Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O:21][C:22]1[C:31]([CH2:32][CH:33]=O)=[C:30]2[C:25]([C:26](=[O:37])[CH2:27][C:28]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:20][O:21][C:22]1[C:31]([CH2:32][CH2:33][N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:13]=4)[CH:9]=[CH:10]3)[CH2:15][CH2:16]2)=[C:30]2[C:25]([C:26](=[O:37])[CH2:27][C:28]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1
Reactant: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
120 mg of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide and 120 mg of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were dissolved in 8 ml of methylene chloride. Thereafter, 0.05 ml of acetic acid and 0.15 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then filtered. The filtrate was then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate), so as to obtain 210 mg of the subject compound.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1>O>[CH3:1][CH2:5][CH2:1][CH2:5][O:4][C@H:3]([CH2:2][OH:4])[CH2:3][CH3:2]
Reactant: C1CCOC1
Solvent: O
Product: CCCCO[C@@H](CC)CO
Temperature: 250 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
Into a 300 ml vessel equipped with a stirrer and a reflux condenser, 200 g of THF with a water content of 2.0 wt. % was charged and 100 g of an anhydrous 12-tungstosilicic acid which had been prepared by heating in an electric furnace at a temperature of 250° C. for 3 hours was added thereto (the molar ratio of water existing in the catalyst phase to the heteropoly-acid corresponds to 5.8). After stirring was continued at 50° C. for 4 hours, according to the same procedure as described in Example 1, a PTMG with a number-average molecular weight of 1100 was obtained at a yield of 8%.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)=O.C(O[C:46]1(O[Si](C)(C)C)[CH2:48][CH2:47]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][N:36]([CH:46]6[CH2:48][CH2:47]6)[CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(-c3csc(C4CCN(C5CC5)CC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-piperidin-4-yl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.17 mmol) in MeOH (2 mL) containing 3 Å molecular sieves was added AcOH (99 μL, 1.73 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (180 mg, 1.04 mmol) and sodium cyanoborohydride (49 mg, 0.78 mmol). The reaction was stirred at 60° C. for 17 h. Aqueous NaOH (1N, 5 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (21%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 H), 8.35 (s, 1 H), 8.09 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.28-7.41 (m, 5H), 7.18-7.23 (m, 2 H), 5.67 (s, 2 H), 2.95-3.09 (m, 3 H), 2.30 (t, 2 H), 2.05 (d, 2 H), 1.57-1:72 (m, 3 H), 0.37-0.45 (m, 2 H), 0.25-0.34 (m, 2 H); ES-MS m/z 547.21 HPLC RT (min) 2.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[N:39]=[N:40][NH:41][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(C#N)ccc2-n2c(C)nnc21
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3nn[nH]n3)ccc2-n2c(C)nnc21
Temperature: 100 °C

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-cyano-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 7) (68.4 mg) was dissolved in DMF (5 ml). Triethylamine hydrochloride (45.0 mg) and sodium azide (21.23 mg) were added and the reaction mixture was heated at 100° C., under nitrogen, overnight. The temperature was raised to 120° C. and the reaction mixture was heated overnight. The reaction mixture was allowed to cool to room temperature, partitioned between ethyl acetate and water. The organic phase was washed with water (2×10 ml) and brine (10 ml). The aqueous layer was passed through a pre equilibrated Biotage 103 column. The organic content was eluted with methanol, the methanolic solution was evaporated and the residue was chromatographed (10-20% methanol:DCM). Trituration with diethyl ether gave (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(2H-tetrazol-5-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (25.6 mg) as a yellow solid. LCMS (formate): MH+ 462/464, RT 0.75 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][C:19]([N:21]3[CH2:28][CH2:27][C:24]4([CH2:26][CH2:25]4)[C@H:23]([OH:29])[CH2:22]3)=[O:20])[CH2:10][C@H:9]2[CH3:30])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].C(O)(=O)C>CO.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][C:19]([N:21]3[CH2:28][CH2:27][C:24]4([CH2:26][CH2:25]4)[C@H:23]([OH:29])[CH2:22]3)=[O:20])[CH2:10][C@H:9]2[CH3:30])=[CH:4][C:3]=1[C:31]([F:32])([F:33])[F:34]
Reactant: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)C=CN1c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)CCN1c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 24 h
Yield: 95.6 %

