Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])#[N:2].[CH3:13][N:14]1[C@H:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][O:16][C:15]1=[O:26].CO>O=[Pt]=O.C(Cl)(Cl)Cl>[CH3:13][N:14]1[C@H:18]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][O:16][C:15]1=[O:26].[NH2:2][CH2:1][CH2:3][CH2:4][C@H:5]([CH2:9][C:10]([O-:12])=[O:11])[C:6]([O-:8])=[O:7]
Reactant: N#CCC[C@H](CC(=O)O)C(=O)O
Agent: O=[Pt]=O
Agent: CN1C(=O)OC[C@H]1Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCC[C@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 71 (2.0 g, 5.8 mmol), PtO2 (0.8 g), CH3OH (50 mL), and CHCl3 (5 mL) were shaken on the Parr apparatus under a hydrogen atmosphere (60 PSI) at ambient temperature for 3 hours. The reaction mixture was filtered through a celite pad and then concentrated to furnish the crude amine.HCl 72 as a yellow oil.
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.[CH2:13]([O:15][C:16]([CH:18]1[CH:30]([CH2:31][O:32][CH3:33])[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH2:34][O:35][C:36](=[O:38])[CH3:37])[NH:22][C:21]=2[CH:20](C(O)=O)[NH:19]1)=[O:17])[CH3:14].ClCCl.CO>O=O>[CH2:13]([O:15][C:16]([C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:23]3[C:28]([C:29]=2[C:30]=1[CH2:31][O:32][CH3:33])=[C:27]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH:26]=[CH:25][CH:24]=3)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1NC(C(=O)O)c2[nH]c3cccc(COC(C)=O)c3c2C1COC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1ncc2[nH]c3cccc(COC(C)=O)c3c2c1COC
Reaction time: 9 h
Yield: 98.3 %

Procedure:
90% Azodicarboxylic acid diethyl ester (76 ml) without addition of heat with stirring is added drop by drop to a solution of 5-acetoxymethyl-4-methoxymethyl-1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylic acid-3-ethyl ester (75 g) in oxygen-free dichloromethane (0.6 l) under argon protection. The temperature rises about 10° C. Reflux is performed for about 9 hours, then the mixture is left at room temperature for 60 hours. The precipitate is suctioned off, further end product can be obtained from the evaporated mother liquor after chromatography on silica gel with a mixture of dichloromethane (95%) with methanol (5%). Altogether 65 g of the title compound in the form of colorless crystals with a melting point of 129°-133° C. is obtained.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:23][CH2:24][CH3:25])[NH:8][C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:4])[CH3:3].[C:26]([N:45]1[C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]2[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=2)=[N:48][N:47]=[N:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:23][CH2:24][CH3:25])[N:8]([CH2:60][C:59]2[CH:58]=[CH:57][C:56]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[C:49]3[N:45]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:46]=[N:47][N:48]=3)=[CH:63][CH:62]=2)[C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:3])[CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 18.1 %

Procedure:
Following a procedure similar to that described in Example 61(a), but using 0.456 g of phthalidyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 32), 0.736 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.366 g of potassium carbonate, 0.196 g of the title compound was obtained, melting at 118°-120° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH3:2].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:5](=[O:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CCOC(OCC)C(=O)Cl
Product: CCOC(OCC)C(=O)NCc1ccccc1

Procedure:
Ethyl diethoxyacetate (Ex. Fluka) (25 g) was added to sodium hydroxide (5.68 g) in ethanol (60 ml) and water (30 ml). After heating under reflux for 5 hours the solvents were removed at reduced pressure and the residue dried in vacuo to give sodium diethoxyacetate (23.2 g). The salt was then converted to diethoxyacetyl chloride and reacted with benzylamine to give N-benzyl diethoxyacetamide which was cyclised with conc. sulphuric acid according to Fukumi and Hideshi, Heterocycles, 9, 1197 (1978) to give 3-hydroxyisoquinoline.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][C:21]=2[CH3:23])[N:16]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:15]1=[O:31])[CH3:13].[H-].[Na+].[Cl-].[Cl-].[Ca+2].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][C:21]=2[CH3:23])[N:16]([C:24]2[CH:29]=[CH:28][C:27]([O:30][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[CH:26][CH:25]=2)[C:15]1=[O:31])[CH3:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(C)c21

