Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:7]2)[CH2:2]1.CCN(CC)CC.[F:26][C:27]1[C:28]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[F:26][C:27]1[C:28]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32]([N:1]1[CH2:2][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:7]2)[CH2:4]1)=[O:33]
Reactant: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Reactant: O=C(c1ccccc1)N1CC[C@H](NC2CNC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CC[C@H](NC2CN(C(=O)c3sc4ccc(-c5ccccc5)cc4c3F)C2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et3N (0.07 mL, 0.5 mmol) in CH2Cl2 (2 mL) at 0° C. was slowly added a solution of compound 13e (36.3 mg, 0.125 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, % MeOH/EtOAc) to give compound Cpd 173 (16.7 mg). MS m/z (M+H+) 500.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]3=[N:23][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:19]3[CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(-c2cccnc2N)ccc1-c1ccccc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2=CC=CN3CCS(=O)(=O)N=C23)ccc1-c1ccccc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 1.163 g) in THF (dry) (30 ml) was added 2-chloroethanesulfonyl chloride (1.22 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(2-methylbiphenyl-4-yl)pyridin-2-amine (1.51 g) in THF (dry) (50 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. carefully. Water and EtOAc were added and the precipitates were collected and washed with water and EtOAc, dried in vacuo to give the title compound (339 mg) as a white solid. A part of this was recrystallized from MeCN-THF/IPE.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]([Br:20])=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[Br:20][C:5]1[CH:4]=[N:3][C:2]2[N:17]([CH2:18][CH3:19])[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[C:7]=2[CH:6]=1
Reactant: CCNc1ncccc1NC(=O)c1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN1c2ncccc2NC(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
To a solution of 2-chloro-N-{2-(ethylamino)-3-pyridinyl}-5-bromo-3-pyridinecarboxamide (54.9 g, 154.4 mmol) in pyridine (308 mL) at 50° C. was added drop-wise a 1 M solution of NaHMDS (sodium hexamethyldisilazide) in THF (355 mL, 355 mmol). After 10 min, the reaction was allowed to cool to room temperature, and then was poured over ice water (2 L). The resulting solid was filtered, rinsed with water and then hexane. The solid was dried under reduced pressure to give the title compound (36 g, 75% yield) as a dark green solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:7]=1[F:13])(=[O:5])=[O:4].C([O-])(=O)C.[K+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][CH2:29][C:30]2[NH:39][C:33]3=[N:34][CH:35]=[C:36](I)[CH:37]=[C:32]3[N:31]=2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[F:13][C:7]1[CH:8]=[C:9]([C:36]2[CH:37]=[C:32]3[N:31]=[C:30]([CH2:29][CH2:28][C:24]4[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[CH:26][N:25]=4)[NH:39][C:33]3=[N:34][CH:35]=2)[CH:10]=[CH:11][C:6]=1[S:3]([N:2]([CH3:14])[CH3:1])(=[O:5])=[O:4]
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(C)C)c(F)c4)cnc3[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 0.423 9 of N,N-dimethyl4-bromo-2-fluorobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4methoxypyridin-2-yl)ethyl]6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphos-phine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-22:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.27 g of the title compound as a solid of m.p. 211-212° C. The mass spectrum shows the molecular peak MH+ at 456.3 Da.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](Cl)(=[O:10])[CH3:9]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:8]([N:3]1[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1])(=[O:10])[CH3:9]
Reactant: Cc1c[nH]c(C)n1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)n1cc(C)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 9.6 g (0.10 M) of 2,4-dimethylimidazole in 50 ml of chloroform and 50 ml of toluene was stirred at room temperature and 3.6 ml (0.05 M) of acetyl chloride was added via syringe over 1 minute. The mixture was stirred at room temperature for 2 hours, then the mixture was filtered to remove insoluble solids, and the filtrate concentrated leaving 6.9 g (100%) of 1-acetyl-2,4-dimethylimidazole as a white crystalline solid: nmr (CDCl3) (δ): 7.00 (s, 1H); 2.68 (s, 3H); 2.57 (s, 3H); 2.21 (s, 3H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[C:10]=1[CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:21][C:10]1[C:11]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][OH:7]
Reactant: Cc1c(COC2CCCCO2)cccc1-c1cnccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1c(CO)cccc1-c1cnccn1
Reaction time: 24 h
Yield: 99.9 %

