Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:41][CH:42]=[C:36]([CH:37]=[CH:38]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:45])[CH3:44])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:38][CH:37]=[C:36]([CH:42]=[CH:41]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:44])[CH3:45])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
0.71 g (1.10 mmol) of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]hexanoate was dissolved in 11 ml of dichloromethane, and the same volume of trifluoroacetic acid was added. Stirring at RT for 4 h was followed by concentration and fractionation of the residue by preparative HPLC. The required fractions were combined and, after evaporation of acetonitrile, mixed with dilute hydrochloric acid, concentrated further and finally freeze dried. 0.42 g of the title compound was obtained as hydrochloride.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[C:14]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C.C(OCC)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.2 %

Procedure:
Methyl 3-formyl-4-hydroxybenzoate (2.06 g, 11.4 mmol) and K2CO3 (2.36 g, 17.1 mmol) were stirred in 50 mL of DMF. Methyl iodide (1.42 mL, 22.8 mmol) was added via syringe, and the reaction was stirred for 6 hours at rt. The reaction was poured into H2O and diethyl ether, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with diethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford 2.24 g of crude desired product. 1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.20 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([CH2:16][CH:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>C1COCC1.[Ag]=O>[CH2:1]([O:8][C:9]([C:11]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC1(C(=O)OCc2ccccc2)CCCC1
Reactant: [OH-]
Agent: O=[Ag]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CC1(C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of 1-(2-oxo-ethyl)-cyclopentanecarboxylic acid benzyl ester (200 mg, 0.81 mmol) in THF (5 mL) is added silver(II) oxide (201 mg, 1.62 mmol) and aqueous 1M NaOH (0.81 mL of 1.0 N, 0.81 mmol) and the suspension is stirred at room temperature for 18 hours. The mixture is acidified to pH 3 with aqueous 1M HCl and is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to furnish 1-carboxymethyl-cyclopentanecarboxylic acid benzyl ester MS 263.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C@@H:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:17][OH:18])=[O:14])=[C:11]([F:28])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:44])=[N:31]1.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:1][C:2]1[C:3]([C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C@@H:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:17][OH:18])=[O:14])=[C:11]([F:28])[CH:10]=2)=[N:4][C:5]([C:33]2[C:32]([CH3:44])=[N:31][N:30]([CH3:29])[CH:34]=2)=[CH:6][N:7]=1
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ncc(Br)nc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1nn(C)cc1-c1cnc(N)c(-c2ccc(C(=O)N[C@H](CO)c3cccc(Cl)c3)c(F)c2)n1
Temperature: 120 °C
Yield: 60.4 %

Procedure:
To the reaction mixture of (S)-4-(3-amino-6-bromopyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (40 mg, 0.086 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.2 mg, 0.172 mmol), PdCl2(dppf)-DCM (6.28 mg, 8.59 μmol), and DME (644 μL), 2 M Na2CO3 (215 μL) were added. The reaction mixture was heated at microwave synthesizer (120° C., 12 min). To the reaction mixture, anhydrous sodium sulfate was added, filtered, and concentrated. The crude product was purified by auto-prep to provide 25 mg of desired product as a TFA salt. LCMS (m/z): 481.3 (MH+), 0.73 min; 1H NMR (500 MHz, CD3OD) δ ppm 8.66 (d, J=6.26 Hz, 1H) 8.17 (s, 1H) 8.02 (s, 1H) 7.76-7.51 (m, 3H) 7.45-7.16 (m, 3H) 5.07-4.09 (m, 1H) 3.72 (s, 3H) 3.62 (m, 2H) 2.33 (s, 3H).
Reaction SMILES: N1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2C=N1.FC(F)(F)C(OCC)=[O:17].C[O-].[Na+]>CO>[C:9]1(=[O:17])[C:8]2[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: c1ccc2c(c1)CCc1cn[nH]c1-2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCCc2ccccc21

