Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]2[CH2:22][O:21]C(C)(C)[O:19]2)[CH:13]=[C:12]([C:25]([OH:27])=[O:26])[CH:11]=1)#[N:2].Cl>C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:19])[CH2:22][OH:21])[CH:13]=[C:12]([C:25]([OH:27])=[O:26])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(OCC3COC(C)(C)O3)cc(C(=O)O)c2)c(C#N)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(OCC(O)CO)cc(C(=O)O)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2′-cyano-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4′-methylbiphenyl-3-carboxylic acid (63 mg, 0.17 mmol) in THF (3 mL) was added 1 M of aq. HCl solution (3 mL, 3 mmol). The reaction mixture was stirred at room temperature for 4 hours, and then concentrated in vacuo. The residue was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.77 (t, 1H, J=1.6 Hz), 7.67 (m, 2H), 7.58 (dd, 1H, J=8.0, 2.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.38 (t, 1H, J=2.0 Hz), 4.19 (dd, 1H, J=9.6, 4.0 Hz), 4.10 (dd, 1H, J=9.6, 6.0 Hz), 4.02 (m, 1H), 3.72 (dd, 1H, J=11.2, 5.6 Hz), 3.67 (dd, 1H, J=11.2, 5.6 Hz), 2.45 (s, 3H).
Reaction SMILES: C(OC([N:8]=[C:9]([N:11](C(OC(C)(C)C)=O)[O:12][CH2:13][CH2:14][NH:15][C:16](=[O:39])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:26][CH2:27][C:28]([F:37])([F:36])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)[C:19]=1[F:38])[NH2:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:9]([NH:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:39])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:26][CH2:27][C:28]([F:36])([F:37])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)[C:19]=1[F:38])(=[NH:8])[NH2:10]
Reactant: Cc1ccc(C(F)(F)CNc2ccc(C#N)c(CC(=O)NCCON(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c2F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(F)(F)CNc2ccc(C#N)c(CC(=O)NCCONC(=N)N)c2F)nc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
N-[2-(N′,N″-Bis(tert-butoxycarbonyl)amidinoaminooxy)ethyl]-2-{3-[(2,2-difluoro-2-(5-methylpyridyl)ethyl)amino]-6-cyano-2-fluorophenyl}acetamide (832 mg, 1.28 mmol), as prepared in the previous step, was dissolved into CH2Cl2 (6 mL), cooled to 0° C. and treated with TFA (2 mL), then allowed to warm to rt. After 12 h, the reaction was concentrated in vacuo to afford a yellow oil. Purification via flash chromatography (inactivated with NH3, 10% MeOH/CH2Cl2) afforded the product as a white solid (413 mg, 0.92 mmol, 72% yield). 1H NMR (300 Hz, CD3OD) δ 8.49 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 6.82 (t, J=8.2 Hz, 1H), 4.07 (t, J=13.8 Hz, 2H), 3.79 (t, J=5.3 Hz, 2H), 3.72 (d, J=1.98 Hz, 2H), 3.42 (t, J=5.3 Hz, 2H), 2.39 (s, 3H); LC/MS (m/z) [M+1]+ 450.2 (calculated for C20H23F3N7O2, 450.4).
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([F:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:30])[CH:21]=1.[C:31]([NH:35][C:36](=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([F:29])=[CH:27][C:23]([C:24]([N:47]2[CH2:46][CH2:45][N:44]([CH2:43][C:39]3[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=3)[C:36]([NH:35][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:50])[CH2:49][CH2:48]2)=[O:26])=[C:22]([F:30])[CH:21]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(N)cc3F)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (2.91 g, 9.2 mmol, 2.73 mL) was added dropwise to a solution of 4-amino-2,5-difluorobenzoic acid (792.9 mg, 4.6 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.3878 g, 5 mmol) and triethylamine (1.39 g, 13.9 mmol, 1.91 mL) in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.52 g). MS (ESI) m/z 431.9 [M+H]+
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:39])([F:38])[C:8]1[CH:9]=[C:10]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:11][N:12]([CH3:30])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH:16]1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])=[O:14]>C1COCC1>[CH3:1][S:2]([O:21][CH:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[N:12]([CH2:11][C:10]2[CH:9]=[C:8]([C:7]([F:6])([F:38])[F:39])[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=2)[CH3:30])[CH:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])[CH2:17]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1C1CC(O)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C1CC(OS(C)(=O)=O)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride (20 μL) was added to a solution of 2-(4-fluoro-2-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methylamide (intermediate 11a and 11b—mixture of syn and anti diastereoisomers—85 mg) and TEA (50 μL) in dry THF (5 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 1.5 hours, the solution was quenched with brine (4 mL) and extracted with AcOEt (3×5 mL). The organic layer was dried and concentrated in vacuo to a residue which was purified by flash chromatography (CH/AcOEt 7:3) to give methanesulfonic acid, 1-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl ester in two fractions:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH2:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 92.9 %