Procedure:
Triisopropylsilyl chloride (2.384 mL) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2 g) and NaH (0.594 g) in DMF (20 mL) at 20° C. The mixture was stirred at 20° C. under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was poured into sat. NaHCO3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-25% EtOAc in hexane) to give 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.0 g) as light brown crystals.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][N:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc2nc3ccc4ccncc4c3nc12
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4ccncc4c3nc12

Procedure:
Pyrido [3,4-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrido[3,4-α]phenazine-11-carboxylic acid (II.2) and N,N-dimethylethylenediamine
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[F:10][C:6]1[C:3]2[CH:4]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[S:13][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c(F)cccc2s1

Procedure:
Using 5.0 g (35.2 mmol) of 2,6-difluorobenzaldehyde, 2.11 g (52.8 mmol) of sodium hydride (60% pure) and 4.11 g (38.7 mmol) of methyl mercaptoacetate, 5.61 g (72.8% of theory) of the title compound are obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:25]=[CH:24][C:12]3[N:13]([C@H:17]4[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]4)[CH2:14][CH2:15][O:16][C:11]=3[CH:10]=2)O1.[CH2:27]([N:31]1[CH:36]=[CH:35][C:34](OS(C(F)(F)F)(=O)=O)=[C:33]([Cl:45])[C:32]1=[O:46])[CH2:28][CH2:29][CH3:30].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[CH2:27]([N:31]1[CH:36]=[CH:35][C:34]([C:9]2[CH:25]=[CH:24][C:12]3[N:13]([CH:17]4[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]4)[CH2:14][CH2:15][O:16][C:11]=3[CH:10]=2)=[C:33]([Cl:45])[C:32]1=[O:46])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O
Reactant: CC1(C)OB(c2ccc3c(c2)OCCN3[C@H]2CC[C@H](O)CC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCn1ccc(-c2ccc3c(c2)OCCN3C2CCC(=O)CC2)c(Cl)c1=O
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A mixture of intermediate D15 (0.15 g, 0.418 mmol), intermediate D4 (0.139 g, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0241 g, 0.0209 mmol) and an aqueous saturated NaHCO3 solution (1 ml) in dioxane (4 ml), was heated at 150° C. for 10 min. under microwave irradiation. After cooling to r.t., the r.m. was filtered through diatomaceous earth, treated with EtOAc and the organic layer was washed with water and then with brine. The organic fraction was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; 0-10% EtOAc/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield D23 (0.027 g, 15.59%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:7][CH:6]=1.C1COCC1.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44].CCN(C(C)C)C(C)C>O>[CH2:43]([NH:45][C:46]([N:31]1[CH2:30][C:29]([CH3:37])([CH3:36])[N:28]([CH2:27][C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=3)[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]=23)[CH2:33][C:32]1([CH3:35])[CH3:34])=[O:47])[CH3:44]
Reactant: CCN=C=O
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(OCOC)cc3)nc3c2c(C)nn3C2CCCCO2)CC1(C)C
Yield: 98.3 %

