Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.ClCCl.[S:10]([O-:14])(=[O:13])(=[O:12])[CH3:11].[OH:15][CH:16]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:17][S:18]([CH2:21][CH2:22][CH2:23][N+:24]([CH3:27])([CH3:26])[CH3:25])(=[O:20])=[O:19].[CH2:48]=[C:49]1[O:53][C:51](=[O:52])[CH2:50]1>CO>[S:10]([O-:14])(=[O:13])(=[O:12])[CH3:11].[C:51]([O:15][CH:16]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:17][S:18]([CH2:21][CH2:22][CH2:23][N+:24]([CH3:26])([CH3:25])[CH3:27])(=[O:20])=[O:19])(=[O:52])[CH2:50][C:49]([CH3:48])=[O:53]
Reactant: C=C1CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CS(=O)(=O)CCC[N+](C)(C)C
Agent: CS(=O)(=O)[O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCC[N+](C)(C)C)OC(=O)CC(C)=O

Procedure:
In a mixed solvent consisting of 5 ml of pyridine and 20 ml of dichloromethane is dissolved 2.35 g of 3-[(2-hydroxy-3-octadecyloxypropyl)sulfonyl]propyltrimethylammonium mesylate, to which 2.5 ml of diketene is added dropwise with stirring under ice cooling. Thereafter, the mixture is stirred at room temperature for 5 hours, to which is then added 3 ml of methanol. The solvent is distilled off under reduced pressure to leave a residue which in turn is purified by silica gel column chromatography to yield 0.5 g of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[CH:12][C:11]1=[O:21].[CH:28](C1C(=O)NC2C(C=1O)=CC=CC=2)=[O:29]>>[Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([CH:28]=[O:29])[C:11]1=[O:21]
Reactant: O=Cc1c(O)c2ccccc2[nH]c1=O
Reactant: COc1ccc(OCCCOCn2c(=O)cc(O)c3ccccc32)c(Cl)c1
Product: COc1ccc(OCCCOCn2c(=O)c(C=O)c(O)c3ccccc32)c(Cl)c1

Procedure:
Following the procedure set forth in Preparation B, 1-[3-(2-chloro-4-methoxyphenoxy)propyloxymethyl]-4-hydroxy-2(1H)-quinolinone was converted to 1[3-(2-chloro-4-methoxy)phenoxy)propyloxymethyl]-3-formyl-4-hydroxy-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 417 (M·+); NMR (CDCl3): δ2.01 (q, 2H, CH2), 3.75 (s, 3H, OCH3), 3.85 (q, 4H, CH2 --O), 10.21 (s, 1H, CHO).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.Br[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Br>>[O:1]([C:8]1[CH:9]=[C:10]([N:11]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: BrCCNCCBr
Agent: Br
Product: c1ccc(Oc2cccc(N3CCNCC3)c2)cc1

Procedure:
In the manner described in example 1 starting from 49 parts of meta-phenoxyaniline and 83.3 parts of bis-(β-bromoethyl)amine dihydrobromide there was obtained a clear solution. After evaporation of the solvent in vacuo, the residue was treated with 700 part of water, rendered alkaline with 60 parts of concentrated NaOH and extracted twice with 200 parts of ether. Th solution was dried. Upon distillation, there were obtained 26 parts of 1-(3-phenoxyphenyl)-piperazine, B.P./0.5 mm Hg: 180°-190° C.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:25])[C:16](=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[NH:13][C:12]1=[O:26])[CH3:10])(C(C)(C)C)(C)C.Cl.OP([O-])([O-])=O.[K+].[K+]>CO.C(OC(=O)C)C.O>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:25])[C:16](=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[NH:13][C:12]1=[O:26])[CH3:10]
Reactant: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
The keto ester 2 (1.047 g, 2.73 mmol) in methanol (12.3 ml) was treated with 6N HCl (1.37 ml, 8.22 mmol, 3 eg) and stirred 1 hour at room temperature. The solution was treated with 1M K2HPO4 (8.2 ml) and stirred a few minutes, then diluted with ethylacetate and water. The organic layer was separated, washed with 5% NaHCO3 and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to give the product 3 (0.653 g, 89%) as a clear oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[CH2:4][C:5]([O:7][CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:6].[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[Cl:1][CH2:2][C:3](=[O:14])[C:4](=[N:15][OH:16])[C:5]([O:7][CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:6]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)CCOC(=O)CC(=O)CCl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)CCOC(=O)C(=NO)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In 315 ml of glacial acetic acid was suspended 156.3 g (0.644 mole) of methylsulfonylethyl 4-chloroacetoacetate as obtained in Example 1. The suspension was cooled to 5° C. or below and a solution of 44.4 g (0.644 mole) of sodium nitrite in 140 ml of water was added at 0°-5° C. over a period of about 2 hours. The mixture was stirred for 30 minutes, poured in ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give 148.7 g of methylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: CNOC
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of 2-chlorobenzoyl chloride (8 g, 46 mmol) in dichloromethane (200 mL) at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (4.9 g, 50 mmol) followed by pyridine (11 mL, 137 mmol). The mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and organic layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave 2-chloro-N-methoxy-N-methylbenzamide (21) (7.8 g, 39.2 mmol, 85%) as clear oil.
Reaction SMILES: [CH2:1]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].[O:24]1[CH2:28][CH2:27][O:26]C1.[CH3:29]N(C)C=O>CCCCCC.CCOCC>[CH2:1]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:29][CH:28]([OH:24])[CH2:27][OH:26])=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc(O)cc1
Reactant: C1COCO1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)cc1
Temperature: 80 °C