Procedure:
A mixture of 1-(4-hydroxy-3-nitrophenyl)ethanone (5.92 g, 32.70 mmol), sodium iodide (4.90 g, 32.70 mmol), potassium carbonate (13.55 g, 98.00 mmol), and benzyl bromide (5.04 mL, 42.50 mmol) in acetone (120 mL) was stirred under reflux for 66 h. After removal of solvent by rotary evaporation, the resulting residue was diluted with dichloromethane and insoluble inorganics were filtered off. The filtrate was concentrated in vacuo and the resulting residue was purified by flash silica gel column chromatography eluting with dichloromethane to give benzyl ether 2 as a white solid (8.24 g, 93%): 1H NMR (500 MHz, CDCl3) δ 2.60 (s, 3H), 5.32 (s, 2H), 7.18 (d, 1H), 7.41 (m, 5H), 8.12 (dd, 1H), 8.44 (d, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11]Cl)[C:8]([CH2:13]Cl)=[CH:7][C:6]=1[O:15][CH3:16].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>C(O)(=O)C>[C:17]([O:20][CH2:13][C:8]1[CH:7]=[C:6]([O:15][CH3:16])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:10][C:9]=1[CH2:11][O:20][C:17](=[O:19])[CH3:18])(=[O:19])[CH3:18]
Reactant: COc1cc(CCl)c(CCl)cc1OCCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(COC(C)=O)c(COC(C)=O)cc1OCCCl
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of 5.67 g (0.020 mole) of 1-(2-chloroethoxy)-4,5-bis(chloromethyl)-2-methoxybenzene in 75 ml acetic acid is added a solution of 3.5 g of anhydrous sodium acetate in 100 ml acetic acid. This mixture is refluxed with stirring for 2 hours. Solids are removed by filtration and washed with acetic acid. The filtrate is evaporated to approximately 30 ml, then poured into water and extracted with ether. The organic phase is washed with aqueous sodium carbonate, water and brine. After drying over sodium sulfate, the solution is filtered and evaporated to give 5.69 g (86%) of 2-[(acetyloxy)methyl]-4-(2-chloroethoxy)-5-methoxybenzyl acetate as a white solid, m.p. 79-80° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[O:13].C1C(=O)N([Br:23])C(=O)C1.CCCCCC>C1COCC1>[Br:23][C:10]1[CH:9]=[C:8]([CH:12]=[O:13])[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1cccc1C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde (4.51 g) in THF (79 mL) was added NBS (4.27 g) at −20° C., and the mixture was stirred at 0° C. for 6 hr. To the reaction mixture was added hexane (240 mL), the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[N:6][CH:7]=1.[CH3:16]OC(OC)(N(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:13][C:12](=[O:14])[N:11]([CH3:16])[C:10]2=[O:15])=[N:6][CH:7]=1
Reactant: COC(C)(OC)N(C)C
Reactant: O=C1CN(Cc2ccc(Br)cn2)C(=O)N1
Solvent: Cc1ccccc1
Product: CN1C(=O)CN(Cc2ccc(Br)cn2)C1=O
Temperature: 150 °C
Yield: 83.6 %

Procedure:
1-((5-bromopyridin-2-yl)methyl)imidazolidine-2,4-dione (9J3) (0.926 mmol, 250 mg) was mixed with toluene (2.5 ml) and N,N-dimethylacetamide dimethyl acetal (9J4) (3.70 mmol, 490 mg) and heated in the microwave at 150° C. for 15 minutes. The volatile components were removed under high vacuum and the resulting oil purified on silica eluting with 0-100% ethyl acetate/heptane to afford 1-((5-bromopyridin-2-yl)methyl)-3-methylimidazolidine-2,4-dione (9J5) 220 mg (84%); 1H NMR (400 MHz, CDCl3) 8.62 (d, 1H) 7.81 (dd, 1H) 7.20 (d, 1H) 4.63 (s, 2H) 3.98 (s, 2H) 3.05 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[Li]CCCC>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:10]([OH:11])[C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)c1ccccn1

