Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@@H:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]1[CH2:33][CH3:34])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[CH2:33]([C@H:21]1[C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH2:25][CH2:24][NH:23][CH2:22]1)[CH3:34]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate (288 mg, 0.618 mmol) in dichloromethane (5.0 ml) cooled to 0° C. was added trifluoroacetic acid (288 μl, 3.74 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 1 hr. After removal of the solvent in vacuo, the residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate, water, and brine; dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (227 mg, 0.618 mmol, 99% yield) as a white solid. LCMS (Method K) m/z 368.4 ([M+H]+).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[CH:18][C:19]3[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[C:20]=3[N:21]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20]([NH:22][CH3:26])[C:19]([CH2:24][CH2:23][OH:25])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1C(=O)Cc2cnc(N3CCN(Cc4ccccc4)CC3)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1nc(N2CCN(Cc3ccccc3)CC2)ncc1CCO
Yield: 29.6 %

Procedure:
Sodium borohydride (2.24 g) was added to 8.0 g of 2-(4-benzylpiperazino)-5,6-dihydro-7-methyl-6-oxo-(7H)pyrrolo[2,3-d]pyrimidine (produced in accordance with Referential Example 54 of Japanese Laid-Open Patent Publication No. 140568/1986) and 400 ml of ethanol, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated. The residue was mixed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol:chloroform=1:10), and recrystallized from toluene to give 2.4 g (yield 30%) of 2-(4-benzylpiperazino)-5-(2-hydroxyethyl)-4-methylaminopyrimidine as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:25][C:24]([F:26])([F:27])[C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][O:1][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[CH2:4][OH:5])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 89.1 %

Procedure:
A solution of 4.59 g (36.94 mmol) of 2-hydroxybenzyl alcohol in 200 ml of dry acetonitrile is mixed with 10 g (36.94 mmol) of 4-chloromethyl-4′-trifluoromethylbiphenyl from Example 23A and 6.13 g (44.33 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting organic phase is concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 11.8 g (32.92 mmol, 89% yield) of a solid are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH2:8][C:9]#[CH:10])[CH:2]=1.[I-].[CH3:14][N+]1C=CC=CC=1.[BH4-].[Na+]>>[CH3:14][N:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH2:8][C:9]#[CH:10])[CH2:2]1
Reactant: C#CCC(=NO)c1cccnc1
Reactant: C[n+]1ccccc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Product: C#CCC(=NO)C1=CCCN(C)C1

Procedure:
Employing the general method of Example 6 above, 2.12 g (12.2 mmol) of 1-(3-pyridinyl)-3-butyne-1-one oxime were converted to the corresponding 1-methyl pyridinium iodide and subsequently reduced by the action of sodium borohydride to produce 1.2 g of 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-3-butyne-1-one oxime which was isolated as the ethanedioate salt, mp 55°-57° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)C=CCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(-n2nc(CCCCCC(=O)O)c3c2CCCC3)cc1

Procedure:
A solution of 6-[4,5,6,7-tetrahydro-1-(4-nitrophenyl)-1H-inda-zol-3-yl]hexenoic acid n acetic acid (75 ml) was treated with 10% palladium/C (0.80 g) and reduced at 40 psi hydrogen pressure for 2 hours. The catalyst was filtered and the filtrate was evaporated to yield crude 1-[4-(amino)phenyl]-4,5,6,7-tetrahydro-1H-indazole-3-hexanoic acid. Acylation with acetic anhydride (5 ml) and pyridine (10 ml) gave crude title compound (0.45 g). An analytical sample (m.p. 175° C.) was obtained from methanol-ether solution.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:19])[CH:7]=[C:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=2)[N:4]=1.[OH-].[Na+]>Cl>[CH3:19][C:6]1[CH:7]=[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[C:10]2[C:5]=1[NH:4][C:3](=[O:2])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(-c3cccnc3)cc(C)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(-c2cccnc2)cc2ccc(=O)[nH]c12

