Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:6]2=[N:5][CH:4]=1)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[CH:10][CH:9]=3)#[CH:2].[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>ClCCl>[C:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][O:20][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[C:6]2=[N:5][CH:4]=1)=[CH:12][C:11]([C:21]([F:22])([F:23])[F:24])=[CH:10][CH:9]=3)#[CH:2]
Reactant: C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: ClCCl
Product: C#Cc1cnc2c(NCCCOC3CCCCO3)nc3cc(C(F)(F)F)ccc3n12
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 3-{[1-ethynyl-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 30 (334 mg, 1.0 mmol) in anhydrous dichloromethane (10 mL) cooled at 0° C., were added 3,4-dihydro-2H-pyran (109 μL, 1.2 mmol) and para-toluenesulfonic acid (19 mg, 0.1 mmol). The mixture was stirred at room temperature overnight and then poured onto a saturated aqueous solution of sodium hydrogenocarbonate and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol 20/1) to afford the title compound (302 mg, 72%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]1([C:7]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccccc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepared by the method of example 3.3 using 2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.59 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (3.3 mmol). Chromatography on silica gel (100 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and 10% methanol in dichloromethane gave the title compound: Rf =0.41 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27](O)=[O:28])[CH:21]=3)[NH:16]2)=[CH:11][C:10]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:28])[CH:21]=3)[NH:16]2)=[CH:11][C:10]=1[N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a suspension of methanesulfonamide (150 mg, 1.55 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (62 mg, 1.55 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.31 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (36 mg, 25%) as a white solid: LC/MS m/e calcd for C23H28FN3O4S (M+H)+: 462.6, observed: 462.4.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]2[O:17][CH2:16][O:15][C:14]=12)[C:8]([O:10]C)=O.[C:18]([O:21][CH3:22])(=[O:20])[CH3:19].C(O)(=O)C>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]2[O:17][CH2:16][O:15][C:14]=12)[C:8]([CH2:19][C:18]([O:21][CH3:22])=[O:20])=[O:10]
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Reactant: COC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
2.08 g (52 mmol) of 60% NaH was suspended in 8 ml of N,N-dimethylformamide (DMF) containing 4.20 g (20 mmol) of methyl 3-methoxy-4,5-methylenedioxybenzoate (9), and to this mixture was added dropwise with stirring 2.8 ml (35 mmol) of methyl acetate in 3 ml of dimethylformamide at such a rate that the temperature of the reaction mixture could be maintained at 50°-60° C. After this addition was over, the reaction mixture was kept at 55° C. for one hour, then cooled to room temperature and added with 3.8 ml of acetic acid to stop the reaction. The reaction mixture was added with 30 ml of ice-cold water and extracted with toluene (15 ml×2). The toluene layer was washed with water, further washed with a saturated sodium hydrogencarbonate aqueous solution, then dried over anhydrous magnesium sulfate and concentrated. The residue was washed several times with a small quantity of n-hexane and recrystallized from methanol (10 ml) to obtain 3.61 g of methyl 3-methoxy-4,5-methylenedioxybenzoylacetate (10) (yield: 71.6%). Melting point: 65.5°-66.5° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CN(C)C(=O)C.O>[Cl:37][C:33]1[CH:32]=[C:31]([CH:26]([NH:25][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:4])[CH2:27][C:28]([OH:30])=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC(CC(=O)O)c1cccc(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2cccc(Cl)c2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 25 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-3-(3-chloro-phenyl)-propionic acid (156 mg, 0.78 mmol) (commercially available from Alfa Aesar L19797) in N,N-dimethylacetamide (DMA) (2 mL) was added sodium methoxide (34 mg, 0.62 mmol). The resultant suspension mixture was heated in a 150° C. oil bath for 4 h. After cooled, reaction mixture was diluted with water (50 mL), acidified by 1 N HCl to pH=3-4, and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with EtOAc/hexanes (10%-100%), to provide the title compound 20 mg (0.04 mmol) in 26% yield. LC-MS ESI−: 486 (M−1)−.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[S:15][C@H:14]([N:16]2[CH:31]=[CH:30][C:20]([NH:21]C(=O)C3C=CC=CC=3)=[N:19][C:17]2=[O:18])[CH2:13][O:12]1)(=O)C1C=CC=CC=1>N>[OH:9][CH2:10][C@@H:11]1[S:15][C@H:14]([N:16]2[CH:31]=[CH:30][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:13][O:12]1
Reactant: O=C(Nc1ccn([C@@H]2CO[C@H](COC(=O)c3ccccc3)S2)c(=O)n1)c1ccccc1
Agent: N
Product: Nc1ccn([C@@H]2CO[C@H](CO)S2)c(=O)n1
Reaction time: 8 h

