Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]1[N:33]=[C:32]([Cl:34])[C:31]([C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.C(Cl)Cl>CC(N(C)C)=O>[Cl:34][C:32]1[C:31]([C:35]([F:37])([F:36])[F:38])=[CH:30][N:29]=[C:28]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)[N:33]=1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
10 g (44 mmol) benzyl 4-aminobenzoate are dissolved in 200 mL DMA, 8 mL Hünig base (0.97 eq) are added and 10.4 g (48.21 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine, dissolved in 50 mL DMA, are added dropwise at RT to this solution. The reaction mixture is stirred at 60° C. overnight, then combined with 300 mL DCM and extracted with water (3 times 300 mL). The organic phase is dried and the solvent is eliminated in vacuo. The crude product is combined with 100 mL MeOH, digested and left to stand for 2 h. Then it is stirred for 10 min, the precipitate is filtered off and washed with MeOH. Finally the crude product is again suspended in MeOH, filtered off, washed with a little MeOH and dried in the vacuum dryer at 60° C. 8.5 g A-2a are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1N=C2N=CN(C3C=CC(C)=CC=3)C2=CC=1)C1C=CC=CC=1>CCOC(C)=O.[Cu]I.CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: Cc1ccc(-n2cnc3nc(OCc4ccccc4)ccc32)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2cnc3ccc(OCc4ccccc4)nc32)cc1
Temperature: 25 °C

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (0.204 g, 0.906 mmol), 4-bromotoluene (0.123 mL, 0.996 mmol), potassium carbonate (263 mg, 1.90 mmol), copper(1) iodide (8.6 mg, 0.045 mmol) and NMP (3 mL) were heated at 210° C. for 1 h under microwave irradiation in a heavy walled sealed tube. The mixture was cooled to room temperature and diluted with EtOAc. The solution was washed with water and the organics were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give a mixture of the title compound and its regioisomer 5-(benzyloxy)-1-p-tolyl-1H-imidazo[4,5-b]pyridine (154 mg). LCMS m/z=316.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[O:35])[CH2:31][CH2:32]1)=[O:29]
Reactant: Nc1cccnc1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
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(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5cccnc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 30 h
Yield: 31.8 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added 3-aminopyridine (15.5 mg), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 30 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (14.7 mg, 32%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[N:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cc(-n2cccn2)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccn2)ccn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, 2-bromo-4-(1H-pyrazol-1-yl)pyridine (0.15 g, 0.67 mmol) was dissolved in THF (4.4 mL). The light yellow solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 0.57 mL, 0.74 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 25 min and at room temperature for 1.5 h. Additional isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 0.29 mL, 0.38 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. and tributyltin chloride (0.21 mL, 0.77 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with ˜5 mL water and ˜5 mL brine then dried over sodium sulfate, filtered and concentrated to provide 4-pyrazol-1-yl-2-tributylstannanyl-pyridine as a light brown oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]=3)=[CH:11][CH:12]=2)[N:7]([CH3:21])[CH:6]=1)=[O:4]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[N:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(C)c2cc(C3=CCC(O)CC3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cn(C)c2cc(C3CCC(O)CC3)ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
A solution of 6-(4-hydroxy-cyclohex-1-enyl)-1-methyl-1H-indole-3-carboxylic acid methyl ester (0.251 g, 0.880 mmol) in tetrahydrofuran (10 mL) is added to a slurry of palladium (0.200 g, 5% in carbon) in THF (2 mL). The mixture is stirred under an atmosphere of hydrogen (balloon) at room temperature for 12 h. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to yield the title compound (0.202 g, 80%). MS m/z 288.3 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:24]1([C:28]([C:30]2[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:24]1([C:28]([C:30]2[N:31]=[CH:32][C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCOCC3)c2)n1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(OC3CCOCC3)c2)n1
Temperature: 120 °C
Yield: 12.3 %