Procedure:
To a solution of 290 mg 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine in 3 ml abs. THF were added 41 mg ethyl isocyanate and 75 mg Hünig's base. After 16 h at rt water was added, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate twice and the combined organic layers were dried and concentrated in vacuo. 325 mg of the title compound were obtained, which were subjected to the subsequent reaction without further purification.
Reaction SMILES: N1CCCCC1.O[CH:8]1[CH2:13]SC(O)C[S:9]1.[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]>>[NH2:16][C:15]1[S:9][CH:8]=[CH:13][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC#N
Reactant: OC1CSC(O)CS1
Solvent: C1CCNCC1
Product: CCOC(=O)c1ccsc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Piperidine (20.7 ml) was added dropwise with stirring to a mixture of 2,5-dihydroxy-1,4-dithiane (17.5 g) and ethyl cyanoacetate (23.7 g). The mixture was stirred at room temperature for 4 hours and then allowed to stand overnight. It was filtered and the filtrate evaporated to dryness. The residue was dissolved in ether, filered and evaporated to dryness. The residue was triturated with light petroleum (b.p. 60-80° C.) containing a small amount of ethyl acetate. The gummy solid obtained was purified by silica gel column chromatography and the semi-solid product was triturated with water, filtered and washed with light petroleum (b.p. 60-80° C.) and dried to give the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: BrCC1CC1
Product: CCOC(=O)c1c([N+](=O)[O-])cnn1CC1CC1
Yield: 23 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and bromomethyl-cyclopropane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 179 mg (46%) of the desired regioisomer and 88 mg (23%) of 2-cyclopropylmethyl-4-nitro-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([OH:18])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][N:62]([C:16]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][N:10]=2)=[O:18])[CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:48]=[CH:49][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:51][CH:52]=1)=[O:46]
Reactant: O=C(O)c1cnccn1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cnccn2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of pyrazine-2-carboxylic acid (31.9 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 90% EtOAc in hexane as eluent) to afford 43 mg (38.9% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(pyrazine-2-carbonyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 86.93%, 1H NMR: (DMSO) δ 8.9 (s, 1H), 8.8 (s, 1H), 8.7 (q, 2H), 8.0 (d, 2H), 7.8-7.7 (q, 4H), 7.5 (t, 2H), 7.4 (t, 1H), 4.2 (dd, 2H), 3.8 (s, 1H), 3.7 (d, 3H), 3.6-3.5 (m, 4H).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][OH:18])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH:17]=[O:18])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cnn(Cc2cc(CO)no2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: N#N
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(Cn2cc([N+](=O)[O-])cn2)on1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(4-nitro-pyrazol-1-ylmethyl)-isoxazol-3-yl]-methanol (1.82 g, 8.20 mmol) in CH2Cl2 (25.0 mL) was added to an ice-chilled suspension of pyridinium chlorochromate (5.35 g, 24.36 mmol) in CH2Cl2 (25.0 mL). The reaction mixture was stirred for 4.5 h at rt. It was filtered over celite and the solvent was removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a colorless oil. TLC: rf (50:50 hept-EA)=0.36. LC-MS-conditions 02: tR=0.60 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([C:27]([NH:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32])=[O:28])[CH:24]=[C:23]([N+:35]([O-])=O)[CH:22]=2)=[O:20])[CH:7]=[C:8]([C:10]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[O:11])[CH:9]=1)([O-])=O.CO.[ClH:40]>[Pd].O>[ClH:40].[ClH:40].[NH2:1][C:4]1[CH:5]=[C:6]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([C:27]([NH:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32])=[O:28])[CH:24]=[C:23]([NH2:35])[CH:22]=2)=[O:20])[CH:7]=[C:8]([C:10]([NH:12][CH:13]([CH2:14][OH:15])[CH2:16][OH:17])=[O:11])[CH:9]=1
Reactant: O=C(Nc1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1)c1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(NC(=O)c2cc(N)cc(C(=O)NC(CO)CO)c2)cc(C(=O)NC(CO)CO)c1

Procedure:
3-Nitro-5-(1,3-dihydroxyprop-2-ylaminocarbonyl)phenylaminocarbonyl-[3'-nitro-5'-(1,3-dihydroxyprop-2-ylaminocarbonyl)benzene] (1.03 g, 1.98 mmol) was hydrogenated in a solution containing methanol (40 ml), concentrated HCl (2 ml), water (2 ml) and a Pd/C catalyst (10%, 0.2 g) at 60 psi. The catalyst was filtered off and the solvent was evaporated. Water (150 ml) was then added and the solution was lyophilized. Yield: 0.98 g (93%).
Reaction SMILES: [CH3:1][CH:2]([CH:6]=[CH2:7])[C:3]([OH:5])=[O:4].[Cl:8][CH2:9][CH2:10]O>C(OCC)C.CC1C=CN=C(N)C=1C>[Cl:8][CH2:9][CH2:10][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH:6]=[CH2:7]
Reactant: C=CC(C)C(=O)O
Reactant: OCCCl
Agent: Cc1ccnc(N)c1C
Solvent: CCOCC
Product: C=CC(C)C(=O)OCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
45.1 g (0.45 mol) of 2-methyl-3-butenoic acid, 45.33 g (0.56 mol) of 2-chloroethanol and 4.1 g (34 mmol) of dimethyl-aminopyridine were placed in 450 ml of diethyl ether under argon. 102.2 g (0.495 mol) of N,N-dicyclohexylcarbodiimide were added thereto in 5 portions at 0° C. within 30 minutes, the mixture was stirred at room temperature for a further 2 hours and the separated urea was filtered off. The filtrate was washed in succession with 200 ml of 0.5N aqueous hydrochloric acid, 100 ml of saturated sodium bicarbonate solution and 100 ml of saturated sodium chloride solution. The organic solution was dried over anhydrous 2 0 sodium sulphate and, after concentration, the product was distilled on a Vigreux column (20 cm) at 80°-81° C./10 mbar. This gave 62.3 g (83% yield) of 2-methyl-but-3-enoic acid 2-chloroethyl ester as a colourless oil with a content of 97.5% according to GC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1O
Yield: 75 %

