Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:10][CH2:9][C:8]1=O)=[O:5])[CH3:2]>O1CCCC1>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)CCNc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCNc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (173 mg) in tetrahydrofuran (5 ml) was added diborane dimethylsulfide complex (10 mol solution, 0.5 ml) and the mixture was stirred at ambient temperature for 8 hours. The solution was washed with water and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo and a residue was purified by silica gel column to give 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (125 mg) as a pale brown oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])[CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:9])[CH2:2]1
Reactant: O=C(OCC1CCOC1)N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(OCC1CCOC1)N1CCNCC1
Yield: 103.3 %

Procedure:
4-Benzyl-piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester (11.0 g) was dissolved in 100 ml ethanol. Palladium on carbon (10% Pd/C, 0.5 g) was added, and a hydrogen atmosphere was applied overnight at room temperature. The solution was filtered through Celite to remove the catalyst, and the Celite cake was rinsed with 50 ml ethanol. The combined filtrates were evaporated to dryness to yield piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester (8.0 g) as a colorless oil.
Reaction SMILES: CN1CCN(C2C=CC(N[CH:15]=[C:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([C:36]6[C:40]([Cl:41])=[CH:39][N:38]([CH2:42][CH3:43])[N:37]=6)=[O:35])[CH:30]=[CH:31][CH:32]=5)=[O:26])=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:44])=CC=2)CC1.C1COCC1.[N:50]1([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[CH2:54][CH2:53][CH2:52][CH2:51]1>CCOC(C)=O.CCCCCC>[O:44]=[C:17]1[C:16](=[CH:15][NH:62][C:59]2[CH:58]=[CH:57][C:56]([CH2:55][N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:61][CH:60]=2)[C:24]2[C:19](=[CH:20][C:21]([C:25]([C:27]3[CH:28]=[C:29]([NH:33][C:34]([C:36]4[C:40]([Cl:41])=[CH:39][N:38]([CH2:42][CH3:43])[N:37]=4)=[O:35])[CH:30]=[CH:31][CH:32]=3)=[O:26])=[CH:22][CH:23]=2)[NH:18]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN4CCCC4)cc3)c2)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 342, 100 mg, 0.229 mmol) and THF (2.5 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (40.3 mg, 0.229 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. acetone (˜10 mL) affording the title compound in 31% yield (0.043 g, 0.072 mmol).
Reaction SMILES: CN1C(=O)N(C)CC1.CS(O[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O.Cl.Cl.[N:32]1([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CCOC(C)=O>[C:38]1([N:32]2[CH2:33][CH2:34][N:35]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:36][CH2:37]2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][N:39]=1
Reactant: c1ccc2c(N3CCNCC3)nccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOS(C)(=O)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCCN2CCN(c3nccc4ccccc34)CC2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A DMI (20 ml) suspension of tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (1.00 g), 1-piperazin-1-yl-isoquinoline dihydrochloride (980 mg), cesium carbonate (1.02 g) and sodium iodide (467 mg) was stirred at 140° C. for 1 hour. EtOAc was added to the reaction liquid, washed with water and aqueous saturated sodium hydrogencarbonate solution in that order, then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain tert-butyl 4-[3-(4-isoquinolin-1-ylpiperazin-1-yl)propyl]piperidine-1-carboxylate (1.07 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:12]=2[C:13](O)=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].Cl.C[N:33](C)CCCN=C=NCC.C1C=C2N=NN(O)C2=CC=1.O.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:12]=2[C:13]([NH2:33])=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(N)=O)c1
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenzoic acid (Example 4) (130 mg, 0.34 mmol) in DMF (5 mL) were added ammonium chloride (22 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol), HOBT hydrate (56 mg, 0.41 mmol), and triethylamine (0.17 mL, 1.20 mmol). The reaction mixture was stirred for 16 h and then concentrated under reduced pressure. The residue was purified by HPLC (45-90% acetonitrile in water) to afford the product (63 mg, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (s, 9H), 1.97 (s, 3H), 3.71 (s, 3H), 6.03 (s, 1H), 7.04 (dd, 1H), 7.24-7.37 (m, 6H), 7.44 (s, 1H), 8.05 (s, 1H), 10.01 (s, 1H); ES-MS m/z 379.3 (MH+); HPLC RT (min) 2.83.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:7][CH2:8]Cl)[CH:3]=[C:4]([Cl:6])[Cl:5].N1C2C(=CC=CC=2)C=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:5][C:4]([Cl:6])=[CH:3][C:2]([CH3:10])([CH3:1])[CH:7]=[CH2:8]
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(C)C=C(Cl)Cl
Yield: 73.3 %

