Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.C[CH2:28][N:29]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10]([NH:29][CH3:28])=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(C(=O)c2cnn(-c3cc(C(=O)O)ccc3C)c2N)c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(OC)c3)c2N)c1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a stirred solution of 3-[5-Amino-4-(3-methoxybenzoyl)-pyrazol-1-yl]-4-methylbenzoic acid C (50 mg, 0.14 mmol, 1.0 eq) in 10 mL of DMF was added EDCI (41 mg 0.21 mmol, 1.5 eq), HOBt (29 mg, 1.5 mmol, 2.0 eq), and diisopropylethylamine (55 mg, 0.43 mmol, 3.0 eq) and the solution was stirred for 15 minutes at room temperature when methylamine hydrochloride (13 mg, 0.19 mmol, 1.5 eq) was added and the reation stirred for 1 hour. The mixture was diluted with EtOAc (300 mL) and washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4) and concentrated. The product was purified by flash chromatography on silica gel to provide the product to provide the product (15 mg, 32%) as a brown solid: HPLC (4 minute 10-90 gradient) tR 1.97 min; MS m/z 365.2 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]12[CH:17]([CH2:18][OH:19])[CH:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12]2.C(N(CC)CC)C>ClCCl>[CH:14]12[CH:17]([CH:18]=[O:19])[CH:11]([CH2:16][CH2:15]1)[CH2:12][CH2:13]2
Reactant: OCC1C2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1C2CCC1CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
In a flask under argon was placed dichloromethane (10 mL) and a 2M solution of oxalyl chloride in dichloromethane (1.43 mL, 2.85 mmol) cooled to −78° C. To this mixture was slowly added dimethyl sulfoxide (303 μL, 4.26 mmol) and gas evolution occurred. The mixture was stirred at −78° C. for 30 min. After this time, a solution of bicyclo[2.2.1]hept-7-yl-methanol (180 mg, 1.43 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred at −78° C. for another 15 min and triethylamine (784 μL, 5.58 mmol) was added and the reaction was slowly warmed to 0° C. and stirred for 1 h. After this time, the mixture was quenched with a 1M aqueous sodium bisulfate solution (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography system (4 g column, 10% ethyl acetate/hexanes) afforded bicyclo[2.2.1]heptane-7-carbaldehyde (170 mg, 96%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH2:41][CH:42]1[CH2:44][CH2:43]1)([O:17][C:18]1[CH:40]=[CH:39][C:21]2[C:22]3[N:26]([CH2:27][CH2:28][O:29][C:20]=2[CH:19]=1)[CH:25]=[C:24]([C:30]1[N:31]([CH:36]([CH3:38])[CH3:37])[N:32]=[C:33]([CH3:35])[N:34]=1)[N:23]=3)[C:12](OCC)=[O:13])C.CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH:42]1([CH2:41][C:11]([O:17][C:18]2[CH:40]=[CH:39][C:21]3[C:22]4[N:26]([CH2:27][CH2:28][O:29][C:20]=3[CH:19]=2)[CH:25]=[C:24]([C:30]2[N:31]([CH:36]([CH3:38])[CH3:37])[N:32]=[C:33]([CH3:35])[N:34]=2)[N:23]=4)([CH2:10][OH:9])[CH2:12][OH:13])[CH2:44][CH2:43]1
Reactant: CCOC(=O)C(CC1CC1)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)CC4CC4)cc2OCC3)n(C(C)C)n1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
To a suspension of LiAlH4 (65.5 mg, 1.724 mmol) in THF (7 mL) cooled to 10° C. was added a solution of 2-cyclopropylmethyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-malonic acid diethyl ester (309 mg, 0.575 mmol) in THF (5 mL). The reaction mixture was stirred at RT for 1.5 h. To the reaction mixture was added EtOAc (1 mL) and stirring was continued for 10 min. An aqueous solution of Rochelle salt was then added and stirring continued for a further 1.5 h. EtOAc was added and the mixture was filtered through a Celite® pad and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 4-12% MeOH in DCM) affording the title compound as a colourless foam (0.20 g, 77%). LCMS (Method B): RT 2.72 min [M+H]+ 454.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][C:12]2([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[N:28]1([CH2:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([C:12]3([CH2:11][NH:10][C:5]4[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:19][CH:20]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=[N+]([O-])c1cccnc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccnc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 83.9 %