Procedure:
31 (1.3 g, 6.54 mmol), 2-bromopyridine (0.70 ml, 7.19 mmol), n-BuLi (1.6M) (4.5 ml, 7.19 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]3[C:17]4[C:12](=[C:13]([C:20]([F:21])([F:23])[F:22])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=4)[CH:11]=[C:10]3[CH3:24])[CH:3]=2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(Br)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
Synthesized as described in Example 310D using 1-[(3-bromophenyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 318A) and [3,5-bis(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 527 (M+1).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.[CH:25]([C:27]1[S:31][C:30]([B:32]([OH:34])[OH:33])=[CH:29][CH:28]=1)=O>C(Cl)Cl.C([O-])(O)=O.[Na+].CO>[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:25][C:27]1[S:31][C:30]([B:32]([OH:34])[OH:33])=[CH:29][CH:28]=1
Reactant: CC1CCCN1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC1CCCN1Cc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 7 %

Procedure:
Batch 1: NaBH(OAc)3 (271 mg, 1.28 mmol), HOAc (0.07 mL), and 2-Methylpyrrolidine (0.043 mL, 0.42 mmol) were added to a solution of (5-formyl-2-thienyl)boronic acid (100 mg, 0.64 mmol) in CH2Cl2 (4 mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 15 h. The reaction mixture was loaded directly onto a 2 g SCX cartridge (pre-equilibrated with MeOH), eluting in sequence with MeOH (12 mL) and a 2 M solution of NH3/MeOH (8 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHCO3 (2 mL) and extracted with EtOAc (3×2 mL) to give 6.6 mg of crude {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH3:26])=[N:15][N:16]2[CH3:25])=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=[C:17]3[C:13]=2[C:14]([CH3:26])=[N:15][N:16]3[CH3:25])=[N:9]1)([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc2c(c(C)nn2C)c1C(=O)NC(C)(C(N)=O)C(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c(C)nn2C)c1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 85.7 %

Procedure:
A mixture of methyl 4-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-1,3-dimethyl-1H-indazole-5-carboxylate (0.600 g, 1.67 mmol), phosphorus pentachloride (1.04 g, 5.00 mmol) and dry toluene (7.0 mL) is stirred for 3.5 hours at 90° C. cooled and filtered. The filter cake is washed with toluene, slurried in water, treated with sodium bicarbonate (0.370 g, 4.40 mmol) to pH 8.5 and filtered to afford the title product as a white solid (0.490 g, 85.7%), mp 130°-150° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9](Br)[CH:8]=[CH:7][CH:6]=2.[CH2:13]([CH:17]([Sn])C=C(CCCC)CCCC)[CH2:14]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2)[CH:13]=[CH2:14]
Reactant: Cc1cc2c(Br)cccc2cn1
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1cccc2cnc(C)cc12