Procedure:
201.5 g (1 mol) of 3,3-dimethyl-1,1,5-trichloro-1-pentene are slowly added dropwise into 1 l of quinoline, and 83 g potassium carbonate at 225° to 230° C., and distillate is simultaneously taken off via the head of a column. The temperature in the flask is raised to the boiling point of the quinoline, and a total of 126 g of distillate is isolated, the distillate again being fractionally distilled. 121 g (73% of theory) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene are obtained at a boiling point of 59°-53° C./20 mm Hg.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:14][C:15]([C:17]1[CH:21]=[C:20]([CH2:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])[N:19]([CH2:34][CH2:35][CH3:36])[N:18]=1)=O.C(N(CC)CC)C>ClCCl>[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])[N:19]([CH2:34][CH2:35][CH3:36])[N:18]=1)#[N:14]
Reactant: CCCn1nc(C(N)=O)cc1CC(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCn1nc(C#N)cc1CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
A solution of trifluoroacetic anhydride (3.93 mL, 27.8 mmol) in dichloromethane (51 mL) was added slowly to a 0° C. solution of tert-butyl 2-[3-(aminocarbonyl)-1-propyl-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate (8.21 g, 25.3 mmol) and triethylamine (10.6 mL, 75.9 mmol) in dichloromethane (51 mL). After the addition was complete, the cooling bath was removed and the solution was stirred for 90 minutes. The solution was transferred to a separatory funnel and washed with 2 M aqueous sodium carbonate (200 mL). The aqueous layer was extracted twice with chloroform. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an off white solid that was recrystallized from 10% ethyl acetate in hexanes, isolated by filtration, and dried to yield 6.77 g of tert-butyl 2-(3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate as a white crystals, mp 115-116° C. MS (ESI) m/z 307 (M+H)+; Anal. Calcd for C16H26N4O2: C, 62.72; H, 8.55; N, 18.28. Found: C, 62.61; H, 8.46; N, 18.52.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][CH:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[Cl-].[NH4+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][CH:25]([CH:28]([OH:30])[CH3:29])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1
Reactant: CC(=O)C1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)C1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
1-(1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidin-4-yl)ethanone (100 mg, 0.25 mmol) was dissolved in 10 ml of methanol. This solution was cooled down to 0° C. using an ice bath and sodium tetraborohydride (19 mg, 0.50 mmol) was added in portions. The reaction mixture was stirred for 4 hours at ambient temperature, and then saturated aqueous solution of ammonium chloride (5 mL) was added. The methanol was evaporated off under reduced pressure then the reaction mixture was taken up in ethyl acetate. The organic layer was separated from the aqueous layer. This extraction was repeated one more time and then the organic layers were combined and dried over magnesium sulphate, followed by concentrating under reduced pressure. The residue was purified by column chromatography on silica gel to give (racemic mixture) 1-(1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidin-4-yl)ethanol (75 mg, 0.19 mmol, 75% yield). ESI-MS (M+1): 406 calc. for C23H27N5O2 405.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OC(=O)C)C>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NCCc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 90307.4 %

Procedure:
1-Chloro-4-(2-nitro-vinyl)-benzene (I-1a: 3.4 g, 0.0185 mmol) dissolved in dry THF (50 mL) was added dropwise to a stirred suspension of LAH (1.3 g, 0.03707 mmol) in dry THF (50 mL) over a period of 20 minutes at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 45° C. for 3 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was cooled to room temperature, quenched with 10% NaOH solution (3 mL), and filtered through Celite® bed. The filtrate was washed with ethylacetate and concentrated under reduced pressure to afford 2.6 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15]Cl.O>CC(C)CC(=O)C>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=C(CCl)c1ccc(F)cc1F
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(Cn1cccn1)c1ccc(F)cc1F
Yield: 77.9 %

