Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH2:17])=[C:5]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:4]=1.Cl[CH2:30][C:31](Cl)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]([C:10]2[C:11]3[NH:17][C:31](=[O:32])[CH2:30][O:16][C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:18])=[C:5]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:4]=1
Reactant: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3N3CCCCC3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2-amino-3-hydroxybenzamide 22b (2.5 g, 6.4 mmol) was dissolved in 20 ml of DMF and at 0° C. TEA (1.8 ml, 2 equiv.) and chloroacetyl chloride (0.6 ml, 1.2 equiv.) were added. The mixture was stirred at rt for 2 hours. K2CO3 (1.77 g, 2 equiv.) was added and the reaction was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 1/petroleum ether 1 as eluant gave 1 g of a white solid. Yield=36% 1HNMR (DMSO, 200 MHz) δ 1.57 (2H, bs), 1.69 (4H, bs), 2.82 (4H, m), 4.60 (2H, d, J=5.4 Hz), 4.67 (2H, s), 7.09 (1H, t, J=7.8 Hz), 7.20 (1H, dd, J=8 Hz, J′=1.2 Hz), 7.33 (1H, m), 7.41 (2H, m), 7.57 (1H, m), 9.38 (1H, bt), 11.02 (1H, bs); [M+1] 434.3 (C22H22F3N3O3 requires 433.4).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:30])[NH:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:29])[C:23]3([CH3:30])[CH3:22])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)NCCNC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-dimethylpiperazin-2-one hydrochloride (CAN 1104383-07-4) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=395.4 [MH+].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[H-].[Na+].[CH:15]([NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23](Br)[N:22]=1)=[O:20])([CH3:17])[CH3:16]>CN(C=O)C.C(OCC)(=O)C.[Cu](Cl)Cl>[CH:15]([NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:11])([F:1])[F:12])[CH:5]=2)[N:22]=1)=[O:20])([CH3:17])[CH3:16]
Reactant: Oc1cccc(SC(F)(F)F)c1
Reactant: COc1cc(Br)nc(C(=O)NC(C)C)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(SC(F)(F)F)c2)nc(C(=O)NC(C)C)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
1.25 g (0.0029×2.2 mol) of 3-(trifluoromethylthio) phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.23 g (ca. 60% in mineral oil; 0.0029×2.0 mol) of NaH and then with 0.80 g (0.0029 mol) of N-(i-propyl)-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.15 g (0.0029×0.5 mol) of copper chloride (I), the obtained solution was stirred at about 110° C. for about 6 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH3:40])=[O:38]>>[CH3:40][O:39][C:37](=[O:38])[N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13](=[O:23])[NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[CH:15][CH:16]=1)[CH3:22]
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide (100 mg, 0.24 mmol), pyridine (29 μl, 0.36 mmol) and methyl chloroformate (24 μl, 0.32 mmol) were dissolved in dichloromethanel (5 ml) and stirred at ambient temperature for 18 h. Workup and purification as described in the general procedure C afforded the title compound as light yellow solid (66%), MS: m/e=471 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:15]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O:17][CH3:18])=[O:16].N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][N:13]([C:23]3[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2c[nH]cn2)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(-n2cnc(-c3ccc(C(C)C)cc3)c2)c1
Reaction time: 14 h

Procedure:
A solution of 4-(4-isopropyl-phenyl)-1H-imidazole (190 mg), 3-carbomethoxy-phenylboronic acid (360 mg) and Cu(OAc)2 (300 mg) in dichloromethane (15 mL) is treated with pyridine (160 mg) and 4 Å molecular sieves (500 mg). The mixture is stirred in the presence of air for 14 h then filtered through celite, and the celite pad is washed well with ethyl acetate. The filtrate and washing are combined and evaporated, and the residual material is separated by column chromatography to afford the product, methyl 3-[4-(4-isopropyl-phenyl)-imidazol-1-yl]-benzoate, as a yellow solid (190 mg).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1C
Agent: [Pd]
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1C