Procedure:
Synthetic Scheme III shows the procedure for preparation of 4,5-dihydrobenz[g]indazole compounds embraced by Formula I. In step 1, ethyl trifluoroacetate is reacted with base, such as 25% sodium methoxide in a protic solvent, such as methanol, and a 1-tetralone derivative (9) to give the intermediate diketone (10). In step 2, the diketone (10) in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the free base or hydrochloride salt of a substituted hydrazine at reflux for 24 hours to afford a mixture of pyrazoles (11) and (12). Recrystallization gives the 4,5-dihydro benz[g]indazolyl-benzenesulfonamide (11). ##STR28##
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18](Cl)[N:17]=1>>[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][NH:22]2)=[C:18]([O:11][C:7]2[C:6]([CH3:12])=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:8]=2[CH3:10])[N:17]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-cyclopropyl-2,6-dimethylphenol (263 mg, 1.62 mmol) in 1-methyl-2-pyrridone (3 mL) at 0° C. was added NaH (65 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,6-dichloropurine (102 mg, 0.54 mmol) in 1-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 100° C. for 16 h and then cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (MeOH:CHCl3=5:95) yielded 114 mg (67%) of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17](Br)[C:16]([F:20])=[CH:15][C:14]=3[CH3:21])[CH3:2].[C:26]([Cu])#[N:27]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:26]#[N:27])[C:16]([F:20])=[CH:15][C:14]=3[CH3:21])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(Br)c21
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Temperature: 220 °C
Yield: 93.9 %

Procedure:
5-Bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (496 mg, 1.20 mmol) and CuCN (162 mg, 1.81 mmol) was dissolved in N-methyl-2-pyrrolidinone (6 mL) and the solution was divided into the 2 microwave reaction vessels (3.0 mL each). The reaction vessels were heated in microwave at 220° C. for 15 minutes. The reaction mixtures in 2 vessels were combined and then diluted with water (10 mL). The crude mixture was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 25% EtOAc in hexanes) to give 404 mg (94%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[OH:26][CH2:27][CH2:28][N:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][NH2:32]>C(O)C>[OH:26][CH2:27][CH2:28][N:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][NH:32][C:21](=[O:22])[CH2:20][N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[N:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[N:9]1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: NCCN(CCO)CCO
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCN(CCO)CCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 1.0 g of N,N-bis(2-hydroxyethyl)ethylenediamine are boiled under reflux for 24 h in 8 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, N-{2-[bis(2-hydroxyethyl)amino]ethyl}-2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetamide remains as a colorless foam. Rf value: 0.35 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 2.5 (m, 6H), 3.1 (m, 2H), 3.4 (m, 4H), 4.2 (bs, 2H), 4.9 (s, 2H), 7.0 (m, 4H), 7.4 (m, 3H), 7.95 (d, 1H), 8.1 (t,1H), 11.0 ppm (s, 1H).
Reaction SMILES: Cl.[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]([NH:23][CH:24]([C:33]([O:35]CC)=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:7]1=[O:38])([OH:4])=[O:3].[OH-].[Na+]>C(O)C>[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]([NH:23][CH:24]([C:33]([OH:35])=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:7]1=[O:38])([OH:4])=[O:3]
Reactant: CCCCCCCCC(NC1C(=O)N(CC(=O)O)c2ccccc2SC1c1ccccc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCC(NC1C(=O)N(CC(=O)O)c2ccccc2SC1c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
300 mg of the compound obtained in Example 28 was dissolved in a mixture consisting of 1.6 ml of a 1N aqueous solution of sodium hydroxide and 1 ml of ethanol. The resulting solution was stirred at room temperature for 3 hours and then at 60° C. for an hour. After the addition of ethanol, the precipitated crystals were separated by filtration and washed with ethanol. These crystals were dissolved in a small amount of water and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The precipitated crystals were separated by filtration and washed with water to obtain 170 mg of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[CH:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[CH:3]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1cn(C)cc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cn(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 28.5 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrrole-3-carboxylic acid (270 mg, 1.94 mmol), tetrahydrofuran (7 mL), oxalyl chloride (203 μL, 2.32 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (79.2 mg, 28%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][NH2:13])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])[CH3:24]>C(Cl)Cl>[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:13][NH:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:15][CH:14]=1)=[O:29])[CH3:24]
Reactant: CCCCCc1ccc(C(=O)NN)cc1
Reactant: CCSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C(=O)NNC(=O)c2ccccc2SCC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 4-pentylbenzohydrazide (1-C) (206 mg, 1.0 mmol) and triethylamine (153 μL, 1.1 mmol) in methylene chloride (5 mL) was added a solution of 2-(ethylthio)benzoyl chloride (1-B) (210 mg, 1.0 mmol) in methylene chloride (2.0 mL). After stirring at room temperature for 18 h, the mixture was diluted with methylene chloride and washed with water, 10% NaHCO3, brine, dried (MgSO4) and evaporated in vacuo to give 2-(ethylthio)-N′-(4-pentylbenzoyl)benzohydrazide (1-D). MS m/z 371 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=O)[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.NN.Cl>>[Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1c(Br)ccc2c1NC(=O)C2=O
Agent: Cl
Agent: NN
Solvent: O
Product: Cc1c(Br)ccc2c1NC(=O)C2
Temperature: 130 °C

