Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:18]=[C:17]([C:19]2[O:24][C:23](=[O:25])[C:22]3[CH:26]=[C:27]([N+:31]([O-:33])=[O:32])[CH:28]=[C:29]([CH3:30])[C:21]=3[N:20]=2)[N:16]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[N:15]=1>O.CN(C)C=O>[Br:13][C:14]1[CH:18]=[C:17]([C:19]([NH:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([N+:31]([O-:33])=[O:32])=[CH:26][C:22]=2[C:23]([N:4]([CH3:3])[NH:5][CH3:6])=[O:25])=[O:24])[N:16]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[N:15]=1
Reactant: CNNC
Reactant: Cc1cc([N+](=O)[O-])cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNN(C)C(=O)c1cc([N+](=O)[O-])cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.26 g of N,N′-dimethylhydrazine dihydrochloride, 2 ml of water, 0.5 g of potassium carbonate and 10 ml of N,N-dimethylformamide was added 0.20 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-6-nitro-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-bromo-1-(3-chloro-2-pyridinyl)-N-[2-(N,N′-dimethylhydrazinocarbonyl)-6-methyl-4-nitrophenyl]-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>C(Cl)(Cl)Cl>[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13]
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: COC[C@H]1CCCN1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a stirred cold suspension of 2,3-dioxo-2,3-dihydro-1H-indol-5-sulfonyl chloride (5.00 g, 20.4 mmol) in a 1:1 mixture of THF: CHCl3 (140 mL) was added dropwise, via syringe pump, a solution of N,N-diisopropylethylamine (7.11 mL, 40.8 mmol, 2 eq) and (R)-2-(Methoxymethyl)pyrrolidine (3.27 mL, 26.5 mmol, 1.3 eq) in CHCl3 (60 mL) over a period of 1.5 hours with cooling in an ice bath. After stirring an additional 1 h, the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with 95/5 CH2Cl2/CH3OH followed by a second chromatography on silica gel eluting with EtOAc to give 4.21 g (63.8% ) of the title compound. NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].Cl.ClCCN(CCC1C=C[C:37]([O:40]C)=[C:36](OC)C=1)CCCl>>[OH:17][CH2:16][CH2:15][N:13]([CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:36][CH2:37][OH:40]
Reactant: OCCBr
Reactant: COc1ccc(CCN(CCCl)CCCl)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CCN(CCO)CCO)cc1OC
Yield: 88 %

Procedure:
2-(3,4-Dimethoxyphenyl)ethylamine (80.0 g), 2-bromoethanol (182 g) and potassium carbonate (201 g) were added to ethanol (1) and the mixture was refluxed for 16 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The oily residue was dissolved in chloroform. The solution was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 104.5 g(88% ) of N,N-bis(2-hydroxyethyl)-2-(3,4-dimethoxyphenyl)ethylamine in oily form.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1sccc1N(C)C(=O)C(F)(F)F
Reaction time: 48 h
Yield: 97.3 %

Procedure:
A mixture of 2 g of 3-(2,2,2-trifluoro-acetylamino)-thiophene-2-carboxylic acid methyl ester (7.9 mmol), 1.31 g of potassium carbonate (9.48 mmol) and 596 μl of methyl iodide (9.48 mmol) in DMF (7.5 ml) was stirred for 2 d. The reaction mixture was then poured into water and extracted with DCM. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to give 2.055 g (97%) of 3-[methyl-(2,2,2-trifluoro-acetyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white solid. MS (ISP) 268.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[N+](N[C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:26][N:25]=1)([O-])=O>N1C=CC=CC=1>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:26][N:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NCCCN(Cc1ccccc1Cl)c1ccccn1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCN(Cc3ccccc3Cl)c3ccccn3)[nH]c2=O)cn1

