Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:17].N1C=CC=CC=1.[Br:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=O>C(OCC)(=O)C>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:26][C:25]([Br:24])([CH3:30])[CH3:29])=[C:3]([OH:17])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(Br)C(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(Br)CNc1ccc(S(=O)(=O)c2ccccc2)cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-benzenesulfonyl-phenol (1.06 g., 4.26 mmol) in 8 mL ethyl acetate was added pyridine (0.345 mL, 4.26 mmol). The solution was cooled to 0° C. and 2-bromo-2-methyl-propionyl chloride (0.553 mL, 4.47 mmol) was added dropwise and stirring was continuted for 2 hours. The reaction mixture was diluted with 50 mL ethyl acetate and washed with 50 mL 10% aqueous hydrogen chloride, 50 mL saturated aqueous sodium bicarbonate, 50 mL water, then 50 mL brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to yield 5-benzenesulfonyl-2-(2-bromo-2-methyl-propylamino)-phenol as a crude oil, which was used directly in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:28]3[CH:27]=[CH:26][C:25]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:24]([F:23])[CH:29]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccc(-c4ccccc4)c(F)c3)o2)c1
Temperature: 85 °C

Procedure:
The furyl bromide (99) (100 mg, 0.28 mmol) was coupled to 2-Fluoro-biphenyl-4-boronic acid (65 mg, 0.30 mmol) acid using Method E, except that the reaction was heated at 85° C. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[Br:10]Br>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([Br:8])=[CH:6][CH:7]=1)[CH2:9][Br:10]
Reactant: BrBr
Reactant: Cc1cc(Br)ccc1Br
Product: BrCc1cc(Br)ccc1Br
Temperature: 25 °C

Procedure:
In a 250 ml three-necked round-bottom flask equipped with a reflux condenser, thermometer, a pressure-equalizing dropping funnel, a magnetic stirring bar, and 74.9 g (0.30 mol) of 3,6-dibromotoluene, 15.5 ml (47.9 g, 0.30 mmol) of bromine was added dropwise under exposure to 500 W lamp for 3 hours at 190° C. The resulting mixture was cooled to room temperature. Fractional distillation gave a colorless liquid, b.p. 132-135° C./3 mm Hg. Yield, 84.3 g (85%).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[NH2:29][C:30]1[S:31][CH:32]=[C:33](/[C:35](=[N:48]/[O:49][CH:50]([C:59]([O:61][CH:62]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)/[C:36](ON2C3C=CC=CC=3N=N2)=[O:37])[N:34]=1>C1COCC1.C(OCC)(=O)C>[NH2:29][C:30]1[S:31][CH:32]=[C:33](/[C:35](=[N:48]/[O:49][CH:50]([C:59]([O:61][CH:62]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)=[O:60])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)/[C:36]([NH:1][CH:2]2[C:27](=[O:28])[N:4]3[C:5]([C:11]([O:13][CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]23)=[O:37])[N:34]=1
Reactant: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)On2nnc3ccccc32)cs1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
To a solution of diphenylmethyl 7-amino-3-chloromethyl3-cephem-4-carboxylate (VIa) (685 mg, 1.65 mmol) in THF (8.3 ml) was added benzotriazol-1-yl 2-(2-aminothiazol-4-yl)2-(Z)-(diphenylmethyloxycarbonyl-(3,4-dihydroxyphenyl) methyl]oxyiminoacetate (IIIa) (955 mg, 1.50 mmol) and the mixture was stirred for 5 hr at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on a column of silica gel to afford 566 mg (41% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22][CH2:23]O>>[CH2:22]([O:19][C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20])[CH3:23]
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 92 %