Procedure:
A mixture of 1H-pyrazole (1.3 mol) in 4-methyl-2-pentanone (500 ml) was stirred and refluxed. 1-(2,4-difluorophenyl)-2-chloroethanone (0.26 mol) dissolved in 4-methyl-2-pentanone (500 ml) was added dropwise and the mixture was stirred and refluxed for 3 h. The mixture was cooled, poured into water and separated. The organic layer was evaporated. The residue was stirred up in HCl/water, filtered off and washed with water. The precipitate was stirred up in hexane, filtered off and dried in vacuo at 45° C., yielding 45 g (78%) of 1-(2,4-difluorophenyl)-2-(1H-pyrazol-1-yl)ethanone; mp. 76.4° C. (interm. 12).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>O1CCCC1>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[CH3:23])=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[O:22])=[O:18])[CH3:21]
Reactant: Cc1ccccc1CN
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1NCc1ccccc1C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
In a flame-dried, three-necked round-bottomed reaction flask equipped with reflux condenser, magnetic stirring bar and rubber septum, there was placed 1.0 g (0.0031 mole) of 4-chloro-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline (the product of Preparation C) dissolved in 10 mL of dry tetrahydrofuran. Stirring was commenced and 0.8 mL (750 mg, 0.0062 mole) of 2-methylbenzylamine (available from the Aldrich Chemical Company, Inc. of Milwaukee, Wis.), was added over a two-minute period at room temperature (ca. 20° C.). The well-stirred reaction mixture was then heated to 60° C. and thereafter kept at that temperature for a period of approximately 16 hours (i.e., overnight). Upon completion of this step, the resulting reaction mixture was then filtered to remove 2-methylbenzylamine hydrochloride that had precipitated from the mixture and the filtrate was subsequently evaporated to near dryness while under reduced pressure to afford a crude solid product as the residue. The latter material was then purified by means of column chromatography over silica gel, using a 1% solution of diethylamine in ethyl acetate as the eluant. In this manner, there was ultimately obtained a 43 mg (3%) yield of pure 3-(3-ethoxycarbonylpropionyl)-8-methoxy-4-(2-methylbenzylamino)quinoline as the free base compound (isolated as a 0.25 hydrate), m.p. 152°-155° C. The pure product was further characterized by means of mass spectrum (MS) analysis and nuclear magnetic resonance (NMR) data, in addition to elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1)C(=O)OCC
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10 g of 3,4-dimethoxyaniline in 13.2 cm3 of diethyl ethoxymethylenemalonate was stirred for 1.5 hours at a temperature in the region of 110° C. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. 21.1 g of diethyl 2-[(3,4-dimethoxyphenylamino)methylene]malonate were obtained in the form of a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26](O)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[Cl-].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:45]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26]([Cl:45])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(Cl)ncn3)ccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 200 mg (0.453 mMol) 6-(6-hydroxy-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide in 15 ml CH3CN, 165.7 mg (1.0 mMol) tetrmethylammonium chloride, 127 μl (1.0 mMol) N,N-dimethylaniline and 0.55 ml (6.0 mMol) POCl3 are added. The mixture is heated up to 75° C. for 1 h, cooled to rt and poured into 30 g ice. After 1 h of vigorous stirring, the title compound can be filtered off and washed with 6 ml CH3CN/H2O 1:2: MS: [M+1]+=460/462; HPLC: tRet=16.5.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[N:10]([CH3:19])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:17][N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][S:30]([C:24]4[C:25]([CH3:29])=[N:26][N:27]([CH3:28])[C:23]=4[Cl:22])(=[O:31])=[O:32])=[CH:3][CH:4]=3)=[N:8][C:9]=2[N:10]([CH3:19])[C:11]1=[O:18]
Reactant: Cn1c(=O)c2[nH]c(Cc3ccc(N)cc3)nc2n(C)c1=O
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of crude 8-(4-amino-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (0.2 mmol) in pyridine (2 mL) at 0° C. was added 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.2 mmol) and the mixture left to stir and warm slowly to ambient temperature overnight. The reaction mixture was poured into ethyl acetate, washed with 1M aqueous hydrochloric acid until all pyridine was removed from the organic phase and the combined aqueous washings back extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo to give an orange solid. Purified by trituration with warm acetonitrile to give 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide as a pale orange solid (51%); EI-HRMS m/e calculated for C19H20ClN7O4S (M+) 477.0986, found 477.0994.
Reaction SMILES: C(=O)(O)[O-].[Na+].[O:6]=[C:7]1[N:15]([C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH2:14][CH2:13][C:8]21[NH:12][CH2:11][CH2:10][CH2:9]2.[C:21](=O)([O:37]N1C(=O)CCC1=O)[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>O.CC(C)=O>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([N:12]3[C:8]4([CH2:13][CH2:14][N:15]([C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:7]4=[O:6])[CH2:9][CH2:10][CH2:11]3)=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: C[C@@H](C(=O)O)N1CCC2(CCCN2)C1=O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](C(=O)O)N1CCC2(CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Reaction time: 18 h
Yield: 72.1 %

