Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[CH:4]([OH:8])[C:5]([OH:7])=[O:6])[CH3:2].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([CH:3]([CH2:9][CH3:10])[CH:4]([OH:8])[C:5]([O:7][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:6])[CH3:2]
Reactant: CCC(CC)C(O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)C(O)C(=O)OCc1ccc(OC)cc1
Yield: 96.2 %

Procedure:
To 1.2 g (8.2 mmol) of 3-ethyl-2-hydroxyvaleric acid (step A) in 15 mL of dry DMF, 1.4 mL (9.6 mmol) of 4-methoxybenzyl chloride and 1.3 g (9.4 mmol) of K2CO3 were added. After stirring the reaction overnight, it was partitioned between Et2O and water. The aqueous layer was extracted with Et2O. The combined organic layer was washed with water, brine, dried and concentrated. The residue was purified on a flash column using a gradient of 10-30% EtOAc in hexane to obtain 2.1 g of the desired product. 1H NMR (CDCl3) 0.84 (t, 3H), 0.96 (t, 3H), 1.2-1.6 (m, 5H), 2.67 (d, 1H), 3.83 (s, 3H), 4.27 (dd, 1H), 5.17 (ABq, 2H), 6.91(m, 2H), 7.31 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)#[N:2].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:1]([C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)#[N:2]
Reactant: N#Cc1c(-c2cccc(F)c2)c(C(N)=O)c2n1CCNC2
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)N1CCn2c(C#N)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Yield: 78.7 %

Procedure:
To a suspension of 0.50 g (0.53 mmol) of 6-cyano-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide is added 0.07 ml (0.6 mmol) of tert-butyl isocyanate. After reaction for 2 hours at room temperature, the solvent is evaporated off under reduced pressure and the solid residue is recrystallized from acetonitrile, to give 0.16 g of 6-cyano-7-(3-fluorophenyl)-N2-(tert-butyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white powder after filtering off and drying under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH2:4][CH2:3]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[N:23]=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:21]=1>CN1C(=O)CCC1>[F:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([F:17])[CH:13]=1)[C:9]([NH:8][C@H:5]1[CH2:4][CH2:3][C@@H:2]([NH:1][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[N:23]=[C:22]([C:31]([F:32])([F:33])[F:34])[CH:21]=2)[CH2:7][CH2:6]1)=[O:18]
Reactant: NC1CCC(NC(=O)c2cc(F)cc(F)c2)CC1
Reactant: Fc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Solvent: CN1CCCC1=O
Product: O=C(N[C@H]1CC[C@@H](Nc2cc(C(F)(F)F)nc3ccc(F)cc23)CC1)c1cc(F)cc(F)c1

Procedure:
A solution of N-(4-Amino-cyclohexyl)-3,5-difluorobenzamide (30 mg, 0.12 mmol) in NMP (1.0 mL) was treated with 4-chloro-6-fluoro-2-trifluoromethyl-quinoline (1 eq) and 3 eq (0.045 mL) TEA. The reaction was heated to 220 C in the microwave for 15 minutes. The crude compound was purified by reverse phase HPLC to provide the desired compound. MS (ESI (+)) m/e 468 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 8.32 (m, 2 H), 7.98 (m, 1 H), 7.67 (m, 1 H), 7.58 (m, 2 H), 7.44 (m, 1 H), 7.15 (d, 1 H), 6.82 (s, 1 H), 1.95 (m, 4 H), 1.65-1.88 (m, 4 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[N:14]([C:17]1[CH:26]=[C:25]2[C:20]([C:21]([CH3:28])=[CH:22][C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[C:15]=[O:16]>C1COCC1>[CH3:28][C:21]1[C:20]2[C:25](=[CH:26][C:17]([NH:14][C:15](=[O:16])[O:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)=[CH:18][CH:19]=2)[O:24][C:23](=[O:27])[CH:22]=1
Reactant: Cc1cc(=O)oc2cc(N=C=O)ccc12
Reactant: OCc1ccc(-c2ccco2)cc1
Solvent: C1CCOC1
Product: Cc1cc(=O)oc2cc(NC(=O)OCc3ccc(-c4ccco4)cc3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.3 %

