Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[N:16][N:15]4[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CN.C1C[N:35]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:34]C1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([NH:35][CH3:34])=[O:22])=[N:16][N:15]4[C:23]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: NC1(c2ccc(-c3nc4ccc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 25 h
Yield: 55 %

Procedure:
To a solution of 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid that was prepared in a manner analgous to that described for Example 8 (0.15 g, 0.39 mmol) and methylamine (2 M in THF, 1.43 mL, 2.93 mmol, 7.5 equiv) in DMF (1 mL) was added PYBOP (0.22 g, 0.43 mmol 1.10 equiv) and N,N-diisopropylethylamine (0.27 mL, 1.56 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 25 h, then was treated with water (10 mL). The resulting aqueous mixture was extracted with EtOAc (4×15 mL). The combined organic phases were washed with water (2×15 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was triturated with MeOH to give 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide (0.085 g, 55%):
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][C:14]=3[CH3:24])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2].[OH-].[Na+].C1COCC1.CO>O>[CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[CH3:24])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3CC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoate (5.0 g, 11.8 mmol, prepared using B from Example #2, Step A with ethyl hydrazine oxalate, C with 4-bromo-2-methylbenzaldehyde (Asta Tech) and 2-mercaptoacetic, D with borane-THF complex, E with PdCl2(dppf), TEA, DMF and EtOH), NaOH (0.95 g, 23.6 mmol), THF (30 mL), MeOH (30 mL) and water (15 mL) was stirred at rt for about 3 h. The organic volatiles were removed under reduced pressure. The aqueous layer was adjusted to about pH 6 by the addition of 1N aqueous HCl. The precipitate was collected by filtration and dried under reduced pressure to afford 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoic acid (4.5 g, 11.4 mmol, 96%) as a white solid. LC-MS (Table 1, Method 1) Rt=1.15 min, m/z 395 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:30])[N:16]([CH2:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:30])[N:16]([CH2:18][C:19]4[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:36]2[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=2)=[CH:9][CH:10]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Reactant: COc1nccc(B(O)O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ncc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4C)nc23)cn1
Temperature: 90 °C

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (125 mg, 0.25 mmol) in THF (4 mL) at room temperature under argon was added 2-methoxy-4-pyrimidinylboronic acid (116.0 mg, 0.75 mmol), Pd(dppf)Cl2.CH2Cl2 (23 mg, 0.025 mmol), and K3PO4 (160 mg, 0.75 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 90° C. for 12 h, and then cooled to room temperature. Analysis by HPLC/MS indicated that starting material was absent and one major new product had formed. The reaction mixture was diluted with EtOAc and washed once with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions, washing with saturated aq. NaHCO3 solution to eliminate any possible boronic acid contaminant, drying the organic phase (MgSO4), filtering and evaporation provided the title compound as a yellow solid, 147 mg, 80%. HPLC/MS: retention time=3.89 min, [M+H]+=527. 1H NMR (CDCl3): δ 8.43 (s, 2H), 7.86 (d, J=7.2 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.50 (d, J=7.7 Hz, 2H), 7.13 (d, J=7.7 Hz, 2H), 6.66 (d, J=7.7 Hz, 1H), 5.25 (s, 2H), 4.01 (s, 3H), 2.76 (s, 3H).
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].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCC=C1CCNCC1
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccccc32)CC1
Yield: 64.3 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.441 g, 1.33 mmol) and 4-butylidenepiperidine (111MF05) (0.204 g, 1.47 mmol) in MeCN (½ mL) were reacted according to GP14 to give the title compound (108LM33-30) (0.293 g, 64%). 1H NMR (CDCl3) δ 7.19 (bd, J=7.0 Hz, 1H), 7.04-6.97 (m, 3H), 5.13 (t, J=7.9 Hz, CH), 4.60 (ABq, J=14.1 Hz, J=16.2 Hz, CH2), 4.00 (d, J=7.0 Hz, CH2), 2.50-2.38 (m, 2H), 2.35-2.05 (m, 9H), 1.95 (dt, J=7.0 Hz, CH2), 1.50-1.40 (m, 2H), 0.94-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.0, 145.8, 136.3, 128.9, 123.8, 122.8, 122.7, 117.3, 115.7, 67.9, 63.7, 56.5, 55.7, 45.5, 36.4, 29.4, 28.6, 23.4, 17.1, 13.9; HPLC-MS (ammonium acetate) [M+H]+=343.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][OH:34])([CH2:30][C:31]#[CH:32])[C:26]([O:28][CH3:29])=[O:27])=[C:18]([Cl:35])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH2:43](Cl)[O:44][CH3:45].O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][O:34][CH2:43][O:44][CH3:45])([CH2:30][C:31]#[CH:32])[C:26]([O:28][CH3:29])=[O:27])=[C:18]([Cl:35])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: C#CCC(CO)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)OC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C#CCC(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COCOC)C(=O)OC

