Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13].Cl>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]2[CH2:16][CH2:15][O:14][C:12]2=[O:13])=[CH:5][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1OCCC1Oc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Sodium (23 g, 1 mol) is added in pieces to a reactor containing ethanol (1 l). The temperature of the reaction medium is stabilised at 70° C. (exothermic) before adding a solution of 4-bromophenol (173 g, 1 mol) in ethanol (150 ml). After cooling to room temperature, α-bromo-γ-butyrolactone (83 ml, 1 mol) is added slowly. The reaction medium is stirred for ten hours and is then treated by adding 1N hydrochloric acid solution (600 ml). The aqueous phase is extracted with ethyl acetate (2×1 l) and the combined organic phases are washed with water (1 l), dried over sodium sulphate, filtered and concentrated. The residue obtained is recrystallised from isopropanol (2.2 l) to give the expected compound in the form of a white powder (80.1 g, 31%).
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=O.Cl.[NH:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[NH:23].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:14][C:9]1[CH:8]=[C:7]([C:5]2[N:23]=[C:18]3[NH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:3](=[O:15])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: COC(=O)CC(=O)c1ccc(C)c(C)c1
Reactant: N=C1NCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(=O)n3c(n2)NCCC3)cc1C

Procedure:
A suspension of 3-(3,4-dimethyl-phenyl)-3-oxo-propionic acid methyl ester (1.2 g, 5.8 mmol), tetrahydro-pyrimidin-2-ylideneamine hydrochloride (0.78 g, 5.8 mmol), and potassium carbonate (0.80 g, 5.8 mmol) in ethanol (20 mL) was heated to reflux for 4 h. Water (5 mL) was added to the reaction at room temperature and tan solid was collected by filtration. M+1=256.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][C:26]([O:28][C:29](C)(C)C)=[O:27]>>[CH3:29][O:28][C:26](=[O:27])[CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@@H]2CCCN2)cc1
Product: COC(=O)CN1CCC[C@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 68.6 %

Procedure:
The title compound was prepared from product from 3-chloro-2-[4-((S)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.33 g, 0.94 mmol) and t-butyl bromoacetate (0.22 g, 1.1 mmol) using the procedure of step 1 of the Example 15 to provide the title compound (0.258 g, 63%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.0 min; [M+H]+=391.44.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11]Br)[CH:5]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11][O:21][C:18]2[CH:19]=[CH:20][C:15]([I:14])=[CH:16][CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(CBr)c1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(F)c(COc2ccc(I)cc2)c1
Yield: 74.5 %

Procedure:
3-Bromomethyl-4-fluorobenzoic acid methyl ester (3.0 g, 12.1 mmol) was mixed with 4-iodophenol (3.2 g, 14.6 mmol) in acetone (75 mL) containing dry potassium carbonate (2.5 g, 18 mmol). The mixture was refluxed for 6 hrs and then filtered. The filtrate was concentrated and extracted with ether and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was purified through flash column chromatography (120 g silica gel, 0% to 20% ethyl acetate in hexanes over 40 minutes) to give clear oil as 4-fluoro-3-(4-iodophenoxy)methylbenzoic acid methyl ester (3.48 g, 74.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[Li+].[OH-]>O1CCOCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2F)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.9 %

Procedure:
Tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4.6 g, 13.59 mmol) was suspended in 1,4-Dioxane (Volume: 68.0 ml) and treated with 1N LiOH (68.0 ml, 68.0 mmol). The reaction mixture was stirred at room temperature for 23 h. The reaction mixture was concentrated in vacuo until most of the dioxane was gone and acidified with HCl (4.5 N) until a thick precipitate resulted. It was filtered off, washed with water and dried in vacuum to afford 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (4.40 g, 13.57 mmol, 100% yield) as a brown solid. ESI-MS: m/z 325 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[NH:7][CH2:6]1)=[O:4].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.CO.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[N:7]([C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2NC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)Nc2ccccc2)C1

Procedure:
To a 100 ml round-bottom flask containing a solution of (6aR,9R)-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid methyl ester (0.89, 2.98 mmol) in dichloromethane (20 ml) is added phenylisocyanate (0.45 ml, 4.5 mmol, 1.5 eq.). The reaction mixture is stirred at room temperature for 16 hours by which time TLC in 10% methanol/DCM showed conversion of starting material to give product as a mixture of diastereomers. The volatiles are concentrated in vacuo and purified directly using Normal Phase Flash column chromatography (Biotage Flash 40, 90 g cartridge) using 30% ethyl acetate/hexane to isolate the product as a 1:1 diastereomeric mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)(=[O:38])=[O:37])[CH:31]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)(=[O:37])=[O:38])[CH:31]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(S(=O)(=O)N5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(S(=O)(=O)N6CCOCC6)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 25.9 %

