Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:8](/[C@H:11]1[CH2:16][CH2:15][C@H:14]([C@H:17]2[CH2:22][CH2:21][C@H:20](/[CH:23]=[CH:24]/[CH2:25]O)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[CH:9]\[CH3:10]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:7][CH2:25]/[CH:24]=[CH:23]/[C@H:20]1[CH2:21][CH2:22][C@H:17]([C@H:14]2[CH2:13][CH2:12][C@H:11](/[CH:8]=[CH:9]/[CH3:10])[CH2:16][CH2:15]2)[CH2:18][CH2:19]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C/C=C/[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/CO)CC2)CC1
Reactant: CC(C)(C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/COC(=O)C(C)(C)C)CC2)CC1

Procedure:
0.4 g of pivalic acid, 1.0 g of 3E-[trans-4-(trans-4-[1E-propenyl]cyclohexyl)cyclohexyl]allyl alcohol and 0.1 g of 4-(dimethylamino)pyridine were dissolved in 50 ml of dichloromethane and the solution was treated portionwise within 10 minutes while stirring with 0.9 g of N,N'-dicyclohexylcarodiimide. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulphate, filtered and then concentrated. Chromatography of the residue on silica gel with toluene gave 1.3 g of 3E-[trans-4-(trans-4-[1E-propenyl]cyclohexyl)cyclohexyl]-allyl pivalate.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH3:14].[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:19][CH2:20]2)=[CH:29][CH:28]=1)=[O:35]
Reactant: CCOC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.096 mol) was added at room temperature to a mixture of 4-(4-aminophenyl)-1-piperazinecarboxylic acid ethyl ester (0.08 mol), 2-iodo benzoic acid (0.096 mol) and 1-hydroxybenzotriazole (HOBT) (0.096 mol) in DCM (500 ml). The mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was taken up in DIPE. The precipitate was filtered off and dried, yielding 39 g of 4-[4-[(2-iodobenzoyl)-amino]phenyl]-1-piperazinecarboxylic acid, ethyl ester (intermediate 27).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(OC)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of methyl 1-methoxycyclopentanecarboxylate (1.00 g, 6.32 mmol) in THF (10 mL) was treated with a solution of LiOH (0.531 g, 12.64 mmol) in water (5 mL), stirred at RT overnight and concentrated to dryness. The residue was diluted with water, acidified with HCl (2M, 6 mL), extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-methoxycyclopentanecarboxylic acid (900 mg, 99%). 1H NMR (400 MHz, CDCl3): δ 3.31 (s, 3H), 2.05-2.03 (m, 4H), 1.78-1.77 (m, 4H) [CO2H not observed].
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: Nc1ccc(B(O)O)cc1
Agent: Cl
Product: Nc1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-aminophenyl-boronic acid hydrochloride gives “A65”; method 2: HPLC/MS: 1.53 min, [M+H]=306;
Reaction SMILES: OC(C1CCN(CC2C=CC([N+]([O-])=O)=C(N[C@@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]3)C=2)CC1)(C)C.C1N=C[N:33](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[CH:22]1([C:25]([NH2:33])=[O:27])[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)O)CC3)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.6 %

Procedure:
To a solution of cis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid (0.53 g, 1.263 mmol) in DMF (7 mL) was added CDI (0.410 g, 2.53 mmol) and aqueous ammonium hydroxide (100 μL, 2.53 mmol). The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was partitioned between water and DCM and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide cis-4-(5-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamide as an orange foam (0.213 g, 40.3% yield). MS, m/z (C22H34FN4O4): calcd, 418.3. found, 419.1 [M+H].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:21])[CH3:20])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([O:19][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:21])[CH3:20])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)c1ccc(C2c3cc(O)ccc3OC2(C)C)cc1
Product: COc1ccc(COc2ccc3c(c2)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 75 %

Procedure:
Using (4-isopropylphenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].CCN(C(C)C)C(C)C>CCOC(C)=O>[C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][N:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:10]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CO[C@@H]1CCNC[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCN(c2ccncc2[N+](=O)[O-])C[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
Method 1 was followed using trans(+/−)-3-(bis(tert-butoxycarbonyl)amino)-4-methoxypiperidine (1.0 equiv.), 4-chloro-3-nitropyridine (1.2 equiv.), and DIEA (4.0 equiv.) to give trans(+/−)-N,N-di-BOC-4-methoxy-1-(3-nitropyridin-4-yl)-piperidin-3-amine after column chromatography (EtOAc and hexanes, 50%) in 59% yield for two steps. LCMS (m/z): 453.2 (MH+), LC Rt=3.24 min.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[Cl-].[CH2:18]([O:20][N:21]=[C:22]1[CH2:28][CH:27]2[NH2+:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH3:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:18]([O:20][N:21]=[C:22]1[CH2:28][CH:27]2[N:29]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH3:19]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCON=C1CC2CCC(C1)[NH2+]2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 24.5 %

