Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].[C:27](O)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C(N(C(C)C)CC)(C)C>C(#N)C>[C:2]([NH:4][C@@H:5]1[C:15]2[CH:16]=[C:17]([O:20][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:35])[CH:18]=[CH:19][C:14]=2[C:13]2[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:1]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: O=C(O)CCCCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCCCC(=O)O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
N-Acetyl-colchicinol (0.3 g; 0.84 mmol) was added under argon atmosphere to a solution of adipic acid (0.147 g; 1 mmol, O-(7-(azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.383 g; 1 mmol) and diisopropylethylamine (0.352 ml; 2 mmol) in acetonitrile (20 ml). The reaction mixture was stirred at ambient temperature overnight and evaporated to dryness. The residue was taken up in water (4 ml), the pH was adjusted to 6.5 with 0.1M hydrochloric acid. The solution was purified by preparative HPLC eluting with a 0–40% gradient of methanol/ammonium carbonate buffer (2 g/l pH7) to give 5-[{(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl}oxycarbonyl]pentanoic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O.O.O.C([O-])(=[O:22])C.[Na+].[Cl-].[OH-].[Na+]>C(O)C.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:22]
Reactant: CC(=O)[O-]
Reactant: BrCCCCCCOCCc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCCCCOCCc1ccccn1
Yield: 70.3 %

Procedure:
A mixture of 2-[2[(6-bromohexyl)oxy]ethyl]pyridine (9.0 g), sodium acetate trihydrate (34.24 g), trictylpropylammonium chloride (1.9 g) and water (25 ml) was stirred under reflux for 2 h. 2N sodium hydroxide solution (50 ml) and ethanol (50 ml) were added to the cooled mixture which was further stirred for 10 min at room temperature. The ethanol was evaporated in vacuo and the residue diluted with brine (150 ml) and extracted with ether (2×100 ml). The combined organic extracts were washed successively with water (150 ml), brine (100 ml), dried and evaporated in vacuo to give a yellow oil. Purification by FCC eluting with ether gave the title compound as a colourless oil (4.94 g), t.l.c. (ether) Rf 0.31.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH:8]([OH:14])[C:9]([CH3:13])([CH3:12])[CH2:10][Cl:11])=[CH:4][CH:3]=1.[Cl:22][CH:23]([Cl:27])[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH:8]([O:14][C:24](=[O:25])[CH:23]([Cl:27])[Cl:22])[C:9]([CH3:12])([CH3:13])[CH2:10][Cl:11])=[CH:20][CH:21]=1
Reactant: CC(C)(CCl)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Reactant: O=C(Cl)C(Cl)Cl
Product: CC(C)(CCl)C(OC(=O)C(Cl)Cl)C(Oc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
19.8 g (0.06 mol) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-3,3-dimethyl-4-chlorobutan-2-ol were added to 200 ml of dichloroacetyl chloride at 0° C. The mixture was stirred at room temperature for 24 hours and excess dichloroacetyl chloride was distilled off in vacuo. The oil which remained was taken up in 400 ml of methylene chloride, the methylene chloride mixture was neutralized with 500 ml of aqueous sodium bicarbonate solution, the organic phase was separated off, washed with 200 ml of water and dried over sodium sulphate. The solvent was distilled off and the residue was taken up in 200 ml of diisopropyl ether. After leaving the mixture to stand for several hours, colorless crystals precipitated. 7.5 g (29% of theory) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-2-dichloroacetoxy-3,3-dimethyl-4-chloro-butane of melting point 108°-110° C. were obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)N1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 90.8 %

Procedure:
Add acetic anhydride (0.084 ml, 0.89 mmol) to a solution of (2R,3S,5R)-5-[(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (400 mg, 0.85 mmol) in dry dichloromethane (9 mL). Add triethylamine (0.179 mL, 1.27 mmol), stir 1 hour at room temperature, concentrate and purify (silica gel cartridge chromatography, eluting with 1:1 hexanes:ethyl acetate) to give the title compound as a white solid (397 mg, 91%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:23][CH2:22][CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 41.3 %

