Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH:6]2[CH2:8][CH2:9][N:3]1[CH2:4][CH2:5]2.[CH2:10](O)[CH3:11]>[Ni]>[ClH:1].[ClH:1].[N:3]1[CH:2]=[CH:7][CH:6]=[C:10]([CH:11]=[C:2]2[CH2:7][CH:6]3[CH2:8][CH2:9][N:3]2[CH2:4][CH2:5]3)[CH:4]=1
Reactant: ClC1CC2CCN1CC2
Reactant: CCO
Agent: [Ni]
Product: C(=C1CC2CCN1CC2)c1cccnc1
Product: Cl
Reaction time: 6 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (3 g, 140 mmol) was dissolved in 200 ml methanol and sodium borohydride (3 g, 79.6 mmol) was added in portions (exothermic reaction) with vigorous stirring. After 1 hr of continued stirring, acetone (100 ml) was slowly added to neutralize the remaining borohydride reagent. The mixture was evaporated to dryness and the resulting residue suspended in water (200 ml) and extracted three times with 200 ml portions of chloroform. The chloroform phases were combined, dried over MgSO4, and rotary evaporated to give a clear oil; crystallization of the free base gave a quantitative yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a white precipitate. 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7 mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol) stirred under a nitrogen atmosphere at 0° C., the reaction was than brought to room temperature and stirred for one additional hour. Rotary evaporation at 60° C. produced a viscous oil which when suspended in ether afforded 3-chloro-2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). The chloroquinuclidine (0.3 g, 1.3 mmol) was combined with 50 ml ethanol in a hydrogenation vessel, then wet Raney nickel (2.5 grams) was added in one portion. Hydrogenation (50 psig) was carried out for 6 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave the desired 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a white reside which easily recrystallized from ethanol-ether to give a white crystalline solid (0.21 g 70%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@H:7]([C@@H:9]([CH2:11][O:12][S:13]([CH3:16])(=[O:15])=[O:14])[OH:10])[OH:8])(=[O:4])=[O:3].[CH2:17]=O.S(=O)(=O)(O)O>>[CH3:16][S:13]([O:12][CH2:11][C@@:9]1([CH2:17][O:8][C@@H:7]1[CH2:6][O:5][S:2]([CH3:1])(=[O:3])=[O:4])[OH:10])(=[O:15])=[O:14]
Reactant: C=O
Reactant: CS(=O)(=O)OC[C@@H](O)[C@H](O)COS(C)(=O)=O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)OC[C@H]1OC[C@@]1(O)COS(C)(=O)=O
Yield: 61 %

Procedure:
D-threitol 1,4-bis(methanesulfonate) was reacted with formaldehyde and concentrated sulfuric acid as described in J. Med. Chem., 7, 14 (1964) to yield 2,3-O-methylene-D-threitol 1,4-bis(methanesulfonate) in 61% yield.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1)(=[O:4])=[O:3].[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[Na+].O.CC(C)=O>C(O)(=O)C.O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: O=C1CSC(=O)N1
Reactant: CS(=O)(=O)Oc1ccccc1CCOc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CS(=O)(=O)Oc1ccccc1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
1.7 g (5.3 mmole) 2-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate, 0.77 g (6.6 mmole) 2,4-thiazolidinedione and 1.06 g (13.2 mmole) sodium acetate were heated to 130° C. and allowed to stay at 130° C. for 10 minutes. The reaction mixture was taken off the heat and water:acetone (2:1) was added, the formed solid material was stirred with water and acetic acid, the precipitate was collected by filtration and washed with diethyl ether and recrystallized in dichloromethane to give 1.63 g (yield 61%) of 5-(4-[2-(2-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][CH:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(NO)C1CCCC1
Reactant: O=C(O)CC1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(C5CCCC5)no4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