Procedure:
A solution of (3-Nitro-pyridin-2-yl)-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine (465 mg, 1.06 mmol) in ethanol (˜10 mL) was hydrogenated for 4 hours at room temperature at 40 psi in the presence of 10% Pd/C (45 mg, 10% w/w). The reaction mixture was filtered over Arbocel® and rinsed with ethanol (30 mL), 2M HCl (20 mL) and EtOH (30 mL). The filtrate was concentrated in vacuo to give the title compound (365 mg, 84%). HRMS ESI+ m/z 411.2750 [MH]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.[NH2:9][C@H:10]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:11][C@:12]([CH2:17][O:18][CH2:19][CH3:20])([CH3:16])[C:13]([OH:15])=[O:14]>>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([CH2:21][C@@H:10]([NH:9][C:6]([C:4]2[N:3]=[N:2][NH:1][CH:5]=2)=[O:8])[CH2:11][C@:12]([CH2:17][O:18][CH2:19][CH3:20])([CH3:16])[C:13]([OH:15])=[O:14])=[CH:27][CH:26]=1
Reactant: CCOC[C@](C)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: O=C(O)c1c[nH]nn1
Product: CCOC[C@](C)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O

Procedure:
1H-[1,2,3]Triazole-4-carboxylic acid and (2S,4R)-4-amino-5-biphenyl-4-yl-2-ethoxymethyl-2-methylpentanoic acid were reacted as described herein to yield the title compound (0.8 mg). MS m/z [M+H]+ calc'd for C24H28N4O4, 437.21. found 437.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[Br:9]Br.O>C(O)(=O)C>[Br:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrBr
Reactant: Oc1ccc(Cl)cn1
Solvent: O
Solvent: CC(=O)O
Product: Oc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-hydroxypyridine (100 g) and bromine (40.1 mL) in acetic acid (400 mL) was stirred at r.t. for 1 h. The mixture was poured into 3 L of water and stirred for 30 min then filtered. The residual solid was washed with 2 L of cold water, air dried and then coevaporated with toluene three times and with benzene two times. The white solid (81 g) so obtained was used in the subsequent reaction.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]1([NH:54][C:55]2[C:56](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:57](O)=[O:58])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:57](=[O:58])[C:56]3[CH:60]=[CH:61][CH:62]=[CH:63][C:55]=3[NH:54][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3Nc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) with N-phenylanthranilic acid (21 mg) and N,N-diisopropylethylamine (33 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:21])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)Cl)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under Argon atmosphere, Intermediate 3 (147.08 mg; 0.65 mmol) was stirred in anhydrous DCM (5 mL). Oxalyl chloride (57.75 μL; 0.68 mmol) was added followed by DMF (0.50 μL; 0.01 mmol). The reaction mixture was stirred 3 hours at RT. Solvents were evaporated to give 2,2′-dimethylbiphenyl-4-carbonyl chloride as a yellow oil. The latter was dissolved in anhydrous THF (3 mL), Intermediate 46 (136.62 mg; 0.65 mmol) and DIEA (221.08 μL; 1.30 mmol) were added under argon. The mixture was heated in the microwave at 150° C. for 15 min. The reaction mixture was diluted in water and extracted with EtOAc, the organic phase was then washed with NH4Cl, NaHCO3 and NaCl sat. solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. LC/MS (Method A): 398.9 (M−H)−, 400.8 (M+H)+. HPLC (Method A) Rt 6.37 min (Purity: 98.8%).
Reaction SMILES: CC([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21])=C.S(=O)(=O)(O)O.[OH-].[Na+].O>C(O)C>[O:21]=[C:5]1[N:6]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:4]1
Reactant: C=C(C)n1c(=O)n(CCCC(=O)OCC)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCn1c(=O)[nH]c2ccccc21
Reaction time: 5 h
Yield: 81.4 %