Procedure:
An about 43.5 g portion of 4-tetradecyl phenol was added in portions to a suspension of about 10.8 g of prewashed sodium hydride in dimethylformamide. The mixture was refluxed about 11/2 hours, allowed to cool and about 37.8 g of 2,2-dimethyl-4-[[methylsulfonyl)oxy]methyl]-1,3-dioxolane was added. This mixture was heated to about 80° C. for about 24 hours; diluted with hexane and ether, washed with water and brine and evaporated. The residue was heated on a steam bath with about 500 ml of methanol and about 80 ml of dilute hydrochloric acid for one hour, cooled, partially evaporated, the solid collected and recrystallized from methanol, giving about 38 g of the desired title compound, mp 81.5°-83.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O.CO>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[NH2:12]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCOc1ccc(N)c(C)c1
Reaction time: 4 h
Yield: 84.9 %

Procedure:
Compound 404b (3.78 g, 19.4 mmol) was dissolved in EtOAc (20 mL) and MeOH (20 mL) and transferred to a 250 mL hydrogenation flask. 10% Pd/C (378 mg, 10% w/w) was added and the sample was hydrogenated for 4 h at 35 psi H2. Upon completion, the mixture was filtered over a bed of Celite and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with NaHCO3 (100 mL×3). The organic layer was separated and then dried over Na2SO4 to provide a crude brown oil which was further purified by chromatography (20% to 50% EtOAc/hexanes) to yield an amber oil (2.72 g, 85%): TLC Rf 0.27 (20% EtOAc/hexanes). 1NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.62 (m, 2H), 3.85-3.38 (t, 2H, J=6.66 Hz), 2.16 (s, 3H), 1.79-1.73 (sex, 2H, J=7.44 Hz), 1.02-1.00 (t, 3H, J=7.44 Hz). 13C NMR (150 MHz, CDCl3) δ 152.3, 137.8, 124.1, 117.2, 116.1, 112.9, 70.1, 22.7, 17.7, 10.5. Elemental analysis calculated for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.42; H, 9.14; N, 8.46.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].[CH3:24][N:25]([CH3:28])[CH:26]=[O:27]>>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:4][CH2:5][C:6]4[C:26](=[O:27])[N:25]5[CH:28]=[CH:3][CH:17]=[C:16]([O:21][CH3:18])[C:24]5=[N:8][C:7]=4[CH3:10])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Product: COc1cccn2c(=O)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c(C)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
A mixture of intermediate (6) (0.009 mol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride (0.009 mol) and sodium carbonate (0.025 mol) in N,N-dimethylformamide (50 ml) was stirred for 6 hours at 80°-90° C. The reaction mixture was cooled to room temperature and the precipitate was filtered off, stirred in water and filtered off again. The solid was crystallized from N,N-dimethylformarnide/H2O. The crystals were filtered off and dried, yielding 1.9 g (48%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 209.3° C. (comp. 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([N:23]3[CH2:27][CH2:26][O:25][C:24]3=O)[CH2:18]2)[N:3]=1.[OH2:29].[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([N:23]3[CH2:27][CH2:26][O:29][C:24]3=[O:25])[CH2:18]2)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:30][NH:31]3)=[CH:14][CH:15]=2)[N:7]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N4CCOC4=O)C3)nc(N)n2)cc1F
Reactant: NN
Reactant: O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@@H](N3CCOC3=O)C2)n1
Temperature: 100 °C
Yield: 43.2 %