Procedure:
To a solution of 588 mg (0.995 mmol) of the amide compound in methanol (10 ml) was added 190 mg (0.999 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 1 hour. The reaction mixture was diluted with water and adjusted to a pH value of 10 by the addition of aqueous solution of sodium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure, The residue was subjected to Sephadex column chromatography, eluted with methanol, to give 375 mg (0.746 mmol) of N-[3-(3,5-dimethoxy-4-hydroxyphenyl) -2-propenoyl]-N'-(2-benzhydroxyethyl) piperazine. Spectrophotometric data of the product support the structure shown below. ##STR92##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]([C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1)[CH3:12].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N-]=C=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]([CH:11]([C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1)[CH3:12])[C:28]([NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29]
Reactant: COc1ccc(Cl)c(NC(C)c2cnc(Cl)nc2Cl)c1
Reactant: O=C=Nc1ccccc1
Agent: [N-]=C=O
Product: COc1ccc(Cl)c(N(C(=O)Nc2ccccc2)C(C)c2cnc(Cl)nc2)c1
Temperature: 150 °C

Procedure:
(±)-(2-Chloro-5-methoxy-phenyl)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-amine (70 mg; 0.21 mmol) (from Example 12a supra) was combined with phenyl isocyanate (60 μL; 0.55 mmol) (Aldrich) and heated (neat) at 150° C. for 65 minutes. Thin layer chromatography analysis showed some unreacted starting material remained. Additional isocyanate (20 μL; 0.18 mmol) was added and the mixture heated at 150° C. for an additional 30 minutes. Upon cooling, hexanes was added. After stirring, the supernatant was decanted off and the residue dried to give the intermediate (±)-1-(2-chloro-5-methoxy-phenyl)-1-[1-(2-chloropyrimidin-5-yl)-ethyl]-3-phenyl-urea which contained about 20% starting material by HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][C:3]=1C.B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O>>[OH:14][CH2:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[CH:7][CH:6]=2)[N:12]=1
Reactant: Cc1cc(-c2noc(CO)n2)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccc(-c3noc(CO)n3)cc2)cc1

Procedure:
3-(4-Bromo-3-methylphenyl)-1,2,4-oxadiazol-5-ylmethanol (EP 0533268 A1) (1.0 g, 3.7 mmol) was reacted with 4-boronobenzoic acid using similar conditions to Description 11 to afford 4'-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid. This was dissolved in methanol (70 ml), treated with conc. sulphuric acid (2 ml) and heated under reflux for 4 hours. The solution was concentrated in vacuo and the residue basified with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound (0.76 g, 68%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:14][CH2:13][CH:12]2[C:15]([O:17]C)=[O:16])[CH2:7][CH2:6]1)(=[O:4])=[O:3].O.[OH-].[Li+:21]>>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[CH2:14][CH2:13][CH:12]2[C:15]([O-:17])=[O:16])[CH2:9][CH2:10]1)(=[O:3])=[O:4].[Li+:21]
Reactant: COC(=O)C1CCN1C1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)N1CCC(N2CCC2C(=O)[O-])CC1

Procedure:
The reaction of methyl 1-(1-(methylsulfonyl)piperidin-4-yl)azetidine-2-carboxylate 19L and lithium hydroxide monohydrate yielded lithium 1-(1-(methylsulfonyl)piperidin-4-yl)azetidine-2-carboxylate as light brown solid (quant.). MS ISP (m/e): 263.1 (100) [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20]([O:22]CC)=[O:21].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)COc1ccc2c(=O)c3c(F)cccc3oc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc2c(=O)c3c(F)cccc3oc2c1Cl
Yield: 82.3 %

Procedure:
A mixture of 2.6 g of 4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 2.8 g of potassium carbonate, 3.3 g of ethyl bromoacetate and 40 ml of N,N-dimethylformamide (DMF) was stirred at 60°-70° C. for 4 hours. After cooling the mixture, water was added thereto and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 3.4 g of ethyl 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetate. A mixture of this ester (3.3 g), sodium hydroxide (1.9 g) and water (100 ml) was refluxed for 30 minutes. After cooling, the mixture was rendered acidic with concentrated hydrochloric acid and the resulting crystal was recovered by filtration and dried. Recrystallization from DMF gave 2.5 g of 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 300° C.