Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13])([O-])=O.[N+:16](C1C=C(OC(F)(F)F)C=CC=1Br)([O-:18])=[O:17]>>[N+:16]([C:8]1[CH:9]=[CH:4][C:5]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:6][CH:7]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1Br
Reactant: O=[N+]([O-])c1cc(Br)ccc1OC(F)(F)F
Product: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1

Procedure:
2-nitro-4-bromotrifluoromethoxybenzene and 3-nitro-4-bromotrifluoromethoxybenzene: 48%
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:11]([F:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[C:10]([N:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:11]([F:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([CH:29]=[CH2:30])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2c(OCc3ccccc3)cc3ccc(Br)cc3c2F)S(=O)(=O)N1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc2cc(OCc3ccccc3)c(N3CC(=O)NS3(=O)=O)c(F)c2c1
Temperature: 110 °C

Procedure:
To a microwave vial is added 5-(3-benzyloxy-7-bromo-1-fluoronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (340 mg, 0.73 mmol) (intermediate from preparing Example 16), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.24 mL, 1.46 mmol), polystyrene tetrakis(triphenylphosphine)palladium(0) (0.1 mmole/g) (365 mg, 0.0365 mmol), Na2CO3 (2 M, 1.83 mL, 3.65 mmol) and DME (2.5 mL). The mixture is then heated in a microwave at 110° C. for 30 min. The resin is then filtered and the residue is purified quickly by Biotage reverse phase, eluting with 10-90% EtOH/water to give fractions containing the title compound: MS (M+H)+=413. The fractions are combined and used in the next step without concentration.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].Cl.[NH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1.C(N(CC)CC)C>>[CH:19]1([CH2:18][NH:17][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:21][CH2:20]1
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1Cl
Yield: 75.7 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.2 mmol), aminomethyl cyclopropane hydrochloride (0.56 g, 5.2 mmol) and triethylamine (1.8mL, 12.9 mmol) were reacted to form the desired product (1.28 g, 84%). LC-MS m/z 325 (M+).
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC=C(CSCCO)C=2)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:17]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1cccc(CSCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (2.1 g, 6.64 mmol, 1 eq.) in anhydrous THF was treated with phenol (0.88 g, 9.30 mmol, 1.4 eq.), triphenylphosphine (2.44 g, 9.30 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (1.88 g, 1.83 mL, 9.30 mmol, 1.4 eq.). When complete, the reaction was worked up as described leaving a yellow oil
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@H:6]([OH:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@H:6]([OH:13])[CH2:5][CH2:4]1)[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CN[C@@H]1CC[C@H](O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CC[C@H](O)c4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1S,4R)-1,2,3,4-tetrahydro-4-(methylamino)-1-naphthalenol and its enantiomer (283 mg, 1.6 mmol) (i.e. the product of Example 26, Step A) and triethylamine (0.5 mL, 3.6 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (605 mg, 1.44 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 1 h, diluted with dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 0-20% of acetone in ethyl acetate as eluant to give 700 mg of the title compounds, compounds of the present invention as an off-white powder.
Reaction SMILES: Cl.C(OCC)C.C([Si](C)(C)[O:12][CH2:13][C@H:14]([NH-:25])[C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=1)(C)(C)C>CO>[NH2:25][C@H:14]([C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=1)[CH2:13][OH:12]
Reactant: CCCOc1ccc([C@@H]([NH-])CO[Si](C)(C)C(C)(C)C)cn1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCCOc1ccc([C@@H](N)CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A 2.00 M solution of hydrogen chloride in diethyl ether (28 mL, 56 mmol) was added to a stirred solution of [(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide (2.33 g, 5.62 mmol) dissolved in MeOH (11 mL) at 0° C. under Ar. After the addition was completed the cooling bath was removed and the solution was stirred at room temperature overnight. The mixture was then evaporated to dryness and the residue was suspended in methylene chloride and transferred to a short silica gel column. After eluding with EtOAc:EtOH:Et3N (90:5:5) (R)-2-Amino-2-(6-propoxy-pyridin-3-yl)-ethanol, IM36, was obtained as an oil (0.813 g, 74%). The overall yield from 5-bromo-2-propoxypyridine IM3 was 36%.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:39]#[C:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][OH:44])=[CH:13][C:14]=1[N:15]([CH:25]1[CH2:30][CH2:29][CH:28]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:27][CH2:26]1)[C:16]([CH:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]1)=[O:17])=[O:9].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:39]#[C:40][C:41]([CH3:45])([CH3:46])[CH2:42][CH2:43][O:44][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:13][C:14]=1[N:15]([CH:25]1[CH2:30][CH2:29][CH:28]([O:31][Si:32]([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:34])[CH3:33])[CH2:27][CH2:26]1)[C:16]([CH:18]1[CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH2:23]1)=[O:17])=[O:9]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1sc(C#CC(C)(C)CCO)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)CCO[Si](C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
TMSCl (0.08 mL, 0.596 mmol) was added dropwise to a solution of 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (300 mg, 0.497 mmol) and triethylamine (0.11 mL, 0.745 mmol) in dichloromethane at 0° C. After stirring for 1 h, the reaction was warmed to room temperature and stirred for an additional 1.5 h. The solution was washed with water, brine, dried and concentrated to give crude 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-5-trimethylsilanyloxy-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (330 mg) which was carried to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>CCO.N1CCCCC1>[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: O=Cc1cccc(O)c1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1cccc(O)c1
Yield: 55 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in EtOH (10 mL) and 3-hydroxybenzaldehyde (559 mg, 1 eq.) and piperidine (10 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((3-hydroxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (800 mg, 55% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH:14]=[C:4]1[C:5](=[O:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: CN1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CN(C)C=C1CN(C)CCC1=O