Procedure:
Into a 5 mL sealable vial were added 4-{2-amino-6-[(3R)-3-(2-oxo-1,3-oxazolidin-3-yl)-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (83 mg, 0.217 mmol) and ethanol (3 mL) followed by hydrazine monohydrate (0.319 mL, 6.51 mmol). The reaction vial was capped and was heated at 100° C. overnight. The reaction was concentrated, then dissolved in 2 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 mL/min, 10% CH3CN/H2O, 0.1% TFA to 25% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the water left behind was added saturated NaHCO3 and then extracted with EtOAc (5×100 mL). The organic was washed with brine, dried over MgSO4, filtered, concentrated, and transferred to a haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (37 mg) as a light yellow solid. LC-MS (ES) m/z=395 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.45-1.58 (m, 1H), 1.68-1.89 (m, 3H), 2.82 (t, J=11.6 Hz, 1H), 2.99 (t, J=11.8 Hz, 1H), 3.54 (ddd, J=11.1, 7.0, 4.2 Hz, 1H), 3.60 (dd, J=9.6, 8.6 Hz, 2H), 4.29 (td, J=8.0, 2.2 Hz, 2H), 4.40 (dd, 2H), 5.38 (s, 2H), 6.14 (bs, 2H), 6.63 (s, 1H), 7.57 (dd, J=8.3, 1.3 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C@:10]([C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([NH:26][C@@H:27]([CH2:41][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:28][N:29](C)[C:30](=O)OCC4C=CC=CC=4)=[O:25])[CH2:19]3)([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>CCOC(C)=O.Cl[Pd]Cl>[CH:42]1([CH2:41][C@H:27]([NH:26][C:24]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([C@@:10]([C:6]3[C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=[CH:8][CH:7]=3)([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:19]2)=[O:25])[CH2:28][NH:29][CH3:30])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: COCCCC[C@@](O)(c1cccc2ccoc12)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCC2)CN(C)C(=O)OCc2ccccc2)C1
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Product: CNC[C@H](CC1CCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc3c2OCC3)C1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a solution of benzyl (S)-2-((R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclopentylpropylmethylcarbamate (98.5 mg, 0.156 mmol) in EtOAc (10 mL) was added PdCl2 (30 mg) and the mixture was stirred under a hydrogen balloon at rt for 3˜5 hrs. After filtration, the filtrate was evaporated and the residue, was purified by prep HPLC to afford (3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide (36.2 mg, 46.5%). 1H NMR (CD3OD, 400 MHz) δ 0.89 (m, 1H), 1.12-2.15 (m, H), 2.58 (m, 2H), 2.71 (s, 3H), 2.93 (m, 1H), 3.15 (m, 3H), 3.23 (s, 3H), 3.98 (m, 2H), 4.26 (m, 1H), 4.48 (m, 2H), 6.83 (m, 1H), 7.12 (m, 1H), 7.21 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CNS(C)(=O)=O)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in dichloromethane (DCM) (750 μl) was treated with Et3N (8.14 μl, 0.058 mmol) and MsCl (3.64 μl, 0.047 mmol), stirred for 1 hour, and then warmed to rt for 1 hour. Additional Et3N (8 uL) and MsCl (4 uL) were added at 00° C., the reaction was stirred at rt for 1 hour, and then concentrated. The residue was purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (17 mg, 0.033 mmol, 85% yield) as yellow solid. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (14 mg, 0.027 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1 H), 7.59-7.50 (m, 1 H), 7.40-7.29 (m, 1 H), 7.29-7.24 (m, 1 H), 7.17 (dd, J=8.4, 12.5 Hz, 1 H), 7.08-6.99 (m, 1 H), 5.35 (s, 1 H), 5.15-5.03 (m, 1 H), 4.44 (d, J=5.7 Hz, 2 H), 3.67 (s, 3 H), 2.97-2.89 (m, 3 H), 2.37 (s, 3 H), 2.32 (s, 3 H), 1.09-1.02 (m, 9 H); LCMS (m/z) ES+=501 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1.CCOC(C)=O>CCO.[Pt]>[Cl:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To 1-[2-chloro-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (1.38 g, 3.65 mmol) in EtOH (30 mL) was added EtOAc to help with solubility. The catalyst, 5% sulfided platinum on carbon (0.138 g, 0.035 mmol) was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo, adsorbed onto silica gel and flash chromatographed. The desired fractions were combined and concentrated to give the title compound of step B (0.880 g, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.58-6.70 (m, 2H), 4.64 (s, 2H), 3.74 (s, 3H), 3.22-3.37 (m, 2H), 3.04 (s, 3H), 2.84 (t, J=4.4 Hz, 4H), 2.74 (t, J=6.7 Hz, 2H), 2.50-2.63 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[N:9]1[CH2:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=[O:22])[C:14]=12.[Cl-].[NH4+]>ClCCCl.CCOCC>[OH:22][C:15]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]2[CH2:12][CH2:11][CH2:10][N:9]=[C:14]12
Reactant: COCCCCBr
Reactant: O=C1C2=NCCCN2c2ccccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCCl
Product: COCCCCC1(O)C2=NCCCN2c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ether (60 ml) and 4-bromo-1-methoxy-butane (10.2 g) were added to magnesium turnings (1.46 g). After formation of the Grignard reagent, the mixture was cooled to 0° and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° C. for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml) and the mixture was stirred for a further 20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound or the free base (3.55 g), m.p. 128°-139° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 178°-179° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]([F:16])([F:15])[C@H:12]([OH:14])[CH3:13]>>[F:10][C:11]([F:16])([F:15])[C@H:12]([O:14][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[CH3:13]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@@H](O)C(F)(F)F
Product: C[C@@H](Oc1ccc(C#N)cn1)C(F)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (592 mg, colorless oil) from 6-chloronicotinonitrile (500 mg, 3.61 mmol) and (R)-1,1,1-trifluoropropan-2-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][C:27]3([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]=2C=O)[S:32][CH2:31][CH2:30][CH2:29][S:28]3)=[CH:21][C:20]=1[CH3:40].[CH2:41]1C[O:44][CH2:43][CH2:42]1>CCOCC>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][C:27]3([CH2:33][C:34]([CH3:38])([CH3:39])[C:35]=2/[CH:41]=[CH:42]/[CH:43]=[O:44])[S:28][CH2:29][CH2:30][CH2:31][S:32]3)=[CH:21][C:20]=1[CH3:40]
Reactant: C1CCOC1
Reactant: Cc1cc(C2=C(C=O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cc(C2=C(/C=C/C=O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a -20° C. solution of LDA (19.0 mmol) in 60 mL anhydrous THF was added ethylidenecyclohexylamine (Org. Syn. 50, 66) (2.38 gm, 19.0 mmol). The solution was stirred for 30 min, cooled to -78° C. and a solution of 8 (3.50 g, 10.0 mmol) in 60 mL was added. The mixture was stirred for 3 h, diluted with ether and quenched with H2O. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by HPLC. using 10:1 hexanes:EtOAc provided 1.6 g of the orange color gum.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[CH2:20]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:21](=[CH2:23])[CH3:22]>C(O)CCC>[CH:25]1([N:24]([CH2:20][C:21](=[CH2:22])[CH3:23])[C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C=C(C)CNC1CCCCC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCCCO
Product: C=C(C)CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)C1CCCCC1
Yield: 43 %

