtually complete.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([N+:11]([O-])=O)[CH:5]=1.[C:15]1([NH:21][C:22](=O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22]([CH3:23])=[N:11][C:6]=2[CH:5]=1)=[O:14]
Reactant: CC(=O)Nc1ccccc1
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Product: COC(=O)c1ccc2c(c1)nc(C)n2-c1ccccc1
Yield: 58.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 4-Bromo-3-nitrobenzoic acid methyl ester (130 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as colorless crystals (78 mg, 59%). mp 108-110° C. 1H NMR (DMSO) δ 2.55 (s, 3 H), 3.78 (s, 3 H), 7.30 (d, J=8.2 Hz, 1 H), 7.52-7.71 (m, 5 H), 7.92 (d, J=8.2 Hz, 1 H), 8.30 (br s, 1 H); 13C NMR δ 13.6, 52.1, 110.8, 118.5, 124.7, 124.8, 127.0, 129.7, 130.1, 134.0, 137.9, 153.7, 157.8, 166.2. HRMS (FAB): cal. for C16H15N2O2 [M+H]+: 267.1134; found: 267.1128.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(C(=O)O)c(-c2ccncc2)s1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of ethyl 2-amino-5-(4-pyridyl)-4-thiazolecarboxylate (5.0 g) and sodium hydroxide (1.6 g) in a mixture of methanol (50 ml) and water (10 ml) was stirred at ambient temperature for an hour. The reaction mixture was evaporated in vacuo and the residue was dissolved in water. The aqueous solution was adjusted to pH 5 with 10% hydrochloric acid. The precipitate was collected by filtration and dried over phosphorus pentoxide in vacuo to afford 2-amino-5-(4-pyridyl)-4-thiazolecarboxylic acid (3.54 g).