Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6]([O:8][CH:9]([Cl:11])[CH3:10])=[O:7].N1C=CC=CC=1>C(OCC)C>[C:6](=[O:7])([O:4][CH:1]([CH3:3])[CH3:2])[O:8][CH:9]([Cl:11])[CH3:10]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)OC(=O)OC(C)Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
0.66 g of isopropanol was added to 1.43 g of 1-chloroethyl chloroformate, and the solution was cooled to 0° C. in an ice-water bath. The mixture of 0.84 g of pyridine and 10 ml ethyl ether was added dropwise into the solution. The solution was reacted for 1 hour at that temperature, following 4 hours at room temperature. The reaction was stopped and the mixture was filtered, and the filtrate was washed respectively with 10% hydrochloric acid and water once. The organic phase was dried and concentrated to give 1.461 g of a light yellow liquid 1-chloroethyl isopropyl carbonate with a yield of 87.7%. The crude was directly used in the next reaction without purification.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]1=[O:16].C(OCC)C>C(OCC)(=O)C>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1=[O:16]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN1CCNCC1=O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
14 ml of 3M hydrogen chloride in ethyl acetate were added to 3.0 g of the product obtained in step (1) above, and the mixture was stirred at 35° C. for one hour. Diethyl ether was added to the reaction mixture, and the crystals which precipitated out were collected by filtration, washed with diethyl ether and dried, to give 2.1 g of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:24])[C:22]=1[F:23].C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>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.O.CCO>[F:13][C:12]([F:15])([F:14])[C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[C:17]([F:16])[C:22]([F:23])=[C:21]([F:24])[CH:20]=2)[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1
Reaction time: 0.17 h

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-1,3-dihydrobenzoimidazol-2-one (1.12 g, 4 mmol, Example 6a), 3,4,5-trifluorophenylboronic acid (1.1 g, 6 mmol, Lancaster), PdCl2(PPh3)2 (35 mg, 0.05 mmol, Aldrich), Na2CO3.H2O (1 g, 8 mmol), dimethoxyethane (7 mL), H2O (3 mL) and EtOH (2 mL) was subjected to microwave irradiation at 120° C. with stirring for 10 min. Water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography, eluting with 35% EtOAc/hexane to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 333 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C@@H:16](C)[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[S:35][C:34]=2[CH:42]=1.O>C(#N)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([S:38]([C:36]4[S:35][C:34]5[CH:42]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]=5[CH:37]=4)(=[O:40])=[O:39])[CH2:16][C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1NCCN(Cc2ccc3c(Cl)ccnc3c2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2c(Cl)ccnc2c1
Yield: 67.9 %

Procedure:
1-(4-chloroquinolin-7-ylmethyl)-3-(S)-methylpiperazin-2-one hydrochloride (0.49 g, 1.4 mmol), EXAMPLE 89, is treated with acetonitrile (20 mL), triethyl amine (1.2 ml, 8.4 mmol) and a solution of 6-chlorobenzo[b]thiophen-2-sulfonyl chloride (0.41 g, 1.54 mmol), EXAMPLE 1, in acetonitrile (10 mL) at 0° C. After 2 h the solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrated to yielded the title compound (0.45 g, 0.95 mmol). MS m/z: 506, [M+1]+; 1H NMR (CD3OD, 300 MHz) δ8.8 (d, 1H), 8.15 (d, 1H), 7.9 (d, 2H), 7.85 (s, 1H), 7.4-7.5 (m, 2H), 6.8 (s, 1H), 4.8 (s, 2H), 4.0 (s, 2H), 3.4-3.45 (m, 4H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>CCO>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][O:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCOCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1nc(C(=O)NCCOCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 150 °C
Yield: 12.6 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol), (2-amino-ethoxy)-acetic acid (60 mg, 0.50 mmol), and NaOMe (20 mg, 0.37 mmol) in EtOH (5 mL) was refluxed for 16 h, then heated at 150° C. in a microwave reactor for 2 h. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH about 2, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (5-80% EtOAc/hexanes+2% AcOH) to give 4 mg of the title compound as a pale yellow solid. MS: (+) m/z 423.19 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(OCC)(=O)C.[OH-].[K+]>O>[F:1][C:2]1[CH:22]=[C:21]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)C(c1ccc(C(F)(F)F)cc1)=NCC2
Temperature: 165 °C
Reaction time: 0.25 h

