Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.Cl.[C:13]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1)#[N:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol, 1.0 eq) and 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.71 g, 2.48 mmol, 1.0 eq) in dimethylformamide (10 mL) was added triethylamine (1.21 mL, 8.66 mmol, 3.5 eq) and HATU (1.13 g, 2.97 mmol, 1.2 eq). The reaction mixture was stirred at room temperature 14 hours before partitioning between EtOAc (120 mL) and water (100 mL). The organics were washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0%, 5%, 10% MeOH—CH2Cl2, 0→5→25→35 min) yielded 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide as a waxy brown solid: 1H nmr (CDCl3) 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, d, J 8.5 Hz, pyH-3), 7.97 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (1H, d, J 7.5 Hz, NH), 7.63 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.50 (2H, d, J 8.0 Hz, 2H of C6H4CN), 4.00 (1H, m, pipH-4), 3.63 (2H, s, CH2C6H4CN), 2.88 (2H, m, 2H of pip), 2.30 (2H, m, 2H of pip), 2.04 (2H, m, 2H of pip), 1.70 (2H, m, 2H of pip); m/z 399, 401 [M+H]+. To a mixture of the 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide (0.040 g, 0.100 mmol, 1.0 eq) 4-(4-piperidinyloxy)benzonitrile (0.024 g, 0.120 mmol, 1.2 eq), sodium t-butoxide (0.019 g, 0.201 mmol, 2.0 eq) and S-Phos (0.004 g, 0.010 mmol, 0.1 eq) was added toluene (1.0 mL). The resulting mixture was degassed by bubbling argon through the mixture. Tris(dibenzylideneacetone)dipalladium (0.005 g, 0.005 mmol, 0.05 eq) was added and the mixture further degassed before sealing the reaction and heating to 105° C. for 14 hours. The reaction was filtered through celite, eluting with 5% MeOH—CH2Cl2 (3×15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by RP-HPLC to yield Compound 165: 1H nmr (CDCl3) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.04 (1H, d, J 9.0 Hz, pyH-3), 7.72 (1H, d, J 8.5 Hz, NH), 7.60 (4H, m, 2H of OC6H4CN, 2H of CH2C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH2C6H4CN), 7.24 (1H, dd, J 8.0, 3.0 Hz, pyH-4), 6.97 (2H, d, J 9.0 Hz, 2H of OC6H4CN), 4.64 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.63-3.57 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH2C6H4CN), 3.38-3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16-2.05 (2H, m, 2H of PhOpipH-3, H-5), 2.01-1.92 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 522 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][CH2:18][CH:19]1[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[ClH:17].[CH2:25]([N:21]1[CH2:22][CH2:23][O:24][CH:19]([CH2:18][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:16])[CH2:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1[nH]c2ncccc2n1-c1ccccc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: Cl
Product: O=c1n(CC2CN(Cc3ccccc3)CCO2)c2ncccc2n1-c1ccccc1
Yield: 43.5 %

Procedure:
The condensation of 0.1 mol of 1-phenyl-2,3-dihydro-imidazo(4,5-b)pyridin-2-one and of 0.1 mol of 2-chloromethyl-4-benzyl-morpholine is carried out in accordance with the procedure of Example 1. Recrystallization of the product from a 50/25 mixture of ethyl acetate and isopropanol gives 19 g of 4-benzyl-2-(1-phenyl-2,3-dihydroimidazo(4,5-b)pyridin-2-on-3-yl-methyl)-morpholine hydrochloride, m.p. 214° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c(CCCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-3-yl)pentanoate (1.1 eq., prepared in Synthetic Example 9) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 172 to 173° C./DMF-EtOH. 1H NMR(CDCl3) δ: 2.02-2.11(2H, m), 2.71-2.79 (4H, m), 7.18-7.24 (2H, m), 7.54-7.92(5H, m), 8.19-8.20 (1H, m), 8.34-8.49(4H, m).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>>[C:10]([CH2:12][C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)=[O:14])#[N:11]
Reactant: Cc1cc(N)ccc1F
Reactant: CCOC(=O)CC#N
Product: Cc1cc(NC(=O)CC#N)ccc1F
Temperature: 180 °C
Reaction time: 14 h
Yield: 93.7 %

