Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CC([O-])(C)C.[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[N:7]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2cnc(Cl)nc21
Yield: 60 %

Procedure:
To a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.54 mmol) in 25 mL THF was added t-BuOK (1.1 g, 9.81 mmol) and ethyl 2-bromoacetate (1.31 g, 7.84 mmol). The mixture was stirred and heated to reflux temperature for 2 h. After cooling the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to yield a crude product which was used in next step without further purification (940 mg Yield 60%). LCMS (m/z): 240.1 (M+1).
Reaction SMILES: O=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][CH2:5][CH2:4][NH:3]1.O.[OH-].[Na+]>C1COCC1>[C:8]1([CH:7]2[CH2:2][NH:3][CH2:4][CH2:5][NH:6]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCCNC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
2-Oxo-3-phenyl-piperazine (1.76 g, 10 mmol), in 30 mL of anhydrous THF was added dropwise to a 20 mL (20 mmol) of 1M solution of LiAH4 in THF, and the mixture was stirred at room temperature for 24 h. After workup (water, 20% NaOH addition to destroy excess LiAH4), the mixture was filtered and the filter cake was reextracted with ethyl acetate. The combined organic filtrate and extracts were dried over MgSO4, filtered and evaporated to give an slightly yellow solid that was purified by silica gel column chromatography (CHCl3:MeOH:NH4OH/9:1:0.1). The reduced product was isolated as a colorless solid (960 mg, 6 mmol, 60%). 1H NMR (CDCl3): δ 2.69 (1H, t, J=11.3), 2.85-3.10 (7H, m), 3.76 (1H, br d, J=8.9), 7.21-7.38 (5H, m). mp (free base): 79°-81° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=3[F:33])(=[O:21])=[O:20])[C@@H:15]([C:34](=[O:46])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH3:45])=[CH:39][CH:38]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:47])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:33][C:23]1[CH:24]=[C:25]([O:28][C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:27][C:22]=1[S:19]([N:16]1[CH2:17][CH2:18][N:13]([C:11]2[S:12][C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH3:47])[N:10]=2)[CH2:14][C@@H:15]1[C:34](=[O:46])[NH:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][CH3:45])=[CH:41][CH:42]=1)(=[O:20])=[O:21]
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2S(=O)(=O)c2ccc(OC(F)(F)F)cc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)O)s3)CCN2S(=O)(=O)c2ccc(OC(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a solution of the compound (59 mg) obtained in Step 7 in chloroform (0.3 ml) was added, with stirring at room temperature, trifluoroacetic acid (0.3 ml). After stirring at room temperature for 7 hr, the reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2-10% methanol/chloroform) to give the title compound (45 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:11]([C:12]([C:14]([O:16]C)=[O:15])=[CH2:13])[CH:10]([CH:18]([OH:20])[CH3:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO>[CH2:1]([N:8]1[CH:11]([C:12]([C:14]([OH:16])=[O:15])=[CH2:13])[CH:10]([CH:18]([OH:20])[CH3:19])[C:9]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OC)C1C(C(C)O)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(C(=O)O)C1C(C(C)O)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of 30 mg (0.1 mmol) of 1-benzyl-3-(1-hydroxyethyl)-4-(1-methoxycarbonylethenyl)-2-azetidinone dissolved in 1 ml of methanol, 1 ml (1 mmol) of 1N potassium hydroxide was added with ice bath. After the mixture was stirred at room temperature for 4 hours, 1 ml of 1N hydrochloric acid was added and the extraction with ethyl acetate was conducted three times. The extract was washed with a saturated solution of NaCl, dried with magnesium sulfate and concentrated to give 19 mg of 1-benzyl-4-(1-carboxyethenyl)-3-(1-hydroxyethyl)-2-azetidinone (yield: 68%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH2:27]([O:29][C:30]([O:32][CH:33](Cl)[CH3:34])=[O:31])[CH3:28]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:28][CH2:27][O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:13])(=[O:7])=[O:6]
Reactant: CCOC(=O)OC(C)Cl
