Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]=[O:11]>>[O-:10][OH:11].[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=O
Solvent: CC(C)c1ccccc1
Product: [O-]O

Procedure:
Isopropanol 42 is fed to a cumene process alkylation unit 50 for use as a benzene alkylating material. Fresh propylene 55 may be needed to supplement the isopropanol 42 as the C3 alkylating agent. Byproduct water 54 and cumene product 52 are produced. The cumene stream 52 from alkylation system 50 is mixed with cumene stream 45 from stage 40, and the combined stream 57 is sent to oxidation stage 60, where the cumene is reacted with oxygen in air feed stream 64 to form cumene hydroperoxide stream 62 for feeding to cleavage reactor 10. Stream 62 will typically include about 5-20% of unoxidized cumene plus various impurities and byproducts as discussed above.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[NH3:32]>>[O:11]=[C:9]1[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][C:2]([NH2:32])=[O:1])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10]1
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: N
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 2 tR=1.381 min, m/z=430.2; 1H NMR (CDCl3) 1.56 (m, 3H), 1.92-2.03 (m, 3H), 2.18-2.37 (m, 5H), 2.51 (m, 1H), 2.94 (m, 1H), 5.29-5.61 (m, 2H), 5.71 (m, 1H), 7.03 (m, 2H), 7.21-7.38 (m, 8H), 7.77 (m, 1H), 8.53 (m, 1H), 8.72 (s, 1H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Br)=[CH:3][CH:2]=1.[Mg].[CH:10]12[O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C1COCC1>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:3][CH:2]=1
Reactant: C1CCC2OC2C1
Reactant: Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C2CCCCC2=O)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
To a solution of p-tolylbromide (17.1 g, 100 mmol) in dry THF (100 mL) was added magnesium (2.43 g, 100 mmol) and then the resulting mixture was cooled to −20° C. and (CuBr-dimethylsulfide complex (2.0 g, 10 mmol) was added and the mixture stirred at −20° C. for 10 min. Then a solution of cyclohexene oxide (10 mL, 100 mmol) in dry THF (10 mL) was added dropwise and the reaction warmed to 0° C. at which point an exothermic reaction initiates. With ice-bath cooling the temperature can be maintained below 25° C. The reaction mixture was then stirred at 0–5° C. for an additional 2 h, then quenched with ammonium chloride solution (saturated, 30 mL) and the product extracted with tert-butyl methyl ether. The combined organic extracts were then washed with water, dried over sodium sulfate, filtered and evaporated. Recrystallisation from hexane afforded the title compound (9.9 g, 52%) as white crystals. MS: m/e=190.1 (M).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](C(C)C)=[N:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.Cl.[NH:24]1[CH:28]=[C:27]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:26]=[CH:25]1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu-]=O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:6]2[C:7]3[C:3](=[C:2]([N:24]4[CH:28]=[C:27]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)[N:26]=[CH:25]4)[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)=[CH:17][CH:16]=1
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: COc1ccc(Cn2nc(C(C)C)c3c(Br)cccc32)cc1
Agent: O=[Cu-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2ncc3c(-n4cnc(-c5cccnc5)c4)cccc32)cc1
Temperature: 125 °C

Procedure:
A solution of the colorless oily substance (4-bromo-3-(isopropyl)-1-(4-methoxybenzyl)-1H-indazole) (2.4 g), 3-(1H-imidazol-4-yl)pyridine hydrochloride (1.75 g), copper(I) oxide (96 mg), poly(ethylene glycol) (1.34 g), 8-quinolinol (194 mg), and cesium carbonate (8.7 g) in DMSO (22 mL) was stirred overnight under heating at 125° C. After completion of the reaction, the reaction solution was allowed to standing still for cooling, filtered, and the filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (chloroform/ethyl acetate/methanol) to obtain 3-isopropyl-1-(4-methoxybenzyl-4-(4-(pyridin-3-yl)-1H-imidazol-1-yl)-1H-indazole (710 mg, yield 250) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:21][C:10]1[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 75 °C
Yield: 86.2 %

Procedure:
To a suspension of ethyl 5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (3.3 g, 11.6 mmol) in acetic acid (60 mL) was added N-chlorosuccinimide (3.1 g, 23.2 mmol). Upon heating to 75° C., a homogenous solution formed. After heating for 16 hours a further portion of N-chlorosuccinimide (1.5 g, 11.2 mmol) was added and the reaction was heated at 75° C. for another 16 hours. After cooling to ambient temperature, the reaction mixture was poured over ice. The white crystals which formed were collected by vacuum filtration and purified by silica gel chromatography, eluting with dichloromethane to obtain the title compound (3.2 g, 10.0 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccncc2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-4-ylmethyl-ethylamine (726 mg.; 2.23 mmol, from Example 8) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.62 mL; 4.45 mmol) and 1-methyl-1-cyclohexanecarbonyl chloride (356 mg.; 2.23 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to yield the free base of the title compound as a clear oil (695 mg.; 69%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as a white amorphous solid, m.p. 145° C.; MS EI M+ @ m/z 450; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2C4H4O4.0.5H2O Calculated: C, 64.68; H, 7.53; N, 9.73 Found: C, 64.97; H, 7.53; N, 9.66
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1.O.[ClH:20]>C(#N)C.[Cu](Cl)Cl.C(Cl)Cl>[Cl:20][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1csc(Cl)n1
Temperature: 62.5 °C

