Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH3:11][O:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>>[CH3:11][O:12][N:13]([CH3:17])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:15]
Reactant: CON(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Product: CON(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 94.7 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N-methoxy-N-methylcarbamoyl chloride, the reaction is run as in Example 1, whereby 1-methoxy-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 94.7%. Melting point is 106.0° to 107.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH3:25][N:26]=[C:27]=[S:28]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:27]([NH:26][CH3:25])=[S:28])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 56.6 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.53 mmol) in dichloromethane (10ml) and methyl isothiocyanate (0.11 g, 1.5 mmol) was stirred at room temperature for twenty six hours. The solvent was evaporated, and the residue washed with diethyl ether to give 0.34 g of 6-nitro-2,2-dimethyl-3-(N'-methylthioureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 225° C.
Reaction SMILES: [Mg].Br[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.N1(N[C:19](=[O:27])[CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])CCCCC1.S(=O)(=O)(O)O>C(OCC)C>[CH2:22]([O:21][C:20]([O:24][CH2:25][CH3:26])([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH:19]=[O:27])[CH3:23]
Reactant: BrC1Cc2ccccc2C1
Reactant: CCOC(OCC)C(=O)NN1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(C=O)(OCC)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.73 g of magnesium turnings are covered with 90 ml of dry diethylether. To that mixture is then added 6 g of 2-bromoindane in 20 ml of dry diethylether at such a rate that a gentle boiling is maintained. When the magnesium turnings have reacted the solution containing the Grignard reagent is cooled to room temperature. The reaction mixture is then added dropwise, over a period of 3 hours, to a cooled (0°-5° C. solution of diethoxyacetic acid piperidinyl amide (6.4 g) in 20 ml of dry diethylether. After the addition is complete, the reaction mixture is stirred for two hours at about 5° C. The mixture is then poured into a cold 2% sulfuric acid solution (50 ml). The solution is extracted with ether and the combined ether extracts are washed with water and evaporated to dryness to give a residue of crude product, which is used without purification in step (b).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:8](I)[CH2:9][CH2:10][CH3:11]>C(OCC)(=O)C>[CH2:8]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)C(C)O
Reactant: CCCCI
Solvent: CCOC(C)=O
Product: CCCCOC(C)C(=O)OC
Temperature: 60 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
20.0 g of optically active methyl lactate and 47.8 g of n-butyl iodide were dissolved in ethyl acetate, and 20 g of Ag2O and 2.0 g of Molecular Sieve 3A were added thereto, followed by 7 hours of stirring at 60° C. After filtration of the insoluble matter, the solvent was distilled off and the remainder was distilled under reduced pressure (66° C./4 mmHg) to obtain 18.4 g of the product. (Yield: 42.8 %)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2)[CH3:2].OS(O)(=O)=O.[CH3:20]O>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:20])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2)[CH3:2]
Reactant: CO
Reactant: CCc1cc(C(=O)O)cc2cn[nH]c12
Agent: O=S(=O)(O)O
Product: CCc1cc(C(=O)OC)cc2cn[nH]c12
Yield: 47 %

Procedure:
To a solution of 7-ethyl-1H-indazole-5-carboxylic acid (500 mg, 2.63 mmol) in MeOH (15 mL) was added conc. H2SO4 (0.25 mL). The mixture was heated at reflux overnight. The solvent was removed under reduced pressure to afford a tan solid that was purified by flash chromatography (40 g column) using 15-30% EtOAc/heptane to afford methyl 7-ethyl-1H-indazole-5-carboxylate (252 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1cc(N)ccc1O
Solvent: CCO
Product: COC(=O)c1cc(N=Cc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 68.7 %