Procedure:
(S)-5-Methyl-2-(1-((5-(3-(morpholinosulfonyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (90 mg, 0.12 mmol) was treated with trifluoroacetic acid (2 ml, 25 mmol) and a solution of ammonia (7N in methanol, 2 ml, 91 mmol) according to the method described in Example 27. The residue was purified by reverse phase using SP1® Purification System to obtain 19 mg (25% yield) of the title compound. Purity 98%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37](S(C)=O)=[N:38]3)=[CH:33][CH:32]=2)[CH:26]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].[O-]S(C(F)(F)F)(=O)=O>>[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37]([NH:16][C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:11]=4)=[N:38]3)=[CH:33][CH:32]=2)[CH:26]=1)(=[O:23])=[O:24])([CH3:20])([CH3:18])[CH3:19]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4cccc(OCCN5CCOCC5)c4)nn23)c1

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a triflate salt. 1H-NMR (DMSO) δ 9.9 (br s, 1H), 9.6 (s, 1H), 9.15 (s, 1H), 8.5 (s, 1H), 8.4 (d, J=8.0 Hz, 1H), 7.9 (d, J=8.0 Hz, 1H), 7.75 (m, 1H), 7.6 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.3 (m, 2H), 7.2 (d, J=4.7 Hz, 1H), 7 (d, J=4.7 Hz, 1H), 6.7 (d, J=10.4 Hz, 1H), 4.3-3.3 (m, 12H), 1.1 (s, 9H); LC/MS (ESI+): 551 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>>[CH3:10][O:9][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(OC)c1C
Product: COc1ccc([N+](=O)[O-])c(OC)c1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.62 g (76.45 mmol) of 2,6-dimethoxytoluene were introduced in portions into 40 ml of concentrated nitric acid cooled to 0° C. After stirring at 0° C. for 15 min, the reaction solution was poured onto 250 ml of ice and extracted 3× with EA. The combined EA extracts were dried over Na2SO4, the solvent was removed in vacuo, and the brown oily residue was purified by means of column chromatography on SiO2 (EA/heptane 1:8). 8.59 g of the title compound were isolated in the form of a red oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH:67](=O)[CH2:68][CH2:69][CH2:70][CH3:71].C([BH3-])#N.[Na+].Cl>CO>[O:63]=[C:57]1[NH:58][C:59](=[O:62])[CH:60]=[CH:61][N:56]1[C@@H:51]1[O:50][C@H:49]([C@H:9]([O:8][CH:6]2[C@H:5]([O:64][CH3:65])[C@@H:4]([OH:66])[C@@H:3]([CH2:2][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:7]2)[CH:10]([C:46]([OH:48])=[O:47])[N:11]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@@H:53]([OH:54])[C@H:52]1[OH:55]
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Reactant: CCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNC[C@H]1OC(O[C@H](C(C(=O)O)N(CCCCC)CCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](OC)[C@H]1O
Reaction time: 0.08 h

Procedure:
To a solution of 50 mg (53 μmol) 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 0.4 ml of methanol is added 9.5 mg (2.0 eq., 110 μmol) of valeraldehyde and 3.3 mg (1.0 eq., 53 μmol) of sodium cyanoborohydride. After stirring for 5 minutes, 0.04 ml of 1 N methanolic hydrochloric acid is added. The reaction mixture is then stirred for 0.5 hour (the reaction is monitored by MS). The solvent is removed under reduced pressure to give a yellow gum. The desired product is identified by LC/MS and separated by preparative HPLC to give 4.9 mg (9.0% yield) of the desired product as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([F:19])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(O)C.[H][H]>[Pd].C1COCC1>[F:19][C:12]1[CH:11]=[C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:15]=[CH:14][C:13]=1[NH2:16]
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])c(F)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(N)c(F)c2)n1
Yield: 39.2 %

Procedure:
A mixture of 570 mg (2.03 mmol) 2-methylsulfanyl-4-(3-fluoro-4-nitrophenoxy)-pyrimidine, 10 ml ethanol, 10 ml THF, and 200 mg 10% palladium/C is hydrogenated at 50 mbar hydrogen pressure at r.t. for 8 h. The catalyst was removed by filtration, washed with 10 ml ethanol and evaporated. The residue was purified by chromatography on silica (ethyl acetate/n-heptane 1:2) to give 200 mg (39%) 2-fluoro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:38]C)=[CH:6][C:7]([O:36]C)=[C:8]([C:10]2[N:11]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[CH:30]=[CH:29]4)[C:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].N1C=CC=CC=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[N:11]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[CH:30]=[CH:29]4)[C:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)=[N:13][N:14]=2)[C:7]([OH:36])=[CH:6][C:5]=1[OH:38])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(C(C)C)cc1-c1nnc(Nc2ccc3ncccc3c2)n1-c1ccc2c(ccn2C)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2nnc(Nc3ccc4ncccc4c3)n2-c2ccc3c(ccn3C)c2)c(O)cc1O
Temperature: 210 °C
Yield: 38.9 %

