Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:29]=[CH:28][C:24](C(O)=O)=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CNC[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:63][N:64]([CH3:67])[CH:65]=[O:66]>C(N(CC)CC)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:65]([N:64]([CH3:67])[CH2:63][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:66])=[CH:28][CH:29]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(Br)c2c1
Reactant: CCOC(=O)CCNC
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2Br)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a mixture of 4-{[(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (125 mg) synthesized in Example A102(6), ethyl 3-(methylamino)propanoate (53.8 mg), 1-hydroxybenzotriazole monohydrate (62.9 mg), triethylamine (114 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.6 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (35% ethyl acetate/hexane) to give the title object compound (124 mg, 79%) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C)C=O.O1CCCC1>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCOc1ccc2cc(C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14 g (69 mmol) of methyl 6-hydroxynaph-thalene-2-carboxylate in 90 ml of dimethylformamide and 90 ml of tetrahydrofuran are introduced into a round-bottomed flask and under a nitrogen stream. 3.3 g (82 mmol) of sodium hydride at 60% are added in small portions. When the gas emission has ceased, 8.7 ml (76 mmol) of 2-methoxyethoxymethyl chloride are added and the reaction medium is stirred for 3 hours at room temperature. It is then poured into ice-cold water and extracted with ether. The organic phase is dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (80/20) mixture and 17 g (85%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=[C:13](Br)[C:12]=2[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1>CN1CCCC1=O.[Cu]I>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=[C:13]([N:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]3=[O:41])[C:12]=2[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(Br)c32)C1=O
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(-n4ccccc4=O)c32)C1=O
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-4-bromo-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.15 g, 0.28 mmol), copper (I) iodide (27 mg, 0.14 mmol), potassium carbonate (76 mg, 0.55 mmol), and 2-hydroxypyridine (52 mg, 0.55 mmol) in N-methyl-2-pyrrolidinone (2.7 mL) was stirred in an oil bath at 140° C. for 3 hours. The resultant mixture was filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1-5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound. ES MS M+1=560
Reaction SMILES: C(C1C=CC=CC=1C(C)C)(C)C.C(C1C=CC=CC=1C(C)C)(C)C.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[CH:29]=1)([CH3:27])[CH3:26].[O:37]=[O:38].[OH:39][O:40]O.C(C1C=CC=C(C(C)C)C=1)(C)C>>[O-:39][OH:40].[O-:37][OH:38].[CH:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=1)([CH3:36])[CH3:35]
Reactant: O=O
Reactant: OOO
Agent: CC(C)c1cccc(C(C)C)c1
Agent: CC(C)c1ccccc1C(C)C
Product: [O-]O

Procedure:
The objects of the present invention are achieved by a process in which diisopropylbenzene, comprised of m-diisopropylbenzene diisopropylbenzene and less than 6% o-diisopropylbenzene, is oxidized under anhydrous, non-alkaline conditions with oxygen or air at about 85° C.-95° C. in a continuous process. The hydroperoxidation method of the present invention produced a 92.8% yield of m-diisopropylbenzene dihydroperoxide (m-DHP) and m-diisopropylbenzene hydroxyhydroperoxide (m-HHP), of which approximately 75% was m-DHP and 25% was m-HHP. Furthermore, the composition remains substantially the same through at least ten cycles of batch operations.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:33])=[C:30]([CH3:32])[CH:31]=2)=[CH:20][N:19]=1)([O-])=O>C1(OC)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:33])=[C:30]([CH3:32])[CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: COc1ccccc1
Product: Cc1cc(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)cnc1C
Yield: 47 %

Procedure:
A mixture of 5-bromo-2-(4-aminobutyl)-3-methyl pyridine, (0.68 g) and 2-nitroamino-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.83 g) in anisole (25 ml) were refluxed for 4 hrs. Excess petroleum ether was added to precipitate the product which was then chromatographed on a silica gel column in CHCL3. The product crystallised under ether to give 2-[4-(5-bromo-3-methyl-pyrid-2-yl)-butylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.6 g) m.p. 126°-128° C.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[CH:13]1([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:15][CH2:14]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[C@:29]3([C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28]2)=[CH:23][CH:22]=1>>[CH:13]1([S:16]([NH:19][C:3](=[O:12])[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C@:29]4([CH2:28][C@H:27]4[C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[C:30]3=[O:38])[CH:5]=2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(F)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)C1CC1)c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(F)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 3-bromomethyl-benzoic acid methyl ester, cyclopropanesulfonamide (commercially available), (1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C27H23FN2O4S: 490, observed (M+H)+: 491.2 1HNMR (400 MHz, DMSO-d6) δppm 0.84-0.94 (m, 2 H) 0.94-1.04 (m, 2 H) 2.08-2.18 (m, 1 H) 2.32-2.40 (m, 1 H) 2.98-3.09 (m, 1 H) 3.21 (t, 1 H) 5.06 (s, 2 H) 6.09 (d, 1 H) 6.68 (t, 1 H) 6.89 (d, 1 H) 7.00-7.18 (m, 4 H) 7.33-7.50 (m, 4 H) 7.80-7.92 (m, 2 H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][C:11](=[O:23])[N:10]([CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.O>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])=[CH:3][CH:4]=3)=[N:9][N:10]([CH3:24])[C:11](=[O:23])[CH2:12][C:13]=2[CH:18]=1
Reactant: COc1cc2c(cc1OC)C(c1ccc(I)cc1)=NN(C)C(=O)C2
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)C(c1ccc(-c3ccccc3OC)cc1)=NN(C)C(=O)C2
Temperature: 90 °C
Yield: 73.4 %