Procedure:
Methyl 2-hydroxy-5-aminobenzoate (43.6 g, 0.261 mole) was dissolved in benzaldehyde (26.6 ml, 0.26 mole) by heating to 100° C. for 10 minutes and cooled with ice-water after which 95% ethanol (40 ml) was added, and the resulting crystalline material was isolated by filtration. The product was recrystallized from 96% ethanol to give the title compound (45.6 g, 69%), m.p. 58°-59° C. Found (Calc. for C15H13NO3) C 70.60 (70.58), H 5.06 (5.10), N 5.50 (5.49).
Reaction SMILES: BrC1C2C(Cl)=NC=NC=2[N:4](C(C)C)C=1.CON(C)C(C1C=C(Cl)C=CN=1)=O.[NH2:28][C:29]1[C:30]2[C:37]([C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42](N)[N:41]=3)=[O:39])=[CH:36][N:35]([CH:47]([CH3:49])[CH3:48])[C:31]=2[N:32]=[CH:33][N:34]=1>>[NH2:28][C:29]1[C:30]2[C:37]([C:38]([C:40]3[CH:45]=[C:44]([NH2:4])[CH:43]=[CH:42][N:41]=3)=[O:39])=[CH:36][N:35]([CH:47]([CH3:49])[CH3:48])[C:31]=2[N:32]=[CH:33][N:34]=1
Reactant: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Agent: CON(C)C(=O)c1cc(Cl)ccn1
Product: CC(C)n1cc(C(=O)c2cc(N)ccn2)c2c(N)ncnc21

Procedure:
The title compound was prepared from 5-Bromo4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (6.5 g, 23.7 mmol) and 4-Chloro-pyridine-2-carboxylic acid methoxy-methyl-amide (5.7 g, 28.5 mmol) by procedures analogous to those described for the preparation (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(6-amino-pyridin-2-yl)-methanone. MS:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:32]4[CH:33]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=4[Cl:34])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4cc(Cl)ccc4Cl)cc3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.12 g, 0.25 mmol) and 2,5-dichloro-phenyl boronic acid (0.057 g, 0.30 mmol) to afford 0.098 g, (79%). LC/MS, Retention time=5.29 min; (m/z): calcd for C25H24Cl2N4OS: 499.5; found: 499.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])(O)[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(O)(c1cccc(OC)c1)c1ccccc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC=C(c1cccc(OC)c1)c1ccccc1C
Yield: 77.2 %

Procedure:
A mixture of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol (26.2 g, 0.10 mol), isopropanol (300 ml) and a 6 N solution of sulphuric acid (150 ml) was stirred at room temperature for 2 h. The reaction mixture was neutralised with a 4 N sodium hydroxide solution and extracted with ethyl acetate (2×200 ml). The combined organic phases was dried (MgSO4) and the solvent was evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (800 g) using n-heptane as eluent to give 18.4 g (76%) of 1-(3-methoxy-phenyl)-1-(2-methylphenyl)-1-propene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CC(O)C.O>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCc2cc(OCCCCl)ccc2N1
Reactant: C1CCNC1
Solvent: O
Solvent: CC(C)O
Product: O=C1CCc2cc(OCCCN3CCCC3)ccc2N1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of 6-(3-chloropropoxy)-3,4-dihydroquinolin-2(1H)-one prepared in Example 10-(1) (10 g) and pyrrolidine (15 g) in 2-propanol (15 mL) was stirred at 90° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1), and the resulting solid was subjected to recrystallization from ethyl acetate to give the titled compound (7.5 g, 65%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CO>[CH2:32]([O:31][C:29]1[CH:28]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][NH:42][CH:39]([CH3:41])[CH3:40])[CH:15]=2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)oc2c1

Procedure:
3′,5′-Dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 28 (2.5 g, 4.9 mmol) and iso-propyl amine (1.8 mL, 14.7 mmol) in dry methanol (150 mL) were reacted in a similar manner to that described under 34 to afford 35. Yield 2.2 g (79%); mp 173-174° C.; MS (FAB) 566 (M++1); IR (KBr) 3431, 1637; 1H NMR (200 MHz, CDCl3) δ 8.05 (d, J=8.6 Hz, 1H), 7.59-7.34 (m, 10H), 7.15 (d, J=1.8 Hz, 2H), 7.06 (s, 1H), 7.03 (d, J=9.4 Hz, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 5.13 (s, 4H), 4.14-4.11 (m, 3H), 3.18-3.16 (m, 1H), 2.93-2.79 (m, 2H), 1.11 (d, J=6.2 Hz, 6H); 13C NMR δ 177.9, 163.8, 162.9, 160.6, 158.1, 136.7, 133.9, 128.9, 128.5, 127.8, 127.1, 118.1, 115.3, 108.0, 105.8, 105.3, 101.5, 71.7, 70.7, 68.4, 49.8, 49.3, 23.1, 23.0. Analysis Calcd for C35H35NO6: C, 74.32; H, 6.24; N, 2.48. Found: C, 74.16; H, 6.17; N, 2.29.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)(Cl)=O.[C:19]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][CH2:28][NH2:29])([CH3:22])([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCN(CC)CC.CN(C=O)C>[C:19]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][CH2:28][NH:29][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a stirred solution of 3-nitroquinolin-4-ol (8.15 g) in DCM (100 mL) was added DMF (3.33 mL) and thionyl chloride (3.47 mL) and the reaction mixture was refluxed for 2.5 h when all solids dissolved. The solution was cooled to 0° C. and a solution of (3-aminopropyl)-carbamic acid tert-butyl ester (8.3 g) and Et3N (6.5 mL) in DCM (20 mL) was added dropwise. The reaction mixture was stirred overnight then poured into saturated sodium bicarbonate solution and the product extracted using DCM. The combined organic layer were washed with brine, water, dried, filtered and the solvents evaporated. The residue was trituated with diethylether to leave the subtitle compound (13 g).
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7](Cl)=[O:8])([O:3]C)=[O:2].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1>>[C:1]([CH2:5][CH2:6][C:7]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1)=[O:8])([OH:3])=[O:2]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 27.3 %