Procedure:
2-[N-(3-aminopropyl)-N-(2-chlorobenzyl)amino]pyridine (1 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.78 g) were heated together under reflux in pyridine (10 ml) for 20 hr. After stripping, the residue was triturated with ether and recrystallised twice from ethanol/water to give 2-[3-[N-(2-chlorobenzyl)-N-pyrid-2-ylamino]propylamino]-5-(6-methylpyrid-3-ylmethyl)-pyrimid-4-one 0.4H2O, 0.34 g (20%) mp softens 94°-102° C. melts 120°-26° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[NH2:8][C:9]1[C:18]([F:19])=[C:17](F)[C:16]([O:21][CH:22]([F:24])[F:23])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:28]([OH:30])=[O:29])=[CH:13][N:14]2[CH:25]1[CH2:27][CH2:26]1>N1C=CC=CC=1>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([N:6]2[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]2)[C:16]([O:21][CH:22]([F:23])[F:24])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:28]([OH:30])=[O:29])=[CH:13][N:14]2[CH:25]1[CH2:26][CH2:27]1
Reactant: CC1CNCCN1
Reactant: Nc1c(F)c(F)c(OC(F)F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: c1ccncc1
Product: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC(F)F)CCN1
Reaction time: 2 h
Yield: 64.9 %

Procedure:
1.30 g (0.013 moles) of 2-methylpiperazine was added to a solution of 0.90 g (0.0026 moles) of 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Preparation 11) in 8 ml of pyridine, and the mixture was stirred at 105°-110° C. for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and the resulting mixture was neutralized (to about pH 7) by the addition of acetic acid; the mixture was then extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was washed with ethanol to give 0.72 g of 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a yellow powder, melting at 283°-286° C.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.CO[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=NC=1.[NH2:36]C1CCOCC1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH2:36])=[O:25])=[C:5]([CH:34]4[CH2:33][CH2:32][O:35][CH2:28][CH2:29]4)[N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cccnc1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(N)=O)c(C2CCOCC2)n1
Yield: 47 %

Procedure:
As described for example 84f, 6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, instead of [64342-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (61 mg, 47%) which was obtained as a white solid. MS: m/e=429.5 [M+H]+.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C.CO>O.C1COCC1>[CH3:31][S:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(SC)c3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CSc1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Lithium hydroxide (168 mg, 1.76 mmol) in water (1.7 ml) is added to a solution of 4-[8-(3-methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (650 mg, 1.6 mmol) in THF (3.2 ml) under argon. Methanol is added to maintain solution (4 ml) and the mixture is stirred at room temperature for 5 hours. The mixture is evaporated to dryness then partitioned between ethyl acetate and water. The aqueous layer is acidified to pH 2 then extracted into ethylacetate and dried over magnesium sulfate, Evaporation gives a green gum which is reevaporated from methanol then DCM/diethylether to give a yellow/green foam. The foam is triturated with 3:1 hexane:diethyl ether, 2:1 hexane:diethylether, ethylacetate/hexane/ether mixtures and finally 5:1 diethylether:ethanol to yield an off-white solid. This is then recrystallised from ethanol to yield the title compound. M.p 177.6-178.2° C., MS (AP+) 379.05
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH2:8][Br:9])=[CH:6][CH:7]=1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)C>CN(C)C=O>[Br-:9].[CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH:8]=[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]2[PH+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CBr)nc1-c1ccccn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(C=C2C=CC=CC2[PH+](c2ccccc2)c2ccccc2)nc1-c1ccccn1
Product: [Br-]

Procedure:
1.16 g (4.4 mmols) of 3-methyl-6-bromomethyl-2,2'-bipyridine together with 1.39 g (5.3 mmols) of triphenylphosphine in 50 ml of N,N-dimethylformamide are heated at 80° C. for 3 hours. At 23° C. and with rapid stirring, 50 ml of diethyl ether are added. The precipitating oily product crystallises after a short time and is filtered off with suction. After recrystallisation from 25 ml of water, 1.14 g (49% of theory) of [3-methyl-2,2'-bipyridin-6-yl-(methylene)]-triphenylphosphonium bromide are obtained in the form of colourless crystals; melting point 214°-215° C.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH3:27].CO.C(Cl)(Cl)Cl>C(O)C.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:26][CH3:27])[CH2:16][CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CCBr
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 24 h
Yield: 74.1 %