Procedure:
(4-(Furan-2-yl)phenyl)methanol (100 mg, 0.57 mmol) and 76 (139 mg, 0.69 mmol) were dissolved in THF (10 mL). The resulting mixture was stirred at room temperature for 15 min and then at 80° C. for 1 h. THF was evaporated off in vacuo. The residue was adsorbed on silica and purified by flash chromatography, eluting with CH2Cl2/EtOAc (1:1) to give the target compound (20 mg, 9%) as a white solid. m/z=376.11 (M+H), 751.22 (2M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[S:56][CH3:57])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[S:56][CH3:57])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: CSc1ccccc1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1NC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 49 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1-isocyanato-2-(methylthio)benzene as starting materials in 49% yield. LCMS for C32H32ClN7O2S (M+H)+: m/z=614.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[N:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.Cl.Cl.[CH3:32][C:33]1([CH3:42])[CH2:38][NH:37][CH2:36][C:35]2[CH:39]=[N:40][NH:41][C:34]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:32][C:33]1([CH3:42])[CH2:38][N:37]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[N:21]=2)=[O:27])[CH2:36][C:35]2[CH:39]=[N:40][NH:41][C:34]1=2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)O)n3)CC1)C(=O)N2
Reactant: CC1(C)CNCc2cn[nH]c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)N4Cc5cn[nH]c5C(C)(C)C4)n3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.11 g (0.26 mmol) 4-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylic acid, 59 mg (0.26 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride and 0.15 mL (1.1 mmol) TEA were placed in 1.5 mL DMF. 93 mg (0.29 mmol) TBTU were added and the reaction mixture was stirred for three days at RT. The substance was purified by HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)(C)C.[C].[Pd]>[CH2:2]1[CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)C1CCCCC1

Procedure:
One mole of 4-hyroxybenzoic acid was reacted with two moles of hydrogen in the presence of 5% palladium-carbon catlyst. This reaction was carried out in isopropyl alcohol at a temperature of 130°-140° C. and a hydrogen pressure of 20-40 kg/cm2 (gauge). After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to recover the solvent. The resulting residue was recrystallized from a mixture of benzene and hexane to obtain cyclohexane-4-carboxylic acid. This product had a melting point of 67.0°-68.0° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]#[N:21])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(=O)([O-])[O-:23].[Na+].[Na+]>S(=O)(=O)(O)O.O.C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]([NH2:21])=[O:23])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cc(C#N)nc2ccccc12)OCC
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(Cc1cc(C(N)=O)nc2ccccc12)OCC
Temperature: 0 °C

Procedure:
A solution of 5.9 g of 4-(diethylphosphonomethyl)-2-cyanoquinoline in 24 ml of concentrated sulfuric acid is heated at 80° for 5 minutes, cooled to 0° and added slowly to an ice-cooled mixture of 50 g of sodium carbonate in 50 ml of water and 100 ml of methylene chloride. The organic layer is separated, dried over sodium sulfate and evaporated to dryness to yield 4-(diethylphosphonomethyl)-quinoline-2-carboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][C@H:26]([NH2:29])[CH2:27][CH3:28]>>[C@@H:26]([NH:29][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([N:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH3:24])[CH:10]=[N:11]2)=[N:16][CH:17]=1)([CH2:27][CH3:28])[CH3:25]
Reactant: CC[C@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CC[C@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-butan-2-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.33 Hz, 3 H) 1.17 (d, J=6.57 Hz, 3 H) 1.46-1.63 (m, 2 H) 2.44 (s, 3 H) 3.95 (dt, J=13.83, 7.11 Hz, 1 H) 7.67 (dd, J=8.08, 1.26 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.17 (br. s., 1 H) 8.32-8.58 (m, 3 H) 8.87-8.95 (m, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 376.2.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[CH3:17][C:18]([CH3:21])([O-:20])[CH3:19].[K+].C1(C)C=CC=CC=1.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[C:18]([O:20][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][C:7]([F:13])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=2)[N:10]=1)([CH3:21])([CH3:19])[CH3:17]
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1F
Reactant: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1nc2cc(F)c([N+](=O)[O-])cc2nc1Cl
Yield: 69.9 %