Procedure:
A solution of 2.4 g (0.008 mol) of 2-methyl-3-(pyrazinyl)-benzenemethanol tetrahydropyranyl ether and 0.21 g of the pyridinium salt of 4-methylbenzenesulfonic acid in 35 mL of ethanol was warmed to 50° C.±5° C., and stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue stirred for one hour with a mixture of 50 mL of methylene chloride and 50 mL of water. The organic layer was separated, dried, and concentrated under reduced pressure to give 1.6 g 2-methyl-3-(pyrazinyl)phenylmethanol as an oily solid residue.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13]3=[O:21].N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)OC2)C1=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:43][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:37])[C:13]3=[O:21]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: COCCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Product: COCCOCCN1C(=O)C2(COc3cc(OCCOC)ccc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 6-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (94%) as a colorless oil: 1H NMR (300 MHz, DMSO-d6) δ7.32-7.27 (m, 1H), 7.12 (d, J=7.2 Hz, 1H), 7.07-6.98 (m, 2H), 6.85 (d, J=8.7 Hz, 1H), 6.76 (dd, J=8.7, 2.6 Hz, 1H), 6.32 (d, J=2.6 Hz, 1H), 4.78 (ABq, 2H), 4.08-3.88 (m, 4H), 3.82-3.74 (m, 2H), 3.68-3.59 (m, 4H), 3.52-3.47 (m, 2H), 3.37 (s, 3H), 3.34 (s, 3H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: FC(F)(F)c1cccc(Cl)c1
Reactant: CC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-3-(trifluoromethyl)benzene (1.0 g, 5.5 mmol) in THF (10.0 mL) was added 2.5 M of n-BuLi in hexane (2.2 mL) at −78° C. and stirred for 1 h. Propylene oxide (370 mg, 6.4 mmol) was added to the reaction mixture at −78° C. and slowly warmed to rt. The reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.33 (d, J=6.1 Hz, 3H), 1.40 (d, J=6.3 Hz, 1H), 3.08-3.22 (m, 2H), 4.21-4.33 (m, 1H), 7.29-7.34 (m, 1H), 7.58-7.64 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([OH:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1.[Cu-]=O>[O:10]([C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: Brc1ccccc1
Agent: O=[Cu-]
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(Oc2cnc3[nH]ccc3c2)cc1
Temperature: 115 °C

