Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:31]=[CH:30][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].[CH2:36]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[C:37]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][O:40][C:39]=2[CH:38]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:36]([N:46]1[CH2:51][CH2:50][N:49]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([O:14][C:11]4[N:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:32]=[CH:33][C:34]([Cl:35])=[C:2]([Cl:1])[CH:3]=5)=[CH:9][CH:10]=4)=[CH:31][CH:30]=3)=[O:20])[CH2:22][CH2:23]2)=[O:28])[CH2:48][CH2:47]1)[C:37]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][O:40][C:39]=2[CH:38]=1
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(C(=O)O)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(C(=O)N4CCN(Cc5ccc6c(c5)OCO6)CC4)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (7.96 g, 15.5 mmol) in DMF (160 mL) were added 1-piperonylpiperazine (3.75 g, 17.6 mmol), 1-hydroxybenzotriazole monohydrate (2.85 g, 18.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.56 g, 18.6 mmol) under ice cooling, and the resulting solution was stirred for overnight at room temperature. This reaction solution was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the resulting solution was vigorously stirred. The resulting precipitates were collected by filtration and recrystallized from a dichloromethane-methanol mixed solvent, to thereby yield 7.36 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[C:6]2[C:11]([C:12]=1[CH2:13]Br)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH2:34]([N:36](CC)CC)C.CN>C1COCC1>[C:30]([O:29][C@@H:23]([C:4]1[C:3]2[CH2:2][N:36]([CH3:34])[CH2:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[O:15][S:16]([C:19]([F:21])([F:22])[F:20])(=[O:17])=[O:18])[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:32])([CH3:31])[CH3:33]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CBr)c(CBr)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CN
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c2c(c3ccccc3c1OS(=O)(=O)C(F)(F)F)CN(C)C2
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(3,4-bis(bromomethyl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.1356 g, 0.219 mmol) and triethylamine (61 μL, 0.438 mmol) in anhydrous THF (10 mL) at 0° C. was added a 2M solution of methylamine in THF (109 μL, 0.219 mmol). The reaction mixture was stirred for 1 hour, then stirred overnight at room temperature. LC/MS shows some desired product. Reaction mixture was heated at 45° C. for 1.5 hours, then additional 2M solution of methylamine in THF (109 μL, 0.219 mmol) was added. After 1 hour, 2M solution of methylamine in THF (0.9 mL) was added and stirred for 45 minutes. LC/MS showed no starting material. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 30 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H27F3NO6S: 490.2. Found: 490.1.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 3-ethynyl-N-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-8-amine 5 (0.048 g, 0.154 mmol), 0.069 g (0.170 mmol) of 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 0.009 g (0.008 mmol) of Pd(PPh3)4, 0.002 g (0.012 mmol) of CuI, and 0.04 mL (0.23 mmol) of diisopropylethylamine in 0.8 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 10% EtOAc/hexanes to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m/z (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20]([CH:24]=[CH2:25])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc3ccc(Br)cn23)CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ncc(C3CCN(C(=O)OC(C)(C)C)CC3)n2c1
Temperature: 25 °C
Yield: 110 %

Procedure:
To a solution of 95 mg of 1-(t-butoxycarbonyl)-4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-piperidine (from Example 274, Step A), and 158 mg of tributyl(vinyl)tin in 6 mL toluene was added 5.3 mg of dichlorobis (triphenyl phosphine)-palladium(II). The mixture was refluxed for 2 hours. The reaction was cooled down to r.t. and partitioned between CH2Cl2and water. Aqueous layer was extracted with CH2Cl2 (3×). The combined organic phase was washed with brine and dried over MgSO4. After concentration, the residue was purified by prep TLC (100% EtOAc) to give 90 mg of the title compound as a viscous oil, which was used in next step without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].O>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1)=[O:16]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc(N)nc(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(NC(=O)N(C)C)nc(C)c1Cl
Reaction time: 1 h

