Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C1CCN2C(=NCCC2)CC1.[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[N:31]=[C:32]=[O:33]>ClCCCl.C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[N:31]1[C:7](=[O:9])[CH:2]2[CH2:3][O:4][CH2:5][CH2:6][N:1]2[C:32]1=[O:33]
Reactant: O=C(O)C1COCCN1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C1C2COCCN2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Temperature: 160 °C
Yield: 54.2 %

Procedure:
To a stirred solution of 3-morphline carboxylic acid (0.100 g; 0.627 mmol), DBU (187 μL; 1.25 mmol) in 1,2-dichloroethane (2.8 mL) was added 2-chloro-4-nitrophenylisocyanate (0.149 g; 0.752 mmol) and the resulting mixture was heated at 160° C. in the microwave for 10 min. The reaction was diluted with methylene chloride (15 mL), washed with 1N HCl (10 mL), sat. NaHCO3 (10 mL) and concentrated under vacuum to give the crude product. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 40% to give 106 mg of 2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]oxazine-1,3(2H)-dione, 1.1.21, (54%).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1.BrCCSCC1C2C(=CC=C(C(OC)=[O:34])C=2)NC=1.SCCO>>[OH:34][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)c1ccc2[nH]cc(CSCCBr)c2c1
Reactant: COC(=O)c1ccc2[nH]cc(CSCCCl)c2c1
Agent: OCCS
Product: COC(=O)c1ccc2[nH]cc(CSCCO)c2c1

Procedure:
A solution of 28.4 g of methyl 3-(4-chloro-2-thiabutyl)-indole-5-carboxylate [or 32.8 g of methyl 3-(4-bromo-2-thiabutyl)-indole-5-carboxylate; obtainable by reacting methyl gramine-5-carboxylate with 2-mercaptoethanol to give methyl 3-(4-hydroxy-2-thiabutyl)-indole-5-carboxylate and subsequently reacting the latter with SOCl2 or PBr3 ] and 16 g of 4-phenyl-1,2,3,6-tetrahydropyridine in 100 ml of acetonitrile is stirred for 12 hours at 20° and is worked up in the customary manner to give methyl 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-indole-5-carboxylate ("P"); hydrochloride, m.p. 202°-203°.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:20])[C:11](=[O:21])[C:10]=2[CH3:22])=[C:4]([F:23])[CH:3]=1.Cl.N([O-])=O.[Na+].[I-:29].[K+]>C(O)(=O)C.O.II>[F:23][C:4]1[CH:3]=[C:2]([I:29])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:18]2[C:17](=[O:19])[NH:16][CH:15]=[N:14][C:13]=2[N:12]([CH3:20])[C:11](=[O:21])[C:10]=1[CH3:22]
Reactant: Cc1c(Nc2ccc(N)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: [I-]
Agent: Cl
Agent: II
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reaction time: 0.33 h
Yield: 51.6 %

Procedure:
The title compound was synthesized from compound 9E (1.74 g, 5.5 mmol) which was first dissolved in a 1:1 mixture of acetic acid and water (10 mL) at 0° C. Concentrated HCl (1.2 mL) in water (2 mL) was slowly added and the mixture stirred for 20 minutes. Sodium nitrite (381 mg, 5.5 mmol, 1 eq) in water (800 μL) was added and the solution stirred for 20 minutes. Potassium iodide (4.58 g, 27.6 mmol, 5 eq) and iodine (20 mg, cat) was added and the reaction allowed to RT then stirred for 1 hour at 90° C. After cooling, the mixture was evaporated in vacuo. The residue was purified by silica chromatography eluting with 10% methanol in DCM to give 1.21 g of the title compound (51%). [M+H] calc'd for C15H12FIN4O2, 427. found, 427.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:12]([CH:14]=[O:15])=[N:13][N:7]3[C:6]=2[CH:22]=1.[CH2:23]([Mg]Cl)[CH3:24]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:12]([CH:14]([OH:15])[CH2:23][CH3:24])=[N:13][N:7]3[C:6]=2[CH:22]=1
Reactant: CC[Mg]Cl
Reactant: O=CC1=NN2c3cc(F)ccc3OCC2C1c1ccccc1
Solvent: C1CCOC1
Product: CCC(O)C1=NN2c3cc(F)ccc3OCC2C1c1ccccc1