Procedure:
The compound of Example 212 (1.12 g) was dissolved in acetonitrile (30 mL). To this solution, diisopropylamine (0.58 mL) and MOMCl (0.25 mL) were added while the solution was stirred and chilled in an ice bath. The mixture was stirred overnight. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous magnesium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=5:1) to give the desired product as a colorless oil (1.12 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[CH:20]([CH3:24])[C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCCCCC.O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:24])[C:21]([NH2:23])=[O:22])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Cl)C(N)=O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(N)=O

Procedure:
A mixture containing 10.0 g (0.039 mole) of 4-(4-trifluoromethylphenoxy)phenol, 5.0 g (0.039 mole) of 2-chloropropanamide, 6.9 g (0.05 mole) of anhydrous potassium carbonate, and 50 ml of dimethylsulfoxide is stirred at 90° until reaction is complete, as indicated by vpc techniques. The resultant slurry is cooled, poured into 600 ml of water, and tested with 1:1 hexane/tolune, and the product is isolated by filtration, mp 147°-149° . Recrystallization from hexane affords highly pure product, mp 149°-151°.
Reaction SMILES: Cl.[CH3:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:4][NH2:5].C(N(CC)CC)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.CCOC(C)=O>[CH3:6][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:2])[CH2:4][NH:5][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(CN)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 2-methyl-2-phenylpropan-1-amine hydrochloride (5.32 g, 28.6 mmol) in dry DCM (60 mL) at 0° C. was added triethylamine (8.3 mL, 60.1 mmol) and then slowly 4-(trifluoromethyl)benzoyl chloride (4.48 mL, 30.1 mmol). Then, the mixture was stirred at RT for 45 min, diluted with EtOAc, washed with 10% HCl, sat NaHCO3 and water. After drying over Na2SO4 the solvent was removed under vacuum and the title compound was obtained as a white solid. MS (ESI, positive ion) m/z: 322 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11]#[N:12])[N:6]=1.N1C=CC=CC=1.[C:25]1([CH2:31][CH2:32][O:33][C:34](Cl)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:11](/[C:10](=[N:9]\[O:8][CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:34](=[O:35])[O:33][CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:3][CH:4]=1)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:12]
Reactant: O=C(Cl)OCCc1ccccc1
Reactant: N#C/C(=N\OCc1csc(N)n1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#C/C(=N\OCc1csc(NC(=O)OCCc2ccccc2)n1)c1ccccc1
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a solution of (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (1 g, 3.87 mmol, 1 eq.) in dry dichloromethane (15 ml) at room temperature was added pyridine (0.38 ml, 4.65 mmol, 1.2 eq). After stirring for 15 min at room temperature 2-phenylethylcarbonochloridate (858 mg, 4.65 mmol, 1.2 eq) was added and stirring was allowed during 5 h. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in DCM (5 mL) and 5 ml of 1N NaOH was added. The layers were separated and the organic phase was dried over MgSO4 then concentrated to give 2-phenylethyl {4-[({[(Z)-cyano(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}carbamate (1.2 g, 55% yield) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10]([O:14][C:15]([NH:17][C:18](=NC(OC(C)(C)C)=O)SC)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.C(O)(=O)C>[C:10]([O:14][C:15](=[O:16])[NH:17][C:18]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[N:1]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(O)cc1N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc2cc(O)ccc2[nH]1
Reaction time: 3 h
Yield: 61.8 %

Procedure:
5.75 g of 3,4-diaminophenol were combined with 15.5 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea in 150 ml methanol and 22 ml acetic acid in a round bottom flask. The reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduce pressure yielding 7.13 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.Br[CH2:19][CH2:20][CH:21]1[O:23][CH2:22]1>CN(C=O)C.CCOC(C)=O>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:19][CH2:20][CH:21]3[CH2:22][O:23]3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: BrCCC1CO1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CCC1CO1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Crushed KOH (0.0054 g, 0.0954 mmol, 1.2 equiv) was added to 3,6-dibromocarbazole (0.0258 g, 0.0795 mmol, 1 equiv.) in 0.5 mL DMF solution and the mixture was stirred for 30 min. 1-Bromo-3,4-epoxybutane (0.0300 g, 0.199 mmol) in 0.5 mL DMF solution was dropwise added into the mixture and it was stirred at room temperature for overnight. Reaction crude was diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford 31.2 mg white solid as product, yield 97.9%.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Br:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>CO>[NH2:17][C:2]1[C:3]2[C:10]([Br:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCOCn1cc(Br)c2c(Cl)ncnc21
Reactant: N
Solvent: CO
Product: Nc1ncnc2c1c(Br)cn2COCCO
Temperature: 125 °C