Procedure:
2-(S)-benzoyloxymethyl-4-(S)—(N-benzoylcytosin-1-yl)-1,3-oxathiolane (1.0 g, 0.0022 mol) was dissolved in a methanolic ammonia (approximately 2M) solution (20 mL). The initial slurry was stirred overnight. After overnight stirring, the resulting clear solution was evaporated to dryness and slurried in acetone (20 mL). This yielded off-white powdery solid which was filtered and washed with acetone (2×10 mL), and dried to yield the product. 0.47 g (88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1cccc(N2CCOCC2)c1
Yield: 95.9 %

Procedure:
According to the general procedure B, 3-bromoanisole (82 mg, 0.44 mmol) reacted with morpholine (36 mg, 0.41 mmol) using 1 mol % of catalyst and sodium tert-butoxide (42 mg, 0.44 mmol) at 100° C. for 21 h to give the title compound (76 mg, 96%) as an oil: 1H-NMR (300 MHz, CDCl3): δ 7.21 (t, 1H, J=8.1 and 8.7 Hz), 6.57-6.45 (m, 3H), 3.87 (t, 4H, J=4.5 and 5.1 Hz), 3.81 (s, 3H), 3.17 (t, 4H, J=4.5 and 5.1 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 160.00, 152.67, 129.83, 108.43, 104.68, 102.18, 66.86, 55.15, 49.25. GC/MS(EI): m/z 193 (M+).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[H-].[Na+].[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].CCOCC>CN(C=O)C>[CH:4]1([C:2](=[O:3])/[CH:1]=[C:12](\[OH:18])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)C1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)/C(O)=C/C(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93.6 %

Procedure:
To a solution of cyclohexyl methyl ketone (10.4 g, 82.4 mmol) in DMF (90 ml) at rt, was added 60% NaH (3.96 g, 98.9 mmol). The mixture was stirred 45 min, cooled to 0° C., diethyl oxalate (13.4 ml, 98.9 mmol) was added and the temperature allowed to warm and stay at rt for 3 h. The reaction mixture was poured into Et2O, extracted with H2O (3×), and the aqueous phase was acidified with conc. HCl and extracted with EtOAc (3×). The organic extracts were washed with brine, dried (Na2SO4), and concentrated to afford 17.45 g (94%) of 9.1. MS (ESI) 225.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])=[C:15]([O:30]C)[CH:14]=1.Br.C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])=[C:15]([OH:30])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(CNC(=O)c2ccc(Nc3ncc(Br)n4ncnc34)cc2O)cn1

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (285 mg, 1.03 mmol) and 4-amino-2-methoxy-N-[(6-methylpyridin-3-yl)methyl]benzamide (280 mg, 1.03 mmol) are stirred in iPrOH (5 mL) and HBr (48% aq., 380 μL) is added. The mixture is heated at reflux for 24 hours. The cooled suspension is poured into NaHCO3 (sat. aq., 25 mL) and water (25 mL) and extracted with CHCl3 (4×30 mL). The extracts are dried over MgSO4 and evaporated. The residue is purified by column chromatography, eluting with 10% CH2Cl2/MeOH. The product-containing fractions are evaporated and the residue is triturated with MeOH to afford the title compound as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: C1COCCN1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Product: CC1CCN(c2cc(N3CCOCC3)ccc2[N+](=O)[O-])CC1
Yield: 99.9 %