Procedure:
A solution of racemic aldehyde (2-1) (0.03 g, 0.1 mmol) in THF (6 mL) at −78° C. was treated with a solution of ethylmagnesium chloride (0.05 mL of a 2M soln in THF). A heavy precipitate formed immediately. The reaction was quenched with water and the mixture extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in MeCN (0.5 mL) and purified by reverse phase HPLC (YMC J-sphere H80 20×50 mm; eluted with 5-95% MeCN/water+0.1% TFA) to provide (2-2) as a mixture (˜2:1) of isomers. LRMS nm/z (M+H) 327.2 found, 327.2 required.
Reaction SMILES: [CH3:1]NN.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]5[CH:31]=[CH:30][NH:29][N:28]=5)=[CH:25][N:26]=4)[CH:23]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][C:10]=1[F:11].FC1C=CC(C2C(C3C=C4C(=CC=3)N(C(N3C5C(=CC(C6C(C7C=CC(F)=C(C)C=7)=NC=CC=6)=CC=5)C=N3)=O)N=C4)=CC=CN=2)=CC=1C>>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]5[CH:31]=[CH:30][N:29]([CH3:1])[N:28]=5)=[CH:25][N:26]=4)[CH:23]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CNN
Reactant: Fc1ccc(-c2ncccc2-c2ccc3ncc(-c4cc[nH]n4)n3c2)cc1Cl
Agent: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)n3ncc4cc(-c5cccnc5-c5ccc(F)c(C)c5)ccc43)c2)ccc1F
Product: Cn1ccc(-c2cnc3ccc(-c4cccnc4-c4ccc(F)c(Cl)c4)cn23)n1

Procedure:
6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine was prepared by the reaction of MeNHNH2 and enamine, analogous to the preparation of 6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine. 1H NMR (300 MHz, DMSO-d6): δ 8.74 (dd, J=4.8, 1.6 Hz, 1H), 8.43 (dd, J=1.7, 0.9 Hz, 1H), 8.42 (s, 1H), 8.04 (dd, J=7.8, 1.6 Hz, 1H), 7.89 (dd, J=9.4, 0.8 Hz, 1H), 7.73 (dt, J=8.1, 1.1 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.56 (dd, J=7.8, 4.8 Hz, 1H), 7.51 (dd, J=9.3, 1.6 Hz, 1H), 7.31-7.21 (m, 2H), 6.74 (d, J=2.0 Hz, 1H), 3.82 (s, 3H). 19F NMR (282 MHz, DMSO-d6): δ −116.76 (q, J=7.3 Hz). LCMS: rt 5.09 min (A), purity 99%, MS (m/e) 404 MH+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[O:23][C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC1CN(Cc2ccccc2)CCC1=O)c1ccccc1
Agent: Cl
Product: c1ccc(CN2CCc3oc(-c4ccccc4)cc3C2)cc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of 1-benzyl-3-(2-oxo-2-phenylethyl)piperidin-4-one (4.0 g, 0.0129 mol) in conc. HCl (50 mL) was heated at reflux for 3 h. After consumption of the starting material as determined by TLC, the reaction mixture was cooled down to RT and made alkaline by the addition of NH4OH, then extracted with diethyl ether. The organics were dried over Na2SO4 and concentrated to afford 5-benzyl-2-phenyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine (2.0 g, 66.66%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C(O)(=O)C>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccc(Oc2ccc(N)cn2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]acrylate (2.02 g, 6.43 mmol) in methanol (100 mL) were added zinc (6.3 g, 96.3 mmol) and ammonium chloride (710 mg, 13.27 mmol). The resulting reaction solution was stirred for 2.5 hours under reflux, then acetic acid (5 mL) was added, and stirred for 20 minutes under reflux. Insoluble matter was filtered off through Celite, after which the filtrate was concentrated under reduced pressure. To the residue was added 5% potassium hydrogensulfate (150 mL), the mixture was extracted with dichloromethane, and the dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.78 g of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5].Br[C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([NH2+]CCC1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[C:17]([O:16][C:14]([C:13]([O:1][N:2]=[C:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])([CH3:22])[CH3:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)C(=NO)c1cccs1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: c1ccc(CC[NH2+]Cc2ccccc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)O)c1cccs1
Yield: 78 %