Procedure:
To 1H-Pyrrolo[2,3-b]pyridin-5-ol (6, 645 mg, 4.81 mol) and copper(I) oxide (860 mg, 6.0 mmol) in pyridine (10 mL), bromobenzene (31, 422 uL, 4.01 mmol) was added. The mixture was heated to 115° C. for 24 hours. The reaction mixture was treated with 1N HCl and extracted with ethyl acetate. The organic layer was washed with NH4OH/NH4Cl (1:4), saturated aqueous NH4Cl twice, water, and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography (50-70% ethyl acetate/hexane) to provide the compound (P-0035, 88 mg, 10%). MS (ESI) [M+H+]+=211.2.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](F)=[CH:13][CH:12]=1)#[N:10].C1CCN2C(=NCCC2)CC1>[OH-].[Na+]>[F:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: FC1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc(N2CCCC(F)C2)c2ccccc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
3-Fluoropiperidine hydrochloride (106 mg, 0.76 mol) was dissolved in sodium hydroxide (1 M, 10 mL) and extracted with dichloromethane (4×10 mL), the combined extracts were dried over sodium sulfate, filtered and evaporated. Pyridine (2 mL) was added, followed by 1-cyano-4-fluoronaphthalene (108 mg, 0.63 mmol) and the vial was shaken at 110° C. overnight. GC-MS and TLC showed only very little conversion. DBU (10 μL) was added and the shaking was continued for 2 weeks at 110° C., after which GC-MS showed ˜50% conversion. The reaction was worked up in the same way as 165RL60 and purified by silica gel column chromatography eluted with a stepwise gradient of 0-60% ethyl acetate in n-heptane to give the title compound (29.3 mg, 12%) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[CH:2]1>[Pd].C1COCC1.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[CH:2]1
Reactant: CCOC(=O)C=Cc1cccc2cc[nH]c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCc1cccc2cc[nH]c12
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A solution of ethyl 3-(indol-7-yl)acrylate (13.0 g, 60.5 mmol) in 1:1 THF/MeOH (120 mL), was added to a Parr bottle containing 10% Pd/C (0.87 g, 0.83 mmol). The mixture was hydrogenated in a Parr shaker over 3 h. The mixture was filtered over Celite and concentrated to afford the title compound (12.8 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 11.09 (s, 1H), 7.36 (dd, J=6, 2.4 Hz, 1H), 7.29 (t, J=2.4 Hz, 1H), 6.86–6.90 (m, 2H), 6.40 (dd, J=2.8, 2.0 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H), 1.13 (t, J=6.8 Hz, 3H). MS (electrospray, m/z) 218.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH3:12][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1C=Cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of 5-fluoro-1-indanone (25 g, 0.17 mol) in dry THF (100 ml) was added dropwise to a solution of methyl magnesium bromide (70 ml of 3N in diethyl ether, 0.21 mol) in dry THF (50 ml) at 0° C. The mixture was stirred at RT overnight. The reaction mixture was quenched with aq. HCl to pH 1 and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give the title compound as an oil (22.3 g, 91%).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH:23]4[CH2:27][CH:26]([CH2:28][OH:29])[NH:25][CH2:24]4)[CH3:22])=[N:18][C:17]3=[O:30])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:48][C:49]([NH2:51])=[O:50]>CN(C=O)C>[F:40][C:2]([F:39])([F:1])[C:3]1[CH:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:22])[CH:23]4[CH2:24][N:25]([CH2:48][C:49]([NH2:51])=[O:50])[CH:26]([CH2:28][OH:29])[CH2:27]4)=[N:18][C:17]3=[O:30])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CNC(CO)C1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CC(CO)N(CC(N)=O)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
To a solution of 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-hydroxymethyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one (20 mg, 0.034 mmol) (Example 43) (30 mg, 0.051 mmol) in DMF (1 mL) was added potassium carbonate (11 mg, 0.072 mmol) followed by 2-Bromo-acetamide (30 mg, 0.22 mmol). The reaction mixture was stirred at 70° C. for 1 hour and partitioned between water and dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (100% ethyl acetate) to yield the title compound (24 mg, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:7][CH:8]=1)#[N:2].[NH2:20][OH:21]>C(O)C>[OH:21][N:20]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[N:7][CH:8]=1)[NH2:2]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cn1
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cn1
Yield: 76.4 %

Procedure:
A solution of tert-butyl 2-(((5-cyanopyridin-2-yl)methyl)(methyl)amino)acetate (2.17 g; 8.31 mmol) and 50% aqueous hydroxylamine (2.50 mL; 40.8 mmol) in ethanol (40 mL) was heated at 60° C. for 2 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo. The residue was triturated with ether to afford the title product as an off-white solid (1.87 g, 77%). 1H NMR (DMSO-d6, 400 MHz) δ 9.81 (1 H, s), 8.79 (1 H, d, J=2 Hz), 8.03 (1 H, dd, J=8.2, 2.2 Hz), 7.48 (1 H, d, J=8.2 Hz), 5.97 (2 H, br s), 3.80 (2 H, s), 2.32 (3 H, s), 1.46 (9 H, s).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:4]=12.[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:4]=12)[CH3:20]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Reaction time: 1 h

Procedure:
Sodium (0.55 g, 23.7 mmol) was added portionwise to anhydrous ethanol (25 ml) at 20° C. under an atmosphere of nitrogen. After stirring for 1 hour the solution was added to Intermediate 1 (4.622 g, 18.22 mmol) and the reaction mixture heated at reflux for 2 hours. The mixture was evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified on SPE cartridges (silica, 4×20 g) eluting with dichloromethane, ethyl acetate:petroleum ether (1:4, 1:2 then 1:1) followed by ethyl acetate). Appropriate fractions were combined and evaporated in vacuo to afford Intermediate 35 as white solid (4.33 g). LCMS showed MH+=264, TRET=2.77 min.
Reaction SMILES: [C@@H:1]1(N2C3N=CN=C(O)C=3N=C2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[NH:19]1[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]1=[O:21].N1C(=O)C2NC=NC=2NC1=O>C([O-])(=O)C.[NH4+]>[C@@H:1]1([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Agent: CC(=O)[O-]
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [NH4+]
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 1 h
Yield: 68 %