Procedure:
3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide (209 mg, 0.66 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (159 mg, 0.80 mmol) and potassium carbonate (184 mg, 1.33 mmol) were dissolved/suspended in acetonitrile (3.5 mL). The reaction mixture was heated in a microwave reactor for 4 hours at 120° C. then cooled, filtered and reduced in vacuo. The crude product was purified by chromatography on silica, eluting with 0-5% methanol in DCM, to give the required product as a white foam (39 mg). 1H NMR δ (d6-DMSO): 1.57-1.68 (m, 2H), 1.97-2.05 (m, 2H), 2.26-2.36 (m, 2H), 3.47-3.55 (m, 2H), 3.78 (s, 3H), 3.84-3.91 (m, 2H), 4.10 (t, 2H), 4.57 (t, 2H), 4.67-4.75 (m, 1H), 6.58 (d, 1H), 7.11 (t, 1H), 7.43 (t, 1H), 7.54 (t, 1H), 7.60 (d, 1H), 8.56 (d, 1H), 8.68 (d, 1H), 10.80 (s, 1H); m/z 479 (M+H)+
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([C@@:12]1([CH3:39])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N+:14]2[C@@H:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:33][O:34][C:13]1=2)[CH:10]=[CH2:11].C([O-])(O)=[O:41].[Na+]>ClCCCl>[CH2:9]([C@@:12]1([CH3:39])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:14]([C@@H:32]([C:35]([CH3:37])([CH3:38])[CH3:36])[CH2:33][OH:41])[C:13]1=[O:34])[CH:10]=[CH2:11]
Reactant: O=C([O-])O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C(C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C(C)(C)C)C1=O

Procedure:
To a solution of (3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium trifluoromethanesulfonate (290 mg, 0.478 mmol; Example 363, Step B) in 1,2-dichloroethane (4.78 mL) was added 5 mL of sat. aq. NaHCO3 solution. The reaction mixture was heated to 50° C. for 3d. The reaction mixture was poured into a separatory funnel and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and the filtrate was concentrated. Purification by column chromatography using 25-35% ethyl acetate in hexanes on a 4 g silica gel column afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Product: CN(CCCn1c(=O)c(C(=O)NCCCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21)C(=O)OCc1ccccc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-1-butanol using conditions similar to Step 5 from Example 497 and obtained as a white solid: ES+ MS: 591 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][C:20](O)=O)C1C=CC=CC=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH2:52][CH:51]([CH2:54][NH2:55])[O:50][C:49]=2[CH:56]=1>CN(C=O)C>[OH:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH2:52][CH:51]([CH2:54][NH:55][CH2:20][CH2:19][CH2:18][C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][CH:13]=3)[O:50][C:49]=2[CH:56]=1
Reactant: O=C(O)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: NCC1COc2ccc(O)cc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccc(O)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
5-Benzyloxyindole-3-propionic acid (1.5 g, 5.0 mmole), 1-hydroxybenzotriazole hydrate (0.8 g, 6.0 mmole) and 1,3-diisopropylcarbodiimide (1.9 ml, 12.0 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.1 g, 5.0 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on silica gel using ethyl acetate as eluant. Fractions containing product were concentrated and recrystallized from ethyl acetate to give 1.6 g (68%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(5-hydroxy-1H-indol-3-yl)-propanamide, as a white solid.
Reaction SMILES: [NH3:1].O.C[O:4][C:5]([C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:8]=1[S:17](Cl)(=[O:19])=[O:18])=O>O1CCCC1>[CH3:13][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=[C:8]2[C:7]=1[C:5](=[O:4])[NH:1][S:17]2(=[O:19])=[O:18]
Reactant: N
Reactant: COC(=O)c1c(S(=O)(=O)Cl)ccc([N+](=O)[O-])c1C
Solvent: C1CCOC1
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2c1C(=O)NS2(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
104 ml of 25 percent ammonia solution are initially taken, 100 ml of water are added and a solution of 48.7 g (0.166 mol) of 2-methoxycarbonyl-3-methyl-4-nitrobenzenesulfonyl chloride in 70 ml of tetrahydrofuran is then added dropwise at 10° C. After stirring at 25° C. for three hours, the mixture is concentrated on a rotary evaporator to remove water and THF. The residue which remains is stirred with ethyl acetate, filtered off with suction and washed with ethyl acetate. After drying under reduced pressure, 34 g (0.131 mol)=79% of theory of a white solid of m.p.: 312° C. (dec.) are obtained.
Reaction SMILES: C1(PC2C=CC=CC=2)C=CC=CC=1.[C:14]([NH:17][C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])(=[O:16])[CH3:15].[H][H]>C1COCC1>[C:14]([NH:17][C@H:18]([C:19]([OH:21])=[O:20])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:16])[CH3:15]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
110 μmol of the optically active diphenylphosphine ligand of Example 3 were dissolved in 5 ml of THF and, after addition of 100 μmol of Rh(COD)2BF4, stirred at RT for 20 min. 100 mmol of α-acetamidocinnamic acid and 250 ml of THF were added to the clear yellow solution. This solution was hydrogenated under 20 bar of hydrogen at 30° C. The reaction was complete after 20 min. N-Acetyl-(S)-phenylalanine was isolated after workup in 97% yield and an optical purity of 99.6% ee.
Reaction SMILES: [C:1]([O:6]C)(=O)[C@@H:2]([CH3:4])[OH:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[OH:3][C@H:2]([CH3:4])[C:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:6]
Reactant: COC(=O)[C@@H](C)O
Reactant: C1COCCN1
Product: C[C@@H](O)C(=O)N1CCOCC1
Temperature: 85 °C