Procedure:
A suspension of N-(4-fluorophenethyl)-4-(trifluoromethyl)benzamide (5.3 g, 17.1 mmol) and phosphoric pentoxide (1.2 g, 8.6 mmol) in polyphosphoric acid (40 g) was heated at 165° C. for 4 h and The reaction was cooled to RT and ice was added followed by ethyl acetate (100 mL), KOH (3N, 25 mL), and water (75 mL). The mixture was stirred for 15 min and the organic layer was separated. The aqueous layer was neutralized with KOH (3N) till pH˜7.0 was achieved and extracted with ethyl acetate (250 mL). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide 7-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline. MS (ESI pos. ion) m/z: 294 (M+H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[S:20])[CH:12]=[CH:13]C2C=CC=CC=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1(C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(Cl)(Cl)=O>CN(C=O)C.C(N(CC)CC)C>[C:1]1([S:7]([N:10]=[C:11]([S:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=[CH:13][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=S(=O)(NC(=S)C=Cc1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(N=C(C=CSc1ccccc1)Sc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
N-phenylsulfonyl-3-phenylthioacrylamide (0.50 g) was suspended to toluene (10 ml), then thionyl chloride (0.20 ml), triethylamine (0.40 ml) and one drop of DMF were added thereto at room temperature. The mixture was stirred on the 60° C. oil bath for three hours. Then it was cooled and filtered off the insoluble matter. The filtrate was concentrated under reduced pressure. The residue was dissolved to DMF (8 ml). DMF (2 ml) solution of sodium salt of thiophenol (0.30 g) was added thereto under ice-cooling, and it was stirred at room temperature for 1.5 hours. Ethyl acetate (80 ml) was added to the reaction mixture, and it was successively washed with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered off an inorganic salt, concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl N-phenylsulfonyl-3-(phenylthio)thioacrylimidate (0.14 g) as light yellow oil.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)[CH2:3]1.F[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[CH3:31][NH:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([N:32]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH3:31])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: O[C@H](CN1CC[C@H](F)C1)c1ccccc1
Agent: OC[C@@H](c1ccccc1)N1CC[C@H](F)C1
Product: COC(=O)c1ccc(N(C)[C@H](CN2CC[C@H](F)C2)c2ccccc2)cc1
Yield: 54 %

Procedure:
This was prepared from 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 4-methylaminobenzoate in 54% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=3)[S:8][C:7]=2[CH:17]=1>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[S:8][C:7]=2[CH:17]=1
Reactant: COc1ccc2cc(C3=CCCCC3)sc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C3CCCCC3)sc2c1
Yield: 49.6 %

Procedure:
5 g of 6-methoxy-2-(1-cyclohexenyl)benzo[b]thiophene was dissolved in 20 ml of ethyl acetate, 800 mg of 5% palladium-carbon was added, and hydrogenation was carried out at room temperature and at atmospheric pressure. The reaction mixture was filtered, and the filtrate was concentrated to obtain 2.5 g of 6-methoxy-2-cyclohexylbenzo[b]thiophene.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:43])[CH2:29][CH2:30][C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[O:32])[CH2:24][CH:23]1[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:51].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:51].[F:50][C:46]1[CH:45]=[C:44]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28](=[O:43])[CH2:29][CH2:30][C:31]([NH:33][C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=3)=[O:32])[CH2:24]2)[CH:49]=[CH:48][CH:47]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CCC(=O)Nc2ccc(C(=O)O)cc2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: C[C@@H](NCC1CCN(C(=O)CCC(=O)Nc2ccc(C(=O)O)cc2)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 107 mg of 4-({4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoyl}amino)benzoic acid in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. Diisopropylether was added thereto, and the resulting precipitate was collected by filtration, and dried under reduced pressure to obtain 28 mg of 4-({4-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-4-oxobutanoyl}amino)benzoic acid hydrochloride as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cn1

Procedure:
Key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII) can be prepared according to Scheme 8. Starting with commercially available 5-bromo-2-iodo-pyridine (XXXV), copper-catalyzed reaction with malonic acid diethyl ester furnishes 2-(5-bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI). Hydrolysis and decarboxylation under basic conditions gives (5-bromo-pyridin-2-yl)-acetic acid (XXXVII), which subsequently can undergo nucleophilic acyl substitution with thionyl chloride in methanol to provide (5-bromo-pyridin-2-yl)-acetic acid methyl ester (XXXVIII). Deprotonation of XXXVIII with strong base followed by alkylation with 1-bromo-3-chloropropane gives 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (XXXIX), which can then be hydrolyzed under aqueous basic conditions to furnish key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:13]2[CH:23]=[C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]3[C:15](=[O:24])[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCO)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCOc2cc3n(c(=O)n2)CCCN3C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To a solution of 2-(4-methoxyphenyl)ethanol (183 mg, 1.202 mmol) and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (200 mg, 1.002 mmol) in dimethyl sulfoxide (DMSO) (5 mL) stirred at room temp was added NaH (100 mg, 2.505 mmol) portionwise. The reaction mixture was stirred at room temp for 2 hr. The reaction was quenched with water and purified by prep-HPLC to give the title product as a white solid (150 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)C)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1cccc(OC2CCN(C)CC2)c1
Agent: Cl
Solvent: CCO
Product: CN1CCC(Oc2cccc(N)c2)CC1