[(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]acetic acid (140 mg, 0.41 mmol) prepared in Example 75 was dissolved in N,N-dimethylformamide (5 mL). 1,1′-Dicarbonyldiimidazole (73 mg, 0.45 mmol) was added thereto, and the mixture was stirred for 30 min at room temperature. N-hydroxy-cyclopentanecarboxamidine (260 mg, 2.03 mmol) was added thereto, and the mixture was stirred for 5 h at 80° C. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by column chromatography to give the title compound (100 mg, Yield 56%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:38])(C)C.CCCCCC>CC(CC)=O>[ClH:38].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:9]1=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Agent: CCC(CC)C(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one (654 mg, 1.5 mmol) was dissolved in ethyl methyl ketone (5 mL), and water (15 μL) and TMSCl (210 μL) were added and the mixture was stirred overnight. Hexane (10 mL) was then added. The precipitated solid matter was isolated by filtration and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 671 mg (95%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.Cl[C:14]([CH:17]1[CH:21]([O:22]CC2C=CC=C(OC3C=CC=CC=3)C=2)[O:20][C:19](=[O:37])[CH2:18]1)([CH3:16])[CH3:15].Cl>C1CCCCC1.O1CCCC1>[CH3:16][C:14]1([CH3:15])[CH:18]2[CH:17]1[CH:21]([OH:22])[O:20][C:19]2=[O:37]
Reactant: CC(C)(Cl)C1CC(=O)OC1OCc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C1CCCCC1
Product: CC1(C)C2C(=O)OC(O)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
0.25 ml of a solution of 2M butyllithium in cyclohexane was added at -20° C. to 0.55 ml of a molar solution of diisopropylamine in tetrahydrofuran and 5 ml of tetrahydrofuran and the temperature was allowed to rise to 0° C. and was then cooled to -60° to -70° C. 180 mg of the product of Step B were added all at once to the mixture at -60° to -70° C. and the mixture was heated over 2 hours at 0° C. The mixture was held at 0° C. for one hour and was poured into 2N hydrochloric acid. The mixture was stirred for 17 hours at 20° C. and the decanted aqueous phase was extracted with chloroform. The organic phase was dried and evaporated to dryness and the residue was taken up in a mixture of isopropyl ether and petroleum ether. The solution was extracted with water and the aqueous extract was evaporated to dryness under reduced pressure to obtain 30 mg of crystalline dl 6,6-dimethyl-4-hydroxy-3-oxabicyclo-[3,1,0]-hexan-2-one melting at 80° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.Br[CH:14]([CH2:26][O:27][CH3:28])[C:15]([NH:17][C:18]([CH3:25])([CH3:24])[C:19]#[C:20][CH2:21][O:22][CH3:23])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:14]([CH2:26][O:27][CH3:28])[C:15]([NH:17][C:18]([CH3:25])([CH3:24])[C:19]#[C:20][CH2:21][O:22][CH3:23])=[O:16])=[CH:7][CH:6]=2
Reactant: COCC#CC(C)(C)NC(=O)C(Br)COC
Reactant: Oc1ccc2ncc(Br)cc2c1
Product: COCC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ncc(Br)cc2c1

Procedure:
In a similar procedure to Example 6 Stage 2, 3-bromo-6-hydroxyquinoline was reacted with 2-bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl) 3-methoxypropionamide to give 2-(3-bromo-6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl) 3-methoxypropionamide as a gum. 1H NMR (CDCl3) δ: 1.58(3H, s); 1.59(3H, s); 1.77(3H, s0; 3.44(3H, s); 3.87-3.95(2H, m); 4.73(1H, m); 6.52(1H, s); 7.08(1H, m); 7.48(1H, dd); 8.02(1H, d); 8.21(1H, m); 8.79(1H, m).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH:2]=[CH2:3].[O-]CC.[Na+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.C(O)(=O)C>C(O)C>[O:20]=[C:21]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])=[N:8][CH:28]=[C:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: C=CCOc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