Procedure:
Excess solid sodium bicarbonate was added to (S)-2-(6-oxo-1,7-diazaspiro[4.4]non-7-yl)propionic acid (0.42 g) in water (2 ml) and then 9-fluorenylmethyl succinimidyl carbonate (0.7 g) in acetone (3 ml) was added. The mixture was stirred for 18 hours. The mixture was then added to water (10 ml), extracted with ether (10 ml) and the aqueous layer separated. (The ether extracts were discarded). The pH of the aqueous layer was adjusted to ˜3 with concentrated hydrochloric acid and then it was extracted with dichloromethane (2×10 ml). The combined extracts were separated, dried (MgSO4) and evaporated to give (S)-2-[1-(9-fluorenylmethyloxycarbonyl)-6-oxo-1,7-diazaspiro[4.4]non-7-yl]propionic acid (0.62 g) as a white foam; NMR (d6-DMSO (373K)): some doubling of peaks due to the mixture of diastereoisomers, 1.3 (2d, 3H), 1.6-2.0 (m, 6H), 3.05 (m, 1H), 3.2-3.45 (m, 3H) 4.2-4.4 (m, 1H), 4.5 (m, 1H), 6.2 (s, 2H), 7.35 (m, 4H), 7.8 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][CH:7]=1.C(OC(CC1C2SC=CC=2C(O[CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=CC=1)C(O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=[CH:8][CH:7]=1
Reactant: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)O)c3sccc23)c(C)o1
Reactant: COC(=O)C(Cc1ccc(O)c2ccccc12)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OC)C(=O)OC)c3ccccc23)c(C)o1

Procedure:
In analogy to the procedure described in example 17 a], [rac]-3-(4-hydroxy-naphthalen-1-yl)-2-methoxy-propionic acid methyl ester was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (example 95) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-methoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-methoxy-propionic acid as colorless solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH3:9][N:10]1[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH2:18])[C:12]([CH2:19][CH2:20][CH3:21])=[N:11]1>ClCCl>[NH2:17][C:15]([C:14]1[N:10]([CH3:9])[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[C:13]=1[NH:18][C:5]([CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[O:16]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: O=C1COCC(=O)O1
Solvent: ClCCl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)COCC(=O)O
Reaction time: 1 h

Procedure:
1.1 13.5 g of diglycolic anhydride are added at 15° to a solution of 20.5 g of 1-methyl-3-propyl4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”) in 400 ml of dichloromethane, and the mixture is stirred for a further 1 hour. The mixture is subjected to conventional work-up, giving 32.5 g of [(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol4-ylcarbamoyl)methoxy]-acetic acid (“Z7”).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][CH:16]([CH2:18][O:19][CH3:20])[O:15][C:14]3=[O:21])=[CH:9][C:8]=2[N+:22]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:22][C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][CH:16]([CH2:18][O:19][CH3:20])[O:15][C:14]2=[O:21])[CH:11]=[CH:12][C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCC1CN(c2ccc(C3CCCCC3)c([N+](=O)[O-])c2)C(=O)O1
Agent: [Pd]
Solvent: CCO
Product: COCC1CN(c2ccc(C3CCCCC3)c(N)c2)C(=O)O1
Yield: 32.9 %

Procedure:
0.5 g (1.5 mmol) of (RS)-3-(4-cyclohexyl-3-nitrophenyl)-5-methoxymethyl-oxazolidin-2-one (from the mother liquor of the foregoing reaction) in 75 ml of ethanol was treated with 100 mg of 10 percent palladium-on-charcoal and hydrogenated at room temperature for 5 hours. Filtration, concentration and recrystallization from ethyl acetate gave 150 mg of white crystals with m.p. 130°-132°.