Procedure:
In 100 ml of ethanol were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35), 1.66 g of anhydrous potassium carbonate and 5.45 g of ethyl bromide, and the reaction was carried out at an external temperature of 70° C. for 24 hours. After the reaction solution was filtered, the filtrate was condensed and the residue was dissolved in 50 ml of chloroform, and the solution was extracted twice with a 2N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted twice with 50 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: 2% methanol-chloroform) to give 2.26 g of 1-(5-isoquinolinesulfonyl)-4-ethylpiperazine, i.e., Compound (42) in a yield of 74%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:24]1=[CH:25][C:26]2[C:27]([CH:32]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:34]1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:24]2=[CH:25][C:26]3[C:27]([CH:32]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:43]([CH3:45])[CH3:44])[CH:37]([CH3:38])[CH3:39])[CH2:33][CH2:34]2)=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)[Si](OC1CCC(OS(=O)(=O)C(F)(F)F)=Cc2cccnc21)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)[Si](OC1CCC(c2ccc(F)c(F)c2)=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 80 °C

Procedure:
The mixture of 3,4-difluorophenylboronic acid (0.083 g, 0.527 mmol), sodium carbonate (0.406 mL, 0.813 mmol), (E)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridin-6-yl trifluoromethanesulfonate (0.2045 g, 0.439 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol) in Toluene (5 mL) and MeOH (1 mL) was heat to 80° C. under N2 for 3 hours. LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed with water one time. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated to give the crude product. The Crude was used as it is. MS(ESI)[M+H+]=430.36.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][N+:21]=1[O-].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(N)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol), 2-chloro-4-nitro-pyridine oxide (2.2 g, 12 mmol) and Cs2CO3 (5.7 g, 18 mmol) were mixed in DMF (50 mL) and stirred at room temperature for 1 h. Water was added and the reaction mixture was adjusted to pH 3. The reaction mixture was extracted with ethyl acetate. The organic layers were concentrated to give a residue. The residue was purified by flash column chromatography (dichloromethane:methanol=15:1) to give the title compound (0.77 g, 29%) as a brown solid. MS found (electrospray): (M+H)+=389.1.
Reaction SMILES: C1(C)C=CC=CC=1.CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.CSC.[F:33][C:34]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]2[C:35]=1[C:36](=[O:45])[CH2:37][CH2:38][O:39]2>O1CCCC1>[F:33][C:34]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]2[C:35]=1[CH:36]([OH:45])[CH2:37][CH2:38][O:39]2
Reactant: O=C1CCOc2cc(F)cc(F)c21
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CSC
Product: OC1CCOc2cc(F)cc(F)c21
Reaction time: 0.33 h

Procedure:
To a mixture of 1 M (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole toluene solution (5.43 mL, 5.43 mmol) and tetrahydrofuran (40 mL) was added 2M borane-methyl sulfide complex tetrahydrofuran solution (29.8 mL, 59.7 mmol) at 0° C. and the mixture was stirred for 20 minutes. To the mixture was added a solution of 5,7-difluoro-2,3-dihydro-4H-chromen-4-one (10.0 g, 54.3 mmol, STEP 7) in tetrahydrofuran (70 mL) at 0° C. over a period of 1 hour, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with methanol (50 mL) and stirred for 30 minutes at room temperature. The mixture was concentrated in vacuum and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 as an eluent) to afford crude white solids (8.85 g, 86% ee). The solids were recrystallized from hexane (300 mL) to give the title compound as a colorless needle crystal (5.90 g, 58%, >99% ee).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]2[CH2:15][NH:14][C:13](=[O:16])[NH:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CS(C)=O>[CH:23]1([O:1][C:2]2[CH:3]=[C:4]([CH2:10][CH:11]3[CH2:15][NH:14][C:13](=[O:16])[NH:12]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(CC2CNC(=O)N2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC2CNC(=O)N2)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To the solution of 22.22 g (100 mmoles) of the product obtained in Example 3, step (a) in 220 ml of dimethylsulphoxide, 27 g of powdered anhydrous potassium carbonate are added and the suspension is stirred at 60° C. for 30 minutes, then 12.9 ml (120 mmoles) of cyclopentyl bromide are portionwise added during 60 minutes while the temperature is kept at 60° C. The suspension is further stirred at 60° C. for 20 hours, then cooled to 25° C. and poured into 800 ml of water. The aqueous emulsion is extracted four times with 400 ml of chloroform. The collected organic phases are washed twice with 50 ml of 1 N sodium hydroxide solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. To the oily residue 200 ml of benzene are added and the evaporation is repeated. The residue is triturated with 150 ml of ether and the crystals obtained are filtered after 30 minutes and washed with 50 ml of ether to give 21.30 g (73.4%) of the title compound, m.p. 104°-107° C. After recrystallization from acetone this melting point rises to 115°-116° C. On the basis of its physical properties, this product is identical with the compound obtained in Example 2, step (d).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1CBr>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:27]([F:37])([F:36])[F:26]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: Cl
Product: FC(F)(F)c1ccccc1CSc1c(Cl)ccc2c1CCNCC2