Procedure:
31.4 g of the product of Step A were added at 0° to 5° C. to a mixture of 15.5 ml of sulfuric acid in 155 ml of ethanol and the mixture was stirred at 0° to 5° C. for 5 hours. The mixture was neutralized with sodium hydroxide and was poured into 1.5 liters of iced water. The mixture was stirred for 5 minutes and was vacuum filtered. The product was washed with water to obtain 22 g of ethyl 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate melting at 88° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C=O)C>O>[CH2:12]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(SCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 35.5 g (115.2 mmol) 2-bromo-5-nitro-O-benzylphenol, 26.3 g (190 mmol) potassium carbonate, 15 mL (127 mmol) benzyl mercaptan, and 200 mL DMF were stirred at room temperature 18 h. TLC analysis indicated a complete reaction, so the thick reaction mixture was transferred to a 2 L Erlenmeyer containing 1 L water and the resulting mixture was stirred in a ice/water bath 30 min. The precipitate was filtered, washed with three 300 mL portions of water, dried at 40° C. 18 h under vacuum to give 2-benzyloxy-4-nitro-S-benzylthiophenol 40.5 g (115.2 mmol, 100%) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:11]1(=[O:17])O[C:14](=[O:15])[CH2:13][CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[C:11]1(=[O:17])[NH:1][C:14](=[O:15])[CH2:13][CH2:12]1.[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: O=C1CCC(=O)O1
Agent: NCCCC[C@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(=O)N1
Temperature: 60 °C

Procedure:
In this example that demonstrates how this method could be performed, 2 g of L-lysine is dissolved in 200 ml dry N,N-dimethyl formamide (DMF) in a 500 ml round bottom flask. 10.7 g succinic anhydride and 20 ml triethyl amine are added under nitrogen atmosphere. The mixture is heated to 60° C. for 6 h. At the end of 6 h period, the solution is cooled and solvent is removed by vacuum distillation. The crude product is purified by flash chromatography. It is then immediately used in next reaction.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:28]=[CH:27]2.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35]([N:4]1[CH2:3][CH2:2][N:1]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][N:18]=4)(=[O:14])=[O:15])=[CH:9][CH:8]=3)[CH2:6][CH2:5]1)=[O:36])[CH:28]=[CH:27]2
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCn1ccc2cc(Cl)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCn1ccc2cc(Cl)ccc21)N1CCN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CC1

Procedure:
Synthesized according to general procedure 5, method A. The reaction was set up with 0.11 mmol 4-(piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide, 0.17 mmol 3-(5-chloro-1H-indol-1-yl)propanoic acid, 0.17 mmol BOP reagent, 0.17 mmol triethylamine and 300 μL DMF. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=525.2; tR=2.87 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[N-:13]=[C:14]=S.[Br-].[OH-].[Na+]>CO>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[C:14]1[NH2:13]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: [N-]=C=S
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(N)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N1-Methyl-4-nitro-benzene-1,2-diamine (5 g, 30 mmol) in MeOH was added bromide isothiocyanate (4.4 g, 42 mmol) and the mixture was stirred at rt. After 16 h. 6N NaOH solution was added to the reaction mixture until Ph˜10 and MeOH was then removed in vacuo. H2O was added and the solid was filtered and dried to give the title compound as an off white solid (5.2 g, 90%). MS (ESI) m/z=193 [M+H]+.
Reaction SMILES: [N:1]1([C:5]2[S:6][C@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:15][CH2:14][C@H:12]2[O:13][C@H:7]3[C@H:8]([N:9]=[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)[S:6]3)[C@@H:10]([OH:17])[C@@H:11]2[OH:16])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H]3SC(N4CCC4)=N[C@@H]3[C@@H](O)[C@@H]2O)cc1
Yield: 12.7 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5.0 g, 19 mmol) and triethylamine (3.88 g, 38 mmol) in DMF (50 mL) was treated with 4-methylbenzene-1-sulfonyl chloride (4.4 g, 23 mmol) overnight at room temperature. The reaction mixture was quenched by water (100 mL), extracted with dichloromethane (3×80 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 1%-5% methanol in dichloromethane to give crude compound 4 as a light yellow solid (1.0 g). This material was employed in the next step without further purification. (ES, m/z) [M+H]+ 415.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccnc1-c1c(-c2ccc(Cl)cc2)c(C)n[nH]c1=O
Product: Cc1cccnc1-c1c(Cl)nnc(C)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
0.34 g of 5-(4-chlorophenyl)-6-methyl-4-(3-methyl-2-pyridyl)-2H-pyridazin-3-one and 3.6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.33 g of the resultant residue was subjected to silica gel column chromatograph, to obtain 0.21 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(3-methyl-2-pyridyl)pyridazine (hereinafter, described as compound (2) of the present invention.).
Reaction SMILES: C(N1C=NN=N1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:25]([C:29]1[N:33](CC2C=CC(C3C(C(O)=O)=CC=CC=3)=CC=2)[N:32]=[C:31]([C:50]([CH:52]2CCC[CH2:54][CH2:53]2)=O)[N:30]=1)[CH2:26][CH2:27][CH3:28]>>[CH2:50]([C:31]1[N:30]=[C:29]([CH2:25][CH2:26][CH2:27][CH3:28])[NH:33][N:32]=1)[CH2:52][CH2:53][CH3:54]
Reactant: CCCCc1nc(C(=O)C2CCCCC2)nn1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnnn2)cc1
Product: CCCCc1n[nH]c(CCCC)n1