Procedure:
In a manner similar to that described in Example 3, 3-carbomethoxy-propionyl chloride (0.051 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.020 g of 4-[4-(3-carboxy-propionylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+294.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:30](C(C)C)C(C)C.C(OC(Cl)=O)C(C)C.N.C(O)(C)C>C1COCC1>[C:21]([O:20][C:18](=[O:19])[O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:25](=[O:27])[NH2:30])=[CH:12][CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)OC(C)(C)C)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)OC(C)(C)C)cc1)C(N)=O
Yield: 62.2 %

Procedure:
N,O-Bis-Boc-(S)-tyrosine from example 64 (5.00 g, 13.11 mmol) was dissolved in THF (20 mL), the solution stirred under an argon atmosphere and cooled in an ice bath. DIEA (5.70 mL, 32.7 mmol) was added followed by isobutylchloroformate (2.55 mL, 19.6 mmol). After 45 min a solution of 2M ammonia in isopropanol (39.3 mL, 78.6 mmol) was added and the mixture stirred at room temperature for 18 h. The solvent was evaporated, the residue taken in EtOAC (100 mL), washed with 5% aqueous citric acid (2×50 mL), 5% aqueous sodium bicarbonate (2×50 mL) and brine. After drying (MgSO4) and evaporation of the solvent, the residue was dissolved in chloroform (15 mL), stirred vigorously and Et2O (150 mL) was added. The suspension was stirred for 20 min. then the solid filtered and air dried to yield 3.10 g (62%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][S:19][C:13]=3[CH:12]2[CH2:20][CH2:21][CH2:22][CH3:23])=[O:7])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH2:20]([CH:12]1[C:13]2[S:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][N:11]1[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:25][CH:24]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC1c2sccc2CCN1CCNC(=O)c1ccc(N)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCC1c2sccc2CCN1CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Yield: 80 %