Procedure:
5-Bromo4chloro-7(2-hydroxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (8b, 0.75) was dissolved in dry methanol (10 mL) and methanol saturated with ammonia (40 mL) was then added to this solution. The reaction mixture was heated at 125° C. in a sealed reaction vessel for 10 hours The solvent was removed at 40° C. under reduced pressure and the resulting solid was then subjected to column chromatography. Elution of the silica get column (20×3 cm) with 5% MeOH in CHCl3 yielded a solid after evaporation of the appropriate UV absorbing fractions.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH:7]=[CH:8][CH:9]=[C:2]12.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[C:17]([N:6]1[CH2:5][CH2:4][N:3]2[CH:7]=[CH:8][CH:9]=[C:2]2[CH2:1]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1cc2n(c1)CCNC2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccccc1)N1CCn2cccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 12.2 g of 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine and 22.2 g of triethylamine in 50 ml of anhydrous benzene, 15.4 g of benzoyl chloride was added in small portions at 10°-15° C. The reaction mass was stirred for 3 hours at room temperature and then poured into water. The organic phase was separated, and washed with a 5% solution of sodium carbonate and then water. The solvent was removed by distillation, the residue was distilled under vacuum, and the fraction with a boiling point of 189°-191° C. at 1 mm Hg was collected. The yield of the title compound was 15 g (66.5%). Nmr (CDCl3): δ3.7-3.9 (m) (4H, 3,4-CH2); 4.58 (s) (2H, 1-CH2); 5.6-5.8 (m) (1H, 7-H); 5.8-6.0 (m) (1H, 8-H); 6.2-6.4 (m) (1H, 6 -H); 7.2-7.4 (m) (5H-C6H5). Anal. calculated for C14H14N2O: C 74.31%; H 6.24%; N 12.38% and found: C 74.21%; H 6.24%; N 12.45%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](C(O)=O)([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.N1C=CC=CC=1.O.Cl>[Cu-]=O.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1(C(=O)O)CCOCC1
Agent: O=[Cu-]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)C1CCOCC1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
In a flask made of glass equipped with a stirring device, a thermometer and a reflux condenser and having an inner volume of 50 ml were charged 1.0 g (5.74 mmol) of tetrahydropyran-4,4-dicarboxylic acid with purity of 100%, 21 mg (0.14 mmol) of copper(I) oxide and 3.0 ml of pyridine under nitrogen atmosphere, and the mixture was reacted at 110 to 120° C. for 1 hour under stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 5 ml of water, 5 ml (60 mmol) of conc. hydrochloric acid and 10 ml of ethyl acetate were successively added in this order to the reaction mixture. The aqueous layer and the organic layer (the ethyl acetate layer) were separated, the aqueous layer was extracted three times with each 10 ml of ethyl acetate, then, the organic layer and the ethyl acetate extracts were combined and the mixture was concentrated under reduced pressure to give 534 mg (Isolation yield: 72%) of tetrahydropyran-4-carboxylic acid with purity of 100% (analytical value by differential refractometry) as white crystals.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.[CH2:19]([NH:26][C:27]([C:29]1[S:33][C:32]([N:34]2[CH2:38][CH2:37][NH:36][C:35]2=[O:39])=[N:31][C:30]=1[CH3:40])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:27]([C:29]1[S:33][C:32]([N:34]2[CH2:38][CH2:37][N:36]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:35]2=[O:39])=[N:31][C:30]=1[CH3:40])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCC1CCCCO1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(CC3CCCCO3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 2-(bromomethyl) tetrahydro-2H-pyran to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, CDCl3) δ 7.34-7.30 (m, 5H), 5.86 (s, 1H), 4.56 (d, J=3.0 Hz, 2 H), 4.08 (t, J=9.0 Hz, 2H), 3.98-3.94 (m, 1H), 3.84-3.3.63 (m, 2H), 3.55-3.35 (m, 3H), 3.18-3.16 (m, 1H), 2.62 (s, 3H), 1.86-1.83 (m, 1H), 1.60-1.22 (m, 5H); MS (ES+) m/z 415.3 (M+1).
Reaction SMILES: BrCC1C=CNN=1.C(N)CN.[NH:12]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][NH2:21])=[N:13]1.[C:22]([NH:24][C:25](=[N:28][CH3:29])SC)#[N:23]>>[C:22]([NH:24][C:25]([NH:28][CH3:29])=[N:21][CH2:20][CH2:19][NH:18][CH2:17][C:14]1[CH:15]=[CH:16][NH:12][N:13]=1)#[N:23]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1cc[nH]n1
Agent: BrCc1cc[nH]n1
Solvent: NCCN
Product: CNC(=NCCNCc1cc[nH]n1)NC#N