Procedure:
A mixture of 4-fluoro-3-methylaniline (2.50 g, 20.0 mmol) and ethyl cyanoacetate (2.70 g, 24.0 mmol) was stirred at 180° C. for 14 hr. After the reaction, the mixture was cooled to room temperature, and the obtained solid was washed with hexane and collected by filtration to give the title compound (3.60 g, 95%) as a brownish-red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:16]1[C:15]([OH:17])=[N:14][N:13]2[C:12]=1[CH:11]=[N:10][N:9]=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1cc2cnnc(-c3ccccc3F)n2n1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Oc1nn2c(-c3ccccc3F)nncc2c1Br
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 90.6 %

Procedure:
To a stirred mixture of 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.2508 g, 1.09 mmol) in glacial acetic acid (5 ml) was added dropwise bromine (62 μl, 1.20 mmol) and the mixture was stirred at room temperature for 2.25 h. Water (20 ml) was then added and the resulting solid was collected by filtration, washed with water, and dried under vacuum at 50° C. to yield 0.3054 g (91%) of the title compound as a buff solid; 1H NMR (360 MHz, d6-DMSO) δ 7.43-7.50 (2H, m), 7.72 (1H, m), 7.80 (1H, m), 9.40 (1H, s), 12.67 (1H, s).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10])[CH2:2]2.[Br:27][CH2:28][C:29]([C:31]1[O:35][N:34]=[C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:32]=1)=[O:30]>C(#N)C>[Br-:27].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29]([C:31]4[O:35][N:34]=[C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:32]=4)=[O:30])([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(C(=O)CBr)on1
Reactant: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1CN2CCC1CC2
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)C[N+]23CCC(CC2)C(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)C3)on1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (86 mg, 0.24 mmol, prepared as in example 4) and ethyl 5-(2-bromoacetyl)isoxazole-3-carboxylate (69.4 mg, 0.26 mmol) were dissolved in acetonitrile (3 ml) and stirred at room temperature overnight. The precipitated was recovered by suction filtration to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)-1-(2-(3-(ethoxycarbonyl)isoxazol-5-yl)-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane bromide (26 mg, racemic mixture).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: COCCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 46.7 %

Procedure:
A solution of the product of Example 48 (150 mg, 0.34 mmol) and 2-methoxy-ethylamine (0.09 mL, 1.01 mmol) in DMF (2 mL) was stirred 23° for 16 h. The mixture was diluted with EtOAc and washed with H2O to give the crude material, which was purified as described in Example 198 to give the desired product 70 mg (47%). LC-MS: 441.2 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: O1CCCC1.[NH2:6][CH:7]1[C:28](=[O:29])[N:9]2[C:10]([C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])=[C:11]([Cl:14])[CH2:12][S:13][C@H:8]12.Cl>[Fe].O>[NH2:6][CH:7]1[C:28](=[O:29])[N:9]2[C:10]([C:15]([OH:17])=[O:16])=[C:11]([Cl:14])[CH2:12][S:13][C@H:8]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 1 h