Procedure:
The assay mixture contained 2 g (wet weight) of Bacillus stearothermophilus cells, 5 mM 2′-deoxyinosine, 5 mM thymine, 20 units of xanthine oxidase (from buttermilk) in 10 ml of 50 mM ammonium acetate buffer (pH 5.5). The conversions were run at 55° C. for 1 hour. The reaction mixture was centrifuged and then filtered using an Amicon Ultrafiltration device (YM-3 membrane) and the products were separated and analyzed by HPLC (C-18 column) in 5% methanol and 5 mM phosphate buffer at pH 4.6 using a flow rate of 0.5 ml/ min. Thymidine was isolated in 68% yield (90% conversion).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH2:19]([C@H:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:19]([C@H:21]1[CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH2:24][CH2:23][N:22]1[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:20]
Reactant: CC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Yield: 60.3 %

Procedure:
Heat a mixture of 1-chloro-4-(4-fluorophenyl)phthalazine (5.02 g, 19.4 mmol), (S)-tert-butyl 2-ethylpiperazine-1-carboxylate (5.00 g, 23.3 mmol) and K2CO3 (5.38 g, 38.9 mmol) in DMSO (75 mL) at 120° C. for 1 d. Pour the reaction mixture into water, rinsing with EtOAc. Extract with EtOAc. Wash the organic layer with water (2×), then brine, dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 20 to 80% EtOAc in hexanes) to provide the title compound (5.11 g, 60%). ES/MS m/z 437.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH2:7][C:6](=O)[CH2:5]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:6]1[CH2:5][O:4][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH:7]=1
Reactant: O=C1COc2ccccc2C(=O)C1
Reactant: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C1=CC(=O)c2ccccc2OC1

Procedure:
Dimethylamine is introduced while stirring into a boiling solution of 52.8 g (0.3 mole) 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione and a spatula tip of p-toluene sulfonic acid in 225 ml toluene. The water of reaction is separated by a water separator. After the reaction has ended, the solution is concentrated, the remaining residue is filtered under suction and recrystallized from chloroform/ether. 42 g (69% of the theoretical yield) of 3-dimethylamino-1-benzoxepin-5(2H)-one are obtained. This compound displays a melting point of 136°-136° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]([F:15])([F:14])[CH3:13])=[C:7]([Cl:16])[N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([Cl:16])=[C:8]([C:12]([F:14])([F:15])[CH3:13])[N:9]=1
Reactant: COC(=O)c1nc(Cl)c(C(C)(F)F)nc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(F)(F)c1nc(N)c(C(=O)O)nc1Cl
Reaction time: 1 h

Procedure:
To a solution of 3-amino-6-chloro-5-(1,1-difluoro-ethyl)-pyrazine-2-carboxylic acid methyl ester (136 mg, 0.541 mmol) in THF (5.40 ml) was added 1M LiOH (595 μl, 0.595 mmol) at 0° C. The resulting brown solution was warmed up to it for 5 h. More 1M LiOH (95 μl, 0.095 mmol) was added at 0° C. and the reaction was stirred at it for 1 h. Then 1M HCl (632 μl, 0.632 mmol) was added and then the resulting mixture was evaporated to dryness. The resulting crude material was directly used in the coupling step without further purification.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl.[NH2:16][CH:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:18]1=[O:35]>O>[NH2:16][C:17]1([CH2:3][CH2:2][C:1]#[N:4])[C:25]2[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:18]1=[O:35]
Reactant: C=CC#N
Reactant: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2(N)CCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon gas atmosphere, 29.90 ml of acrylonitrile and 62.70 g of potassium carbonate were added to 210 ml of a dimethyl sulfoxide solution of 70.00 g of 3-amino-1-(2-fluorophenyl)-2,3-dihydro-6-methoxy-1H-indol-2-one hydrochloride, and the whole was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate extract was washed with water successively with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated to afford 70.70 g of 3-[3-amino-1-(2-fluorophenyl)-2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl]propanenitrile as a brown oil.