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)OCCOC(=O)[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (11) (1.0 g, 2.4 mmol) dissolved in 15 mL of anhydrous toluene was reacted with 1.1 g (7.3 mmol) of commercially available 1-chloroethyl ethoxyformate in the presence of 0.81 g (2.9 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.77 g of a mixture of the title compound (36a) and (3R)-4,4-dimethyl-3-[(4-methoxyphenyl)methoxy]-3,4,5-trihydrofuran-2-one. MS (ESI) m/z 546.99 (M+Na)+.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11])[CH:2]1[O:4][CH2:3]1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH2:3][CH:2]([OH:4])[CH2:1][N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11]
Reactant: C[O-]
Reactant: CC(C)C1OCCN1CC1CO1
Agent: [Na+]
Solvent: CO
Product: COCC(O)CN1CCOC1C(C)C
Reaction time: 2 h

Procedure:
Into a 500 ml., three-neck flask equipped with a mechanical stirrer, dropping funnel and condenser with a drying tube was charged 171 g. (1 mole) of 3-glycidyl-2-isopropyloxazolidine and 250 cc. of absolute methanol. While stirring at room temperature an equivalent amount of sodium methoxide (25% solution methanol) was added over a 30 minute period. The mixture was stirred an additional two hours after addition was completed. The solvent was then removed in vacuo to afford 3-(3-methoxy-2-hydroxypropyl)-2-isopropyl-1,3-oxazolidine.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][CH2:10][C@H:11]([CH3:45])[O:12][C:13]1[CH:14]=[C:15]([CH:31]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)[CH:33]=1)[C:16]([NH:18][C:19]1[CH:23]=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1)=[O:17]>C(Cl)Cl>[CH3:8][O:9][CH2:10][C@H:11]([CH3:45])[O:12][C:13]1[CH:14]=[C:15]([CH:31]=[C:32]([O:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)[CH:33]=1)[C:16]([NH:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)=[O:17]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Reaction time: 3 h
Yield: 98.6 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 3-({3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzoyl}amino)-1H-pyrazole-1-carboxylate (180 mg, 0.330 mmol) in dry DCM (3 mL) and the reaction was stirred under argon for 3 h. A further portion of TFA (0.2 mL) was then added and the reaction was stirred for 30 min before all the solvent was removed in vacuo. The residue was taken up in ethyl acetate (30 mL) and saturated aqueous sodium hydrogencarbonate (15 mL) and the residue was evaporated then re-evaporated with DCM/hexanes to produce the title compound as a colourless foam (145 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:14]([NH:21][CH2:4][C:3]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:2]=1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(Br)c(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzaldehyde (3 g, 11.9 mmol), benzylamine (1.94 mL, 17.8 mmol), and sodium cyanoborohydride (1.12 g, 17.8 mmol) were combined in MeOH (30 mL). Acetic acid (1.02 mL, 17.8 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and H2O. The aqueous layer was separated and extracted twice with CH2Cl2, and the combined organic layers were dried, concentrated, and purified by silica gel chromatography (10-40% EtOAc in hexanes) to give benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amine.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH2:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O.C(OCC)(=O)C>[O:4]=[C:3]1[NH:12][CH2:13][C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[O:27][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroacetyl chloride (4.88 mL) was added dropwise to a vigorously stirred mixture at 0° C. of potassium carbonate (17.43 g) in water (78 mL) and tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (10.4 g) in ethyl acetate (92 mL). After 30 minutes at 0° C. the mixture was extracted with ethyl acetate and the organic layer dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (200 mL) and added dropwise over 3 hours to a stirred solution under nitrogen and heated at reflux of potassium tert-butoxide (1M in tert-butanol, 75 mL) and THF (250 mL). The mixture was cooled to room temperature and allowed to stir for 18 hours. Most of the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by trituration with a mixture of ether (30 mL) and isohexane (20 mL) to afford the subtitled product. Yield 8.20 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH2:22].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: COCCOc1ccc2c(Cl)c(C#N)cnc2c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COCCOc1ccc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2c1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
