Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:23])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]2([CH3:22])[CH3:21])=[CH:4][C:3]=1[O:24][CH3:25].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:23])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:21])[CH3:22])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2(C)C)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C2(O)CCNCC2(C)C)ccc1Cl
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (1.36 g, 2.39 mmol) was added 4N HCl in dioxane (10 mL) and stirred for 30 min. The solvents were removed in vacuo and the resulting solids were dried azeotropically with toluene and then further dried under high vacuum to afford 4-(4-chloro-3-methoxyphenyl)-3,3-dimethylpiperidin-4-ol hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@:10](C(OCC)=O)([C:11](=[O:25])[N:12]3[CH2:24][CH2:23][CH2:22][O:21][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]3=4)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:10]([C:11](=[O:25])[N:12]3[CH2:24][CH2:23][CH2:22][O:21][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]3=4)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@]12CN(Cc3ccccc3)C[C@@H]1c1cccc3c1N(CCCO3)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1[C@@H]2CN(Cc3ccccc3)C[C@@H]2c2cccc3c2N1CCCO3
Temperature: 100 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To absolution of (±)-cis ethyl 11-benzyl-9-oxo-6,7,10,11,12,12a-hexahydro-5H-[1,4]oxazepino[2,3,4-ij]pyrrolo[3,4-c]quinoline-9a(9H)-carboxylate (0.45 g, 1.11 mmol) in 20 mL of 1,4-dioxane was added 20 mL of 3N HCl and the resulting mixture was stirred at 100° C. for 24 h. The dioxane and most of the water was removed in vacuo, and the residue was basified with sat'd aq Na2CO3 and extracted with ethyl acetate. The layers were separated and the organics were washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 0.33 g (89%) of the title compound of EXAMPLE 120 as an off-white powder. 1H NMR (CDCl3) δ: 7.41-7.27 (m, 5H), 6.97-6.81 (m, 3H), 4.60 (dt, 1H), 4.40 (ddd, 1H), 4.13 (ddd, 1H), 3.85-3.75 (m, 1H), 3.82 (broad s, 2H), 3.68-3.57 (m, 1H), 3.52-3.40 (m, 2H), 3.28-3.20 (m, 1H), 3.20-3.10 (m, 1H), 2.56 (t, 1H, J=9.9 Hz), 2.25-2.10 (m, 2H). LRMS (ES)+: 335.4 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:30][CH:31]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCCCCCCCc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Octyl-phenol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H38O5 [M+Na]+: 466.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6](C)[C:7](=O)[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.Cl>[OH-].[K+]>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[C:9]([OH:10])=[O:8]
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CNc1ccc(Cl)cc1C(=O)O
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A suspension of 3.955 g of 6-chloro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (18.69 mmol) in 37 ml of 2N KOH was heated to 100° C. for 4 h. The clear solution was then allowed to cool to RT and the pH was adjusted to 6-7 by addition of 3N HCl. The precipitate formed was filtered off and dried to give 3.31 g (95%) of the title compound as a yellow solid. MS (ISP) 183.9 (M−H)−.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl>C(O)(CC)C>[CH:2]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])([CH2:6][CH3:7])[CH3:3]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: Cl
Solvent: CCC(C)O
Product: CCC(C)OC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of sec.-butanol and the suspension is saturated with hydrogen chloride gasfor 4 hours at 75°. After concentration, the residue is dissolved in10 ml of 2-butanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid sec.-butyl ester, m.p. 169°-170°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=C=O)=[CH:14][CH:13]=1.O>[O-]CC.[Na+].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(N=C=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc(C)cc2)cc1
Temperature: 35 °C
Reaction time: 0.87 h

Procedure:
p-Methylbenzoic acid (95.31 grams, 0.70 mole), sodium ethoxide catalyst (0.2144 gram, 0.225% wt. of the p-methylbenzoic acid used) and N,N'-dimethylacetamide (575 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 35° C. to provide a solution. p-Methylphenyl isocyanate (97.87 grams, 0.735 mole) is added over a two minute period inducing an exotherm to 40° C. At this time, heating of the reactor commences and a 160° C. temperature is achieved 52 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. the the contents poured into deionized water (3.50 liters). A precipitated white crystalline product is recovered by filtration of the aqueous slurry then dried in a vacuum oven at 80° C. and 5 mm Hg for fifteen hours. The dry product and methanol (700 milliliters) are stirred together with heating to provide a solution at 63° C. After cooling the methanol solution to 4° C. for fourteen hours, a white crystalline product is filtered off and dried at 70° C. and 5 mm Hg in a vacuum oven to a constant weight of 135.6 grams. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product confirms the product structure of 4,4'-dimethylbenzanilide (amide carbonyl absorbance at 1649 cm-1 and amide N--H stretching absorbance at 3349 and 3290 (shoulder) cm-1.
Reaction SMILES: [P:1]([O:10]C(C)C)([O:6]C(C)C)[O:2]C(C)C.[P:14]([CH:18]1[CH2:22][CH2:21][CH:20](Br)[O:19]1)([OH:17])([OH:16])=[O:15].Cl>>[P:14]([CH:18]1[CH2:22][CH2:21][CH:20]([P:1]([OH:2])([OH:6])=[O:10])[O:19]1)([OH:17])([OH:16])=[O:15]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: O=P(O)(O)C1CCC(Br)O1
Agent: Cl
Product: O=P(O)(O)C1CCC(P(=O)(O)O)O1
Temperature: 170 °C