Procedure:
To a solution of 1-methylpiperidin-4-one (10 g, 88 mmol) in toluene (100 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (52.7 g, 0.442 mol). The solution was heated to reflux overnight. The solvents were evaporated in vacuo, heptane (100 ml) was added and the solvents evaporated again to give the desired product. NMR indicated that the product was 70-80% pure and it was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([O-:3])=[O:2].I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].OO>CS(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Reactant: CCOC(=O)CI
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cccn1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
To a stirred mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g of ethyl iodoacetate and 2.22 g of FeSO4.7H2O in 40 ml of dimethyl sulfoxide is added dropwise 10 ml of 301 hydrogen peroxide while keeping the reaction mixture at room temperature with a cold water bath. The mixture is stirred at room temperature for one day. An additional 2.4 g of ethyl iodoacetate, 1.1 g of FeSO4.7H2O and 5 ml of 30% hydrogen peroxide is added and the mixture stirred at room temperature for 1 day. The mixture is diluted with water and extracted with diethyl ether. The organic extract is washed with water, brine and dried (Na2SO4). The solvent is removed and the residue (2.12 g) chromatographed on silica gel with ethyl acetate-hexane (1:4) as solvent to give 0.30 g of product as a brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-])=O)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)Cc2ccccc2C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(N)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
The compound of step 1 (0.43 g, 1.16 mmol) was dissolved in methanol (30 ml), 10% palladium on charcoal (200 mg) was added, and the flask flushed with argon. A balloon filled with hydrogen was connected, and the mixture was stirred at room temperature overnight. The balloon was removed, the flask flushed with argon, the catalyst filtered off over Celite, and the filtrate was evaporated in vacuo to give 0.38 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:10].[C:20]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)(OCC)=[O:21].P(Cl)(Cl)(Cl)=O>>[OH:1][C:2]1[C:3]([CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][C:5]2[O:8][C:20](=[O:21])[C:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[C:6]=2[CH:7]=1
Reactant: CC(CCCc1ccccc1)c1cc(O)ccc1O
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(CCCc1ccccc1)c1cc2oc(=O)c3c(c2cc1O)CCCC3

Procedure:
A mixture of 5.0 g. (19.5 mmoles) of 2-(2',5'-dihydroxyphenyl)-5-phenylpentane, 3.4 g. (21.7 mmoles) 2-carboethoxycyclohexanone and 1.78 ml. (19.5 mmoles) of phosphorus oxychloride was stirred for five days under a nitrogen atmosphere. The solidified reaction mixture was dissolved in 175 ml. of chloroform, washed with 3×50 ml. of water and 50 ml. of saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to dryness at reduced pressure to obtain 13.8 g. of a partially crystalline solid. Trituration with hexane and evaporation of the filtrate gave 6.0 g. of crude product, M.P. 184°-193° C. Recrystallization from chloroform-hexane provided 2.66 g. of the title compound as tan crystals; M.P. 201°-203° C. A second crop, 1.7 g. was obtained from the mother liquor. 1H-NMR(CDCl3)ppm, (δ): 7.4-7.1 (m,5,phenyl), 7.1 and 7.05 (s,1,aromatic), 3.6-3.0 (m,1,CH), 2.9-2.3 (m,6,benzylic and allylic CH2), 1.9-1.4 (m,8,CH2), 1.2 (d,3,J=7), α-CH3); IR(KBr) 6.0μ; Mass spectrum (m/e): 362(M+).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCOCC1>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([C:4]#[C:3][CH2:2][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(C#CCCl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: COc1cc(C#CCN2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 96.4 %