A mixture of 4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile (262 mg, 1.0 mmol), 2,4-dichloroaniline (195 mg, 1.2 mmol) and pyridine hydrochloride (140 mg, 1.2 mmol) in 10 mL of 2-ethoxyethanol is heated at reflux for 30 minutes. The reaction mixture is cooled to room temperature partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with a 1:1 mixture of saturated sodium bicarbonate and 5 N sodium hydroxide. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography, eluting with a gradient of 1:1 ethyl acetate:hexane to all ethyl acetate provides 103 mg of 4-[(2,4-dichlorophenyl)amino]-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 144-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:28]#[C:27][CH2:26][OH:29])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1
Reactant: C#CCO
Product: O=C1Cc2cnc(Nc3ccc(C#CCO)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-36) and prop-2-yn-1-ol were converted to I-54 (86%): HRMS Calcd. for C21H11ClN4O2: 391.0961, Found 391.0960.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:13]=1>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:13]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1cc(C(=O)Nc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: COc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Yield: 95.7 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-3-(3-fluorophenyl)-5-methoxy-benzamide (600 mg, 1.6 mmol, 1.0 eq) in THF under N2 was added dropwise a solution of BH3 (1M in THF, 8 mL, 8.0 mmol, 8.0 eq) at room temperature. The reaction mixture was heated at reflux for 4 h, then cooled and the reaction quenched by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the product (550 mg, 95%) as yellow oil which was used directly to the next step without further purification.
Reaction SMILES: [CH2:1]=[CH:2]C1C=CC=CC=1.[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C([Mg]Br)C>CCOCC>[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[CH2:1][CH3:2]
Reactant: O=Cc1ccccc1Br
Reactant: C=Cc1ccccc1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)c1ccccc1Br

Procedure:
With the exception of three compounds, the styrene compounds disclosed herein to be utilized for preparing the α-chloro oximes ae known and their preparations are published in the prior art. The compounds not previously prepared are synthesized following well-known published procedures. Thus, 2-bromobenzaldehyde is allowed to react with a Grignard reagent, ethyl magnesium bromide in anhydrous ether, to yield 1(2-bromophenyl)propanol. This propanol derivative is then dehydrated by refluxing it in toluene in the presence of a catalytic quantity of p-toluenesulfonic acid to yield the desired 1-bromo-2-(1-propenyl)benzene. Another previously unknown substituted styrene, namely, 1,2-dichloro-4-(1-propenyl) benzene is prepared by the same general procedure from 3,4-dichlorobenzaldehyde and ethyl magnesium bromide, followed by dehydration of the intermediate substituted propanol.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and ethylamine as starting materials to give the aimed compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[N:22]([C:25]1[N:30]=[C:29]([C:31](OC)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1)[CH2:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:15][C:14]=1[N:22]([CH2:23][CH3:24])[C:25]1[N:30]=[C:29]([C:31]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1
Reactant: Brc1nccs1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(=O)c2nccs2)n1)c1ccc(C(C)C)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of n-butyl lithium in hexanes (2.4 M, 1.34 mL, 3.24 mmol) in anhydrous THF (5 mL) at −78° C. under a nitrogen atmosphere was added 2-bromothiazole (0.49 g, 0.27 mL, 3.0 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 30 min. A solution of methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate (Example 18) (1.0 g, 2.5 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was then warmed to −60° C. and stirred for 4 h. A saturated aqueous solution of NaHCO3 was added and the reaction mixture was warmed to ambient temperature. Three extractions with ethyl acetate, followed by two washings of the combined organic layers with water, drying over MgSO4, filtration and concentration in vacuo gave a dark brown oil. Column chromatography (ethyl acetate: hexanes::1:1) afforded the title product, a brown solid (950 mg, 85% yield, Rf 0.43): mp 97-98.5° C.; NMR (CDCl3, 300 MHz):8.0 (s, 1H), 7.60 (s, 1H), 7.4-7.2 (m, 4H, J=6), 3.05-2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.6 (br s, 3H), 1.4-1.2 (m, 9H); CI-HRMS Calcd: 445.0698 (M+H), Found: 445.0699; Anal.