Procedure:
A mixture of 0.6 g (2.2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.25 g (4.4 mmol) of azetidine and 1 ml of triethylamine in 8 ml of pyridine is heated to 110° C. in a closed vessel for 2 hours. The mixture is allowed to cool and is filtered and the product is washed with water, ethanol and ether. 0.275 g of 1-cyclopropyl-6-fluoro-7-(1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point 291°-4° C., is thereby obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].C[O-].[Na+].O/[N:14]=[C:15](\Cl)/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH3:1][O:2][C:3]([C:4]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][O:8][C:5]=1[CH2:6][CH3:7])=[O:9]
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1onc(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-oxo-pentanoic acid methyl ester (19.3 g, 0.15 mol) in methanol (30 mL) was added a solution of sodium methoxide (8.1 g, 0.15 mol) in methanol (30 mL) dropwise under ice-bath cooling keeping the temperature below 30° C. The reaction mixture was then stirred at room temperature for 30 min. Then a solution of (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (21.7 g, 0.14 mol, in Example 1a) in methanol (78 mL) was added to this mixture under ice-bath cooling keeping the temperature below 0° C. After adding, the ice-bath was removed and stirring was continued overnight at room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulphate and concentrated to give the title compound as a yellow oil which was used in the next reaction without further purification. MS: m/e=232.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)C.ClCCl>[OH:1][C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C[C@H](O)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In 0.5 ml of dried and degassed DMF were dissolved 4.9 mg (15 μmol) of (R,R)-t-Bu-QuinoxP*(1) and 3.4 mg (6.7 μmol) of [RuCl2(η6-C6H6)]2 in a nitrogen atmosphere. The mixture was heated at 100° C. for 10 minutes. After cooling to 50° C., the solvent was removed by evaporation under reduced pressure to give a catalyst as a reddish to purple solid. The resulting catalyst was dissolved in 3 ml of degassed ethanol in a glove box. To the solution was added a solution of 129 mg (0.67 mmol) of ethyl 3-oxo-3-phenylpropionate in 1 ml of dichloromethane, and the mixture was transferred into a stainless steel autoclave. After purging the autoclave with hydrogen four times, hydrogen was introduced into the autoclave to 20 atm. The reaction mixture in the autoclave was stirred at 50° C. for 24 hours. After cooling to room temperature, hydrogen gas was released from the autoclave. The solvent was removed, and the residue was dissolved in diethyl ether. The resulting solution was washed successively with water and a sodium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. Any volatile matter was removed by evaporation, and the residue was purified by silica gel column chromatography to give the title compound, ethyl (S)-3-hydroxy-3-phenylpropionate.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:14][CH3:15])([CH3:13])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:17]1[C:18]([CH3:27])=[CH:19][C:20]2[N:21]([N:23]=[C:24]([CH3:26])[N:25]=2)[N:22]=1>>[CH2:14]([C:10]([CH3:13])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:17]1[C:18]([CH3:27])=[CH:19][C:20]2[N:21]([N:23]=[C:24]([CH3:26])[N:25]=2)[N:22]=1)[CH3:15]
Reactant: Cc1nc2cc(C)c(Cl)nn2n1
Reactant: CCC(C)(CO)CS(=O)(=O)N=CN(C)C
Product: CCC(C)(COc1nn2nc(C)nc2cc1C)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-ethyl-2-methyl-1-propanol and 6-chloro-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 194°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[CH:19][N:18]=[CH:17]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH2:22]=[O:23]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]2[CH2:22][OH:23])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1cncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1cnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 1, 2.96 g. of 5-chloro-2-(5-methylimidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 5-chloro-2-[5-methyl-2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: Br[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6][C:5]=2[S:4][CH:3]=1.[NH4+].[Cl-:16]>CN(C=O)C.Cl[Cu]>[Cl:16][C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6][C:5]=2[S:4][CH:3]=1
Reactant: [Cl-]
Reactant: CCOC(=O)c1cc2c(Br)csc2[nH]1
Agent: Cl[Cu]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)csc2[nH]1
Yield: 86 %

Procedure:
To a solution of ethyl 3-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.25 g, 0.93 mmol) in DMF (37.5 mL) was added CuCl (178 mg, 1.85 mmol). The combined reactants were heated to reflux for 7 h, at which time the cooled mixture was diluted with a saturated solution of NH4Cl (20 mL) and extracted with Et2O (3×40 mL). The combined organic fractions were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification of the crude oil by flash column chromatography (25% EtOAc in hexanes) afforded ethyl 3-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.18 g, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4](Cl)[N:3]=1.CS(C)=O.O.[NH2:16][NH2:17]>O>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][NH2:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(Cl)nc(NN)c1

Procedure:
A solution of 30.6 g of 2,6-dichloropyridine-4-carbonitrile and 100 ml of dimethylsulfoxide was cooled to 0° C. in an ice bath and 26 g of hydrazine hydrate was added dropwise at a rate such that the temperature remained below 30° C. A heavy yellow precipitate formed and, after 2 hours, the reaction mixture was poured into 200 ml of water. The yellow solid was collected by filtration and dried to give 6-chloro-2-hydrazinopyridine-4-carbonitrile melting at about 208°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[NH:46]1[CH2:50][CH2:49][C@@:48]2([C:58]3[CH:57]=[CH:56][N:55]=[CH:54][C:53]=3[C:52](=[O:59])[O:51]2)[CH2:47]1.C(N(CC)C(C)C)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:46]3[CH2:50][CH2:49][C:48]4([C:58]5[CH:57]=[CH:56][N:55]=[CH:54][C:53]=5[C:52](=[O:59])[O:51]4)[CH2:47]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(O)cc2)CC1
Reactant: O=C1O[C@]2(CCNC2)c2ccncc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 193.7 %