Procedure:
A mixture of 6-bromo-7-methylindoline-2,3-dione (G. W. Rewcastle et al., J. Med. Chem. 1991, 34(1), 217-222; 7.65 g, 31.9 mmol) and hydrazine monohydrate (35.9 g, 35 ml, 718 mmol) was heated to 130° C. for 3 h and then cooled to 10° C. 37% HCl (72.2 g, 60.2 ml, 733 mmol) was added slowly. The precipitate was filtered through sintered glass, washed excessively with water, than with little heptane and dried under high vacuum. The title compound was obtained as yellow crystals and used for the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]2=[CH:4][C:3]=1[C:12]#[N:13].C(O)(=O)C>C(O)C.[Zn]>[N:7]1[CH:2]=[C:3]([C:12]#[N:13])[CH:4]=[C:5]2[CH2:11][O:10][CH2:9][CH2:8][C:6]=12
Reactant: N#Cc1cc2c(nc1Cl)CCOC2
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cnc2c(c1)COCC2
Temperature: 25 °C
Yield: 72.8 %

Procedure:
step 3 2-Chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.77 g, 9.09 mmol) obtained in step 2 was dissolved in ethanol (30 mL), acetic acid (9 mL) and zinc (2.60 g) were added thereto, and the mixture was stirred with heating under reflux for 4 hr. The mixture was allowed to cool to room temperature, then filtered through Celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give 7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.06 g, 73%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CC(CO)=CC=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].OCC1C=CC(B(O)O)=CC=1.Br[C:45]1[CH:46]=[N:47][N:48]([CH2:50][C:51]2[CH:52]=[C:53]([CH:63]=[CH:64][CH:65]=2)[CH2:54][NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH:49]=1>>[CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:45]3[CH:46]=[N:47][N:48]([CH2:50][C:51]4[CH:52]=[C:53]([CH:63]=[CH:64][CH:65]=4)[CH2:54][NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH:49]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Cn2cc(Br)cn2)c1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Agent: OCc1ccc(B(O)O)cc1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(CNC(=O)OC(C)(C)C)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 4-(hydroxymethyl)phenylboronic acid was replaced with tert-butyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzylcarbamate. LCMS, [M+H]+=609.4.
Reaction SMILES: Cl.[N:2]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>CO>[CH3:24][O:23][C:19](=[O:22])[CH2:20][CH2:21][N:5]1[CH2:6][CH2:7][N:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CO
Product: COC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate hydrochloride, (200 g, 0.82 mol) in methanol (1 L) was added methyl acrylate (214 g, 2.46 mol) with stirring at approximately 25° C. under N2 atmosphere, and the reaction mixture was refluxed at 70° C. for 48 hours. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (1.2 L) and water (2 L). The organic layer was separated and washed with water (1 L×2) and brine (500 mL), dried over Na2SO4, filtered and concentrated. The crude obtained was purified by column chromatography over silica gel using 30-40% ethyl acetate in petroleum ether to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 9H), 2.20-2.34 (m, 1H), 2.35-2.46 (m, 1H), 2.48 (t, 2H, J=7.2 Hz), 2.76-2.90 (m, 1H), 2.90-3.12 (m, 2H), 3.12-3.30 (m, 1H), 3.32 (t, 1H, J=4.5 Hz), 3.35-3.44 (m, 1H), 3.67 (s, 3H), 3.71 (s, 3H) 3.83-3.94 (m, 1H).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16](Br)[CH:15]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Cl[Mg]c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccccc2)cc1