Procedure:
The procedure of Example 4, step (b) was followed using 304 mg (1.19 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the previous step) and 519 μL (5.95 mmol) of morpholine to afford 363 mg (106%) of the title compound as a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C16H23N3O3, 306.2 (M+H), found 306.1.
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:19]([OH:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:4][CH:5]([C:15]1[CH:19]([O:20][CH3:22])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCc1ccccc1)C1=CC(=O)OC1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1OC(=O)C=C1C(CCCc1ccccc1)OC(C)=O
Reaction time: 0.2 h

Procedure:
A solution of 4-(1-acetoxy-4-phenylbutyl)-5-hydroxy-2(5H)-furanone (0.020 g., 0.069 mmol) and p-toluene sulfonic acid (approx. 3 mg.) in 2.5 ml methanol was stirred for 72 hours at room temperature. The reaction mixture was concentrated and partitioned between ethyl ether and water. The organic portion was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give an oil (0.027 g.) This material was purified by flash chromatography (30% ethyl acetate/hexane) to give a diasteriomeric mixture of the two methoxybutenolides. The mixture was subsequently separated by semi-preparative HPLC on a Whatman Partisil M-9 silica column, with an elution rate of 4 ml/min with 20% ethyl acetate/hexane. One diasteriomer (A) was eluted at 11 minutes, followed by the other (B) at 12 minutes. Concentration gave the purified compounds.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:10].I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:10]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23.0 mL of 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 mg, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 90.9%) as a yellow oil: EI-HRMS m/e calcd for C16H21Cl2O2(M+) 280.1230, found 280.1227.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.[H-].[Na+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([O:14][C@@H:9]1[C@@H:10]([CH2:12][O:13][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@H:8]1[O:15][CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 7 (100 g, 0.4 mol) in DMF (600 mL) was treated with NaH (110 g, 3.2 mol, 70% dispersed by mineral oil) at 0° C. for 30 min, followed by the addition of BnBr (410 g, 2.4 mol) dropwise. After kept additional 2 hours at room temperature, the mixture was poured into ice-water (1.5 kg) slowly and extracted with ethyl acetate (3×500 mL). The organic layers were combined, washed with brine (3×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 10%-30% ethyl acetate in petroleum ether to afford 92 (166 g, 80%) as a yellow oil; (ES, m/z) [M+H]+ 519.0; 1H NMR (300 MHz, CDCl3) δ 7.26-7.48 (m, 15H), 6.40 (d, J=6.6 Hz, 1H), 4.54-4.86 (m, 6H), 4.41 (d, J=4.8 Hz, 1H), 4.17-4.18 (m, 1H), 3.60-3.79 (m, 4H), 3.12 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[NH:8])=[O:7])[CH3:2].[I:11][C:12]1[C:13]([NH2:21])=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](O)=[O:18].C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:21][C:13]1[N:14]=[CH:15][C:16]([C:17]([N:8]=[S:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])([CH3:9])=[O:7])=[O:18])=[CH:20][C:12]=1[I:11]
Reactant: Nc1ncc(C(=O)O)cc1I
Reactant: CCOC(=O)CS(C)(=N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Temperature: 70 °C

Procedure:
A solution of ethyl(S-methylsulfonimidoyl)acetate was dissolved in anhydrous DMF (1 mL) and treated with 5-iodo-6-amino-nicotinic acid (82 mg, 1.05 eq), diisopropylamine (0.1 mL, 2 eq), and BOP (149 mg, 1.1 eq) with stirring. The reaction mixture was heated to 70° C. for 6 hours and then partitioned between EtOAc and aq NH4Cl. The organic layer was separated, washed with saturated aq NaHCO3 (1×) and brine (1×), and dried over Na2SO4. The organic phase was filtered and concentrated. The residue as purified by gradient column chromatography (EtOAc-Hexane 1:9 to 2:3). Concentration of the product containing fractions provided the title compound as a brown oil (24 mg).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.CON(C)[C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].Cl>C1COCC1>[CH3:7][N:5]1[CH:6]=[C:2]([C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=[N:4]1
Reactant: Cn1cc(I)cn1
Reactant: CON(C)C(=O)C1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C2CCOCC2)cn1
Reaction time: 2 h
Yield: 29 %