Procedure:
To a mixture of copper (II) chloride (20 g, 0.15 mol) and 90% t-butyl nitrite (24 mL, 0.18 mol) in 500 mL acetonitrile at 60° C. was added in portions ethyl 2-amino-4-thiazolecarboxylate (21 g, 0.12 mol), maintaining the temperature at between 60-65° C. After the addition, the resulting reaction mixture was heated at 80° C. for 1 h, then cooled to RT and poured into a mixture of water, CH2Cl2 and 25 mL conc HCl. The aq layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water, brine, dried and concentrated to give 21.5 g of ethyl 2-chloro-4-thiazolecarboxylate.
Reaction SMILES: C(O)(C(F)(F)F)=O.O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>>[N:27]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: c1nc[nH]n1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(Cn2cncn2)cc1)c1ccccc1
Yield: 27 %

Procedure:
The title compound was prepared as its TFA salt in 27% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 1,2,4-triazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.34 (s, 2H), 7.15 (br d, 2H), 7.26–7.43 (m, 7H), 8.10 (s, 1H), 8.38 (s, 1H); HPLC-MS: m/z=309.1 (M+1); Rt=2.74 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=2)[N:11]=1
Reactant: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1cc2ccccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of methyl 2-(1-benzofuran-2-yl)-3-(diethylamino)quinoxaline-6-carboxylate (65 mg, 0.17 mmol) in methanol (10 mL) and water (1 mL) was added sodium hydroxide (13 mg, 0.33 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH to 6 with 3N HCl and filtered to give 2-(1-benzofuran-2-yl)-3-(diethylamino)quinoxaline-6-carboxylic acid as a light yellow solid (32.2 mg, 51%).
Reaction SMILES: [CH2:1]([CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([OH:30])=[O:29])[CH:22]=[CH:21]2)[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2>C(O)CO>[OH:2][CH2:1][CH2:16][C:22]1[C:23]([C:28]([OH:30])=[O:29])=[C:24]([CH2:8][CH2:13][OH:14])[C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:17][CH2:16][CH2:1][O:2][C:3]1[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]3)=[CH:27][CH:26]=2
Reactant: O=C(O)c1ccc2cc(OCCOc3ccc4cc(C(=O)O)ccc4c3)ccc2c1
Solvent: OCCO
Product: O=C(O)c1ccc2cc(OCCOc3ccc4c(CCO)c(C(=O)O)c(CCO)cc4c3)ccc2c1

Procedure:
100 parts by weight of 6,6′-(ethylenedioxy)di-2-naphthoic acid, 62 parts by weight of ethylene glycol and 0.085 part by weight of tetra-n-butyl titanate were charged into an autoclave equipped with a 1-liter stirrer and a nitrogen gas introduction port, the inside of the autoclave was substituted by nitrogen, and a nitrogen pressure of 0.2 MPa was applied to carry out a reaction at 230° C. for 6 hours. A crystal which separated out after the reaction was filtered and washed with methanol. After washing, the crystal was dried in vacuum at 120° C. to obtain 115 parts by weight of bis(β-hydroxyethyl)6,6′-(ethylenedioxy)di-2-naphthoic acid. This had an esterification rate of 96%. Its melting point was 240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([F:34])=[CH:4][N:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:36]/[OH:37])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([F:34])=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(Cl)ncc1F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(Cl)ncc1F)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(2-chloro-5-fluoro-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white foam, MS (ESI−): m/z=487.2 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH:27]=[CH:26][C:25](B(O)O)=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:27]2[NH:23][N:24]=[CH:25][CH:26]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2ccn[nH]2)n1
Yield: 26.1 %