Procedure:
A solution of 0.049 g (0.1 mmol) of (R)-1-(4-chloro-3-trifluoromethyl-phenyl)-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-1,2,3,4-tetrahydro-[1,4]diazepin-5-one (73% ds) and 0.006 ml (0.1 mmol) of acetic acid in 2 ml MeOH was treated with 0.005 g of PtO2 and was stirred over H2-atmosphere for 1 days. After filtration and evaporation, the residue was reevaporated (3 times) with toluene and the solvent was removed under vacuum to give 0.048 g (98%) of the titled compound as white foam. MS: 502.21 (MH+, Cl).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1>CC(C)=O.ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][N:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCNCC1
Reactant: ClCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of thiomorpholine 1,1-dioxide (0.72 g, 5.4 mmol) and potassium carbonate (0.74 g, 5.4 mmol) in acetone (10 mL) was added bromo-3-chloromethyl-benzene (0.62 mL, 4.9 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated to a waxy solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(3-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a clear viscous oil that solidified to a white solid (1.0 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.49 (s, 1H), 7.41 (ddd, J=6.9, 1.9, 1.9 Hz, 1H), 7.25-7.19 (m, 2H), 3.62 (s, 2H), 3.10-2.96 (m, 8H). MS=304, 306 (MH)+. 120b) N-{3-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.046 g, 34%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (dd, J=6.7, 1.0 Hz, 1H), 8.23 (d, J=8.H Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.68 (dd, J=7.4, 0.9 Hz, 1H), 7.62-7.60 (m, 1H), 7.48 (dd, J=8.1, 1.8 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.05 (t, J=7.1 Hz, 1H), 6.97-6.93 (m, 2H), 3.70 (s, 2H), 3.13-3.01 (m, 11H). MS=512 (MH)+.
Reaction SMILES: O=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH3:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:18]([N:17]([CH3:16])[CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1COCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (1.30 g (6.04 mmol) 107.1 (prepared as described in WO2004074291) in DCM (20 mL) was treated with N-methyl-benzylamine (0.857 mL, 6.64 mmol) and stirred at rt for 30 min. Sodium triacetoxyborohydride (1.54 g, 7.25 mmol) was then added, and the reaction mixture was stirred at room temperature for 24 hr. Excess hydride was quenched by the addition of H2O and the mixture was extracted with EtOAc (2×). The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo, absorbing onto 8 g SiO2. Purification by flash column chromatography (ISCO 40 g SiO2, 20% EtOAc/Hexanes then gradient to 80% EtOAc/hexanes) afforded tert-butyl 6-(benzyl(methyl)amino)-1,4-oxazepane-4-carboxylate (0.759 g) 107.2 as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.35-7.28 (m, 4H), 7.27-7.19 (m, 1H), 4.19-4.10 (m, 1H), 4.06-4.03 (m, 1H), 3.99-3.95 (m, 1H), 3.87 (m, 1H), 3.77-3.75 (m, 2H), 3.64-3.56 (m, 1H), 3.50 (ddd, J=3.0, 9.9, 12.5 Hz, 1H), 3.26-3.12 (m, 2H), 3.11-2.98 (m, 1H), 2.33-2.22 (m, 3H), 1.53-1.33 (m, 9H); LCMS (ESI) m/z: 321.20 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].C([BH3-])#N.[Na+]>ClC(Cl)C.[I-].[Zn+2].[I-]>[F:1][C:2]([F:12])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(c1ccc(O)cc1)C(F)(F)F
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Oc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-1-(4-hydroxyphenyl)ethanone (5.0 g, 26 mmol) in dichloroethane was added zinc iodide (2.7 ml, 39 mmol) followed by sodium cyanoborohydride (10 ml, 197 mmol). The reaction was stirred at RT for 18 h. Both TLC and LCMS showed one product was formed. MS+=175 (desired mass 192-OH). The mixture was filtered through celite and rinsed with dichloromethane. The filtrate was concentrated and dried in vacuum to afford the title compound as colorless oil. MS m/z: 175(M−H2O).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35]C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:34][C:31]([CH3:32])([CH3:30])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:43])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)c2ccnn12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (38.0 g) in tetrahydrofuran (200 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 200 mL) at 0° C., and the mixture was stirred for 2 hr. The mixture was diluted with ethyl acetate, and then saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (32.1 g, 91%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]([CH:12]=O)C>O>[CH2:1]([NH:8][C:9]1[CH:4]=[CH:3][C:2]([C:1]#[N:8])=[CH:12][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: NCc1ccccc1
Solvent: O
Product: N#Cc1ccc(NCc2ccccc2)nc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Heat 6-chloroniconitrile (0.58 g, 4.2 mmol) and benzylamine (4.6 mL, 42 mmol) in anhydrous DMF (3 mL) at 120° C. for 4.5 h. Cool at room temperature. Dilute with water and extract with EtOAc. Wash the organic phase with brine, dry over MgSO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1, 2:1, 1:2) to give the desired intermediate as a white solid (840 mg, 96%). MS (ES+) m/z: 210 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC>C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([C:25]([O:27][CH2:28][CH3:29])=[CH2:26])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(C(=O)OC)cc(Cl)n1