Procedure:
Triisopropyl phosphite (0.33 ml, 1.2 mmol) was added to the 2-phosphono-5-bromotetrahydrofuran prepared in accordance with the process of Example II. The mixture was heated over a period of one half hour under a nitrogen atmosphere to 170° C. It was held at this temperature for two and one quarter hours and then cooled to room temperature. Concentrated hydrochloric acid (15 ml) was added and the resulting mixture was heated to reflux for five hours. The volatile components were removed under vacuum leaving 2,5-diphosphonotetrahydrofuran ("DPTHF") containing phosphorous acid as an impurity. The identity of the 2,5-diphosphonotetrahydrofuran was established by nuclear magnetic resonance spectroscopy (proton, phosphorus and carbon-13) and fast atom bombardment mass spectroscopy
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[I:10][C:11]1[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[C:14](O)=[N:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[F:1][C:2]1([CH2:8][O:9][C:14]2[C:13]([C:18]([F:19])([F:21])[F:20])=[CH:12][C:11]([I:10])=[CH:16][N:15]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: OCC1(F)CCOCC1
Reactant: Oc1ncc(I)cc1C(F)(F)F
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC1(COc2ncc(I)cc2C(F)(F)F)CCOCC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 37C (0.537 g), 5-iodo-3-(trifluoromethyl)pyridin-2-ol (1.156 g), and triphenylphosphine (1.574 g) in tetrahydrofuran (20 mL) was cooled to 0° C. To this solution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.921 g). The reaction mixture was stirred overnight. The solvent was removed, and the residue was purified with column flash chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to give the desired product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1)(=[O:21])[NH2:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2-amino-3-cyclopropyl-propanamide (CAN 156077-93-9) as starting materials, MS (LC/MS): m/e=344.3 [M+H]+.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:16]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12].[OH-].[K+]>O>[CH3:5][O:8][C:9]1[C:16]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12]
Reactant: OCc1cccc(Sc2ccccc2Cl)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(CO)cccc1Sc1ccccc1Cl
Yield: 96.6 %

Procedure:
Dimethyl sulfate (5.7 g) was added to a mixture of 2-hydroxy-3-(2-chlorophenylthio)benzyl alcohol (6 g) and potassium hydroxide (3.8 g) in water (20 ml) in 10 minutes with stirring. The mixture was stirred at 50° C. for 1.5 hours, and the reaction mixture was treated in a similar manner to that of Example 21-(4) to give oily 2-methoxy-3-(2-chlorophenylthio)benzyl alcohol (6.1 g). This product was purified by column chromatography (silica gel 100 g, benzene-ethyl acetate 10:1) to give purified oily substance (5.6 g). This product was identified with the compound obtained in Example 21-(5) by IR and NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12].O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[C:10]2[C:9]([Cl:15])=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: Cc1sc2ncnc(O)c2c1Br
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1sc2ncnc(Cl)c2c1Br
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 25-mL round-bottom flask containing 5-bromo-6-methylthieno[2,3-d]pyrimidin-4-ol (100 mg, 0.41 mmol, 1.00 equiv) in POCl3 (10 mL) was stirred for 1 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was then quenched with saturated aqueous sodium carbonate, extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After concentrated under vacuum, this resulted 5-bromo-4-chloro-6-methylthieno[2,3-d]pyrimidine (79 mg, 73%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([OH:22])[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([OH:22])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2ccc3cccc(O)c3n2)cc1
Temperature: 60 °C
Yield: 75.2 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.683 g of 2-amino-8-hydroxyquinoline, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.45 g of 2-[(4-nitrophenyl)amino]quinol-8-ol (11) was obtained.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:34])(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31].[Na+]>CC(C)=O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:32][C:30]([CH2:29][CH2:28][C:27]([OH:34])=[O:33])=[O:31])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: O=C([O-])CCC(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.5 %