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methylbenzoate obtained in Example (172a) (39 mg, 0.09 mmol) and a 10% palladium-carbon catalyst (50 mg), to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:32])[CH:7]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([OH:31])=[O:30])[N:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C=O)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1>O>[C:1]([NH:5][C:6](=[O:32])[CH:7]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([OH:31])=[O:30])[NH:8][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C(c1c(C(=O)O)[nH]c2cc(Cl)ccc12)N(C=O)Cc1ccc(Cl)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)C(NCc1ccc(Cl)cc1)c1c(C(=O)O)[nH]c2cc(Cl)ccc12
Yield: 89.2 %

Procedure:
Compound 9l (24 mg, 0.05 mmol) was treated with 0.4 mL of dioxane (2M HCl), 0.1 mL of water stirring overnight under 60° C. After evaporation, the product was obtained as yellow solids (20 mg, yield: 89%). HPLC/MS: tR=10.42 min; m/z=448.3 [M+H]+ HRMS: C22H22Cl2N3O3, [M−H]−; 446.1038 (calcd.), 446.1050 (found). 1H NMR (600 MHz, MeOD, a mixture of rotamers): 1.25 (s, 9H), 1.31 (s, 6H), 4.27-4.33 (m, 2H), 4.70 (ABd, 1H, J=16.2 Hz), 5.13 (ABd, 1H, J=15.6 Hz), 5.88 (s, 1H), 6.24 (s, 1H), 6.47 (m, 1H), 6.76-7.27 (m, 8H), 7.39-7.60 (m, 6H), 7.79-7.85 (m, 2H), 8.38 (s, 1H), 8.47 (s, 1H), 11.35 (s, 1H), 11.60 (s, 1H). 13C NMR (150 MHz, MeOD, a mixture of rotamers): 27.3, 27.4, 46.5, 50.9, 51.0, 57.1, 111.6, 120.4, 121.3, 125.0, 126.8, 127.3, 127.5, 127.9, 128.6, 128.9, 129.0, 129.6, 131.0, 132.1, 135.3, 135.5, 170.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: BrC1CCCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
NaH (3.8 g, 95.3 mmol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 63.5 mmol) in DMF (50 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, then warmed to room temperature. At this time Cyclopentylbromide (18.9 g, 127 mmol) was added and the reaction was heated to 60° C. After 4 h the reaction was cooled to 0° C. and quenched slowly with water. The aqueous layer was extracted with EtOAc (3×), the combined organic layers were washed with water (1×), dried over Na2SO4, and concentrated. Purification by flash column chromatography (Hexanes/Ethyl acetate 9:1) afforded the title compound (10.6 g, 75%). MS: 222.1/224.1 (MH+); retention time 5.77 min. (HPLC method 4).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: OCC1CCNCC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCC(CO)CC1
Yield: 20.6 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) and piperidin-4-yl-methanol (127 mg, 1.104 mmol) were reacted as described in Example 73. Isolated yield of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (47 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.40 (m, 1H), 4.20 (m, 2H), 3.98 (s, 3H), 3.25 (m, 2H), 2.87 (d, 2H), 2.45 (m, 2H), 2.10-1.80 (m, 4H), 1.65 (d, 2H), 1.30 (s, 10H), 1.15 (m, 2H); LC-MS (ESI) m/z 621 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22]CC)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3].[OH-].[Na+].C(O)COCCO.Cl>O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCOCCCCCc1ccc(-c2ncc(OCC)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCOCCCCCc1ccc(-c2ncc(O)cn2)cc1
Temperature: 180 °C
Yield: 75.8 %