Procedure:
To a solution of 2,3-dichloro-6-fluoro-7-nitroquinoxaline 5.24 g in tetrahydrofran (50 mL), was added dropwise a solution of potassium tert-butoxide 2.51 g in tert-butanol 60 mL at −10 to −8° C. for about 1 hr. After the addition, the mixture was stirred at 0° C. for 1 hr, to which toluene 100 mL and a solution of 0.1M sodium dihydrogen phosphate 20 mL were added, then which was poured into a separatory funnel. The organic layer was washed with water and saturated saline, dried over MgSO4, and evaporated under reduced pressure. The residue was purified with silica gel column (120 g, toluene:hexane=1:1), to give the title compound (pale yellow crystal) 4.19 g.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C@@:18]([CH2:23][C:24]([OH:26])=[O:25])([C:20]([OH:22])=[O:21])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[C:24]([CH2:23][C@:18]1([C:20]([OH:22])=[O:21])[O:17][N:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH2:19]1)([OH:26])=[O:25]
Reactant: O=C(O)C[C@@]1(C(=O)O)CC(c2cccc(OCc3ccccc3)c2)=NO1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@]1(C(=O)O)CC(c2cccc(O)c2)=NO1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (5R)-3-(3-(benzyloxy)phenyl)-5-(carboxymethyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (75.0 g), 10% Pd/C (containing about 55% water, 7.5 g), and THF (750 mL) was stirred at room temperature for 15 hours under a hydrogen atmosphere. To the reaction mixture, methanol (150 mL) was added, then the catalyst was filtered and washed with methanol (375 mL). The filtrate was concentrated under reduced pressure to obtain (5R)-5-(carboxymethyl)-3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid as a crude product.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[O:8][CH:9]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3c(C(F)(F)F)cccc23)co1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=c1cc(CN2CCOCC2)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Temperature: 45 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(8-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 19 (94 mg, 0.187 mmol) was dissolved in dichloromethane (4 mL). Morpholine (41 μL, 0.47 mmol) was added via syringe. The mixture was stirred at 45° C. for 3 h. CH2Cl2 (75 ml) was added and the solution washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:5. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(morpholinomethyl)-4H-pyran-4-one EHT 4687 was obtained (46 mg, 50% yield) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(O)CCBr
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(O)CCN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (7 mL), sodium tert-butoxide (153 mg, 1.588 mmol) and 4-bromo-2-methylbutan-2-ol (243 mg, 1.456 mmol) (306 mg, 74%). ESI-MS m/z [M+H]+ calc'd for C14H21ClN4O2, 313.14. found 313.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1.Cl>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: OC[C@@H]1CCCCN1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2CO)c(C)c1
Reaction time: 1.5 h
Yield: 20 %

Procedure:
(S)-Piperidin-2-ylmethanol (1.1 eq.) was dissolved in dichloromethane (4 ml/mmol) and cooled, and triethylamine (2.5 eq.) was added. A solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (1 eq.) in dichloromethane (2 ml/mmol) was added dropwise at 0° C., and then stirring was carried out for 90 min at room temperature. Hydrogen chloride solution (eq., 0.5 mol/l, 2 ml/mmol) was added, stirring was carried out for 15 min, and the phases were separated. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next stage without being purified further. Yield: 20%
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]([O:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[CH:53]=[CH:52][C:48](C(O)=O)=[CH:47][CH:46]=1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C@H:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:48]3[CH:47]=[CH:46][C:45]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=4)=[CH:53][CH:52]=3)=[CH:13][CH:14]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:35][CH:34]=1)([CH3:37])[CH3:38]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CC(C)c1ccc(O[C@H](Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(O[C@H](Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)OCC[Si](C)(C)C)cc1
Yield: 75 %

