Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].CC([N:35]([CH2:39][CH2:40][N:41]1[CH:45]=[C:44](I)[N:43]=[CH:42]1)[C:36](=[O:38])[O-:37])(C)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(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>[CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:44]3[N:43]=[CH:42][N:41]([CH2:40][CH2:39][NH:35][C:36]([O:37][C:16]([CH3:11])([CH3:7])[CH3:15])=[O:38])[CH:45]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)N(CCn1cnc(I)c1)C(=O)[O-]
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 12 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (333 mg, 0.80 mmol), 1,1-dimethylethyl[2-(4-iodo-1H-imidazol-1-yl)ethyl]carbamate (for a preparation see Intermediate 80) (270 mg, 0.8 mmol), potassium carbonate (443 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) in toluene (10 ml) and ethanol (10 ml) was refluxed under nitrogen for 16 h then cooled to room temperature and the insoluble were filtered off. Potassium carbonate (443 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) were added to the filtrate and the resulting mixture refluxed for 7 h then cooled to room temperature and the insoluble filtered off. The resulting solution was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-imidazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (47 mg, 0.094 mmol, 12%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:25]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)CC1

Procedure:
Using a method analogous to Method A with 2′,4′-difluorobiphenyl-4-sulfonyl chloride and methyl trans-4-aminocyclohexanecarboxylate, the title compound was obtained as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12](O)=O.Cl.[NH2:16][NH2:17].C([O:20][C:21](=[O:30])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Br)C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1=[N:16][N:17]([CH:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21]([OH:20])=[O:30])[C:21](=[O:20])/[C:22](=[CH:24]/[CH3:25])/[C:12]/1=[CH:28]\[CH:27]=[CH2:26]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: NN
Agent: Cl
Product: C=C/C=c1/c(-c2ccc3ccccc3c2)nn(C(C(=O)O)c2ccccc2)c(=O)/c1=C/C

Procedure:
This is made in a analogous fashion to example 11 starting with 2-Naphthyl acetic acid, ring expansion with hydrazine hydrochloride, alkylation with Ethyl-alpha-bromophenylacetate, and saponification to give the title compound. 16.4% overall yield, LC/MS (M++1): 421.4.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[C:19]([CH:14]1[NH:13][CH2:18][CH2:17][N:16]([C:8]2[C:2]([Cl:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:7]=2)[NH2:6])[CH2:15]1)([OH:21])=[O:20]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OC1CCCCC1
Product: Nc1cc(N2CCNC(C(=O)O)C2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 72.1 %

Procedure:
To a solution of 2.10 g of 4,5-dichloro-2-nitroaniline and 2.20 g of 2-piperazinecarboxylic acid in 20 ml of cyclohexanol, 4.80 g of sodium carbonate was added, followed by 14 hours' stirring at 150° C. After cooling the reaction liquid to room temperature, water was added and the system was washed with chloroform. The aqueous layer was purified with an ion-exchange resin (Diaion HP-20, Mitsubishi Kasei, eluent: methanol). Upon condensing the fraction containing the object product under reduced pressure, 2.20 g of the title compound was obtained.
Reaction SMILES: [I-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH2:39][CH:40]=O)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.O>O1CCCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C@H:33]2[CH2:34][CH2:35][C@H:36]([CH2:39][CH:40]=[CH:6][CH2:5][CH2:4][O:3][CH3:2])[CH2:37][CH2:38]2)=[CH:31][CH:32]=1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: COCCC=CC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A suspension, gassed with nitrogen, of 11.4 g of (3-methoxypropyl)triphenylphosphonium iodide in 50 ml of tetra- hydrofuran is cooled to -5° C., treated with 3.36 g of potassium tert.-butylate, stirred at -5° C. for 10 minutes and at room temperature for 1 hour. After cooling the reaction mixture to -5° C. a solution of 4.6 g of [trans-4-(4-chlorophenyl)cyclo-hexyl]acetaldehyde in 25 ml of tetrahydrofuran is added dropwise within 5 minutes, the mixture is stirred at -5° C. for 10 minutes and at room temperature for 1 hour, treated with 50 ml of water and the aqueous phase is extracted with 100 ml of ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered and concentrated. The residue is taken up in 50 ml of toluene and dissolved by heating to 70° C. and stirring for 30 minutes. The solution is cooled to room temperature, treated with 50 ml of hexane, stirred for 2 hours, filtered and washed with 30 ml of toluene/hexane (1:1 vol.). The filtrate is filtered over 100 g of silica gel and the silica gel is washed with 200 ml of hexane/toluene (1:1 vol.). The filtrate; is concentrated and gives 5.4 g of 1-chloro-4-[trans-4-(5-methoxy-2-pentenyl)cyclo-hexyl]benzene. The following compounds can be manufactured in an analogous manner:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][CH2:15][C:16](=[O:23])[C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[C:26]([CH:33]=O)=[CH:25]1.N1CCCCC1>C(O)C>[NH:24]1[C:32]2=[N:31][CH:30]=[CH:29][CH:28]=[C:27]2[C:26]([CH:33]=[C:15]2[O:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:12][CH2:11]3)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:25]1
Reactant: CCOC(=O)C1=C(N2CCC(N3CCOCC3)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCC(N3CCOCC3)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 12.8 %