Procedure:
A solution of N-[3-(1-Methyl-piperidin-4-yloxy)-phenyl]-acetamide (2.604 g) in absolute ethanol (40 mL) was treated with 37% hydrochloric acid and the solution was heated to reflux for 3 hours.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:16]=[C:15](F)[CH:14]=[C:13]([CH3:18])[C:10]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[CH3:8][C:9]1[CH:16]=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[C:13]([CH3:18])[C:10]=1[CH:11]=[O:12]
Reactant: Oc1ccccc1
Reactant: Cc1cc(F)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccccc2)cc(C)c1C=O
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
2.3 g (25 mmol) of phenol and 3.8 g (25 mmol) of 2,6-dimethyl-4-fluorobenzaldehyde were dissolved in 60 ml DMA, combined with 4.8 g (35 mmol) of K2CO3 and stirred at 150° C. for 5 min in a microwave (OEM Discoverer), filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. Taken up in a mixture of acetonitrile/water. The substance crystallised, was filtered off and dried.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([N:7]([C:14]#[N:15])[NH:8][C:9]([O:11]CC)=O)([CH3:6])[CH3:5]>C(O)C>[CH3:1][N:2]([CH3:3])[C:14]1[N:7]([CH:4]([CH3:5])[CH3:6])[NH:8][C:9](=[O:11])[N:15]=1
Reactant: CNC
Reactant: CCOC(=O)NN(C#N)C(C)C
Solvent: CCO
Product: CC(C)n1[nH]c(=O)nc1N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 100 ml of 33% strength dimethylamine in absolute ethanol are added dropwise 35 g (0.2 mol) of ethyl 2-isopropyl-2-cyano-hydrazinecarboxylate. The solution is first stirred for 8 hours at room temperature and then for 1.5 hours at the reflux temperature. Concentration in a rotary evaporator gives an oily residue which slowly crystallizes on standing. Recrystallization from cyclohexane/ethyl acetate (4:1 by vol.) gives 30 g (88% of theory) of 5-dimethylamino-1-isopropyl-1,2-dihydro-3H-1,2,4-triazol-3-one having a melting point of 111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].N1C=CC=CC=1.FC(F)(F)C(O[C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42])=O>CN(C)C=O.C(OCC)(=O)C>[F:38][C:37]1[C:32]([O:13][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[Cl:1])=[C:33]([F:42])[C:34]([F:41])=[C:35]([F:40])[C:36]=1[F:39]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Yield: 91 %

Procedure:
To a solution of the product of Example 6, Step A, 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid (10.0 g, 24.4 mmol), and pyridine (2.16 mL, 26.8 mmol) in anhydrous dimethylformamide (49 mL) was added pentafluorophenyl trifluoroacetate (5.35 mL, 30.5 mmol). The resultant solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ethyl acetate (600 mL) and washed with 0.1 M aqueous hydrochloric acid (2×240 mL), 25% saturated aqueous sodium bicarbonate (2×240 mL), and saturated brine (240 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford an oil that was purified on silica gel. Elution with hexanes-ethyl acetate (19:1) afforded 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid pentafluorophenyl ester (12.8 g, 91%) as a pale-yellow powder: mp. 108.5-110.0° C.; 1H-NMR (400 MHz, CDCl3) δ 8.77 (br s, 1H), 8.07 (br s, 1 H), 7.69 (br s, 1H), 7.48 (br d, J=7.0 Hz, 1H), 6.91 (br d, J=7.2 Hz, 1H), 6.67 (br s., 1H); 19F-NMR (376 MHz, CDCl3) δ −123.74 (s, 1F), −139.17 (d, J=16.8 Hz, 1F), −152.35 (d, J=21.4 Hz, 2F), −156.96 (t, J=21.4 Hz, 1F), −161.81 (t, J=21.4 Hz, 2F). Anal. Calcd/found for C19H6NO2F7ClI: C, 39.65/39.32; H, 1.05/0.91; N, 2.43/2.35; F, 23.10/22.85; Cl, 6.16/6.92; I, 22.05/22.50.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:25]=[CH:24][C:18]2[O:19][C:20]([F:23])([F:22])[O:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:20]1([F:22])[O:19][C:18]2[CH:24]=[CH:25][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:16][C:17]=2[O:21]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)OC(F)(F)O3)C1=O
Yield: 92.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 5-bromo-2,2-difluoro-benzo[1,3]dioxole (200.6 mg, 0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium phosphate (538 mg, 2.539 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 260 mg of the product (92% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
Into a 250 mL round bottomed flask, were added 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 40.6 mmol) and 120 mL dry THF. The solution was cooled in an ice bath, at 0° C. and Nail (2.40 g, 60.0 mmol) was added in three portions. After 20 min, p-toluenesulfonyl chloride (8.70 g, 45.63 mmol) was added, and die reaction mixture was allowed to warm to it over 30 min. The reaction mixture was concentrated and hexanes was added to obtain a precipitate, which was collected and washed with ice cold 2M NaOH. The crude product was recrystallized from EtOAc/hexanes to afford 17.8 g (92%) of the title compound as a light tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.49 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.98 (d, j=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 2.32 (s, 3H); MS: m/z 476.8/478.8 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:40]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(C1CCCCC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
(5-Chloro-benzo[1,3]-dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.22 mmol) and DIEA (0.11 mL, 0.66 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclohexanecarbonyl chloride (0.04 mL, 0.26 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 71 (43 mg, 33% yield) as a white fluffy solid. LC-MS (M+H=453, obsd.=453).