Procedure:
(4-Chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester (350 mg, 1.03 mmol), 1H-pyrazole-3-boronic acid (128 mg, 1.13 mmol) and sodium carbonate (218 mg, 2.06 mmol) in water (1 mL) and ethanol (4 mL) were degassed with argon for 30 minutes before tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.051 mmol) was added. The reaction mixture was heated to reflux over night. Water was added and the mixture was concentrated in vacuo. The remaining aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with brine, dried over sodium sulphate, filtrated and evaporated. The crude product was purified by column chromatography (ethyl acetate/heptane as eluent) to give (4-chloro-phenyl)-[6-(2H-pyrazol-3-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (100 mg, 26%) as a colourless solid.
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][CH:36]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:2]([C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9].[NH2:49][C@H:50]([C:70]([OH:72])=[O:71])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][S:56]([C:59]1[C:68]([CH3:69])=[C:66]([CH3:67])[C:63]([O:64][CH3:65])=[CH:62][C:60]=1[CH3:61])(=[O:58])=[O:57].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[NH:1]([C:32]([O:34][CH2:35][CH:36]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:2]([C:22]([NH:49][C@H:50]([C:70]([OH:72])=[O:71])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][S:56]([C:59]1[C:68]([CH3:69])=[C:66]([CH3:67])[C:63]([O:64][CH3:65])=[CH:62][C:60]=1[CH3:61])(=[O:58])=[O:57])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)ON2C(=O)CCC2=O)c(C)c1C
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNS(=O)(=O)c2c(C)cc(OC)c(C)c2C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C

Procedure:
A stirred solution of Fmoc-Lys(Mtr)-OSu 3 (ca 8.672 mmol) and Lys(Mtr) 2 (3.6294 g, 1 equiv) in DMF (70 mL) at rt was treated with DIEA (4.5 mL, 3 equiv). After 4 h the mixture was diluted with ethyl acetate (250 mL). The solution was washed with pH 4 buffer (0.05M biphthalate) (2×), water and brine, dried over sodium sulfate and evaporated the residue was flushed with methylene chloride (400 mL) to give a pale-yellow foam which was carried on without further purification. 1H-NMR (CDCl3/CD3OD) δ 1.10-1.85 (m, 12H), 2.22 (m, 4H), 3.70 (m, 6H), 4.21 (m, 5H), 6.76 (m, 4H), 7.00-7.75 (m, 32H). MS (ESI) 1041. 6 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[NH2:9][C:4]1[N:3]=[C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc(N)n2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
A mixture of 4,6-dichloropyrimidin-2-amine (1.500 g, 0.0091 mole), tert-butyl piperazine-1-carboxylate (2.044 g, 0.0110 mole), and N-ethyl-N-isopropylpropan-2-amine (11.1 mL, 0.0637 mole) in ethanol (20 mL) was magnetically stirred in a sealed tube at 80° C. for 18 hours. After cooling to ambient temperature, the seal was broken and volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude, white solid that was crystallized from hot methanol. The crystals were collected by filtration and dried under vacuum to provide tert-butyl 4-(2-amino-6-chloropyrimidin-4-yl)piperazine-1-carboxylate (1.95 g, 68.3% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 3.46-3.52 (m, 4H), 3.55-3.61 (m, 4H), 4.90 (sbr, 2H), 5.96 (s, 1H). MS (DCl—NH3) m/z=314 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:17]([CH3:19])[CH3:18])([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+]>CO>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:17]([CH3:19])[CH3:18])([C:13]([OH:15])=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@]1(C(C)C)C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)O)(C(C)C)C1

Procedure:
reacting said methyl (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylate with NaOH and MeOH to form (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:10][C:11]1[N:12]=[CH:13][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=1
Reactant: N#Cc1ccccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccccc2C#N)cn1

Procedure:
In analogy to example 5a, 2-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup the title compound was obtained as a white solid (yield: 60%). MS: m/e=184.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([I:20])[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:12]2=[C:13]([N:24]3[CH2:27][CH2:26][CH2:25]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([I:20])[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(Cl)c2CC1
Product: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(N3CCC3)c2CC1

Procedure:
The product was prepared using 10-chloro-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester and azetidine as the amine in route 1 (step e).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)=[O:21]>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH:17][C:30]3[N:29]=[C:28]([NH:27][C:26]4[CH:25]=[CH:24][S:23][C:22]=4[C:20](=[O:21])[NH:19][CH3:18])[C:33]([Cl:34])=[CH:32][N:31]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCOc2ccc(N)cc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CCOC(=O)N1CCCOc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21

Procedure:
2-[5-Chloro-4-(2-methylcarbamoyl-thiophen-3-ylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester was prepared from 2-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as a tan solid (138 mg, 61%). m.p.=222-224° C.; LCMS (m/e) 503 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.62 (s, 1H), 9.50 (s, 1H), 8.52-8.38 (m, 1H), 8.30-8.20 (m, 2H), 7.74 (d, 1H, J=5.4 Hz), 7.70-7.59 (m, 1H), 7.50-7.38 (m, 1H), 6.98 (d, 1H, J=8.6 Hz), 4.20-3.91 (m, 4H), 3.79-3.55 (m, 2H), 2.77 (d, 3H, J=4.2 Hz), 2.01-1.86 (m, 2H), 1.33-0.90 (m, 3H).