Procedure:
To a mixture of tetrahydrofuran (120 ml) and water (25 ml), p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (10 gm) was added. Iron powder (10 gm) was charged at 30° C., followed by the addition of concentrated HCl (12.5 ml) in a tetrahydrofuran (10 ml) and water (2.5 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0, followed by the addition of activated carbon. After stirring for 10 minutes, the mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried. Yield 4.17 gm (72.3%).
Reaction SMILES: [CH3:1][C:2](=[O:23])[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)(Cl)Cl>[O:29]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][C:18]1=[O:22])[C:3]([C:2](=[O:23])[CH3:1])=[CH:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 5α-pregna- 2,16 -diene-11,20-dione (2.5 g.) in chloroform (50 ml.) was added m-chloroperoxybenzoic acid (85%, 1.8 g.), and the mixture was stirred at room temperature overnight. More chloroform was then added, and the solution was washed with dilute sodium bicarbonate solution and with water, dried over magnesium sulphate and evaporated to an oil which was triturated with ether/petrol to give title compound (1.9 g.) as colourless needles, m.p. 154°-156° , [α]D + 100°.
Reaction SMILES: [NH2:1][CH:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].O1CCOCC1.[ClH:48]>O.CC(C)=O>[ClH:48].[NH2:1][CH:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(N)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2ncc(F)c(C(N)CCC3CCN(CCSc4cc(F)ccc4F)CC3CC(=O)O)c2c1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
A mixture of 0.09 g of methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 0.36-cm3 of a 1 N aqueous sodium hydroxide solution and 3-cm3 of dioxane was heated at a temperature in the region of 55° C., with stirring and under an inert atmosphere, for 4 hours. After cooling in the vicinity of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue obtained was taken up in 5-cm3 of distilled water and acidified with a 1-N aqueous hydrochloric acid solution and was concentrated. The aqueous phase was washed with 8-cm3 of dichloromethane and then concentrated according to the conditions described above. The residue obtained was taken up in 10-cm3 of acetone and then it was filtered on sintered glass. 0.081 g of (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetic acid hydrochloride wereobtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:33](=[O:34])[CH2:32][C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=2)[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 25.8, 35.7, 43.1, 53.3, 55.5, 59.7, 67.4, 68.6, 102.9, 105.4, 112.4, 112.6, 130.9, 136.7, 169.4, 169.5; MS m/z 478.2 (M+1).
Reaction SMILES: C1(CBr)CC1.CC1C=CC(S(O[CH2:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)(=O)=O)=CC=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][NH:35][C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH:19]1([CH2:18][CH2:17][N:35]2[CH2:36][CH2:37][N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[C:34]2=[O:38])[CH2:20][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CCC3CC3)C2=O)nc1C
Yield: 60 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with 2-cyclopropylethyl 4-methylbenzenesulfonate to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 60% yield: 1H NMR (300 MHz, CDCl3) δ 4.13 (q, J=7.2 Hz, 2H), 3.65 (t, J=7.4 Hz, 2H), 3.43 (t, J=7.8 Hz, 2H), 3.22 (t, J=7.8 Hz, 2H), 2.34 (s, 3H), 1.44-1.15 (m, 5H), 0.57-0.51 (m, 1H), 0.32-0.22 (m, 2H), −0.07-0.11 (m, 2H): MS (ES+) m/z 324.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CNc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 11.5 h
Yield: 76.4 %