Procedure:
In a similar manner to that described in Example 73, a reaction was carried out using 2-trimethylsilylethyl (R)-3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (356 mg), 4-pyridine-2-ylbenzoic acid (143 mg), diethyl cyanophosphonate (0.11 ml) and triethylamine (0.10 ml) and the reaction mixture was treated to afford the title compound (307 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:26][CH2:27][CH2:28][OH:29])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: OCCCBr
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCO)c(=O)n2CCC
Temperature: 60 °C
Yield: 71.7 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (3.0 g, 11.1 mmol) in DMF (20 ml) was treated with caesium carbonate (3.7 g, 11.4 mmol) and 3-bromo-1-propanol (1.6 g, 11.5 mmol). The mixture was heated at 60° C. for 4 h and then cooled and evaporated. The residue was partitioned between EtOAc (60 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous phase was extracted with EtOAc (60 ml), the combined organic phases were dried (MgSO4), filtered and evaporated. The product was purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a colourless oil (2.6 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)c1
Yield: 87 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 3.28 (s, 4H), 3.80 (s, 6H), 4.13 (s, 4H), 6.45-6.58 (m, 3H), 7.01 (s, 1H), 7.17-7.23 (m, 2H), 7.37-7.70 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([N:35]=[C:36]=[O:37])[CH:34]=1>C1(C)C=CC=CC=1>[O:38]([C:32]1[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][C:33]=1[NH:35][C:36]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1)=[O:37])[CH3:39]
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: CC(C)(C)OC(=O)n1cc(Cn2ccc3c(N)cccc32)c2cccnc21
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1ccn2Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Yield: 73 %

Procedure:
A solution of 3-[(4-amino-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine from previous step and 5-chloro-2-methoxyphenyl isocyanate (Int-14, 275 mg, 1.5 mmol) in toluene was stirred overnight. The reaction mixture was concentrated and purified by flash column chromatography to afford product 1-(2-methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-indol-4-yl}urea (518 mg, 73% for two steps).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]([C:12]([C:14]1([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]1)=[O:13])[NH2:11].[CH2:26]([O:33][N:34]1[C:40](=[O:41])[N:39]2[CH2:42][C@H:35]1[CH2:36][CH2:37][CH:38]2[C:43](O)=[O:44])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][C:14]1([C:12]([NH:10][NH:11][C:43]([CH:38]2[CH2:37][CH2:36][C@@H:35]3[CH2:42][N:39]2[C:40](=[O:41])[N:34]3[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:44])=[O:13])[CH2:16][CH2:15]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)NN)CC1
Reactant: O=C(O)C1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(C(=O)NNC(=O)C2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
DIPEA (14 g, 0.11 mol) was added to a solution of tert-butyl (1-(hydrazinecarbonyl)cyclopropyl)methylcarbamate (10.0 g, 0.044 mol), (5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (10 g, 0.036 mol), and HATU (15 g, 0.04 mol) in CH2Cl2 (250 mL). The mixture was stirred at rt for 2 hrs. The mixture was diluted with CH2Cl2 (500 mL), washed with H2O (300 mL), dried over Na2SO4, and concentrated. The crude product was washed with EtOAc (200 mL), and filtrated to afford tert-butyl(1-(2-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopropyl)methylcarbamate (15 g, 85%) as a white solid. ESI-MS (EI+, m/z): 488.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][N:25]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1n[nH]c2ccccc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3n[nH]c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1H-indazole-3-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=477.1.