Procedure:
A solution of 4-iodo-1-methyl-1H-pyrazole (0.80 g, 3.9 mmol) in THF (7.04 g, 8.00 ml, 98 mmol) was cooled at 0° C. A solution of isopropylmagnesium chloride lithium chloride complex in THF (5.42 ml, 4.23 mmol, 0.78 molar) was added dropwise and the reaction was stifled for 1½ hour. A solution of N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (0.733 g, 4.23 mmol) in THF (2 mL) was added dropwise. Cooling was removed after 15 min and reaction was then stirred for 2 hours. To the mixture was added 2 M HCl (20 mL) and it was extracted with AcOEt (3×25 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to yield (1-methyl-1H-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone (220 mg, 1.13 mmol, 29.4% yield).
Reaction SMILES: [NH2:1][C@:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:15][C:14]([C@@:2]1([NH2:1])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1)=[O:16]
Reactant: CO
Reactant: N[C@]1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C

Procedure:
The (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid (79 g, 0.28 mol) suspended in MeOH (1.8 L) was cooled in an ice/water bath and thionyl chloride (178 mL, 2.44 mol) was added dropwise. Following the addition the reaction was heated to reflux. After 2 days the reaction mixture was cooled to room temperature, filtered, and rinsed with MeOH (2×200 mL). The filtrate was concentrated in vacuo to provide a white solid. The white solid was triturated with EtOAc (1 L), collected by filtration, rinsed with EtOAc (2×500 mL), and dried under vacuum to give the (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride as a white solid (79 g, 96%).
Reaction SMILES: CO[C:3]([C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]=1)=O.CC(C[AlH]CC(C)C)C.N1C=CC=CC=1.S(=O)(=O)=O>C1COCC1>[CH3:3][C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:7][CH:6]=1
Reactant: COC(=O)C1=CCCC(CCOCc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=CCCC(CCOCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
5-(2-Benzyloxy-ethyl)-cyclohex-1-enecarboxylic acid methyl ester (Intermediate R3 obtained above in Example R1 in accordance with Method R) was reduced with DIBAL. The resulting alcohol (Intermediate R7, 1.18 g, 4.81 mmol) in THF (20 mL) at 0° C. was treated with sulfur trioxide-pyridine. (1.15 g, 7.21 mmol) for 3 h. LIAR (15 mL, 15 mmol) was injected into the mixture at 0° C. The solution was allowed to warm to rt for 18 h. The mixture was subjected to an aqueous work-up and purified by chromatography to give [2-(3-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate R8, 0.90 g, 82%). Deprotection with Na/NH3 and subsequent “Swern” oxidation produced (3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9). (3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9) was subjected to the applicable steps combined from Method A and Method P to yield 4-(3-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 57).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][Br:27])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Yield: 48.3 %

Procedure:
To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-methyl pyrazole(4.0 g, 14.87 mmol) in carbon tetrachloride(50 mL) was added NBS (2.65 g, 14.87 mmol) and benzoyl peroxide (0.36 g, 1.48 mmol). The reaction mixture was brought to reflux overnight. Solvent was removed on rotary evaporator under reduced pressure. Residue was partitioned between ethyl acetate (80 mL) and sodium bicarbonate (sat. 80 mL). Organic phase was separated and washed with water (60 mL); dried over sodium sulfate; filtered, concentrated and subjected to silica-gel flash chromatography (ethyl acetate:hexane, 1:10) to afford 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-bromomethyl pyrazole (2.5 g). CI mass spectrum m/z (rel. intensity) 348 (M+H, 100).