Procedure:
3-Methyl-5-bromoisoquinoline (1.0 g, 4.5 mmol), tributylallyltin (1.6 mL, 5.0 mmol), and dichlrobis(tri-o-tolylphosphine)palladium (II) were combined in toluene (100 mL) and refluxed for 14 hours. The mixture was cooled, diluted with ethyl acetate, and washed twice with aqueous NH4Cl. The organic phase was separated, concentrated, and the residue was purified by chromatography (ethyl acetate:hexanes, 30:70) to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 9.21 (s, 1H), 8.00 (d, 1H), 7.63 (m, 2H), 7.58 (m, 1H), 4.18 (s, 2H), 3.62 (s, 3H), 2.62 (s, 3H). MS (DCI/NH3) m/e 216 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[O:20][N:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[O:20][N:19]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.80-7.61 (m, 4H), 7.57 (d, J=8.5 Hz, 1H), 5.83 (s, 2H), 3.05-2.75 (m, 2H), 1.70-1.41 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (ES) m/z 413 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N+:15]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)([O-:17])=[O:16].O>CN(C=O)C>[CH2:1]([N:19]1[CH:20]=[CH:21][N:22]=[C:18]1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nccn1Cc1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Benzylbromide (3 mmol) and K2CO3 (6 mmol) were added to a solution of 2-nitroimidazole (2 mmol) in DMF (6 mL). The mixture was stirred at 60-70° C. for 4 h or overnight. The contents were cooled to room temperature, and water (30 mL) was added. The mixture was extracted with EtOAc (3×15 mL). The combined extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo to afford 1-benzyl-2-nitro-1H-imidazole. The product used for further transformation without further purification.
Reaction SMILES: [IH:1].[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10](=[NH:13])SC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23]N>ClC1C=CC=CC=1Cl>[IH:1].[C:2]1([CH:8]([NH:9][C:10]2[NH:20][CH2:21][CH2:22][CH2:23][N:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Reactant: NCCCN
Agent: I
Solvent: Clc1ccccc1Cl
Product: c1ccc(C(NC2=NCCCN2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 25 milliliters of o-dichlorobenzene was added 7.41 grams (0.10 mole) of 1,3-diaminopropane, and the mixture heated (below reflux temperature) for four hours with stirring; then the temperature was increased to reflux temperature and maintained under reflux for 12 hours. The mixture was allowed to cool to room temperature, the solvent decanted off and the residue dissolved in methanol. The methanol solution was concentrated while simultaneously adding isopropanol to obtain 24.6 grams (62.6 percent yield) of 2-diphenylmethylamino-1,4,5,6-tetrahydropyrimidine hydroiodide product, m.p. (185° C.) 197°-200° C. After two recrystallizations from methanol-isopropanol, a purified product of melting point 207°-209° C. was obtained.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[CH2:29][CH2:30][F:31])[C:22]([O:24]C)=[O:23])(=[O:18])=[O:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O>[CH2:1]([O:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[CH2:29][CH2:30][F:31])[C:22]([OH:24])=[O:23])(=[O:17])=[O:18])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CCF)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCF)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Temperature: 37.5 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of methyl 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoate (180.00 mg, 400.42 umol, 1.00 Eq) in THF (5 mL) and H2O (1 mL). The formed mixture was stirred at 25-50° C. for 3 hr. The reaction mixture was neutralized with 1N HCl solution and concentrated to give the crude product 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoic acid (160.00 mg, 367.39 umol, 91.75% yield).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:9][N:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]([NH:9][N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN1CC=CCC1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NN1CC=CCC1
Temperature: 5 °C
Yield: 25.4 %

Procedure:
To a solution of tert-butyl isocyanate (0.991 g) in methylene chloride (8 ml) was added dropwise to a mixture of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.012 g) in methylene chloride (40 ml) under ice bath cooling. The mixture was stirred for an hour at about 5° C. The reaction mixture was evaporated to dryness, and then the residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (40 ml), dried over magnesium sulfate and evaporated to dryness. The crude residue was washed with ether and dried to give N-[(tert-butylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (0.50 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1N

Procedure:
The title compound was prepared from (4-chloro-2-nitro-5-piperidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example C12) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as light brown solid (747 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.[CH2:12]1[CH2:19][C:17](=O)[C:15](=[O:16])[CH2:14][CH2:13]1>CO.CC(O)=O.Cl>[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:4]=1[NH:10][C:14]1[C:15](=[O:16])[CH2:17][CH2:19][CH2:12][C:13]2=1
Reactant: NNc1ccc(F)cc1Cl
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCCc2c1[nH]c1c(Cl)cc(F)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
To 2-chloro-4-fluoro phenyl hydrazine hydrochloride (0.3 g, 1.5 mmol) in MeOH (2.5 mL), a solution of 1,2-cyclohexadione (0.17 g, 1.5 mmol) in AcOH (2.5 mL) and conc. HCl (1 mL) were added. The resulting mixture was stirred at 60° C. for 12 h, then cooled to room temperature and MeOH was removed in vacuo. Water (25 mL) was added and the reaction mixture was basified with NaHCO3 (pH 8). The crude residue was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude material which was purified by silica gel chromatography [EtOAc-hexane (1:19) as eluant] to afford the title compound (0.2 g, 55%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.84 (bs, 1H), 7.26-7.17 (m, 2H), 2.99-2.93 (t, J=6.0 Hz, 2H), 2.70-2.64 (q, J=7.4, 5.8 Hz, 2H), 2.34-2.21 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[C-:12]#[N:13].[Na+]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 55.1 %

Procedure:
A solution of 1-(bromomethyl)-3-nitrobenzene (30 g, 0.14 mol) in DMF (200 mL) was heated to 70° C., then sodium cyanide (17 g, 0.21 mol) was added slowly. The reaction mixture was stirred at 70° C. for 5 hours. The reaction was terminated by addition of water. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 2-(3-nitrophenyl)acetonitrile (12.5 g, yield 33%). 1H NMR: 400 MHz CDCl3 δ 8.15-8.14 (m, 2H), 7.66-7.64 (m, 1H), 7.56-7.52 (m, 1H), 3.82 (s, 2H).