Procedure:
To 4-(3-chloro-1-propyn-1-yl)-2-(methyloxy)-1-nitrobenzene (0.250 g, 1.1 mmol) in 10 mL of dioxane was added, piperidine (0.26 g, 3.1 mmol). The mixture was heated to 110° C. for 3 h. The mixture was purified by flash chromatography to give the title compound of step C (0.29 g, 1.06 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J=8.42 Hz, 1H), 7.11 (d, J=1.47 Hz, 1H), 7.06 (dd, J=8.33, 1.56 Hz, 1H), 3.94 (s, 3H), 3.50 (s, 2H), 2.54-2.63 (m, 4H), 1.62-1.70 (m, 4H), 1.41-1.50 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[N:17][OH:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)=NO
Yield: 47.8 %

Procedure:
103.14 g (0.5 mole) 2-oxo-4-phenyl butyric acid ethyl ester, 34.75 g (0.5 mole) hydroxylamine hydrochloride, 104 ml (0.75 mole) triethylamine and 500 ml ethanol were agitated overnight at room temperature. The batch was then evaporated to dryness and the residue taken up in 700 ml methyl-tert-butyl ether. After washing with 200 ml water, 200 ml 0.2N hydrochloric acid and 100 ml water, the organic phase was evaporated to dryness and the residue recrystallized after filtration from 170 ml toluene. 52.9 g (48%) 2-hydroxyimino-4-phenyl butyric acid ethyl ester were isolated in the form of colorless crystals. A 1H-NMR spectrum corroborated the suggested structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: O=C(Cc1ccc(F)cc1)NC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(F)cc1)NC1CCN(Cc2ccc(Br)cc2)CC1

Procedure:
2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 1.00 g), 1-bromo-4-(bromomethyl)benzene (1.06 g) and potassium carbonate (0.877 g) in dimethylformamide (15 ml) were heated to 70° C., under nitrogen for 1 hour. Water was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was triturated with diethyl ether, filtered and recrystallised from ethanol/water to give water crystalline needles of N-[1-(4-bromobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide. m.p. (+veES) 407 ((M+H)+)
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH3:32].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:2]1([N:1]([CH2:30][CH2:31][CH3:32])[C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(c1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 0 °C
Yield: 48.7 %

Procedure:
To a solution of methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate (0.20 g, 0.58 mmol) in N,N-dimethylformamide (4 mL) was added 60% sodium hydride (0.035 g, 0.86 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. n-Propylbromide (0.063 mL, 0.69 mmol) and sodium iodide (0.10 g, 0.69 mmol) were added to this mixture with stirring at 0° C., and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. Then the residue was dissolved in a mixed solution of methanol (3 mL) and tetrahydrofuran (6 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid, separated and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-1/2) to give the title compound (0.11 g, yield 47%) as colorless crystals. MS (APCI−): 388 (M−H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15](=[O:23])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH2:31]([O:30][C:28]([CH2:27][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:25][CH:24]=2)[CH2:13][CH2:14][C:15]1=[O:23])=[O:29])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a suspension of sodium hydride (60% oil suspension, 154 mg) in tetrahydrofuran (4 ml) was added a solution of 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (800 mg) in tetrahydrofuran (6 ml) at 0° C. and the mixture was stirred at 0° C. for 5 minutes. To the mixture was added ethyl bromoacetate (472 mg) and then the mixture was stirred at ambient temperature overnight. The reaction was quenched with saturated ammonium chloride aqueous solution and the resultant mixture was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, and then it was dried over magnesium sulfate. Filtration and evaporation afforded 1-ethoxycarbonylmethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (691 mg) as a slightly yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: Nc1ccc(Br)cc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (114 g, 0.6 mol) in anhydrous THF (750 mL) at −78° C. was added a 1.6M solution of nBuLi in hexanes (1500 mL, 2.4 mol) dropwise keeping the internal temperature below −60° C., under an inert atmosphere. The reaction mixture was treated dropwise with TMSCl (256 mL, 2.0 mol), keeping the internal temperature below −60° C. The reaction mixture was allowed to warm to 0° C. over a 1 hour period and poured into ice-cold 2M HCl (ca. 1 L). The mixture was vigorously stirred for 10 min, then the organic layer was separated, and washed with water and a saturated solution of potassium carbonate, dried (Na2SO4), filtered and concentrated to give the title compound as a light brown oil (89 g, 81%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:35][CH2:36][CH2:37][CH2:38][OH:39])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:40](O)(=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCCCCC>[C:16]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (23.7 g) and 4-(N,N-dimethylamino)pyridine (15.9 g) in methylene chloride (200 ml) was added to a solution of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (33.6 g) and z-octadeca-9-enoic acid (30 g) in methylene chloride (400 ml) under nitrogen at room temperature. On completion of reaction as evidenced by tic analysis the solution was diluted with hexane, filtered, concentrated and purified by dry column chromatography to yield 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(z-octadeca-9-enoyloxy)propane as a free flowing pale yellow oil.