Procedure:
A stirred solution of 2-methoxy-8-methyl-6-(3-pyridyl)quinoline (1.07 g) in 5M hydrochloric acid (10 cm3) was heated under reflux for 2.5 hours and then cooled. The cooled solution was basified to pH 9 with 2M aqueous sodium hydroxide, extracted with chloroform:methanol 9:1 (4×100 cm3), and the combined and dried (MgSO4) extracts were concentrated in vacuo to afford a solid. Recrystallisation of the solid from ethyl acetate-methanol gave 8-methyl-6-(3-pyridyl)-2-(1H)-quinolone, m.p. 235.5°-236.5°, (0.63 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH:13]1(/[CH:16]=[C:17](\[O:19][CH2:20][CH3:21])/[O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1
Reactant: CCOC(=O)CC1CC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCO/C(=C\C1CC1)O[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexanes (1.6M, 26 ml) was added with stirring to a solution of diisopropylamine (6.2 ml) in tetrahydrofuran (8 ml) at below -25° C. under nitrogen. After 30 min, the mixture was cooled to -75° C. and ethyl cyclopropylacetate (4.5 g) added dropwise keeping the temperature below -65° C. The mixture was then maintained below -75° C. for 3 h before chlorotrimethylsilane (3.8 ml) was added below 65° C. The reaction was allowed to warm to ambient temperature and then evaporated to dryness. The residue was slurried with hexane and filtered. The filtrate was evaporated to an orange oil which was distilled in vacuo to give the title compound (4.0 g) as a clear mobile liquid, b.p 80-82° C., 3×10-2 bar.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[C:35]([CH3:36])=[CH:34][S:33][CH:32]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[C:35]([CH3:36])=[CH:34][S:33][CH:32]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cscc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cscc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 42.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.20 g, 0.48 mmol) obtained in Example 19, step 4 and 3-amino-4-methylthiophene (0.110 g, 0.97 mmol), the title compound (0.099 g, 42%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:38])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[CH:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:38])[N:26]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[CH:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(Cl)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and ethyl 3-chloro-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 8).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCC=O
Yield: 91.7 %

Procedure:
A solution of (3-hydroxypropyl)-carbamic acid tert-butyl ester (0.60 g, 3.4 mmol) in anhydrous CH2Cl2 (17 mL) was treated with Dess-Martin reagent (1.74 g, 4.1 mmol) for 3 hours at room temperature. The reaction mixture was diluted with Et2O (30 mL) and washed with a 20% aqueous solution of sodium thiosulfate (15 mL) followed by a saturated aqueous solution of sodium bicarbonate (15 mL). The combined aqueous phase was then extracted with Et2O (2×35 mL) and re-washed with 20% sodium thiosulfate solution (30 mL), saturated NaHCO3 solution (25 mL), and brine (25 mL). The organic component was then dried (MgSO4), filtered, and concentrated under reduced pressure to provide (3-oxopropyl)-carbamic acid tert-butyl ester as a colorless oil (0.54 g, 91%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][CH:12]=1.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C(=O)Nc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 g of boron tribromide are added dropwise to a solution, cooled to -78° C., of 2 g of methyl N-(3-methoxyphenyl)-oxamate in 20 ml of methylene chloride in the course of 5 minutes. The mixture is stirred at room temperature for 5 hours, 5 ml of water are added, with cooling, and the organic phase is separated off. Drying over sodium sulfate and evaporation gives methyl N-(3-hydroxyphenyl)-oxamate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:18][C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][C:7]=1NC(NC1C=CC=CC=1)=O.[OH-].[Na+]>C1COCC1>[C:4]1([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 206.5 %