2-Allyloxybenzamidine hydrochloride1 (19.07 g., 0.0896 mole) was added to a cooled (ice-water), stirred solution of sodium ethoxide (12.25 g., 0.18 mole) in ethanol (100 ml.). To this cooled, stirred mixture was added a solution of diethyl ethoxymethylenemalonate (19.4 g., 0.0896 mole) in ethanol (15 ml.). The mixture was heated under reflux for 2.5 hours and then allowed to stand at room temperature for 18 hours. The mixture was poured into ice-water containing acetic acid. The solid was collected and recrystallized from cyclohexane to give the title compound (24.0 g., 89%), m.p. 118°-120°. Recrystallization from cyclohexane gave product with m.p. 118.5°-120.5°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14]OS(C)(=O)=O)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8].[H-].[Na+].C([N:25]1[CH:29]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]=[CH:27][O:26]1)C=C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:30]([C:29]3[CH:28]=[CH:27][O:26][N:25]=3)[C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: C=CCN1OC=CC1NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCC1CC(c2ccc(I)c(F)c2)=NO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1CC(c2ccc(I)c(F)c2)=NO1)c1ccon1
Reaction time: 0.08 h
Yield: 86.9 %

Procedure:
A solution of (5RS)-3-(3-Fluoro-4-iodophenyl)-5-methanesulfonyloxymethyl-4,5-dihydroisoxazole (1.7 g, 4.26 mM) in dry N,N-dimethylformamide (40 ml) under nitrogen, was treated with sodium hydride (60% in oil, 0.205 g, 5.13 mM), and stirred for 5 minutes. N-Allyl-3-(t-Butoxycarbonylamino)isoxazole (0.86 g, 4.69 mM) was added, and the mixture heated at 60° for 18 hours. After cooling and dilution with water (200 ml), the mixture was extracted with ethyl acetate (3×100 ml), the extracts were washed with water (2×100 ml), brine (100 ml), dried (magnesium sulfate). The residue after evaporation was purified by chromatography on a 50 g silica Mega Bond Elut® column, eluting with a mixture of 25% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (1.61 g). MS (ESP): 488 (MH+) for C18H19FIN3O4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[C:23]#[N:24].[F-].[K+]>C1COCC1.O.C(Cl)Cl.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]2[C:22]([C:23]#[N:24])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC(=O)c1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(F)c(-c2ccc(F)cc2C#N)c1
Temperature: 70 °C
Yield: 58.2 %

Procedure:
To a degassed solution of 1-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethanone (12 g, 45.43 mmol), 2-bromo-5-fluorobenzonitrile (9.09 g, 5.28 ml, 45.44 mmol), potassium fluoride (7.92 g, 136.31 mmol) and tris(dibenzylideneacetone)palladium(0) (0.834 g, 0.908 mmol) in THF (200 ml) and water (10 ml) was added tri-tert butylphosphine (10% weight solution) (0.368 g, 3.63 ml, 1.817 mmol). The reaction was heated at 70° C. for 14 h then allowed to cool to ambient temperature. The reaction was partitioned between water (200 ml) and ether (300 ml). The aqueous phase was extracted with ether (150 ml) and the combined organics washed with brine (200 ml), dried (MgSO4), filtered and evaporated to give a brown solid. The solid was dissolved in DCM and adsorbed onto silica. The crude product was chromatographed on silica (5-20% EtOAc in isohexane) to give the title product as a white solid (6.8 g): δH (400 MHz, CDCl3) 2.63 (3H, s), 7.31 (1H, t, J 9.0 Hz), 7.40-7.44 (1H, m), 7.50-7.53 (2H, m), 8.02-8.10 (2H, m).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22]1[O:33][C:32]2[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:32]3[O:33][CH2:22][O:23][C:24]=3[CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)OCO3)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g -see Preparation 8), 3,4-methylenedioxyphenethyl bromide (0.247 g -see Preparation 16), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 3 hours. The mixture was allowed to cool to room temperature, water (6 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield 0.27 g.