Procedure:
A mixture of methyl (R)-lactate (104 g) and morpholine (260 ml) was heated for 60 hours at 85° C. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by means of a silica gel chromatography (silica gel 800 g, eluent: hexane-ethyl acetate=1:1→etyl acetate) to give N-[(2R)-2-hydroxypropionyl]morpholine (141 g) as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.CCN(C(C)C)C(C)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:34]2[CH2:35][CH2:36][N:37]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:38][CH2:39]2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(c1ccc(F)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 70.3 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.54 mmol), DIPEA (0.094 mL, 0.54 mmol) and 1-[2-(4-fluorophenyl)propan-2-yl]piperazine (obtained as described in J. Med. Chem. 2007, 50, 3528) (120 mg, 0.54 mmol) in DMF (1.5 mL) were stirred and heated at 80° C. for 1 hour. The resulting solution was cooled to room temperature then applied to an SCX column and eluted with MeOH followed by 2M ammonia in methanol. Fractions containing product were combined and evaporated, then purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[1-(4-fluorophenyl)-1-methylethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (155 mg, 70%) as a colourless solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.Cl>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2sc(C(=O)CCCCl)cc2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)N1CCc2sc(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)cc2C1
Yield: 34.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.8 g of 5-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 1.6 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.0 g of 5-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine as an oil, m.p. 235° C. as hydrochloride 1/2hydrate thereof.
Reaction SMILES: CN.[CH2:3]([NH:5][C:6]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[C:17]([CH2:20][N:21]([CH3:23])[CH3:22])[S:18][CH:19]=1)=[N:7][C:8]#[N:9])C>>[CH3:3][NH:5][C:6]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[C:17]([CH2:20][N:21]([CH3:22])[CH3:23])[S:18][CH:19]=1)=[N:7][C:8]#[N:9]
Reactant: CCNC(=NC#N)NCCSCc1csc(CN(C)C)n1
Agent: CN
Product: CNC(=NC#N)NCCSCc1csc(CN(C)C)n1