Procedure:
To a stirred solution of methyl 3-chloro-4-(N′-phenylureido)phenylacetate (1.79 g, 5.62 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 20 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-chloro-4-N′-phenylureido)phenylacetic acid (1.58 g, 92%) as pale brown solid. 1H-NMR (DMSO-d6) δ3.55 (s, 2H), 6.99 (t, J=7.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.29 (t, J=7.6 Hz, 2H), 7.36 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 8.07 (d, J=8.3 Hz, 1H), 8.28 (s, 1H), 9.37 (s, 1H), 12.37 (br, 1H).
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(c2ccccc2)CC1
Agent: Cl
Product: O=C(CN1CCN(c2ccccc2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 28.7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-phenylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 225, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-phenylpiperazin-1-yl)acetamido)propanamide (13.4 mg, 28.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.02 (s, 1H), 7.60 (d, 2H), 7.28-7.29 (m, 4H), 7.19-7.26 (m, 5H), 6.99-7.04 (m, 4H), 6.92 (d, 2H), 6.78 (t, 1H), 4.71 (m, 1H), 4.52 (s, 2H), 3.76 (m, 2H), 3.13 (m, 4H), 3.07 (s, 2H), 2.63 (m, 4H). MS (EI) for C34H35FN4O4. found 583.6 (MH+).
Reaction SMILES: [Li+].[Cl-:2].[C:3]1([CH2:9][CH2:10][CH2:11]O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([CH2:9][CH2:10][CH2:11][Cl:2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Cl-]
Reactant: OCCCc1ccccc1
Agent: [Li+]
Product: ClCCCc1ccccc1
Yield: 98 %

Procedure:
The rates of reaction of LiCl with glycol-containing sulfonate esters 2 were compared with their corresponding ortho-methylcarboxyphenyl sulfonates 3 and tosylates 4 (Table 1). In each case, substrates 2 reacted significantly faster than sulfonates 3. For example, the NALG derivative of 3-phenyl propanol (2a) reacted with LiCl to give 3-phenylpropyl chloride in 0.5 h and in 98% yield which was over 8 times faster than the reaction with the electronically similar 3a (Table 1, entries 1 and 2). Comparing the rates of reaction of 3a with 4a (entry 3) seems to indicate that the ortho-positioned ester of 3a confers a 4 to 5 fold rate enhancement. Thus, it is an advantage of the invention that the diethylene glycol unit of 2a is responsible for the additional 8 fold chloride addition rate enhancement of 2a relative to 3a. Furthermore, when the diethylene glycol unit of 2a was replaced with a linear hydrocarbon chain as in 5a (the hydrocarbon equivalent of the diethylene glycol unit of 2a), the substrate behaved similar to methyl ester derivative 3a (compare entries 2 and 4). Methylcarboxyphenyl sulfonates of secondary alcohols analogous to 3a were prepared (3b and 3c), however, these substrates failed to give the corresponding alkyl chloride product when reacted with LiCl. Instead, numerous unidentified side products were observed. Thus the chlorination rates of diethylene glycol-containing NALG derivatives of 1-phenyl-2-propanol and 4-decanol (2b and 2c) were compared with their corresponding tosylates 4b and 4c (entries 5-8). In both cases a significant rate enhancement was observed. For example tosylate 4c gave only a 5% conversion to the alkyl chloride after 24 h while NALG 2c gave the chloride product in 96% yield after only 6 hours (compare entries 7 and 8).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[S:8](=[O:15])(=[O:14])[NH:7][CH2:6]1)(=O)[CH3:2].CO>O1CCCC1>[CH2:1]([NH:4][CH:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[S:8](=[O:14])(=[O:15])[NH:7][CH2:6]1)[CH3:2]
Reactant: CC(=O)NC1CNS(=O)(=O)c2sccc21
Solvent: CO
Solvent: C1CCOC1
Product: CCNC1CNS(=O)(=O)c2sccc21
Temperature: 70 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A suspension of 4-acetamido-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (4.93 g, 0.02 mol) in tetrahydrofuran (50 ml) was heated in an oil bath at 70° C. Borane-dimethyl sulfide complex (20.0 ml of 10.0M, 0.20 mol) was added dropwise over 1/2 hour and the mixture was stirred at 70° C. for 4 hrs. The mixture was cooled in ice and methanol was added (50 ml) dropwise. The volatile solvents were removed in vacuo and the residual oil was heated with 6N hydrochloric acid (50 ml) on the steam bath for 1/2 hr. Ethyl acetate (200 ml) was added and the mixture was basified with sodium bicarbonate. Methanol (20 ml), was added, the mixture filtered and the aqueous layer was re-extracted with ethyl acetate (100 ml) -methanol (10 ml). The organic solutions were combined, dried and concentrated in vacuo. A colorless viscous oil (4.47 g) was recovered. Yield 96%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].[C:12]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(OCCO)C>[C:2]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:22][CH:21]([OH:23])[CH2:20][O:19][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)(=[O:3])[CH3:1]
Reactant: Cc1cccc(OCC2CO2)c1
Reactant: CC(=O)c1c(O)cccc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1c(O)cccc1OCC(O)COc1cccc(C)c1
Yield: 99.7 %