Reaction SMILES: Cl[C:2]1NC(=O)N[C:4](=O)[CH:3]=1.N1C=[CH:14][C:13](=O)NC1=O.C[Si](C)(C)[CH2:20][CH2:21][O:22][CH2:23][Cl:24]>>[CH2:21]([O:22][CH2:23][Cl:24])[C:20]1[CH:14]=[CH:13][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 6-chloropyrimidine-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 71%) as a white powder.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:15][CH2:14][C@H:11]1[CH2:12][CH2:13][N:9]([C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:10]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: C[C@H](c1ccccc1)N1CC[C@H](CO)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1CC[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of {(3S)-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}methanol (6.62 g, 32 mmol) and imidazole (4.77 g, 70 mmol) in N,N-dimethylformamide (90 ml) was added tert-butyldimethylchlorosilane (5.28 g, 35 mmol) at 0° C. and the resulting mixture was warmed to room temperature. The reaction mixture was stirred overnight and poured into water. Extraction with ethyl acetate was performed. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 75/25) to afford (3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[(1R)-1-phenylethyl]pyrrolidine (8.81 g, 27.6 mmol, 86%) as a colorless oil.
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:30](O)[CH3:31]>>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([O:19][CH2:30][CH3:31])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1S2
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc2c(c1)CCc1cccnc1S2
Temperature: 0 °C
Yield: 85 %

Procedure:
A mixture of 30 mg of (5,6-dihydro benzo[b]pyrido[3,2-f]-thiepin-8-yl)-acetic acid, 3 ml of ethanol and 100 mg of sulfuric acid was refluxed for 1 hour. After the completion of the reaction, the solvent was distilled off to obtain a residue, to which was added ice water, and the mixture was basified with a 5% sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain an oil, which was chromatographed over silica gel and eluted with benzene/chloroform (2/1), thereby yielding 28 mg (yield: 85%) of ethyl (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetate as an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].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.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[Cl:81])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[Cl:81][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][C:75]=1[CH2:74][C@@H:69]([NH:68][C:27]([C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=1)=[O:28])[CH2:70][C:71]([OH:73])=[O:72]
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1Cl
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2Cl)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 257 μmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-chlorophenyl)butanoic acid.HCl (12.8 mg, 0.0514 mmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (20.5 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C30H29ClN8O3, 585.21. found 585.4.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)Cl.S(Cl)(Cl)=O.[NH4+:19].[OH-]>CCOC(C)=O>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:19])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(F)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
A round bottom flask was charged with 6-fluoro-4-methylnicotinic acid (1.13 g, 7.28 mmol, Frontier) and DCM (73 mL) to give a clear solution. Thionyl chloride (5.32 mL, 72.8 mmol) was added drop-wise and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in EtOAc (10 mL) and added drop-wise to a rapidly stirred mixture of EtOAc (40 mL) and concentrated aqueous NH4OH (36.9 ml, 947 mmol). The mixture was stirred for about 1 h, and the layers were separated. The aqueous layer was further extracted with EtOAc (50 mL) and the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give 6-fluoro-4-methylnicotinamide (0.69 g, 61%) as white solid: LC/MS (Table 2, Method d) Rt=1.03 min; MS m/z 153 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33].[C:36]([NH:44][NH2:45])(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:17]([C:16]1[CH:15]=[CH:14][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:5]([C:4]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32]([NH:45][NH:44][C:36](=[O:43])[C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)=[O:33])[CH:3]=3)=[O:6])[CH2:12][CH2:11]2)=[CH:20][CH:19]=1)#[N:18]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1N
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1NC(=O)NNC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(1-(3-Amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 121.1, 0.1 g, 0.31 mmol) and triethyl amine (0.09 ml, 0.62 mmol) in DCM (5 ml) was added to a solution of phosgene (20% in toluene, 0.31 ml, 0.62 mmol) in DCM (5 ml) at 0° C. After the resulting reaction mixture was stirred at room temperature for 1.5 hours, all solvents were removed under reduced pressure. The residue was dried under high-vacuum for 30 minutes then was re-dissolved in EtOH (5 ml). Isonicotinohydrazide (0.05 g, 0.34 mmol) was added. The mixture was heated at 80° C. over night. The ethanol was removed and the residue was purified using prep.-TLC (10% MeOH in DCM) to give the product as a light brown solid. Yield: 0.14 g, 93%. m/z (ES+) 483.2 (M+H)+.