Procedure:
Following the above procedure, but substituting ethylamine for methylamine in the reaction with N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanocarbamidothioate, N-ethyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine was prepared.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5](C)[C:4](=O)[CH:3]=1.O[C:15]1C2C(=CC=CC=2)N(CC)C(=O)C=1.OC1C2C(=CC=CC=2)N(CC=C)C(=O)C=1.OC1C2C(=CC=CC=2)N(C2C=CC=CC=2)C(=O)C=1>>[NH2:5][CH:4]1[CH2:3][CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:15]1
Reactant: Cn1c(=O)cc(O)c2ccccc21
Reactant: CCn1c(=O)cc(O)c2ccccc21
Agent: C=CCn1c(=O)cc(O)c2ccccc21
Agent: O=c1cc(O)c2ccccc2n1-c1ccccc1
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 91, but starting from 4-hydroxy-1-methylcarbostyril, 4-hydroxy-1-ethylcarbostyril, 4-hydroxy-1-allylcarbostyril, or 4-hydroxy-1-phenylcarbostyril and reacting the raw chlorohydrin thus obtained with 2-aminotetralin, the following compounds are prepared respectively:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[C:3]([CH2:8][CH:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1.[CH2:14]=O>Cl>[OH:7][C:5]1[CH:4]=[C:3]2[C:2](=[CH:1][CH:6]=1)[CH2:14][NH:13][CH:9]([C:10]([OH:12])=[O:11])[CH2:8]2
Reactant: C=O
Reactant: NC(Cc1cccc(O)c1)C(=O)O
Agent: Cl
Product: O=C(O)C1Cc2cc(O)ccc2CN1
Temperature: 90 °C
Yield: 155.8 %

Procedure:
To a suspension of DL-m-tyrosine (5.00 g, 11.0 mmol) in 0.05 N HCl (50 mL) was added 37% aq. formaldehyde (5.00 mL, 5.2 g, 64.0 mmol) and the resulting slurry was heated at 90° C. for 1 h and then cooled to RT. The mixture was filtered and the resulting solid was washed with H2O and acetone and dried in vacuo to yield 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3.31 g, 52% yield) as an off-white solid. MS (EI) m/z: 194.0 (M+H+). 1H NMR (400 MHz, CD3OD): δ 7.03 (d, J=8.0 Hz, 1H), 6.69 (dd, J=8.8, and 2.4 Hz, 1H), 7.00 (s, 1H), 4.28-4.19 (m, 2H), 3.80 (dd, J=11.6, and 5.2 Hz, 1H), 3.31-3.27 (m, 1H), 3.05 (dd, J=16.8, and 11.2 Hz, 1H), acid, hydroxy and amine protons not visible.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccs2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the title compound. 1H NMR (400 MHz, CDCl3): 7.32–7.36 (m, 1H), 7.22–7.26 (m, 1H), 7.08 (s, 1H), 7.02–7.08 (dd, 1H), 6.96–7.2 (m, 2H), 6.86–6.92 (m, 2H), 4.3–4.4 (q, 2H), 3.52–3.58 (m, 4H), 3.05–3.25 (m, 4H), 1.3–1.42 (m, 3H). 13C NMR (400 MHz, CDCl3): 164, 130, 126.8, 126.4, 120, 118.2, 115.4, 62.3, 54, 50.5, 42, 44.5, 14.6.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:25])([F:24])[CH2:5][N:6]=[C:7]([NH2:23])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[NH:22])[O:20][CH3:21])[N:10]=1.[CH2:26]([N:28](CC)CC)C.N#CN>CO>[C:26]([N:22]=[C:19]([O:20][CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[N:10]=[C:9]([NH:8][C:7]([NH2:23])=[N:6][CH2:5][C:4]([F:3])([F:24])[F:25])[CH:14]=[CH:13][N:12]=1)#[N:28]
Reactant: CCN(CC)CC
Reactant: COC(=N)CCCCc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: Cl
Agent: N#CN
Solvent: CO
Product: COC(CCCCc1nccc(NC(N)=NCC(F)(F)F)n1)=NC#N
Reaction time: 18 h

Procedure:
To a solution of methyl 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valerimidate dihydrochloride (0.5 g.) in MeOH (10 ml.) was added triethylamine (0.125 g.) and cyanamide (0.08 g.) and the mixture was stirred for 18 hours at 20°. Volatile material was evaporated in vacuo and the residue was triturated with a mixture of ether and EtOH to give crude methyl N-cyano-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valerimidate as a white solid which was used without further purification.