Procedure:
A solution of carboxylic acid 24 (3.5 g, 13 mmol) in HCl/EtOH(100 ml) was refluxed for 2 hr. The reaction was then cooled, concentrated and the product was dissolved in EtOAc, washed with sat NaHCO3, dried over MgSO4, and concentrated to give a solid. The solid was triturated with CH2Cl2, filtered to give the desired product (3.5 g, 92%); Mp=221-223° C.; 1NMR (DMSO-d6) δ 9.90 (s, 1 H), 9.55(s, 1 H), 7.73 (d, 2 H, J=8.5 Hz), 7.23 (d, 1 H, J=2.1 Hz), 7.17 (d. 1 H, J=2.5 Hz), 7.12 (s,1 H), 6.88 (d, 2 H, J=8.5 Hz), 4.43-4.35 (m, 2 H), 1.41 (t, 3 H, J=7.0 Hz); MS 297 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:35][CH:36]([F:38])[F:37])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1.[NH2:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48])[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:35][CH:36]([F:37])[F:38])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1
Reactant: CCOC(=O)CCN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)CC(F)F
Reactant: CCC[C@H](N)CCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CCC(=O)OCC)CC(F)F)cc1OC
Yield: 79 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (190 mg) (S)-3-aminohexan-1-ol (110 mg). The sub-title compound (130 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.91 (1H, s), 6.87 (1H, d), 6.79 (1H, d), 5.72 (1H, tt), 5.69 (2H, br s), 4.19-4.15 (2H, m), 4.11 (2H, q), 3.89 (3H, s), 3.65-3.64 (4H, m), 3.45-3.40 (1H, m), 3.21 (1H, ddd), 2.90 (2H, t), 2.78 (2H, dt), 2.48-2.43 (5H, m), 1.85-1.74 (1H, m), 1.49-1.37 (1H, m), 1.32-1.17 (5H, t), 1.09-0.99 (2H, m), 0.77 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH:12][CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[S:14](N)(N)(=[O:16])=[O:15]>COCCOCCOC>[CH3:13][N:12]1[C:11]2=[CH:10][C:9]3[C:4]([CH:3]=[C:2]2[NH:1][S:14]1(=[O:16])=[O:15])=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: NS(N)(=O)=O
Reactant: CNc1cc2ccccc2cc1N
Solvent: COCCOCCOC
Product: CN1c2cc3ccccc3cc2NS1(=O)=O
Temperature: 160 °C
Yield: 69.7 %

Procedure:
A solution of 2-amino-3-methylamino-naphthalene (168 mg, 0.98 mmol) and sulfamide (44 mg, 0.98 mmol) in anhydrous diglyme (2 mL) was added dropwise over 5 minutes to a flask heated in a 160° C. oil bath. The reaction mixture was heated at 160° C. for an additional 30 minutes, then cooled to room temperature and evaporated under vacuum. The residue was partitioned between ethyl acetate (20 mL) and 2N hydrochloric acid (10 mL). The organic phase was washed with 2N hydrochloric acid (10 mL) and brine (10 mL), dried over magnesium sulfate, and evaporated under vacuum to afford the title compound (160 mg) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CC(O)=O.[Pt]=O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[N:17]=2)=[CH:30][C:31]=1[CH3:36]
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1ccc(F)c(C)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)ccc1F
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-2-(4-fluoro-3-methylphenylamino)nicotinate (75 mg, 0.151 mmol) and platinum oxide (34.2 mg, 0.151 mmol) in DCM (2 mL) and HOAc (0.5 mL) was stirred at RT under H2 atmosphere. The mixture was subsequently filtered through Celite. The filtrate was concentrated and the residue was purified by preparative HPLC to give the title compound (50 mg, 70.6%). [M+H] calc'd for C25H32FN5O3, 470; found, 470.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:6][CH:7]([F:9])[F:8])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:6][CH:7]([F:9])[F:8])[CH3:10])#[N:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C#N)(CC(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-4,4-difluoro-2-methylbutanonitrile hydrochloride product from Example 74A was initially charged in 109 ml of tetrahydrofuran/water (1:1), and 18.94 g (137.06 mmol) of potassium carbonate and 6.27 g (36.77 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.14 g (6.69 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 7.68 g of the target compound were obtained (61% of theory over two stages, 71% purity).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:36]1([S:33]([C:29]2[CH:28]=[C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)[CH:32]=[CH:31][CH:30]=2)(=[O:34])=[O:35])[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Product: O=S(=O)(c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1)N1CCOCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-(3-bromo-benzenesulfonyl)-morpholine (example B.31) (275 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (490 mg, 84%). MS (ISP) 581.2 [(M+H)+]; mp 203–204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1Cl
Product: CC(=O)NCCc1ccccc1Cl

Procedure:
In close analogy to the procedure described above, 2-(2-chloro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH:15](Br)[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH:15]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccccc2)CC1
Yield: 36.4 %

Procedure:
A mixture of 1.03 g (3.33 mmol) of 1-(4-benzyl-piperidine-1-yl)-2-bromo-propan-1-one, 0.5 g (3.33 mmol) of 6-amino-3H-benzoxazol-2-one, 1.0 g (7.2 mmol) of potassium carbonate and 15 ml of dimethylformamide is refluxed for 5 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography using Kieselgel 60 adsorbent (Merck) and hexane:ethyl acetate=4:1 as eluent to yield 0.46 g (36.5%) of the title compound. Melting Point: 91° C. (hexane)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:17](=[O:19])[C@@H:16]([N:15]1[CH2:14][C:5]2[CH2:4][C:3]3[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:6]=2[C:12]1=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: Nc1nccs1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 44.7 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol) (Example 3, Step 1c), commercially available 2-aminothiazole (109 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid thiazol-2-yl-amide (200 mg, 53%), as a light yellow solid. 1H NMR (DMSO-d6) δ: 12.58 (br. s., 1H), 7.50 (d, J=3.4 Hz, 1H), 7.19-7.36 (m, 3H), 7.09 (dd, J=7.1, 2.2 Hz, 1H), 5.05 (dd, J=10.8, 4.9 Hz, 1H), 4.40 (d, J=19.1 Hz, 1H), 4.09 (d, J=18.6 Hz, 1H), 3.76 (br. s., 2H), 1.78-1.92 (m, 1H), 1.63-1.76 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=7.1 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>CCOC(C)=O>[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1O
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccccc3O)nc12