Procedure:
Sodium hydride (6 g., 55%, 0.137 mole) is added to a mixture of 2-amino-4,6-dimethyl-5-chloropyrimidine (19.5 g., 0.125 mole) in 250 ml of toluene. The mixture, under a nitrogen atmosphere is heated to reflux and stirred for one hour. Another portion of sodium hydride (6 g., 55%, 0.137 mole) is added and after two hours of reflux, dimethyl carbamoyl chloride (13.9 g., 0.125 mole) is added. After one hours of reflux the reaction is cooled, water is added, the toluene is removed by vacuum concentration and the product is extracted into petroleum ether from which it is crystallized by evaporation. N,N-Dimethyl-N'-(4,6-dimethyl-5-chloro-2-pyrimidinyl)urea melting at 127°-129° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1F)=[O:5])[CH3:2].[CH2:14]1[O:18][C:17]2[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=2[O:15]1>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][O:18][C:17]=3[CH:19]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[F:12])=[O:5])[CH3:2]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1c(F)cccc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)cccc1Oc1ccc2c(c1)OCO2
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of ethyl-2,6-difluorobenzene-carboxylate (EXAMPLE 1C; 373 mg, 2.0 mmol) in DMSO (0.5 ml) was added to a solution of the solid prepared above in DMSO (1.0 ml). The brownish solution was heated at 80° C. for 2 hours. The solvent was evaporated, the solid filtered, washed with water several times and dried. The crude product was purified by flash column chromatography on silica gel using 3-15% ethyl acetate in hexane to give 371 mg of the product (61% yield) as a light yellow oil and unreacted sesamol.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([CH3:64])=[C:46]([CH:63]=1)[O:47][C:48]1[N:53]=[C:52]2[S:54][C:55]([NH:57][C:58]([CH:60]3[CH2:62][CH2:61]3)=[O:59])=[N:56][C:51]2=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[CH:60]1([C:58]([NH:57][C:55]2[S:54][C:52]3[C:51]([N:56]=2)=[CH:50][CH:49]=[C:48]([O:47][C:46]2[CH:63]=[C:42]([NH:41][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=4)[CH:43]=[CH:44][C:45]=2[CH3:64])[N:53]=3)=[O:59])[CH2:61][CH2:62]1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (44 mg, 0.185 mmol) in pyridine (2.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.185 mmol), and the mixture was stirred at room temperature for 10 min. N-[5-(5-Amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (60 mg, 0.176 mmol) produced in Example C47(i) was added to the obtained solution, and the mixture was stirred at 70° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (2 mL) was added, and the obtained precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (55 mg, 56%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CO>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=C(O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
The product from Example 311a (1.0 g, 3.03 mmol) and borane tetrahydrofuran complex (6.06 mL, 6.06 mmol) were combined in tetrahydrofuran (15.15 mL) and heated at 50° C. for 2 hours, cooled, treated with 10 mL of methanol, heated at 50° C. for 1 hour, cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate in heptanes) afforded the title compound (0.73 g, 76%).
Reaction SMILES: [Br:1][C@H:2]1[C@H:21]([OH:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:17]2[C:16](=[O:24])[CH2:15][C@@:14]2([CH3:25])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:11](=[O:13])[CH3:12].[Br:26]Br>CO.O>[Br:1][C@H:2]1[C@H:21]([OH:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:17]2[C:16](=[O:24])[CH2:15][C@@:14]2([CH3:25])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:11](=[O:13])[CH2:12][Br:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4[C@@H](Br)[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H](O)[C@H](Br)[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4β-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (945 mg) in dry methanol (70 ml.) at 10° was treated with a solution of bromine (0.125 ml.) in methanol (5 ml.) dropwise over 7 hours, at such a rate that the bromine colour was taken up during the addition. The reaction solution was then stirred at room temperature for 30 minutes until it became colourless, and it was then diluted with water (300 ml.) and the white precipitate was extracted into methylene chloride. The organic solution was washed with water, dried over sodium sulphate and evaporated to a white foam (1.2 g.) which was purified by preparative T.L.C. in ethyl acetate/benzene 1/3 the upper (major) band giving 660 mg. of a white solid which was triturated with ether to give title compound (580 mg.) as white crystals, m.p. 164°-166°, [α]D + 76° (c 1.35).
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)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:16]3[N:17]=[C:18]([C:19]4[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]4[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCCCC4)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 63.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (17 mg, 0.034 mmol) in DCM (2 mL) was added 1,4′-bipiperidine (16 mg, 0.10 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (13 mg, 63%). LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.50 (m, 4H), 1.68 (m, 6H), 1.92 (m, 2H), 2.31 (s, 3H), 2.73 (m, 2H), 2.90 (m, 5H), 3.37 (m, 2H), 4.16 (m, 2H), 4.52 (m, 2H), 7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (11.8 g), phenol (5.6 g), and dicyclohexylcarbodiimide (12.4 g) in pyridine (75 ml) was stirred overnight at room temperature. After evaporation of solvent, the residue was treated with 0.1 N hydrochloric acid (200 ml), the insoluble materials removed by filtration and the filtrate was washed with ethylacetate. The aqueous layer was concentrated to 100 ml, the resulting crystals were filtered and washed with isopropylalcohol/isopropylether to give phenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride (12.5 g, 80.2%), m.p. 150°-153° C. This compound was recrystallized from methanol to give white crystal, phenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride, m.p. 159.5°-161.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1.COS(OC)(=O)=O.ClC1C=CC=CC=1OC1[CH:28]=[N+:29](OC)C=CC=1.[C-]#N.[Na+]>O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[C:6]([C:28]#[N:29])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CO[n+]1cccc(Oc2ccccc2Cl)c1
Reactant: [O-][n+]1cccc(Oc2ccccc2Cl)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: N#Cc1ncccc1Oc1ccccc1Cl
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 22 g of 3-(2-chlorophenoxy)pyridine 1-oxide and 22 g of dimethylsulfate is heated at 100° C. for 4 hours. The 3-(2-chlorophenoxy)-1-methoxypyridinium methosulfate is cooled and dissolved in 100 ml of water. This solution is added dropwise with stirring to a 0°-5° C. solution of 50 g of sodium cyanide in 100 ml under a nitrogen atmosphere. The mixture is stirred 16 hours and extracted with 250 ml of chloroform. The extract is dried, concentrated and distilled to yield 3-(2-chlorophenoxy)-2-pyridine-carbonitrile, bp 125°-135° C. at 01. mM, mp 90°-92° C. after recrystallization from isopropanol.
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3][NH:2]1.[H-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([N:2]1[C:1](=[O:14])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3]1)(=[O:20])=[O:19]
Reactant: O=C1NCc2ccc3c(c21)C=CCO3
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1Cc2ccc3c(c2C1=O)C=CCO3
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a solution of 2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one (71) (500 mg, 2.67 mmol) in THF (35 ml) was added NaH (95%, 87 mg, 3.47 mmol) in portions. Resulting mixture was stirred for 40 min before adding MeSO2Cl by syringe. Stirring was continued for 1 hour. The solvent was removed in vacuo and the residue was portioned with CH2Cl2. The organic solution was washed with H2O, sat. NaCl and dried over Na2SO4. Concentration in vacuo gave the title compound (95) as a solid (490 mg, 69%). MS (ES) m/z 266.0.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=[O:2].[N:11]#[C:12][NH2:13].Cl.[OH-].[Na+]>C(O)(=O)C>[N+:1]1([O-:2])[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:12]([NH2:13])[N:11]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2ccccc2[n+]([O-])n1
Temperature: 70 °C
Yield: 77.5 %