Procedure:
The title compound was prepared from 2-hydroxyimino-2-(thien-2-yl)acetic acid (syn isomer) and t-butyl 2-bromo-2-methylpropionate, in a similar manner to that described for Preparation 5, in 78% yield as a colourless oil, and was characterised as the N-benzyl-2-phenylethylammonium salt, m.p. 201.3°-201.9° (from ethanol).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([OH:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:13])[C:2]([Br:1])=[CH:11][CH:10]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1c(O)ccc(Br)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1c(OC(C)=O)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A solution of Example 106B (1.05 g, 4.3 mmol) in pyridine (3 mL) was treated with acetic anhydride (0.82 mL, 8.6 mmol), stirred at room temperature for 2 hours, and partitioned between ethyl acetate and 2N HCl. The organic phase was washed sequentially with aqueous NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated to give 1.19 g (97% yield) of the desired product. MS (ESI(+)) m/e 304, 306 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=1>C1COCC1.CCOC(C)=O.O>[Cl:20][C:13]1[N:12]=[C:11]([O:9][CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1OC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A mixture of THF and 2.4 g NaH (55% in mineral oil, 55 mmol) is cooled to 0° C., 5.2 ml tetrahydro-pyran-4-ol (55 mmol) are slowly added and the mixture stirred for 30 minutes. 10.0 g (52 mmol) 2,6-dichloro-3-nitro-pyridine in THF are slowly added and the mixture is stirred at RT over night. The reaction mixture is diluted with EtOAc and water. The organic phase is separated and washed with water and brine, dried and evaporated. The residual is purified by FC, giving rise to 7.8 g (58%) 6-chloro-3-nitro-2-(tetrahydro-pyran-4-yloxy)-pyridine.
Reaction SMILES: C(OC([NH:11][CH2:12][C@@H:13]([CH2:17][C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([OH:16])=[O:15])=O)C1C=CC=CC=1.[H][H]>>[NH2:11][CH2:12][CH:13]([CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)CCC[C@@H](C)C[C@H](CNC(=O)OCc1ccccc1)C(=O)O
Reactant: [H][H]
Product: CC(C)CCCC(C)CC(CN)C(=O)O
Yield: 67.3 %

Procedure:
2(R)-(Benzyloxycarbonylamino-methyl)-4(R),8-dimethyl-nonanoic acid (0.148 g, 0.566 mmol) was treated with hydrogen in the presence of 20% pd/C to give 0.082 g of 2-aminomethyl-4,8-dimethyl nonanoic acid after filtration and purification via silica gel chromatography (85/15 CH2Cl2/MeOH). m/z 216.3 (M+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:28][OH:29]>>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[C:3]([CH2:2][O:29][CH3:28])[N:4]=1
Reactant: Fc1nc(CCl)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO
Product: COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 1 h

Procedure:
4-Chloromethyl-2-fluoro-1-triphenylmethylimidazole was dissolved in MeOH, and allowed to stand 1 hour, giving 2-fluoro-4-methoxymethyl-1-triphenylmethylimidazole. This was reacted at 60° for 3 hours in CHCl3 /MeOH solution with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate in the presence of toluene-p-sulphonic acid, and the product purified by chromatography to give t-butyl 3-acetoxymethyl-7-(4-methoxymethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following n.m.r. spectrum in d6DMSO: 1.5 (s, 9H); 2.05 (s, 3H); 3.3 (s, 3H); 3.5 (d, 1H); 3.7 (d, 1H); 4.3 (s, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.2 (d, 1H); 5.7 (d, 1H); 7.1 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14]CC)=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([OH:14])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Yield: 99 %