Procedure:
A mixture of 7.5 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-(ethoxy)pyrimidine, 10 g of sodium hydroxide and 120 ml of diethylene glycol was heated at 180° C. for 8 hours. The reaction mixture was poured into 100 ml of water, acidified with concentrated hydrochloric acid, then extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 100 ml of concentrated sodium chloride solution, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 7:3) and recrystallization from ethyl alcohol gave 5.2 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:26]=[CH:25][C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:4](=[O:27])[CH:3]=1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35]O)=[N:33][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:17][CH2:18][C:12]=4[CH:11]=3)[C:4](=[O:27])[CH:3]=2)=[N:33][CH:34]=1
Reactant: O=C(N1CCc2ccc(CCn3ccc(O)cc3=O)cc2CC1)C(F)(F)F
Reactant: Cc1ccc(CO)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(COc2ccn(CCc3ccc4c(c3)CCN(C(=O)C(F)(F)F)CC4)c(=O)c2)nc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To 320 mg (0.84 mmol) 4-hydroxy-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (preparation 21b) in 25 mL DCM is added 129 mg (1.05 mmol) (5-methyl-pyridin-2-yl)-methanol and 221 mg (0.84 mmol) triphenylphosphane. The reaction mixture is cooled to 0° C. and 174 μL (0.84 mmol) diisopropyl azodicarboxylate is added. The reaction mixture is stirred 16 h at RT and then additional 221 mg (0.84 mmol) triphenylphosphane and 174 μL (0.84 mmol) diisopropyl azodicarboxylate is added. The mixture is stirred 2 h at RT, the solvent is evaporated and to the residue water is added. The aqueous phase is extracted with DCM, dried over Na2SO4 and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 5:95).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]([OH:18])[CH:10]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]([O:18][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:10]=1)[CH3:2]
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)CCCOc1ccc(C(N)=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(N)=O)c(OCC2CCCCC2)c1
Temperature: 60 °C

Procedure:
To 4-(4-carbamoyl-3-hydroxy-phenoxy)-butyric acid ethyl ester (3.0 g, 11.22 mmol) in DMF (25 mL) was added Cs2CO3 (5.11 g, 15.71 mmol) followed by (bromomethyl)cyclohexane (1.72 mL, 12.34 mmol). The mixture was heated to 60° C. for 6 h, then dumped onto ice/H2O. The formed solids were collected by filtration (H2O wash)and dried in vacuuo (3.74 g, 92%). MS [M+H]+ 364. m.p. 98-99° C.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[CH2:7]([OH:24])[C:8]([CH2:19][O:20][N+:21]([O-:23])=[O:22])([CH2:14][O:15][N+:16]([O-:18])=[O:17])[CH2:9][O:10][N+:11]([O-:13])=[O:12].S([O-])(O)=[O:26].OS(O)(=O)=O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O.C1C=CC=CC=1>[N+:16]([O:15][CH2:14][C:8]([CH2:19][O:20][N+:21]([O-:23])=[O:22])([CH2:9][O:10][N+:11]([O-:13])=[O:12])[C:7]([OH:26])=[O:24])([O-:18])=[O:17]
Reactant: O=[N+]([O-])OCC(CO)(CO[N+](=O)[O-])CO[N+](=O)[O-]
Reactant: O=S([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Reaction time: 2 h
Yield: 72 %

Procedure:
0.0074 mol of KMnO4 is added in portions, with vigorous stirring, to a solution of 0.0037 mol of pentaerythrityl trinitrate (PETriN), 5.5 ml of benzene, 9 ml of water and 0.15 ml of Aliquat® 336. When the addition has ended, the temperature is kept at 15° C. for 2 hours. Aqueous hydrogensulfite solution is then added, the mixture is acidified with H2SO4 and the benzene layer is separated off. After removal of the solvent, 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid (Tri-PA) is obtained as a solid residue, which is recrystallized several times from methylene chloride. Yield: 72%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.CO.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(N)c1

Procedure:
Methyl-2-(4-hydroxy-3-nitrophenyl)acetate (2.31 g, 10.9 mmol) was dissolved in THF (20 mL) and MeOH (20 mL) and 10% palladium on carbon (210 mg) was added slowly at RT. The reaction mixture was hydrogenated for 2 h at 39 psi hydrogen pressure, filtered through Celite and washed with MeOH. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA=2:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>N1C=CC=CC=1>[CH2:7]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
2-Amino-1,3,4-thiadiazole (439 mg, 4.3 mmol) was suspended in pyridine (1.5 mL). p-Dodecylbenzenesulfonyl chloride (1.0 mg, 2.9 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (15 mL) and the resulting mixture extracted with ethyl acetate (3×30 mL). The organic extracts were washed with water (3×50 mL), brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (600 mg, 1.5 mmol, 51%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 126-127° C.; 1H NMR (500 MHz, CDCl3) δ 0.87 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.54-1.63 (2, m), 2.62 (2, t, J=7.5 Hz), 7.25 (2, d, J=8.0 Hz), 7.83 (2, d, J=8.0 Hz), 8.28 (1, s), 12.81 (1, br s); 13C NMR (125 MHz, CDCl3) δ 14.0, 22.6, 29.2, 29.3, 29.4, 29.5, 29.6, 31.0, 31.8, 35.8, 126.4, 128.9, 138.0, 142.8, 148.5, 167.5; MS (LCQ, ESL+) Calcd for C20H32N3O2S2 410.1936, found 410.10 (M+H)+; HRMS (ESL+, m/z) Calcd C20H32N3O2S2 410.1936, found 410.1932 (M+H)+.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:19][CH:18]([OH:20])[CH2:17][NH:16][C:15]2[C:14](=[O:21])[C:13](=[O:22])[C:12]1=2)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCCl.O>[OH:20][CH:18]1[CH2:17][NH:16][C:15]2[C:14](=[O:21])[C:13](=[O:22])[C:12]=2[N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:19]1
Reactant: CCOP(=O)(CCN1CC(O)CNc2c1c(=O)c2=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCCl
Solvent: O
Product: O=c1c2c(c1=O)N(CCP(=O)(O)O)CC(O)CN2