Procedure:
Heat at 90° C. for 12 hours under an inert atmosphere a mixture of 100 mg (0.229 mmol) of 1-(4-iodophenyl)-7,8-dimethoxy-3-methyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one IIIah, 38 mg (0.25 mmol) of 2-methoxybenzene boronic acid, 215 μl of 2M Na2CO3, 25 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) and 250 μl of EtOH in 5 ml of degassed toluene. Allow to cool to room temperature. Add 80 ml of H2O and extract three times with 50 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt). Recrystallize in Et2O/pentane. The reaction yields 70 mg of the abovenamed product in the form of colorless crystals. Yield: 73%. M: 185–186° C. 1H-NMR (CDCl3, 300 MHz): d 3.40–3.51 (m, 5H, CH2+CH3), 3.78 (s, 3H, CH3), 3.85 (s, 3H, CH3), 3.98 (s, 3H, CH3), 6.80 (s, 1H Ar), 6.89 (s, 1H Ar), 7.04–7.73 (m, 8H Ar).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[C:4](Cl)[CH:5]=[CH:6][CH:7]=1.[Cl:10]C1C(Cl)=C(Cl)C=CC=1.[C:19]([OH:23])(=[O:22])[CH2:20][SH:21].[OH-].[K+]>>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:10])=[CH:7][C:2]=1[CH:20]([SH:21])[C:19]([OH:23])=[O:22]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: Clc1cccc(Br)c1Cl
Reactant: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(S)c1cc(Cl)ccc1Cl

Procedure:
Using the combinations of monobromodichlorobenzene or trichlorobenzene, thioglycolic acid, potassium hydroxide and solvent listed in Table 2, the reaction was carried out in the same manner as in Example 8 or 9 to yield 2,5-dichlorophenylthioglycolic acid. The results are given in Table 2.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])=[CH:5][CH:4]=1.B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])=[CH:7][CH:8]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.9 %

Procedure:
To a solution of 4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (11.8 g) in methylene chloride (100 mL) was added boron tribromide (1.0 M methylene chloride solution, 50 mL), and the mixture was stirred at room temperature for 2 days. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (12.22 g, 100%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=O)[CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C1COCC1>[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][N:25]([CH3:26])[CH3:27])[CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CN(C)C(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.5 %

Procedure:
To a suspension of LAH (276 mg, 7.2 mmol) in THF (20 mL) under nitrogen at rt was added dropwise a solution of 2-[3-(1H-indol-4-yl)-phenyl]-N,N-dimethyl-acetamide (500 mg, 1.8 mmol) in THF (10 mL). After stirring at rt for 6 hours, the reaction was quenched with water (0.6 mL) dropwise. The precipitate was filtered off, washed with ethyl acetate (3×), the filtrate was concentrated t give 640 mg of {2-[3-(1H-indol-4-yl)-phenyl]-ethyl}-dimethyl-amine.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-:25].[Na+].[CH3:27]O>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:27])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [OH-]
Reactant: CO
Reactant: Nc1nc(OCCCCO)nc2c1nc(Br)n2Cc1ccccc1
Agent: [Na+]
Product: COc1nc2c(N)nc(OCCCCO)nc2n1Cc1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
To 6-amino-9-benzyl-8-bromo-2-(4-hydroxybutoxy)purine (185 mg, 0.472 mmol) in 10 ml of methanol was added 1N aqueous sodium hydroxide (40 ml). The mixture was refluxed on heating under stirring for 2 hours. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (123 mg, yield 68%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])=[CH:38][CH:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:49]=[CH:48][C:39]([C:40]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:41])=[CH:38][CH:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(c1ccc(CCl)cc1)N1CCOCC1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C(=O)N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-[4-(chloromethyl)benzoyl]morpholine (0.87 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.16 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9]C)=O)[N:3]=1.C(O)C.[CH3:14][NH2:15]>>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH:15][CH3:14])=[O:9])[N:3]=1
Reactant: CN
Reactant: COC(=O)c1n[nH]c(N)n1
Solvent: CCO
Product: CNC(=O)c1n[nH]c(N)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (800 mg, 5.63 mmol) and methylamine ethanol solution (30%, 10 ml) was stirred for 3 h at 80° C. The resulting mixture was concentrated under vacuum to afford 5-amino-N-methyl-1H-1,2,4-triazole-3-carboxamide as a white solid (0.5 g, 63%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([C:11]3[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([F:28])=[CH:23][N:22]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:20][C:21]1[N:26]=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH3:18])[C:24]([F:28])=[CH:23][N:22]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)ncc1F)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 99.9 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (90 mg, 0.353 mmol), 2,4-dichloro-5-fluoropyrimidine (88 mg, 0.529 mmol), and N-ethyl-N-isopropylpropan-2-amine (190 μL, 1.058 mmol) were combined in acetonitrile (500 μL). The reaction mixture was heated to 120° C. in a microwave reactor for 1 hour. After removal of solvent, the residue was diluted with MeOH and dichloromethane, and was purified by preparative HPLC, eluting with a gradient of 15-25% ACN in H2O with 0.35% TFA. The fractions were collected and solvent was removed in vacuo to give the title compound (136 mg, 100%). ESI-MS m/z [M+H]+ calc'd for C18H17ClFN7, 386; found 386.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:31]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>>[C:28]([N:31]([C:32]1[CH:37]=[CH:36][C:35]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)[CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])(=[O:30])[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamine
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([O:14][C:15]([C@@:17]12[CH2:32][C@H:31]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]([NH3+:33])[C:22](=[O:34])[N:21]1[CH2:35][C@H:36]([O:38][C:39](=[O:49])[C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[CH2:37][C@H:20]1[C:19](=[O:50])[NH:18]2)=[O:16])[CH3:13].[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57](O)=[O:58])[CH:53]=1.CN1C(=O)CCC1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57]([NH:33][C@@H:23]2[C:22](=[O:34])[N:21]3[CH2:35][C@H:36]([O:38][C:39](=[O:49])[C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)[CH2:37][C@H:20]3[C:19](=[O:50])[NH:18][C@:17]3([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:32][C@H:31]3[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:58])[CH:53]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H]([NH3+])C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H]([NH3+])C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Temperature: 25 °C