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the ester to give 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid as a white solid (99%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 13.30 (v br s, 1H), 11.44 (br s, 1H), 9.75 (br s, 1H), 8.06 (s, 1H), 7.76 (dd, J=10.2, 1.9 Hz, 1H), 7.59 (ddd, J=8.3, 1.9, 0.9 Hz, 1H), 7.32 (t, J=8.4 Hz, 1H), 5.40 (d, J=1.1 Hz, 1H). LCMS (APCI+) calcd for C12H9FIN2O3 375 (MH+), found 375.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[CH:22]([O:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=2)[CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].I[CH2:36][C:37]#[N:38]>C1COCC1>[C:37]([CH2:36][N:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:12]2[CH2:13][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:10]([CH:22]([O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=3)[CH3:23])[CH2:11]2)=[O:15])[CH2:17][CH2:18]1)#[N:38]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCN(CC#N)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VIII-B-1) (25 mg, 0.053 mmol) in THF (2 mL) was added NaH (2.4 mg, 55% purity, 0.056 mmol). After 10 min. 2-iodo acetonitrile (13 mg, 0.079 mmol) was added and stirring was continued at RT overnight.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[I:9]I.C([O-])(O)=O.[Na+]>CC(O)=O.O>[I:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=1
Reactant: II
Reactant: CNc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(I)cn1
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a solution of 2-methylaminopyridine (Aldrich; 1.00 g, 9.25 mmol) in 10 mL of 1:1 HOAc and water was added 2.35 g (9.25 mmol) of I2. The resulting brown solution was heated to 80° C. for 3 h. After cooling to room temperature, the mixture was neutralized with saturated NaHCO3 and extracted with Et2O. The extract was washed with water and brine, dried with MgSO4, filtered, and concentrated to provide 540 mg of (5-iodo-pyridin-2-yl)-methyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][S:7]([C:10]2[CH:11]=[C:12]([C:15]([C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=3)=O)[NH:13][CH:14]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28].O>C(O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][S:7]([C:10]2[CH:11]=[C:12]([C:15]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:28][N:27]=3)[NH:13][CH:14]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1cc(S(=O)(=O)Cc2ccc(Cl)cc2)c[nH]1)c1cccnc1Cl
Solvent: O
Solvent: CCO
Product: O=S(=O)(Cc1ccc(Cl)cc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
{4-[(4-chlorobenzyl)sulfonyl]-1H-pyrrol-2-yl}(2-chloropyridin-3-yl)methanone (280 mg, 0.711 mmol) and 359 mg of hydrazine monohydrate (7.11 mmol) were mixed in 4 mL of ethanol. The mixture was stirred at 80° C. overnight (16 hour) and then cooled down to room temperature. Water was added and filtered. Washed with additional water and methanol to collect the product, dried to afford 250 mg (95% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:11]#[N:12])[CH2:7][CH2:6][C:5]([F:10])([CH2:8][OH:9])[CH2:4][CH2:3]1.C(Cl)Cl.[C:16](Cl)(=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:11]([C:2]1([NH:1][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3][CH2:4][C:5]([F:10])([CH2:8][OH:9])[CH2:6][CH2:7]1)#[N:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CC1(N)CCC(F)(CO)CC1
Solvent: ClCCl
Solvent: O
Product: N#CC1(NC(=O)OCc2ccccc2)CCC(F)(CO)CC1
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A flask was charged with 1-amino-4-fluoro-4-(hydroxymethyl)cyclohexanecarbonitrile, Intermediate 32, (12.2 g, 70.8 mmol), CH2Cl2 (200 mL), water (80 mL) and benzyl chlorocarbonate (12.14 mL, 85 mmol) and the mixture stirred under nitrogen overnight. The CH2Cl2 portion of the reaction mixture was separated, washed with water then brine, dried (MgSO4) and concentrated to give a yellow oil. The oil was purified by column chromatography on silica gel, eluted with hexane/ethyl acetate (0 to 100%). The appropriate fractions were combined and the solvent evaporated to provide the title compound (13.1 g, 42.8 mmol, 60.4% yield)] as a colorless oil that crystallized upon standing.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([NH:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[F:24])=[O:13])([CH3:10])([CH3:9])[CH3:8].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[F:24])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)c1c(F)cccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