Procedure:
To a stirred solution of ethyl 2-(4-morpholinopiperidin-1-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.31 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.045 g, 0.31 mmol) in ethanol (10 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.018 g, y. 13%) as solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:11][C:12]3[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:14](=[O:16])[C:23]=2[CH:24]=1
Reactant: COc1ccc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Temperature: 60 °C
Yield: 259.8 %

Procedure:
Sulfuric acid (1.6 L) was added to 2-(4-bromophenoxy)-5-methoxybenzoic acid (530 g, 1.6401 mol) at RT. The resulting dark mixture was heated to 60° C. for 1 hour. The brown solution was cooled to RT and poured onto ice while stirring. The resulting tan precipitate was collected by filtration, washed sequentially with water (2 L), 1N NaOH (2.0 L) and ethanol (800 mL). The derived solid was suspended in 2 L of acetone and stirred vigorously for 1 hour. The mixture was filtered and dried under a vacuum to afford 1.3 kg of 2-bromo-7-methoxy-9H-xanthen-9-one as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CCCc1ccccc1

Procedure:
Following General Procedure BB and using 4-phenylbutanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][N:3]=1.[NH2:19][NH2:20]>>[C:13]1([C:9]2[N:10]=[CH:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([NH:19][NH2:20])=[N:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: Clc1ccc(-c2ocnc2-c2ccccc2)cn1
Product: NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Temperature: 70 °C

Procedure:
A suspension of 2-Chloro-5-(4-phenyl-oxazol-5-yl)-pyridine (2.55 g, 9.9 mmol) in hydrazine (8 mL) was heated at 70° C. until a solution formed (approximately 20 minutes). The hydrazine product was removed from the heat and concentrated in vacuo affording the above named compound as a dark solid (2.5 g, 100%).
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: OO
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
An aqueous solution (10 ml) of sodium dihydrogenphosphate (12.0 g, 0.100 mol), an aqueous solution (30 ml) of sodium chlorite (5.19 g, 0.0577 mol) and aqueous hydrogen peroxide (1.701 ml, 30%) were added to an acetonitrile solution (30 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (5.60 g, 0.0128 mol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (5.20 g, 0.0115 mol, 90%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:35])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)[CH:5]=2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][O:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:11]4[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=4)=[C:2]([Br:1])[C:3]3=[O:35])=[CH:8][CH:7]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of t-Butyl 4-(2-(2-bromo-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yloxy)ethyl)piperidine-1-carboxylate (700 mg, 1.4 mmol) obtained in Step 1 in CH2Cl2 was added TFA (20 eq, 27 mmol). The solution was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was basicified to with 3N aq. NaOH. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated to obtain the title compound (99%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[NH:20]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[C:28]([C:30](O)=[O:31])[N:29]=2)[N:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[N:29]=[C:25]([C:23]4[N:22]=[CH:21][NH:20][CH:24]=4)[S:26][CH:27]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1csc(-c2c[nH]cn2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1csc(-c2c[nH]cn2)n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 2-(1H-imidazol-4-yl)thiazole-4-carboxylic acid (0.25 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the method described in Example 34(d). Yield 65 mg. 1H NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 4.40 (m, 2H), 4.60 (m, 1H), 6.80 (dd, 1H), 7.24 (d, 1H), 7.30 (m, 1H), 7.56 (m, 2H), 7.70 (d, 1H), 8.02 (s, 1H), 8.08 (m, 1H).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.CCCCCC>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([CH:25]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][OH:18])(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](OCCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.3 %