Procedure:
A tube was charged with N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)quinolin-6-amine (114 mg) and pyridine*HCl (4 g.), and placed under a nitrogen atmosphere. It was heated to 210° C. for 50 minutes, and then cooled. The solid was dissolved in ethyl acetate (20 mL) and washed with a saturated solution of ammonium chloride (3×20 mL). The organic layer was dried and evaporated to give 4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol (42 mg). In some cases column chromatography was necessary for purification. 1H-NMR (CDCl3): 8.69 (dd, 1H); 8.50 (d, 1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.45-7.36 (m, 2H), 7.33 (d, 1H), 7.27 (dd, 1H), 6.64 (d, 1H), 6.42 (s, 1H), 6.30 (s, 1H), 3.98 (s, 3H); 2.83 (q, 1H); 0.50 (m, 6H). MS: expected ion=491.4; observed ion=491.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:8]=[C:7]([CH:6]=[CH:5][C:3]=1[OH:4])[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:17]2[S:16][CH:15]=1
Reactant: Oc1ccccc1O
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)c(O)c3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 1.1 g of pyrocatechol in 6 ml of trifluoroacetic acid is mixed with 0.8 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature. It is diluted with an equal quantity of toluene, the mixture is evaporated to dryness under reduced pressure, and the residue is twice triturated with 30 ml portions of diethyl ether to remove the excess pyrocatechol. The residue is worked up in accordance with the process described in example 6 and yields 3-(3,4-dihydroxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid which after crystallisation from a mixture of acetic acid ethyl ester and acetone is obtained in the form of colourless crystals, melting point 114°C; thin layer chromatogram (silica gel): Rf = 0.71 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.73 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.44 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (methanol): λmax 222 mμ (ε = 17600), 250 mμ (ε = 6800) and 283 mμ (ε = 3700); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.72μ, 5.87μ and 6.06μ.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:13][CH:12]([CH3:14])[CH2:11][CH:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][NH:24][C:21]1[CH:20]=[N:19][C:18]([C:17]([F:26])([F:16])[F:25])=[CH:23][CH:22]=1
Reactant: CC(C)CC(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CC(CNc1ccc(C(F)(F)F)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product of tert-butyl(4-methyl-1-oxopentan-2-yl)carbamate was dissolved in chloroform, 2-trifluoromethyl-5-aminopyridine (1.35 g) and sodium triacetoxyborohydride (3.52 g) were added thereto, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The dissicant was filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford tert-butyl (4-methyl-1-{[6-(trifluoromethyl)pyridin-3-yl]amino}pentan-2-yl)carbamate (2.58 g).
Reaction SMILES: Cl[CH:2]1[CH2:14][O:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3]1.ClN1C(=O)CCC1=O.[Br:31]N1C(=O)CCC1=O>>[Br:31][CH:2]1[CH2:14][O:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCC[C@H]1OCC(Cl)C[C@@H]1CCCCCCC
Agent: O=C1CCC(=O)N1Cl
Product: CCCCCCCC[C@H]1OCC(Br)C[C@@H]1CCCCCCC

Procedure:
10-Chloro Thromboxane B2Methyl Ester has been prepared using the same procedure except that N-chlorosuccinimide was substituted for N-bromosuccinimide. This 10-chloro compound can then be utilized in the same manner as the 10-bromo compound in the following examples.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48]>CC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([C:39]3[N:38]([CH2:37][C:33]4[O:32][CH:36]=[CH:35][CH:34]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)=[O:48])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccco4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1-(fur-2-ylmethyl)-1 H-benzoimidazole-2-carbonyl)-piperidine obtain, after chromatography on silica gel eluting with 80% acetone/hexane, the title compound: Mass Spectra (CI/NH3) M++H=677.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38].C(NC(C)C)(C)C>[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:38]#[C:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1
Reactant: CC(C)Oc1cc(OCCCN2CCOCC2)cc2ncnc(Nc3c(Cl)cc(I)c4c3OCO4)c12
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)Oc1cc(OCCCN2CCOCC2)cc2ncnc(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)c12
Temperature: -10 °C

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-5-isopropoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.162 g), 2-ethynyl pyridine (0.03 ml), palladium(II) bis-triphenylphosphine dichloride (0.020 g) and copper (I) iodide (0.006 g) was taken up into ethyl acetate (5 ml) and cooled to −10° C. This was set to stir rapidly, then diisopropylamine (0.047 ml) was added and the reaction was stirred cold for 30 minutes before being warmed to room temperature and left to stir for 18 hours. The reaction mixture was then filtered through Celite under suction (washing the Celite with a further portion of ethyl acetate) then the combined filtrate solutions were evaporated under reduced pressure to give a brown gum. This was then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained the title compound (0.090 g) as a pale brown foam; NMR Spectrum: (CDCl3) 1.54 (d, 6H), 2.04 (quin, 2H), 2.50 (m, 4H), 2.56 (t, 2H), 3.74 (t, 4H), 4.16 (t, 2H), 4.83 (sept, 1H), 6.14 (s, 2H), 6.50 (d, 1H), 6.84 (d, 1H), 7.19 (s, 1H), 7.25 (m, 1H), 7.54 (d, 1H), 7.68 (td, 1H), 8.53 (s, 1H), 8.63 (dd, 1H), 9.46 (s, 1H); Mass Spectrum: M+H+ 602/604.