Procedure:
Use a method similar to the Example 347 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with 2-trifluoromethylbenzyl bromide. Use a method similar to the General Procedure 1-4 to give the title compound as a waxy tan solid. MS (APCI+) m/z: 372 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[N:4]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[NH2:2][C:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:16])=[O:10])[N:4]=1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC1=NC(C(=O)O)CCC1
Agent: Cl
Product: COC(=O)C1CCCC(N)=N1
Temperature: 25 °C
Yield: 31 %

Procedure:
2-Amino-3,4,5,6-tetrahydropyridine-6-carboxylic acid HCl (1.99 g, 11.1 mmol) was suspended in anhydrous methanol (100 ml), and thionyl chloride (0.8 ml, 11.lmmol) was added dropwise with stirring at room temperature. The resulting solution was refluxed overnight and then evaporated to dryness in vacuo. The resulting crude white solid was recrystallized from ethanol to give white crystals 656 mg (31%) mp 132°-134° C., identified as product by 300 MHz nmr and ir 1753 cm-1. Calculated: C 43.64, H 6.8, N 14.55; found: C 43.80, H 6.81, N 14.46.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.O[CH2:28][C:29]1[N:30]=[N:31][N:32]([CH2:34][CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[CH:33]=1>C(Cl)Cl>[I:20][CH2:28][C:29]1[N:30]=[N:31][N:32]([CH2:34][CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[CH:33]=1
Reactant: II
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(CO)nn1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCn1cc(CI)nn1
Yield: 78.9 %

Procedure:
Stir a mixture of triphenylphosphine (0.29 g, 1.10 mmol) and iodine (0.28 g, 1.10 mmol) in DCM (4 mL) for 10 min. Add 1H-imidazole (0.12 g, 1.84 mmol) and stir for 10 min. Add 2-(2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)isoindoline-1,3-dione (0.2 g, 0.73 mmol) and stir overnight at RT. Dilute with DCM and wash with water and aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (DCM to 20% ethyl acetate in DCM) to give the title compound as a yellow solid (0.22 g, 78%). MS (ES) m/z 383 [M+1]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[O:14]1CCC[CH2:16][CH:15]1OC1CCCCO1.[C:27]1([P:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br-:1].[C:40]1([P+:33]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:15](=[O:14])[CH3:16])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCCCCCCCCCCBr
Reactant: C1CCC(OC2CCCCO2)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of 30 g. (0.102 moles) of 11-bromo-undecanol acetate (Formula VI, X=Br, Y=COCH3), 26.72 g. (0.102 moles) of triphenyl phosphine and 0.5 g. of potassium carbonate in 100 ml. of dry acetonitrile is refluxed for 15 hours. The solution is cooled, diluted with 200 ml. of dry ether, and the upper ether phase is decanted from the separated oily substance. This operation is repeated twice with 200 ml. of dry ether. The obtained 45.3 g. (80%) of triphenyl-(11-acetoxy-undecyl)-phosphonium bromide (Formula V, X=Br, Y=COCH3) is dried in vacuo.