Potassium tert-butoxide (1M in THF, 8,67 ml) is added (dropwise over 5 min) to a solution of N-(tert-butyloxycarbonyl)-2-fluoro-6-nitroaniline (XIX, EXAMPLE 21, 1.85 g) in THF (15 ml) cooled at 0°. After 20 min, ethyl bromoacetate (0.96 ml) is added dropwise over several minutes. The ice bath is removed and the reaction is stirred for 2 h, after which it is partitioned between ethyl acetate, aqueous sodium bicarbonate and saline. The phases are separated, the organic phase is dried over magnesium sulfate and concentrated to give the title compound, NMR (CDCl3) 1.26, 1.35, 1.50, 3.98, 4.10, 4.20, 4.42, 4.45, 7.42 and 7.39 δ.
Reaction SMILES: Cl.[CH2:2]([NH2:12])[C:3]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][O:6][C:5]=2[CH:4]=1.[O-:13][C:14]#[N:15].[Na+]>O>[CH2:7]1[O:8][C:9]2[CH:10]=[CH:11][C:3]([CH2:2][NH:12][C:14]([NH2:15])=[O:13])=[CH:4][C:5]=2[O:6]1
Reactant: N#C[O-]
Reactant: NCc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
61.5 ml of 5N HCl was added within 30 minutes to a stirred emulsion of 38.51 ml (300 mM) of 97% piperonylamine and 20.40 g of sodium cyanate in 500 ml of water. After stirring overnight the foamy solid is collected, dried, suspended in 500 ml of ether and collected again: 52.57 g (90.2%) of urea with a melting point of 183-84° C.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[NH:43]1[CH:47]=[N:46][N:45]=[N:44]1>>[N:43]1([CH2:26][C:27]2[N:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]3=[N:29][C:28]=2[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH:47]=[N:46][N:45]=[N:44]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: c1nnn[nH]1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: Clc1ccc(-c2nc3ccccn3c2Cn2cnnn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 1H-tetrazole. M/e+ 311 for C15H12ClN6 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.12 (d, J=6.9 Hz, 1H), 7.73 (d, J=9.1 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.37 (td, J=6.9, 1.1 Hz, 1H), 6.97 (m, 1H), 6.03 (s, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][N:11]([CH3:19])[C:12]=2[CH:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH2:3]1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:2]([O:18][CH:13]([C:12]1[N:11]([CH3:19])[N:10]=[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]=1[C:5]1[CH2:6][CH2:7][C:2]([CH3:26])([CH3:1])[CH2:3][CH:4]=1)[C:14]([O:16][CH3:17])=[O:15])([CH3:7])([CH3:3])[CH3:1]
Reactant: COC(=O)C(O)c1c(C2=CCC(C)(C)CC2)c(-c2ccccc2)nn1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C2=CCC(C)(C)CC2)c(-c2ccccc2)nn1C
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 152.6 %

Procedure:
To a solution of methyl 2-[4-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]-2-hydroxyacetate (1e) (135 mg, 0.38 mmol) in tert-butyl acetate (7 mL) at 0° C. was added perchloric acid (0.87 mL). The mixture was stirred for 80 minutes at room temperature before being slowly quenched with a saturated solution of potassium carbonate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide methyl 2-(tert-butoxy)-2-[4-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetate (1f) (121 mg, 0.29 mmol, 77%) as a clear yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=O)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:23]1([N:22]([CH:19]2[CH2:21][CH2:20]2)[C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:11]2)=[O:18])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCC(NC2CC2)CC1
Reactant: O=C(O)C1CCCN(S(=O)(=O)c2ccccc2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCCN(S(=O)(=O)c2ccccc2)C1)N(C1CCCCC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(phenylsulfonyl)piperidine-3-carboxylic acid (20 mg), N-cyclopropylcyclohexanamine (10 mg) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (36 mg) in DMF (200 μL) was added N,N-diisopropylethylamine (26 μL). The resulting solution was stirred at r.t. for 2 hours and directly purified with prep HPLC. LCMS m/z 391.1 (M+H)+; 803.2 (2M+Na)+.