Procedure:
A solution of 2,6-dihydroxyacetophenone (15.2 g), m-cresylglycidyl ether (16.4 g) and benzyltrimethylammonium hydroxide (10 drops of a 40% solution) in 2-ethoxyethanol (75 ml) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure to give 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-m-cresyloxypropane (31.5 g) as a viscous amber oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:4]([O:18][CH3:19])[CH:3]=1.[Cl-].[NH4+]>CO.O.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: COc1cc(F)ccc1Oc1ccccc1N
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a solution of title compound 90 (9.32 g, 35.4 mmol) in MeOH (30 mL) and water (5 mL) was added ammonium chloride (3.79 g, 70.8 mmol) and zinc chloride (20.83 g, 319 mmol) and the reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and filtered and the solvent removed. The residue was diluted with ethyl acetate and water and the organic phase was washed well with water, dried over Na2SO4, filtered and concentrated to afford title compound 91 (8.3 g, 100%). LRMS (ESI): (calc) 233.09 (found) 234.1 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].OS(O)(=O)=O.[CH3:18][CH2:19]O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:18]([O:11][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)=[O:12])[CH3:19]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cn1
Reaction time: 1.5 h

Procedure:
A mixture of 5-nitro-pyridine-2-carboxylic acid (Step 39.5) (5.74 g, 34.2 mmol), H2SO4 (1 mL) and EtOH (50 mL) was stirred for 1.5 h at reflux. The residue was diluted with EtOAc and saturated solution of NaHCO3. The aqueous layer was separated and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford 6.1 g of the title compound as a white solid: ES-MS: 197.1 [M+H]+; tR=3.22 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:15]([C:24](O)=[O:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:15]([CH2:24][OH:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)C2(c3ccc(Cl)cc3)CC2)C[C@H]1c1ccccc1
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1C[C@@H](CO)[C@H](c2ccccc2)C1)C1(c2ccc(Cl)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S,4R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylic acid (80 mg, 0.0002 mol, example 355) in tetrahydrofuran (2 mL, 0.02 mol) were added triethylamine (0.0316 mL, 0.000227 mol) and methyl chloroformate (20.0 μL, 0.000260 mol) at −15° C. The mixture was stirred at −15° C. for 20 minutes. To the above mixture was added sodium borohydride (16.4 mg, 0.000433 mol) in THF and the resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by water and then was extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated to afford the product. The product was purified with Combiflash eluting with 60% AcOEt in hexanes. LCMS: m/z 356.4 (M+H)+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O>CC(O)=O.[Fe]>[NH2:18][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:5]=1[S:4][CH2:3][CH2:2][Cl:1])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10]
Reactant: CC(C)CNC(=O)c1ccc(SCCCl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)CNC(=O)c1ccc(SCCCl)c(N)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-chloroethylthio)-N-isobutyl-3-nitrobenzamide (2.38 g, 8.32 mmol) in AcOH (100 mL) was added iron (1.859 g, 33.3 mmol). The mixture was heated to 70° C. and the reaction was allowed to stir for 1 hour. The reaction turned from a dark solution to a light grey slurry. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction mixture was concentrated in vacuo and the resulting solid was diluted with H2O (250 mL). The pH of the solution was adjusted to 6 by addition of solid K3PO4. The resulting slurry was extracted with EtOAc (4×100 mL). The combined organics were washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The combined organics were then dried over Na2SO4 and concentrated in vacuo. The product, 3-amino-4-(2-chloroethylthio)-N-isobutylbenzamide, was used without further purification. Product yield was assumed to be 100% (2.38 g, 8.32 mmol) for future calculations. LCMS (+ESI) m/z=287.11 [M+H]+.