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS,Z)-14a-(ethoxycarbonyl)-2-(4-nitrobenzoyloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-aminium 4-methylbenzenesulfonate (9.95 g), 5-methylisoxazole-3-carboxylic acid (2.12 g), and NMP (30.0 g) at 5° C. was added diisopropylethylamine (6.5 g). Propanephosphonic acid anhydride (5.3 g) was charged as a solution in EtOAc (5.3 g) and NMP (10 mL) to the reaction mixture. The reaction was warmed to rt over 14 h. The reaction solution was diluted with 2-Me-THF (150 mL). The diluted reaction solution was washed with water (150 mL), a 1.0 M aqueous solution of H3PO4 (2×50 mL), water (50 mL), a 5% aqueous solution of NaHCO3 (50 mL), and then a 10% aqueous solution of NaCl (2×50 mL). The organic solution was dried over MgSO4, filtered, and then concentrated under reduced pressure, and then co-distilled with THF (200 mL). THF was added and the product-containing solution was filtered and evaporated to an oil (8.5 g, 93% yield).
Reaction SMILES: C([NH+](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH:30]([CH2:34][CH2:35][CH2:36]C)C([O-])=O)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH:45]1[C:50]([F:51])=[C:49]([F:52])[C:48]([O:53][C:54]([C:56](F)(F)F)=[O:55])=[C:47]([F:60])[C:46]=1[F:61]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:29][CH2:30][CH2:34][CH2:35][CH2:36][CH2:56][C:54]([O:53][C:48]2[C:49]([F:52])=[C:50]([F:51])[CH:45]=[C:46]([F:61])[C:47]=2[F:60])=[O:55])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:15]=1
Reactant: CCCCC(NC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)C(=O)[O-]
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The acid 6 obtained as described above (2.2 g, 4.4 mmol) was dissolved in anhydrous CH2Cl2 and treated with 1 ml of triethylamine followed by 0.8 ml of 2,3,5,6-tetrafluorophenyltrifluoroacetate. After being kept at room temperature for 30 min, the reaction was concentrated to an oil (crude 7), which then was re-suspended in 20% ethyl acetate/80% hexane and applied to a silica gel column. Elution with 15% ethyl acetate/85% hexane and concentration of the pure product fractions afforded 2.0 g (82%) of the TFP ester (7) as a colorless, viscous oil.
Reaction SMILES: [F-].[Na+].F[C:4]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]>CN(C)C=O>[CH:16]1([N:15]2[C:19]3[C:5](=[CH:4][C:22]([F:23])=[C:21]([F:24])[C:20]=3[F:25])[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 90 %

Procedure:
21.2 g of sodium fluoride are added to a solution of 107.8 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylamino-acrylate (6) in 400 ml of anhydrous dimethylformamide. Thereafter, the mixture is stirred under reflux for 2 hours, and the hot reaction mixture is poured onto ice. The precipitate is filtered off under suction, washed thoroughly with water and dried over calcium chloride in vacuo at 100° C. 91.2 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (7) of melting point 167°-168° C. are obtained.