Procedure:
A mixture of 4-chloro-2-cyano-pyridine (6.9 g, 0.05 moles), 4-methylamino-3-nitrophenol (8.4 g, 0.05 moles), and K2CO3 (10.4 g, 0.075 moles) in DMSO (80 mL) was heated to 60° C. After 11.5 h, HPLC analysis indicated complete conversion of both starting materials. After cooling to 20° C., water (240 mL) was added to the reaction mixture. The temperature rose to 40° C. before decreasing to ambient temperature. The solid was collected by filtration and washed with water (2×40 mL). The solid was then slurried in heptane (40 mL). The solid was collected and washed with heptane (40 mL). The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 10.33 g (76%) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.5 (m, 1H), 8.2 (m, 1H), 7.9 (m, 1 H), 7.7 (m, 1H), 7.5 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 3.0 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 165.1, 152.9, 144.4, 140.6, 134.1, 130.4, 130.1, 117.9, 117.1, 117.0, 116.5, 114.9, 29.8; APCI MS [M+H]+=271; HPLC >99% (LCAP).
Reaction SMILES: ClC1C=CC=CC=1CS([C:8]1[CH:29]=[CH:28][C:11]2[N:12](C(OC(C)(C)C)=O)[C:13](C3C=CC=CN=3)=[N:14][C:10]=2[CH:9]=1)(=O)=O.ClC1C=CC=CC=1CS(C1C=CC2N=C(C3C=CC=CN=3)N(C(OC(C)(C)C)=O)C=2C=1)(=O)=O.Cl.O1CCOCC1>CO.CCOCC>[NH:12]1[C:11]2[CH:28]=[CH:29][CH:8]=[CH:9][C:10]=2[N:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2cc(S(=O)(=O)Cc3ccccc3Cl)ccc21
Agent: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2ccc(S(=O)(=O)Cc3ccccc3Cl)cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To stirred solution of tert-butyl 5-(2-chlorobenzylsulfonyl)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (or the isomer, tert-butyl 6-(2-chlorobenzylsulfonyl)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate) (0.015 g, 0.031 mmol) in methanol (1 mL) was added 4N HCl in dioxane (0.155 μL, 0.62 mmol). The reaction mixture was stirred for 15 h at room temperature, diluted with Et2O (15 mL) and the white precipitate was filtered and dried under vacuum at 45° C. for 15 h to afford 8.4 mg of 5-(2-chlorobenzylsulfonyl)-2-pyridin-2-yl)-1H-benzo[d]imidazole (59%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[C:40]1(B2OC(C)(C)C(C)(C)O2)[CH2:44][CH2:43][CH2:42][CH:41]=1>>[NH2:32][C:4]1[S:3][C:2]([C:40]2[CH2:44][CH2:43][CH2:42][CH:41]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane gave 271. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.80 (s, 1H), 7.35 (br, J=8.5 Hz, 2H), 6.21-6.14 (m, 1H), 5.22-4.76 (m, 2H), 4.22-3.94 (m, 2H), 3.71 (s, 3H), 3.53-3.40 (m, 1H), 2.76-2.66 (m, 2H), 2.22-2.10 (m, 1H), 2.02-1.87 (m, 3H), 1.84-1.67 (m, 2H). LCMS (ES+) m/z 421 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2.C(N(CC)CC)C.CC(Cl)(Cl)Cl.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:11]([C:8]2[C:7](=[O:14])[N:6]3[CH:15]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[O:13])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCC1
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2ncc(C(=O)NC3CCCC3)c(=O)n2c1
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
A mixture containing 1.22 g (0.006 mol) of 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 0.84 ml (0.006 mol) of triethylamine in 40 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.46 ml (0.006 mol) of methyl chloroform, ,ate in 3 ml of chloroform is dropped to the above mixture at -18° C. during 10 minutes. After stirring for 5 minutes, 0.56 g (0.0066 mol) of cyclopentylamine dissolved in 6 ml of chloroform is dropped to the above solution which is then stirred at -10° C. for 1 hour and allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 15 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 15 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 0.8 g (49.2%) of the named compound as white crystals after recrystallization from ethanol, m.p.: 162°-164° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Cl:5][CH2:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1>C(O)C>[ClH:5].[N+:19]([C:15]1[CH:14]=[C:13]([C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=2[CH2:6][S:3][C:2](=[NH:4])[NH2:1])[CH:18]=[CH:17][CH:16]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccc(C2=C(CCl)CCCC2)c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cl
Product: N=C(N)SCC1=C(c2cccc([N+](=O)[O-])c2)CCCC1
Temperature: 25 °C

Procedure:
Thiourea (495 mg) was added to a solution of 1-(2-chloromethylcyclohex-1-enyl)-3-nitrobenzene obtained in Preparation Example 4-(3) (1.56 g) in ethanol (71.6 mL), and the mixture was stirred with heating under reflux for four hours. The reaction solution was cooled to room temperature and then the solvent was evaporated under reduced pressure. The residual solid was washed with ether to obtain the title compound (2.04 g).
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].O.NN.[OH-].[K+]>C(O)C.C(O)COCCO>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Solvent: CCO
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(CC)cc2)CC1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.35 g of p-[trans-4-(trans-1-pentenyl)cyclohexyl]acetophenone in 16 ml of ethanol and 16 ml of diethylene glycol was treated with 0.486 ml of hydrazine hydrate while gassing with argon and then heated to reflux (bath temperature 110° C.) while stirring for 1.5 hours. The mixture was subsequently treated with 550 mg of solid potassium hydroxide, the bath temperature was increased to 210° C. and the ethanol was distilled off. After 2.5 hours at 210° C., the reaction was interrupted and the mixture was partitioned three times in water/petroleum ether. The organic extracts were washed twice with water, dried over magnesium sulphate and evaporated. Chromatographic separation of the residue (1.23 g) on silica gel with hexane as the eluent gave 1.16 g (91%) of 4-ethyl-1-[trans-4-(trans-1-pentenyl)cyclohexyl]benzene as a colourless oil; m.p. (C--I) -3.1° C.