(C20H21BrN4S): C, 54.05; H, 4.73; N, 12.61; Br, 18.02; S, 7.21; Found: C, 53.86; H, 4.66; N, 12.53; Br, 18.20; S, 7.46.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N+:31]([O-])=O)[CH2:20][CH:19]2[OH:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].O.[Sn](Cl)Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[NH2:31])[CH2:20][CH:19]2[OH:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3[N+](=O)[O-])CC2O)CCCCC1)c1ccco1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-nitrophenyl)piperidin-3-ol (7.0 g, 14.7 mmol) obtained in Step 1 in 70 ml of ethanol, was added tin (II) chloride hydrate (1.13 mg, 44.2 mmol). The reaction mixture was refluxed for about 4 hours at 80° C., and then cooled to room temperature and concentrated. The resulting residue was diluted with 100 ml of ethyl acetate, alkalized with 29% aqueous ammonia solution (pH 8), and then the resulting white solid was filtered out. 100 ml of distilled water was added to the resulting filtrate. The resulting organic layer was dried and concentrated on sodium sulfate to give the titled compound (5.1 g).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15].Cl>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)CCBr
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCOc1ccc(Br)cc1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
To a solution of aqueous NaOH (0.5 M, 0.2 mol) was slowly added 4-bromophenol (34.4 g, 0.2 mol) at room temperature. After heating to boiling, 3-bromopropanoic acid (30.60 g 0.2 mol) in aqueous NaOH (0.5M, 0.2 mol) was added dropwise to the mixture above. The resulting mixture was then refluxed for 2 h. The mixture was cooled to 0° C. and the pH of the mixture was adjusted to 6-7 with 0.5 N HCl. The resulting mixture was filtered to give a solid cake, which was washed with water and n-pentane and dried to give 3-(4-bromophenoxy)propanoic acid (30 g, 60%). 1H-NMR (CDCl3): 2.72 (m, 2H), 4.90 (s, 1H), 5.01 (d, 1H), 5.50 (s, 1H), 6.73 (m, 1H), 7.21-7.43 (m, 6H), 7.61 (m, 1H).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Product: O=S(=O)(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccc(Cl)cc1

Procedure:
Using an analogous procedure to Example 1 3-[2-(4-amino-1-piperidyl)ethyl]indole monohydrate may be reacted with p-chlorobenzenesulphonyl chloride to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Br.[CH3:13][O-:14].[Na+]>CO>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH2:7][O:14][CH3:13])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
2.15 g of 5-chloro-2-nitrobenzylbromide is dissolved in approximately 25 ml methanol at room temperature. 1.86 g of 25% sodium methoxide in methanol is added and stirring continued for 0° C. 1 hour after which 10 wt % additional sodium methoxide is added to complete the conversion. The solvent is evaporated and the residue is dissolved in 100 ml dichloromethane and washed with 25 ml water (2X). Evaporation provided 1.6 g of 4-nitro-3-methoxymethylchlorobenzene. 1H-NMR (500 MHz, CDC13) δ (ppm) 3.527 (s, 3H), 4.838 (s, 2H), 7.399-7.416 (dd, 1H), 7.824-7.826 (d, 1H), 8.066-8.084 (d, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:28]([CH3:40])[CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH2:36])=[O:35].C([BH3-])#N.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][NH:15][CH:28]([CH3:40])[CH2:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:33]([C:34](=[O:35])[NH2:36])[CH:32]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(=O)CCc1cccc(C(N)=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CCc1cccc(C(N)=O)c1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 15 h
Yield: 81.1 %

Procedure:
2.61 g of 3,4-dibenzyloxyphenethylamine hydrochloride and 2.70 g of 3-(3'-oxobutyl)benzamide were dissolved in 50 ml of methanol, to which was added 0.47 g of sodium cyanoborohydride. The reaction was allowed to stand at room temperature for 15 hours. Then, the solvent was distilled off and the residue was extracted with 300 ml of ethyl acetate. The organic phase was washed with water and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel chromatography (solvent chloroform:ethanol:acetic acid=90:8:2) to obtain 2.91 g of N-[2-(3,4-dibenzyloxyphenyl)ethyl]-1-methyl-3-(3-carbamoylphenyl)propylamine as a viscous oil.