Procedure:
Reacting 3-bromomethylpyrazole with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(3-pyrazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(d) gives N-cyano-N'-methyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]([NH2:24])=[CH:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[CH:11][CH:10]=1.O.C(OCC)(=O)C>OS([O-])=O.[Na+].C(O)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:17]2[N:24]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[N:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)[C:16]=2[CH:21]=1
Reactant: O=Cc1ccsc1
Reactant: COc1ccc(N)c(Nc2ccc(F)cc2)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(-c3ccsc3)n(-c3ccc(F)cc3)c2c1
Reaction time: 4 h
Yield: 86.4 %

Procedure:
7.48 g of thiophene-3-aldehyde was stirred in 65 ml of 40% NaHSO3 solution for two hours. After 15 g of N2-(4-fluorophenyl)-4-methoxybenzene-1,2-diamine in 50 ml of ethanol was added, it was boiled for 4 hours, and stirring was continued overnight. The batch was dispersed between water and ethyl acetate, and the organic phase was washed with water. After drying on sodium sulfate and concentration by evaporation of the filtrate, 18.1 g of crude 6-methoxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:30])[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:26][C:27]([OH:29])=[O:28])[CH:20]=2)[O:15]1.[CH2:31](I)[CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[CH3:13][C:14]1([CH3:30])[CH2:23][C:22]([CH3:24])([CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:27]([OH:29])=[O:28])[CH:20]=2)[O:15]1
Reactant: CC1(C)CC(C)(C)c2cc(CC(=O)O)ccc2O1
Reactant: CCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.55 ml of diisopropylamine were dissolved in 60 ml THF and treated dropwise, at 0° C., with 7.2 ml of butyl lithium (2.5M). After 30 min. at 0° C., a solution of 1.8 g of (2,2,4,4-tetramethyl-chroman-6-yl)-acetic acid in 8 ml of THF was dropped in. The reaction mixture was stirred at 0° C. for one hour then at room temperature for 30 min. After cooling back to 0° C., a solution of 1.42 ml of pentyl iodide in 4 ml THF was added dropwise. The mixture was kept at 0° C. for one hour then at room temperature for two hours. The mixture was quenched with the addition of 50 ml of water and the pH was adjusted to 2 with HCl 1N. The mixture was extracted with three portions of 50 ml of ether. The combined organic extracts were washed with two portions of 50 ml of water and one portion of 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), yielding 1.2 g of a pale yellow oil. 1H NMR (CDCl3): 7.17 (d, J=2.2 Hz, 1H), 7.03 (dd, J=8.4, 2.2 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 3.45 (t, J=7.7 Hz, 1H), 2.10-1.90 (m, 1H), 1.81 (s, 2H), 1.80-1.65 (m, 1H), 1.33 (s, 6H), 1.32 (s, 6H), 1.40-1.20 (m, 6H), 0.85 (t, J=6.9 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C1COCC1>[CH2:19]([N:21]([CH2:22][CH3:23])[C:14](=[O:16])/[C:13](/[O:17][CH3:18])=[CH:12]/[CH:11]=[CH:10]/[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:20]
Reactant: CCNCC
Reactant: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a solution of (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4-pentadienoic acid (0.1 g, 0.41 mmol), diethylamine (0.042 ml, 0.41 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 nmol) in DMF/THF 1:1 (50 Ml), DCC (0.093 g, 0.45 mmol) was added at 0° C. The resulting solution was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane, washed successively with 10% HCl, saturated solution of NaHCO3 and water, dried and evaporated under vacuum. The crude material was purified by column chromatography (EtOAc/hexane 4:6) and triturated with isopropyl ether to yield 21 mg (17.2%) of the title compound as a light yellow solid, m.p.=141-143° C.