Procedure:
A 7 ml vial was charged with 4-(3-iodo-2(S)-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (330 mg, 1.0 mmol), crude 3-ethoxyimino-8-azonia-bicyclo[3.2.1]octane chloride (200 mg, 0.98 mmol), and K2CO3 (290 mg, 2.1 mmol) in dry DMF (4 ml) and the reaction was shaken at 60° C. for 3 days. The reaction was then poured into water and extracted with ether. The combined organic phases were washed brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the oily residue was purified by flash column chromatography (SiO2; CH2Cl2/acetone/MeOH, 90:7:3) to yield the diastereomeric mixture of the title compound as an oil (87 mg, 0.24 mmol, 24%). 1H NMR (CD3OD) d 7.28 (dd, J=2.0, 7.6 Hz, 1H), 7.07-6.93 (m, 3H), 4.57 (ABq, J=14.8, 19.6 Hz, 2H), 4.12 (dd, J=6.4, 14.4 Hz, 1H), 4.05-3.92 (m, 3H), 3.30-3.16 (m, 2H), 2.92-2.82 (m, 1 H), 2.54-2.32 (m, 3H), 2.18-1.81 (m, 2H), 1.60-1.34 (m, 2H), 1.20 (m, 3 H), 0.93 (d, J=6.8 H); 13C NMR (CD3OD) d165.8, 156.6, 146.0, 128.6, 124.0, 122.6, 116.8, 115.9, 68.5, 67.4, 60.2, 59.54, 59.48, 58.8, 56.5, 45.0, 37.0, 36.9, 31.9, 31.7, 30.99, 30.96, 27.6, 27.0, 26.7, 26.1, 15.9, 13.7; HPLC-MS (ammonium acetate) [M+H]+=372.21.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1.CO.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH:10]5[CH2:9][N:8]([CH3:2])[CH2:11]5)=[C:14]([O:36][CH3:37])[CH:15]=4)[CH:24]=[CH:23][C:22]=3[CH:25]=2)=[CH:33][CH:32]=1
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C)C1
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
Mix 6-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one trifluoroacetic acid salt (210 mg, 0.48 mmol) with methanol (10 mL) and acetic acid (0.3 mL). Add a solution of formaldehyde (0.20 mL, 2.66 mmol, 37% aqueous solution) and stir the mixture for 15 min. Add sodium cyanoborohydride (110 mg, 1.75 mmol) and stir the mixture at RT overnight. Concentrate the mixture in vacuo and partition the crude material between saturated NaHCO3 (25 mL) and CH2Cl2 (25 mL). Remove the organic solution and extract the aqueous phase with additional CH2Cl2 (2×25 mL). Combine the organic solutions and concentrate in vacuo. Purify the crude material by flash chromatography, using 5% MeOH (2N NH3) in CH2Cl2 as eluent, to give 133 mg (61%) of 2-(4-chloro-phenyl)-6-[3-methoxy-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CO[CH:10](OC)[CH2:11]Br.Br>C(O)C>[N:1]1[CH:10]=[CH:11][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: COC(CBr)OC
Reactant: Nc1cnccn1
Agent: Br
Solvent: CCO
Product: c1cn2ccnc2cn1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
2-Aminopyrazine (100 mg, 1.1 mmol) and bromoacetaldehyde dimethylacetal (253 mg, 1.6 mmol) were dissolved in ethanol (4.5 ml), hydrobromic acid (48%, 0.5 ml) added and the mixture was heated under reflux for 18 h. The solution was allowed to cool to room temperature then pre-adsorbed directly onto silica. Purification by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-4%) gave imidazo[1,2-α]pyrazine (90 mg, 72%) as a white crystalline solid: δH (360 MHz, CDCl3) 6.70 (1H, s), 7.82 (1H, s), 7.88 (1H, d, J 4), 8.29 (1H, d, J 4), 9.12 (1H, s).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[CH3:34]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[CH3:34])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1cnccc1Cl
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccncc2C)c1