Procedure:
6 mol of a 26% strength by weight phenylmagnesium chloride/THF solution are added dropwise in the course of 4 hours to a boiling solution of 6 mol of 1,4-bromochlorobenzene and 100 mg of Pd(dppf)Cl2 *CH2Cl2 in 600 g of tetrahydrofuran (THF). After completion of the addition, the reaction mixture is refluxed for a further 5 hours. After hydrolysis with 3600 g of 8% strength by weight sulfuric acid, phase separation and subsequent removal of the solvent by distillation, crude 4-chlorobiphenyl is obtained, which is purified by fractional distillation in vacuo. Yield 1080 g (96%), purity of the product □ 99.7% (a/a GC).
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].Cl>>[CH2:1]([NH:3][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Agent: Cl
Product: CCNC1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Yield: 112.7 %

Procedure:
Compound 120 (0.26 g, 0.557 mmol) was treated with 1 N aqueous HCl solution at room temperature and the resulting solution was refluxed for 2 h. The reaction was brought to room temperature, filtered and washed with water (5 mL). The solvent was evaporated and crude was recrystallised from ethanol/ether to obtain compound 121 (0.23 g, 94%) as a solid in 2:3 ratio of diastereomers. 1H NMR (DMSO-d6) δ 1.22-1.29 (m, 3H), 1.53-1.62 (m, 2H), 1.80-2.16 (m, 6H), 2.74-3.23 (m, 4H), 7.08 (d, 1H, J=8.4 Hz), 7.24-7.52 (m, 3H), 7.68-7.72 (m, 1H), 8.14-8.18 (m, 2H), 8.59 (s, 1H), 8.97-9.09 (m, 2H), 9.64 (s, 1H), 11.20, 11.27 (2s, 1H), 11.42 (s, 1H); ESI-MS m/z (%): 367 (MH+ for free base, 18), 322 (100), 184 (19), 119 (39); ESI-HRMS calculated for C21H27N4S (MH+, free base), calculated: 367.1959; observed: 367.1950.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([F:14])[C:3]=1[C:4]([NH:6][OH:7])=[NH:5].C(N(CC)CC)C.Cl[C:23](OC1C=CC=CC=1)=[O:24].O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([F:14])[C:3]=1[C:4]1[NH:5][C:23](=[O:24])[O:7][N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(F)c(C(=N)NO)c1F
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(-c2noc(=O)[nH]2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To an ice cold solution of 2,6-difluoro-N-hydroxy-3-methoxybenzamidine in DCM (5 ml) was added triethyl amine (0.07 g, 0.11 ml, 0.77 mmol) followed by dropwise addition of phenyl chloroformate. The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction (TLC monitoring), the organic layer was washed with water until the DCM layer was neutral. The organic layer was dried (Na2SO4), filtered and concentrated to get a white solid. The solid compound was then dissolved in toluene (2 ml) and refluxed it at 100° C. for 2 h. After the completion of the reaction (TLC monitoring), water (100 ml) was added and extracted with ethyl acetate (3×100 ml). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 35% EtOAc-Hexane) to get the desired product (0.09 g, 80%) as a white solid. MS ES+ (229.18).