Procedure:
In 100 ml of 50% aqueous acetone are dissolved 1.5 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 0.7 g of monosodium succinate and the solution is stirred at room temperature (15°-25° C.) for 3 days. The acetone is distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 450 ml of chloroform, elution is carried out with 150 ml of ethyl acetate. The eluate is evaporated under reduced pressure to remove the solvent, giving colorless crystals. The product is washed with petroleum ether and dried to give 0.4 g of the above-identified compound.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Br[C:36]1[CH:45]=[C:44]([C:46]([O:48][CH3:49])=[O:47])[C:43]([N:50]2[C:62]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)=[CH:42][C:37]=1[C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+].N#N>C1(C)C=CC=CC=1.O.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.CCO>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:36]3[C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][C:43]([N:50]4[C:62]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=5[C:56]5[C:51]4=[CH:52][CH:53]=[CH:54][CH:55]=5)=[C:44]([C:46]([O:48][CH3:49])=[O:47])[CH:45]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)c(C(=O)OC)cc1Br
Reactant: OB(O)c1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)c(C(=O)OC)cc1-c1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
91 g (207 mol) of bisbiphenyl-4-yl-(4-boronophenyl)amine, 207 g (474 mmol) of dimethyl 2-bromo-5-carbazol-9-ylterephthalate and 315.9 g (2.29 mol) of potassium carbonate are initially introduced in a mixture of 850 ml of toluene and 850 ml of water and saturated with N2 for 30 min. After addition of 1.36 g (1.18 mmol) of Pd(PPh3)4, the mixture is heated at the boil for 4 h. After cooling to RT and addition of 400 ml of EtOH, the mixture is cooled to room temperature and stirred for 1 h, and the precipitate is filtered off with suction, washed with water, EtOH and heptane and dried at 80° C. in vacuo. The yield is 254 g (336 mmol), corresponding to 72% of theory.
Reaction SMILES: [CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.COC(C1C(C(F)(F)F)=NC(Br)=C(C2C=CC([Cl:54])=C(Cl)C=2)N=1)=O>>[CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:16])[F:17])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23]3)=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([Cl:54])=[C:26]([Cl:30])[CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(OCC2CC2)nc1C(F)(F)F)C1CC1
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Br)nc1C(F)(F)F
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(OCC2CC2)nc1C(F)(F)F)C1CC1

Procedure:
In analogy to example 7 (3-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide) the title compound was prepared by substituting 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester with 5-bromo-6-(3,4-dichloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:27](=[O:28])/[CH:26]=[CH:25]/[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[O:16][CH3:15])=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Product: COc1cccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)c1OC

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.09 min; [M+H]+=394.28.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:25]3[N:26]=[C:27]([CH3:29])[O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:31])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2cccc(Cl)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9](O)=[O:10])[CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:33][C:32](=[O:42])[CH:31]=2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[NH:33][C:32](=[O:42])[CH:31]=3)=[CH:26][CH:25]=2)=[O:10])[CH:7]=1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (purity 82%, 0.37 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate were reacted according to General Method 5A. Yield: 17.8 mg (purity 78%, 6% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.[Br:24]C1C=CC(I)=CC=1>>[Br:24][C:15]1[CH:16]=[CH:17][C:12]([C:11]([C:7]2[NH:8][C:9]3[C:5]([C:6]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[O:19])=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: Brc1ccc(I)cc1
Product: O=C(O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 4-bromoiodobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([CH:19]=[CH2:20])[O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[Na+].[OH-:25].[K+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].I([O-])(=O)(=O)=O.[Na+]>[Ru].[Ru](Cl)(Cl)Cl.O.C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([CH2:19][C:20]([OH:25])=[O:23])[O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Ru]
Agent: O=C([O-])O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)[C@@H](CC(=O)O)OC1(C)C
Temperature: 12.5 °C
Reaction time: 0.25 h

Procedure:
(4S,5R)-2,2-Dimethyl-4-phenyl-5-vinyl-oxazolidine-3-carboxylic acid t-butyl ester is dissolved in a polar solvent. Carbon tetrachloride and water are added, followed by the addition of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate, at a temperature in the range of about 10-50° C. The reaction mixture is stirred for about 10 to 20 minutes and an alkali metal periodate, such as sodium metaperiodate, is added in small portions to the reaction mixture, such as over a period of about 20 to 40 minutes. A ruthenium salt catalyst, such as ruthenium trichloride, is added to the reaction mixture at a temperature in the range of about 20-40° C. and stirred to reaction completion, such as for about 30-40 hours. The reaction mass is filtered and the filtrate is washed with ethyl acetate, then the aqueous layer is cooled to about 10-15° C. and acidified with 10% aqueous hydrochloric acid to pH 2-3. The aqueous layer is extracted with ethyl acetate, then the organic layer is washed with a 2% aqueous Na2S2O3 solution and washed with brine solution. The organic layer is concentrated at about 50° C. under vacuum to get a thick semi-solid. The solid is triturated with petroleum ether and filtered to get the desired white solid (4S,5R)-5-carboxymethyl-2,2-dimethyl-4-phenyl-oxazolidine-3-carboxylic acid t-butyl ester (I).