Procedure:
A solution of 64.5 g (0.50 mol) of ethyl iminovalerate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)] in 100 mL of methanol was added slowly to 58.0 g (0.50 mol) of valeric acid hydrazide (Lancaster Synthesis) in 400 mL of methanol at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to warm to ambient temperature and then stir at reflux for 2 days. The solvent was removed in vacuo; purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (80:20) gave 78.9 g (93%) of a colorless solid: mp 50.5°-51.5° C.; NMR (CDCl3) δ0.88 (t, J=7 Hz, 6H), 1.28-1.33 (m, 4H), 1.63-1.77 (m, 4H), 2.72 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 183 (12%), 182 (100), 181 (3), 180 (6), 152 (8), 139 (4); HRMS. Calcd for M+H: 182.1657. Found: 182.1661.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([C:17](=[O:33])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH:36]=O)[S:14][C:13]=2[CH:42]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]3[CH:17]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:22][CH:23]=4)[O:33][CH2:36][C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[C:15]=3[S:14][C:13]=2[CH:42]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3C=O)sc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c3c(sc2c1)-c1ccccc1COC3c1ccc(OCCN2CCCCC2)cc1
Yield: 66.8 %

Procedure:
Add LAH solution (1M/THF) to a solution of 2-{6-methoxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzaldehyde (410 mg, 0.82 mmol) in THF (5 mL) at r.t. until LCMS analysis indicates complete consumption of starting material. Dilute the mixture with THF (10 mL) and water (2 mL), followed by cautious addition of HCl(5 M) to pH 1. Heat gently for 10 min. Dilute with CH2Cl2 and quench with aq. NaHCO3. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-10% (2M NH3 in MeOH)/CH2Cl2) to afford 1-{2-[4-(10-methoxy-5H,7H-6-oxa-12-thia-dibenzo[a,e]azulen-7-yl)-phenoxy]-ethyl}-piperidine (266 mg, 67%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][CH2:66][CH2:67][NH:68][C:69](=[O:75])[O:70][C:71]([CH3:74])([CH3:73])[CH3:72]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:65][CH2:66][CH2:67][NH:68][C:69]([O:70][C:71]([CH3:72])([CH3:74])[CH3:73])=[O:75])=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25](=[O:26])[O:27][CH:28]([CH3:29])[CH3:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.4 %

Procedure:
To a flask charged with 2-(4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetic acid (for a preparation see Intermediate 50) (85 mg, 0.2 mmol) and HATU (91 mg, 0.240 mmol) was added DMF (2 mL) and the mixture treated with DIPEA (0.105 mL, 0.600 mmol) at room temperature. After 5 min, 1,1-dimethylethyl (2-aminoethyl)carbamate (0.047 mL, 0.300 mmol) was added, the mixture was stirred at room temperature for 3 h and then partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. the residue was purified by chromatography, eluting with a MeOH/DCM gradient, to give 1-methylethyl {(2S,4R)-1-acetyl-6-[4-(2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}-2-oxoethyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (56 mg, 0.099 mmol, 49.4% yield) as a pale yellow foam. LCMS (Formate, 2 min), Rt=0.91 min, MH+=455.