Procedure:
To a solution of [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester (2.5 g, 7.5 mmol) in dry 1,2-dichloroethane (100 mL) under nitrogen, was added bromotrimethylsilane (9.2 mL, 60 mmol). The reaction mixture was refluxed for 20 min and then concentrated in vacuo to yield a yellow-orange foam, which was dissolved in water (100 mL). The water was washed with ether (3×100 mL) and then concentrated in vacuo to yield a solid which was recrystallized from water in isopropanol to yield [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid one sixth hydrate as a pale yellow solid (1.79 g, 86%, mp 268°-270° C. dec); IR (KBr, cm-1): 3480, 3220, 1820; MS (-FAB): 275 (M-H, 22), 148 (100); 1H NMR (DMSO 1 drop of DCl, 400 MHz): δ 3.90 (m, 1H), 3.85-3.74 (m, 2H), 3.46 (d, J=13 Hz, 1H), 3.34 (d of d, J=13 and 7 Hz, 1H), 3.28 (m, 2H), 1.98-1.89 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.C(OCC)(=O)C.O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: Cc1cc(Nc2cc(Cl)nnc2C(N)=O)nc(C(C)C)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc(C(C)C)c1
Temperature: 140 °C
Yield: 40.9 %

Procedure:
To a stirred solution of 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxamide (54 mg, 177 μmol) in NMP (590 μL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (227.1 mg, 883 μmol) in three portions approximately every 12 h and while heating the mixture (in the periods between additions) at 140° C. After a total of 36 h, the mixture was cooled and then diluted with ethyl acetate and water. The organic phase was separated and then washed with water and brine. The organic phase was then concentrated in vacuo and finally purified by chromatography (silica, 30 to 80% ethyl acetate in hexanes) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (35 mg, 72.4 μmol, 41.0%) as a brown oil. MS (EI/CI) m/z: 484.3 [M+H].
Reaction SMILES: Cl.[C:2]12([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][CH:9]=3)[CH2:7][CH:6]1[CH2:5][NH:4][CH2:3]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2([C:48](O)=[O:49])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C>[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2([C:48]([N:4]3[CH2:5][CH:6]4[C:2]([C:8]5[C:16]6[C:11](=[N:12][CH:13]=[CH:14][CH:15]=6)[NH:10][CH:9]=5)([CH2:7]4)[CH2:3]3)=[O:49])[CH2:46][CH2:47]2)=[CH:43][CH:44]=1
Reactant: c1cnc2[nH]cc(C34CNCC3C4)c2c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N1CC2CC2(c2c[nH]c3ncccc23)C1)C1(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
3-(3-azabicyclo[3.1.0]hex-1-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (60 mg, 0.3 mmol) was dissolved in DCM (3 ml) and a few drops of DMF, and cooled to 0° C. Then HOBt (38 mg, 0.33 mmol), EDCI (54 mg, 0.33 mmol) were added followed by triethylamine (106 μL) and 1-(4-fluorophenyl)cyclopropanecarboxylic acid (46 mg, 0.3 mmol). The mixture was stirred at RT overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography (DCM/MeOH 97:3) to yield the title compound as a yellow solid (44 mg).