Procedure:
By carrying out the operation analogously to example 49, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 4-chloro-3-methylpyridine, the desired product is obtained in the form of beige crystals (yield=15%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH2:32])[CH:31]=1)[NH:28][C:27](=[O:33])[CH2:26]2>>[NH2:32][C:30]1[CH:31]=[C:23]([F:22])[CH:24]=[C:25]2[C:29]=1[NH:28][C:27](=[O:33])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3c(N)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 43.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-7-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(7-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 43.8%) as a red solid.
Reaction SMILES: [CH:1]([S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4])=[CH2:2].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH2:8]([N:15]1[CH2:7][CH2:6][S:3](=[O:5])(=[O:4])[CH2:1][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C=CS(=O)(=O)C=C
Solvent: CCO
Product: O=S1(=O)CCN(Cc2ccccc2)CC1
Yield: 39.9 %

Procedure:
Divinyl sulphone (0.8 ml, 10 mmol) was added to a solution of benzylamine (1.09 ml, 10 mmol) in ethanol (4 ml) and heated under reflux for 2 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane (30 ml) and washed with saturated aqueous sodium hydrogencarbonate solution (15 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (100:0 to 99:1) to afford the title compound as a yellow oil (0.9 g).
Reaction SMILES: [CH:1](=O)[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C(=O)([O-])O.[Na+]>CO>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][CH2:1][CH3:2])[CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
367 μL (6.5 mmol) of acetaldehyde, 817 mg (13 mmol) of sodium cyanoborohydride and 3.75 mL (65 mmol) of acetic acid are added to a solution of 1.47 mL (8.4 mmol) of (S)-3-amino-1-tert-butoxycarbonylpyrrolidine in 30 mL of anhydrous methanol. The solution is stirred at room temperature for 24 hours then a saturated aqueous solution of sodium hydrogencarbonate is added to adjust the pH to 7. The compound is extracted with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered then evaporated and the residue is purified by chromatography on silica (eluent dichloromethane/methanol 94/6) to give 970 mg (70%) of (S)-1-tert-butoxycarbonyl-3-ethylamino-pyrrolidine in the form of a yellow oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:24]=1)#[N:2]
Reactant: NCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Solvent: CO
Product: N#CNC(=NCc1cccc(OCc2ccccc2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.30 g, 1.6 mmol) was dissolved in methanol (10 ml), and 3-benzyloxybenzylamine (0.42 g, 2.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was then concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give the title compound (0.26 g, 0.8 mmol, yield: 48%) as colorless crystals.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1[NH2:5].[N:12]([O-])=O.[Na+]>O>[ClH:1].[C:3]1([CH3:2])[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1[NH:5][NH2:12]
Reactant: O=N[O-]
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(NN)c(C)c1
Temperature: -5 °C
Yield: 54 %

Procedure:
A 3.0 L, 3-neck round bottom flask equipped with a mechanical stirrer and an addition funnel was charged with concentrated hydrochloric acid (0.125 L) and deionized water (0.100 L). The solution was cooled to −5° C. in an ice/salt water bath, and 2,4,6-trimethylaniline (70 mL, 0.50 mol, 1.0 equiv.) was added dropwise over 30 minutes; during this time a white precipitate formed. The mixture was stirred for an additional 15-20 minutes before 52.5 mL of a 9.5 M aq. solution of sodium nitrite (70 mL, 0.50 mol, 1.0 equiv.) was added dropwise over 30-45 minutes. The resulting brown solution was allowed to stir for 30 minutes before a 3.3 M solution of stannous chloride dihydrate in 1:1 concentrated HCl:H2O (0.455 L, 1.5 mol, 2.5 equiv.) was added over 4 hours with vigorous stirring. (Upon addition of the stannous chloride solution a thick light orange slurry had formed which sometimes caused seizure of the mechanical stirrer. Addition small amounts of deionized water helped to facilitate stirring again.) The mixture was allowed to warm to room temperature and stirred vigorously for 16 hours. The mixture was cooled to 0° C. for 1 hour before filtering through a fine porosity glass fritted buchner funnel, and the collected orange solid washed with brine and diethyl ether. This orange solid was added to a 2-L round-bottom charged with 10 M NaOH(aq) (1.0 L) and diethyl ether (0.700 L) and cooled to −5° C. Once nearly all of the solid had dissolved (ca. 1 h), the organic layer was removed, and the aqueous layer extracted with diethyl ether (2×0.400 L). The combined organic fractions were dried over Na2SO4, filtered into a flame-dried 2.0 L round-bottom flask, placed under an atmosphere of N2(g), cooled to 0° C., and treated with 4 M HCl in 1,4-dioxane (0.125 L). A white precipitate formed, was collected by vacuum filtration, washed with diethyl ether, and recrystallized from 200 proof EtOH to afford the title compound (50 g, 0.27 mol, 54%) as a white powder. 1H NMR (400 MHz, DMSO) δ 9.57 (3H, s, br, NH, varies), 6.89 (s, 2H), 2.33 (s, 6H), 2.21 (s, 3H); 13C NMR (100 MHz, DMSO) δ 138.06, 136.20, 135.01, 129.17, 20.54, 17.95; IR (thin film) ν 3294, 3002, 2964, 2911, 2680, 1564, 1513, 1481, 852, 825, 753 cm−1; HRESI+/TOF-MS calcd for C9H15N2+ [M]+ 151.1230, found 134.0921 for aniline anion radical (134.0975).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:26][CH2:25]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: C1CCN(CCN2CCNCC2)CC1
Product: CCCCCCC/C=C/C(=O)N1CCN(CCN2CCCCC2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-[2-(1-piperidinyl)ethyl]piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: Br[C:2]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[F:31][C:32]1[CH:33]=[C:34]([C:2]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:5]3[NH:6][C:7]([N:9]4[CH2:10][CH2:11][N:12]([C:15]5[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[CH:17][N:16]=5)[CH2:13][CH2:14]4)=[N:8][C:4]=3[CH:3]=2)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2cc1Br
Product: Fc1ccc(-c2cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c3cc2C(F)(F)F)cc1F