Procedure:
Prepared by Method F using the aminobenzene from Example 15 and methanesulfonyl chloride. The product was isolated as a white solid after flash silica gel chromatography using CH2Cl2 /Methanol/NH4OH (97.5/2.25/0.25 to 95.75/4/0.25). This material was recrystallized from EtOAc/ether to afford the title compound as an near-white solid (80%); mp 98°-105° C.; IR (KBr) 3420, 2930, 1635, 1610, 1553, 1505, 1340, 1310 and 1155 cm-1.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.C([Mg]Cl)(C)C.C(OCC)(=O)C.[C:17]([OH:22])(=[O:21])[CH:18]([CH3:20])[CH3:19]>O>[C:17]([OH:22])(=[O:21])[C:18]1[CH:20]=[CH:5][CH:1]=[CH:2][CH:19]=1
Reactant: CC(C)C(=O)O
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To compound (B-2) (14.16 g, 61.0 mmol) in a second dry round bottom flask under N, is added 70 mL of dry THF. The mixture is cooled to about −10° C. To the cold mixture is slowly added isopropyl magnesium chloride (63.3 ml, 2 M, 127 mmol). The resulting mixture is then stirred at −10° C. for about 20 min. Then, this mixture is slowly cannulated drop wise into the flask containing the (B-1) reaction while maintaining the temperature at −20° C. After addition is complete, the reaction is slowly warmed to RT and stirred at RT for about 1.6 hours. The reaction mixture is then cooled to −10° C. and quickly cannulated to another flask containing 15 mL of ethyl acetate and 10 mL of isobutyric acid at −10° C. under N2. After stirring for about 5 minutes, 10 mL of water is rapidly added. The cooling bath is removed, and the reaction mixture is stirred for 10 minutes at RT. The mixture is transferred to a separation funnel, and water (200 mL) is added. The water layer is extracted with EtOAc (3×400 mL). The aqueous layer is then acidified with HCl (2M) to pH 3, and is extracted with EtOAc (3×500 mL), dried over sodium sulfate and concentrated in vacuo. The resulting material is purified by silica gel column chromatography using 0-10% MeOH in DCM to afford benzoic acid (B-3).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C@H:35]([C:39]([NH:41][C:42]1[CH:47]=[C:46]([F:48])[C:45]([C:49]([CH3:55])([CH3:54])[CH2:50][O:51][CH2:52][CH3:53])=[C:44]([F:56])[CH:43]=1)=[O:40])[NH:34][CH2:33][CH2:32]2)[CH3:27].[C:57]([O:61][C:62](=[O:71])[CH2:63][C@@H:64]1[CH2:67][C@H:66]([C:68](O)=[O:69])[CH2:65]1)([CH3:60])([CH3:59])[CH3:58].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:26]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C@H:35]([C:39](=[O:40])[NH:41][C:42]1[CH:47]=[C:46]([F:48])[C:45]([C:49]([CH3:54])([CH3:55])[CH2:50][O:51][CH2:52][CH3:53])=[C:44]([F:56])[CH:43]=1)[N:34]([C:68]([C@@H:66]1[CH2:65][C@H:64]([CH2:63][C:62]([O:61][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:71])[CH2:67]1)=[O:69])[CH2:33][CH2:32]2)[CH3:27]
Reactant: CCOCC(C)(C)c1c(F)cc(NC(=O)[C@@H]2NCCc3cc(OCC)ccc32)cc1F
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCC(C)(C)c1c(F)cc(NC(=O)[C@H]2c3ccc(OCC)cc3CCN2C(=O)[C@H]2C[C@@H](CC(=O)OC(C)(C)C)C2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (90 mg, 0.24 mmol) was added to a solution of (R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (101 mg, 0.22 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (50.8 mg, 0.24 mmol) and DIEA (0.085 mL, 0.47 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (135 mg, 0.215 mmol, quant.).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 171.7 %

Procedure:
To a solution of 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.379 mmol, 214 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1.14 mmol, 0.085 mL) and 2 drops of acetic acid. Sodium triacetoxyborohydride (1.52 mmol, 339 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (20 mL) and saturated aq. sodium bicarbonate solution (20 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel using 2 M ammonia in MeOH/DCM 1:19 to 1:14, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The yellow solid was dried overnight under high vacuum to provide the title compound (188.2 mg). LCMS: m/z 507 [M+1] 1H NMR (400 MHz, CD3OD) δ 7.85 and 7.93 (1H, s), 7.79-7.85 (1H, m), 7.69 (1H, dd), 7.49-7.53 (1H, m), 5.38-5.56 (1H, m), 4.64-4.69 (1H, m), 4.05 and 4.06 (3H, s), 3.13-3.69 (6H, m), 2.94 (3H, s), 1.97-2.54 (12H, m), 1.30-1.63 (6H, m), 0.84 (3H, dt).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:35])[CH3:34])[CH:36]([CH3:37])[CH3:38])=[CH:24][CH:23]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc(C(CCNC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(C(CCNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
To benzyl 4-(tert-butoxycarbonylamino)-2-(4-(triisopropylsilyloxy)phenyl)butanoate (E304) in EtOAc was added Pd/C (10%) and the solution was kept under a H2 atomosphere for 2 h. The mixture was filtered over Celite and the solvent was evaporated to give 4-(tert-butoxycarbonylamino)-2-(4-(triisopropylsilyloxy)phenyl)butanoic acid (E305).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Reactant: OB(O)c1ccccc1
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+]
Product: Cc1c(-c2ccccc2)nc2ncccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,8-naphthyridine (150 mg, 0.704 mmol), phenylboronic acid (86 mg, 0.704 mmol), sodium carbonate (149 mg, 1.408 mmol) and Pd(PPh3)4. Product used without further purification in the next step. Mass Spectrum (ESI) m/e=255.0 (M+1).