Procedure:
4.3 g. 6-chloro-9-(β-D-ribofuranosyl)-purine and 7.6 g. methallyl-cyclohexylamine were heated under reflux for 2 hours in 50 ml. butanol. The reaction mixture was evaporated in a vacuum and the residue obtained was dissolved in 50 ml. ethyl acetate and then extracted twice with 50 ml. amounts of water. The organic phase was dried, again evaporated and the residue recrystallized from methanol. 2.6 g. (43% of theory) N(6)-cyclohexyl-N(6)-methallyl-adenosine were obtained; m.p. 110°- 112° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH2:11].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][CH2:20][O:21][C:22](Cl)=[O:23]>O.C1(C)C(C)=CC=CC=1>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH:11][C:22]([O:21][CH2:20][CH2:19][Cl:18])=[O:23]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cccc(C)c1NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1NNC(=O)OCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 17.7 g (0.1 mol) 2,6-dimethylphenylhydrazine hydrochloride, 21.2 g (0.2 mol) sodium carbonate in 50 ml water and 50 ml xylene are stirred for 30 minutes at room temperature, then cooled to 5°. 14.3 g (0.1 mol) chloroformic acid 2-chloroethylester is then added over a period of 1 hour, the temperature being maintained at 5°. The mixture is stirred at 5° for another hour, at the end of which 100 ml water are added, the precipitate thus formed filtered off, washed with water and dried. Further work-up as in Example 1b.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@](O)(CN1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 88 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 and N-(piperidin-4-yl)-4-trifluoromethoxyaniline gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenylamino)piperidin-1-yl]propan-2-ol (1.36 g, yield 88%) as a yellow oil in the same manner as in Example 254.