Procedure:
In tetrahydrofuran (20 ml) was dissolved 2-[7-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]heptyl]-1,4-difluorobenzene (786 mg, 1.23 mmol), followed by the dropwise addition of a tetrahydrofuran solution (1.0M, 4.0 ml, 4.0 mmol) of tetrabutylammonium fluoride under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After addition of water (2 ml), the mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (403 mg, 1.00 mmol, 81%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[F:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(-c2cccc(F)c2)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A 25 mL microwave vessel was charged with 1-bromo-3-nitrobenzene (XLVIII) (0.61 g, 3.0 mmol), 3-fluorophenylboronic acid (XLIX) (0.46 g, 3.3 mmol), potassium phosphate tribasic (0.95 g, 4.5 mmol), 1,4-dioxane (15.0 mL), and water (3.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) was added, and the reaction was placed in a microwave reactor for 1 h at 95° C. An additional 3-fluorophenylboronic acid (0.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.05 g) were added, and the reaction was heated for another 1 h at 95° C. in a microwave reactor. The organic solvent was separated from the water and concentrated to a residue. The residue was then purified by flash chromatography using a 25 g Thomson normal phase silica gel cartridge (100% hexanes→1:99 EtOAc:hexanes) to afford 3′-fluoro-3-nitrobiphenyl (L) (0.63 g, 2.91 mmol, 97% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 8.48 (t, J=2.0 Hz, 1H), 8.26-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.78 (t, J=8 Hz, 1H), 7.70-7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 1H), 7.32-7.28 (m, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[N:35]=[C:36]([NH2:43])[CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:43]=[C:36]([CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: NC(Cc1cccs1)=NO
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](c2nc(Cc3cccs3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and N′-hydroxy-2-(2-thienyl)ethanimidamide, the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=459.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[Cl-].[NH4+].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>CN(C=O)C.C(N(CC)CC)C.CCOC(C)=O>[CH3:33][O:32][C:28](=[O:31])[CH:29]=[CH:30][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(C(CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one ((example 74, step 5), 300 mg) in DMF (3 mL) tetrakis(triphenylphosphine)palladium (130 mg), methyl acrylate (0.103 mL) and triethylamine (0.16 mL) were added. The reaction mixture was stirred at 100° C. overnight, was cooled to room temperature and diluted with EtOAc and a saturated solution of ammonium chloride. The phases were separated and the inorganic one extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to yield the title compound (62 mg, 20%) as a yellow oil, MS (ESI+): m/z=400.1912 ([M+H]+).
Reaction SMILES: [I-:1].[Li+].CS(O[CH2:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:12]=[C:11]([Cl:22])[N:10]=1)(=O)=O>O1CCOCC1>[Cl:22][C:11]1[N:12]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[CH:14]=[C:9]([CH2:8][I:1])[N:10]=1
Reactant: [I-]
Reactant: C[C@@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Agent: [Li+]
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1cc(CI)nc(Cl)n1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
Lithium iodide (17.57 g, 131.27 mmol) was added to (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (19.2 g, 59.67 mmol) in dioxane (300 ml) and heated to 100° C. for 2 hours under nitrogen. The reaction mixture was quenched with water (200 ml) and extracted with EtOAc (3×200 ml). The organic layers were combined and washed with 2M sodium bisulfite solution (400 ml), water (400 ml), brine (400 ml) dried over MgSO4 and then evaporated. The residue was triturated with Et2O to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (13.89 g, 66%); 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98-4.02 (2H, m), 4.21 (2H, s), 4.29 (1H, br s), 6.41 (1H, s); m/z: (ESI+) MH+, 354.31.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.CSC(=N)N[N+]([O-])=O.[CH3:19][NH:20][C:21](=[N:24][N+:25]([O-:27])=[O:26])SC>>[S:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:21]([NH:20][CH3:19])=[N:24][N+:25]([O-:27])=[O:26])=[N:7]1
Reactant: NCCSCc1ccsn1
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: CSC(=N)N[N+](=O)[O-]
Product: CNC(=N[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with S-methyl-N-nitroisothiourea by the procedure of Example 70 gives N-[2-(3-isothiazolymethylthio)ethyl]-N' -nitro-guanidine and reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea gives N-[2-(3-isothiazolylmethylthio)ethyl]-N' -methyl-N"-nitroguanidine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[Br:1][C:2]1[C:3]2[S:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cccc(Br)c2s1

Procedure:
Using 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde, 8.2 g (205.7 mmol) of sodium hydride (60% pure) and 16.0 g (150.9 mmol) of methyl mercaptoacetate, 20.57 g of a mixture of the title compound and the corresponding acid (about 1:1) are obtained.