Procedure:
The reaction of 5-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (250 mg, 0.5 mmol, Example 89g) with 3,4-difluorophenylboronic acid (95 mg, 0.60 mmol, Aldrich) under the conditions of Example 88 afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 528.0 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][N:8]=1.[CH3:11][C:12]([CH3:14])=[O:13]>O>[CH3:3][C:4]1[S:5][C:6]([CH:9]=[CH:11][C:12](=[O:13])[CH3:14])=[CH:7][N:8]=1
Reactant: Cc1ncc(C=O)s1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cnc(C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An aqueous solution of 2% sodium hydroxide (3 ml) was added to a solution of 2-methyl-thiazole-5-carboxaldehyde (2.5 g) in acetone (20 ml) and water (10 ml). The mixture was stirred for 24 hours at ambient temperature, diluted with water (150 ml) and extracted with chloroform (2×50 ml). The organic layer was washed with water then dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent gave 1-(2-methyl-5-thiazolyl)but-1-en-3-one as a low-melting point solid (1.4 g, 43%). Pmr spectrum (CDCl3 ; δ in ppm): 2.30 (3H, s); 2.72 (3H, s); 6.36 (1H, d); 7.56 (1H, d); 7.74 (1H, s).
Reaction SMILES: CS[C:3]([S:15][CH3:16])=[C:4]1[CH2:13][CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5]1=[O:14].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>C(#N)C>[CH3:16][S:15][C:3]([N:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[C:4]1[CH2:13][CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5]1=[O:14]
Reactant: CSC(SC)=C1CCC2CC=CC=C2C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: O
Product: CSC(=C1CCC2CC=CC=C2C1=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 48.7 %

Procedure:
2-(Bis-methylthiomethylene)-4,5-dihydro-2H-naphthalen 1-one (11.56 g, 46 mmol) and 1-tert-butyloxycarbonylpiperazine (10.3 g, 55 mmol) were refluxed in acetonitrile (300 ml) for 24 h. The mixture was cooled, water (500 ml) added, and extracted with ethyl acetate (3×200 ml). The combined organics were washed with water and brine, dried (MgSO4), evaporated in vacuo, and the resulting oil purified by flash chromatography, eluting with dichloromethane then dichloromethane:methanol (97:3 v/v) to give 2-(methylthio[4-(tert-butyloxycarbonyl)-1-piperazinyl]methylene)-4,5-dihydro-2H-naphthalen-1-one (8.75 g, 49%) as a foam; δ (360 MHz, CDCl3) 1.49 (9H, s, tBu), 3.31 (3H, s, MeS), 2.86-2.94 (4H, m, CCH2CH2C), 3.3-3.5 (8H, m, NCH2CH2N), 7.18 (1H, d, J=7.5 Hz, H-5), 7.30 (1H, t, J=7.5 Hz, H-7), 7.37 (1H, dt, J=1.4 and 7.5 Hz, H-6), 8.10 (1H, dd, J=1.4 and 7.5 Hz, H-8).