Procedure:
A solution of 1-(4-hydroxyphenyl)cyclopropanecarboxylic acid (0.250 g, 0.00140 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.652 g, 0.00147 mol) in N,N-dimethylformamide (2.0 mL, 0.026 mol) was stirred at rt for 10 minutes. The solution then was cooled to 0° C. and (1R)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (0.53 g, 0.0014 mol) was added to the solution followed by N,N-diisopropylethylamine (610 μL, 0.0035 mol). The resulting mixture was stirred at room temperature overnight. After work-up, 0.95 g of the crude product was obtained, which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([S:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)=[CH:29][CH:28]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: Nc1ccc(Sc2ccccn2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)cc3)c(C#N)cnc2cc1F
Yield: 77 %

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 542.1 mg (2.81 mmol) of 4-(pyridin-2-ylsulfanyl)phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to provide 830 mg of 7-fluoro-6-methoxy-4-[4-(pyridin-2-ylsulfanyl)-phenylamino]quinoline-3-carbonitrile as an off-white solid, mp 231-233° C.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A 4 mol/L aqueous solution of sodium hydroxide (0.3 mL) was added to an ethanol (2.1 mL) solution of the obtained methyl 2-(benzyloxy)-5-(morpholin-4-yl)benzoate (0.26 g), followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were sequentially added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.17 g of 2-(benzyloxy)-5-(morpholin-4-yl)benzoic acid as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCCCCCN
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCN
Reaction time: 7 h
Yield: 77 %

Procedure:
In this synthesis CDTAMA is reacted with the monoprotected diamine N-(t-butyoxycarbonyl)-1,6-diaminohexane to give the corresponding amide. The t-Boc protecting group is then hydrolyzed to give the product. To prepare the monoprotected diamine N-(t-butyoxycarbonyl)-1,6-diaminohexane, first 9.4 g (81.2 mmol) of 1,6-diaminohexane is dissolved in 60 ml dry chloroform and 0.85 ml (6.1 mmol) triethylamine is added. To this solution is added dropwise 1 g (4.1 mmol) [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) dissolved in 20 ml dry chloroform. This solution is stirred 7 hr, filtered and the filtrate evaporated to an oil. This oil is vacuum distilled to remove the excess 1,6-diaminohexane. The residue in the distillation flask is dissolved in acetone and purified on a silica gel chromatography column (eluted with acetone) to give 0.68 g (77%) of N-(t-butoxycarbonyl)-1,6-diaminohexane as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH2:16])=[C:7]([C:14]#[CH:15])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:16][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][C:7]=1[C:14]#[CH:15]
Reactant: C#Cc1cc2cn[nH]c2c(C(=O)OC)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C#Cc1cc2cn[nH]c2c(C(=O)O)c1N
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 200 mg (0.93 mmol) of 6-amino-5-ethynyl-1H-indazole-7-carboxylic acid methyl ester in 4.2 mL of dioxane and 0.2 mL of methanol is added 2.3 mL (2.3 mmol) of a 1N aqueous solution of NaOH. The mixture is stirred for 5 hours at 50° C. The solvents are evaporated and water is added to the residue. The product is precipitated at pH 4 by addition of 1N aqueous HCl, filtrated, washed with a minimum of water and dried by azeotropic distillation with toluene. The yellowish solid obtained is used directly in the next step; LC/MS: 202/203 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9].[CH3:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][C:14]=1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:2][NH:1][C:24]([C:14]1[CH:15]=[N:16][N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[CH3:12])=[O:25]
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cnn(-c3ccccc3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.9 %

Procedure:
A mixture of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (70 mg, 0.46 mmol), 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (93 mg, 0.46 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and triethylamine (70 mg, 0.69 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 15 hours. Then the mixture was filtered and the solid was washed with water (10 mL), methanol (10 mL) and dichloromethane (10 mL) in turns to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide as a white solid (40 mg, 26%). LRMS (M+H+) m/z: calcd 336.16. found 336.
Reaction SMILES: [CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][N:2]=1.[H][H]>[Ni].C(O)C>[CH2:1]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: [H][H]
Reactant: C1=NCCCC12CCCCC2
Agent: [Ni]
Solvent: CCO
Product: C1CCC2(CC1)CCCNC2
Yield: 88.1 %

Procedure:
A solution of 2-azaspiro-[5.5]-undec-1-ene (15 g.; 0.10 mole) and one teaspoon (3 g.) of W2 Raney nickel catalyst in absolute ethanol (300 ml.) is hydrogenated at an initial pressure of B 40 psi until hydrogen uptake ceases (2 hours). The mixture is filtered through celite and the filtrate concentrated under reduced pressure. Distillation of the residual liquid yields 88% of 2-azaspiro-[5.5]-undecane (13.5 g.), b.p. 55°-57° C./0.10 mm.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.