Procedure:
1-[2-(2-Hydroxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 2-hydroxybenzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 5-70% EtOAc in hexanes as eluant gave 53 mg (28%) of a yellow solid. MP 282-283° C., M+H=296.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](Br)=[C:21]([CH3:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1.CS(C)=O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[C:21]([CH3:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C)c3)nc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(C)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-methylphenyl)acetamide 159-1 (65 mg, 0.15 mmol) and 2-methyl-4-(tributylstannyl)pyridine 159-2 (58 mg, 0.15 mmol) in DMF (0.8 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.036 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-methyl-4-(2-methylpyridin-4-yl)phenyl)acetamide 159 as off-white solid. MS m/z 444.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.47 (s, 1H), 8.41 (d, 1H), 7.97 (d, 1H), 7.88 (d, 1H), 7.37 (dd, 1H), 7.21-7.18 (m, 2H), 7.16 (s, 1H), 7.12-7.09 (m, 2H), 3.61 (s, 2H), 3.52 (m, 4H), 3.08 (t, 2H), 3.02 (t, 2H), 2.17 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CNc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To the suspension of ethyl N-(4-chlorophenyl)-glycinate (10.4 g) in ethanol (4 ml) the solution of NaOH (4 g) in water (40 ml) was added. Upon heating a clear solution is formed, which is refuxed for 0.5 h. The solution is decolorized with activated carbon and filtered while hot. The filtrate is cooled in an ice bath and conc. HCl (5 ml) is added dropwise with stirring (pH 1-2). The precipitate formed is collected by suction filtration and washed with water. After drying in vacuo N-(4-chlorophenyl)-glycine (6.51 g) is obtained as colourless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:32]=1.Cl.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:37][CH3:36])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:32]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)(F)F)cc3)sc3cc(O)ccc23)cc1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)(F)F)cc3)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
To a vial containing (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (15.9 mg, 0.035 mmol) was added DMF (1.0 mL), followed by methylamine hydrochloride (7.1 mg, 0.105 mmol), HATU (19.9 mg, 0.052 mmol), and DIEA (0.030 mL, 0.174 mmol). The mixture was stirred at room temperature for 12 h after which the reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide (13.8 mg, 0.029 mmol, 84% yield). 1H NMR (400 MHz, CD3OD) δ ppm=2.82 (s, 3H), 6.43 (d, J=15.66 Hz, 1H), 6.82 (dd, J=8.59, 2.02 Hz, 1H), 6.89-7.02 (m, 2H), 7.13-7.30 (m, 2H), 7.37-7.52 (m, 3H), 7.61 (d, J=8.08 Hz, 2H), 7.85 (d, J=8.08 Hz, 2H). HRMS (m/z, MH+): 470.1018.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>ClC(Cl)C>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(I)cc12
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2ccc(I)cc12
Temperature: 90 °C
Yield: 71.4 %

Procedure:
To a cooled (0° C.) suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138 mL, 791 mmol) in dichloroethane (600 mL) was added POCl3 (44.25 mL, 475 mmol). After heating to 90° C. for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73.8 g) collected by filtration. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. The solids (8.3 g) were triturated with isopropanol (450 mL) and cooled in an ice bath before collecting by filtration and drying under high vacuum. The two solids were combined to provide the product (82.1 g, 71%) as white solid.
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[NH:22][C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C=O.[C:28](=O)(O)[O-:29].[Na+].Cl>O.CCCCCCC>[OH:29][CH2:28][N:22]1[C:23](=[O:25])[CH2:24][CH:19]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:21]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCC=CC1CC(=O)N(CO)C1=O
Temperature: 70 °C

Procedure:
In a reaction vessel was placed 1 liter of heptane and 550 grams of octadecenyl succinimide. The mixture was heated to 70° C. with stirring and a mixture of 137 grams of 36% aqueous formaldehyde and 22 grams of sodium bicarbonate was added. This mixture was stirred at reflux for 4 hours. Then 300 ml of water was added and the mixture neutralized with hydrochloric acid. The aqueous layer was separated and removed, then 500 ml butanol was added to the organic layer and the mixture washed with hot water. The organic layer was separated and heptane, butanol and residual water distilled off leaving as the product N-hydroxymethyl-n-octadecenyl succinimide.