Procedure:
A mixture of 10 g 2-nitroaniline and 20 g cyanamide is heated for 5 min to 100° C., cooled, mixed with 25 ml conc. hydrochloric acid and carefully heated to 70° C. After subsidence of the vigorous reaction, one cools to room temp., adds dropwise thereto 50 ml semiconce. caustic soda lye, heats for 30 min to 100° C., cools, filters and washes the precipitate with hot glacial acetic acid. There remain 9.1 g of title compound (78% of theory) of the m.p. 272°-274° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:20]([O:19][C:17]([NH:16][C@@H:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:31](=[O:33])[CH3:32])=[O:18])([CH3:22])([CH3:21])[CH3:23]
Reactant: CCCC[C@@H](CNc1cccc(C)c1C)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@@H](CN(C(C)=O)c1cccc(C)c1C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product of Step H (500 mg, 1.56 mmol) and triethylamine (0.240 mL, 1.72 mmol) in 10 mL of dichloromethane at 0° C. was added acetyl chloride (0.122 mL, 1.72 mmol). After 20 min, the solution was warmed to room temperature, then stirred another 2 hours. The reaction was poured into CH2Cl2, washed with 10% citric acid and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].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)CC)C>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cc(N2CCNCC2)ncn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 38.2 %

Procedure:
A solution of 4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.0 g, 4.31 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (1.75 g, 6.46 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.86 g, 6.46 mmol), and triethylamine (1.20 mL, 8.61 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (800 mg, 38.3%). LCMS calculated for C23H35F3N5O3: (M+1) 486.2; found 486.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][N:5]2[C:10]=1[C:11]1[S:15][C:14]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1>CS(C)=O.O>[CH3:20][C:16]1[C:14]2[S:15][C:11]([C:10]3[N:5]4[N:6]=[C:7]([NH:33][C@H:34]5[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]5)[CH:8]=[CH:9][C:4]4=[N:3][CH:2]=3)=[CH:12][C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc2cc(-c3c(Cl)nc4cccnn34)sc12
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc12
Temperature: 100 °C

Procedure:
To a solution of -chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.168 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (23 mg, 0.168 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.840 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 32 mg of the yellow solid, 48%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:13]([CH:16]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Temperature: 0 °C
Yield: 94.1 %

Procedure:
A mixture of 2-naphthaldehyde (12 g), nitromethane (13.8 g) and ammonium acetate (5 g) in acetic acid (50 ml) was refluxed for 21/2hours. The brown mixture was poured into ice-water (100 ml) from which a yellow solid separated. Filtration and drying in vacuo afforded the title compound (14.4 g).