Procedure:
Add methyl 2,6-dichloroisonicotinate (2.06 g, 10 mmol), tetrakis(triphenylphosphine)palladium (0) (578 mg, 0.5 mmol), triphenyhlphosphine (263 mg, 1 mmol) and toluene (25 mL) in a previously nitrogen filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(1-ethoxyvinyl)tin (4.05 mL, 12.0 mmol) under nitrogen and heat the sealed mixture at 100° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride respectively. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [H-].[CH2:2]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=O)[C:10]1([CH3:17])[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH2:2]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1([CH3:17])[CH3:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)C(=O)NCCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CNCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of lithiulalluminium hydride (1.078 g, 28.4 mmol) in tetrahydrofuran (200 ml) at 0-20° C. was added 4-benzyl-3,3-dimethylpiperazin-2-one (6.2 g, 28.4 mmol in 100 ml tetrahydrofuran) over 1 h. The reaction mixture was warmed to 25° C. over 15 minutes followed by reflux for 6 h. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to 0-10° C. and 10% sodium hydroxide (50 ml) was added slowly over 1 h. and then allowed to stir for 20 hr at 25° C. The reaction mass was passed through celite and washed with tetrahydrofuran (500 ml). The combined filtrate was concentrated under reduced pressure. Water (100 ml) was added and the aq. phase was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with brine (50 ml) and dried over sodium sulphate, and concentrated under reduced pressure till dryness. The resulting crude product (5.2 g) was carried over to the next step without purification.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:13]([CH:29]=2)[O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[C:19]([O:21]C(C)(C)C)=[O:20])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:13]([CH:29]=2)[O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[C:19]([OH:21])=[O:20])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCCCOc1ccc(C(=O)N2CCOCC2)cc1OCc1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCOc1ccc(C(=O)N2CCOCC2)cc1OCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of the compound obtained in Example 5 (0.17 g; 0.35 mmol) in dichloromethane (17 ml) is added trifluoroacetic acid (3.4 ml) and the medium is stirred at room temperature for 2 hours. After evaporating to dryness, the residue is crystallized from pentane. The powder is filtered off by suction and dried (0.14 g; 93% yield).
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:8]=1.[CH:17]1([CH3:29])[CH2:22][CH2:21][CH:20]([CH:23]([CH3:25])[CH3:24])[CH:19]([C:26](Cl)=[O:27])[CH2:18]1>O1CCCC1>[CH:23]([C@@H:20]1[CH2:21][CH2:22][C@@H:17]([CH3:29])[CH2:18][C@H:19]1[C:26]([NH:16][CH:14]([CH3:15])[CH2:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)=[O:27])([CH3:25])[CH3:24]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: CC(N)Cc1cccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(Cc1cccnc1)NC(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Yield: 72.7 %

Procedure:
In a 25 mL round bottom flask, fitted with magnetic stirrer, 15 mL of tetrahydrofuran, 1.5 mmol (1.5 eq.) of pyridine and 1.1 mmol (1.1 eq.) of 1-(pyridin-3-yl)propan-2-amine were added. p-Menthane carboxylic acid chloride (1.0 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with MTBE and NaOH (1N in water). The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography, obtaining 220 mg of a white solid, mp 108-110° C.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[C:31]2[CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1>ClCCl>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][CH:43]3[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38][C:31]4[C:30]5[C:35](=[CH:36][CH:37]=[C:28]([O:27][CH3:26])[CH:29]=5)[N:34]=[CH:33][CH:32]=4)[CH2:45][CH2:44]3)=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: COc1ccc2nccc(CCC3CCC(=O)CC3)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2nccc(CCC3CCC(NCc4ccc5c(c4)OCO5)CC3)c2c1
Reaction time: 8 h

Procedure:
Piperonylamine (0.038 ml, 0.3 mmol) and sodium triacetoxyborohydride (0.05 g) were added to a solution of 4-[2-(6-methoxy-quinolin-4-yl)-ethyl]-cyclohexanone (0.05 g, 0.176 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred overnight and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc and then EtOAc:MeOH 9/1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].C(ON[C:14]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=N)C>C(O)C>[OH:9][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:14]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:1][C:2]=2[CH:3]=1
Reactant: Nc1ccc(O)cc1N
Reactant: CCONC(=N)C(C)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C)c1nc2cc(O)ccc2[nH]1
Yield: 91.2 %

Procedure:
A mixture comprising of 3,4-diaminophenol (3.661 g, 29.5 mL), ethyl 2-(N-ethoxyamidino)propionate (7.423 g, 38.4 mmol) and ethanol (30 mL) was heated at reflux for 6 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated aqueous sodium hydrogencarbonate (3×20 mL) and brine (1×20 mL), dried (MgSO4) and concentrated in vacuo to provide ethyl 2-(5-hydroxy-1H-benzoimidazol-2-yl)propionate (6.3 g, 91% yield) as a dark solid. The solid was further purified by silica gel flash chromatography (100% ethyl acetate); MS (PB-PCI) C12H14N2O3 m/e calc 234.28; found 235 (MH+).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][CH2:5][C@@H:4]1[NH:8][C:9]([C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:10].BrC([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35])C(N)=O>CN(C=O)C>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:8][C:9]([CH2:11][N:6]1[CH2:7][C@H:3]([OH:2])[C@@H:4]([NH:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:5]1)=[O:10]
Reactant: O=C(N[C@H]1CNC[C@@H]1O)c1ccc(Cl)s1
Reactant: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
22.6 Using general procedure A with DMF as solvent 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-hydroxy-pyrrolidin-3-yl)-amide hydrochloride was reacted with 2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-4-hydroxy-pyrrolidin-3-yl)-amide. Light-yellow solid. MS 491.3 ([M+H]+)