Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=2)=[O:29])[CH:25]=[C:24]([CH3:39])[C:3]=1[C:4]([NH:6][C@H:7]([C:20]([O:22]C)=[O:21])[CH2:8][NH:9][C:10](=[O:19])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1)=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=2)=[O:29])[CH:25]=[C:24]([CH3:39])[C:3]=1[C:4]([NH:6][C@H:7]([C:20]([OH:22])=[O:21])[CH2:8][NH:9][C:10](=[O:19])[C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([OH:17])[CH:16]=1)=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cc(O)cc(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A solution of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine, methyl ester (790 mg, 0.87 mmol) in tetrahydrofuran/methanol (1:1; 8 mL) was added to a solution of lithium hydroxide monohydrate (183 mg, 4.4 mmol) in water (4 mL). The solution was stirred at room temperature overnight and then the solvents were evaporated. Water (15 mL) was added and the solution was acidified with 3 M HCl. The mixture was extracted with ethyl acetate (3×20 mL) and the combined extracts were washed with brine and evaporated. The residue was dissolved in methanol (14 mL) and purified in two portions by HPLC to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine (65 mg, 14%).
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[N+](=C)=[N-].[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O.CN(C=O)C>[C:20]([O:28][CH3:3])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C(O)c1ccccc1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1

Procedure:
In a 1.5 l double-walled glass reactor 531 g of aqueous 30% KOH solution are submitted and are heated, respectively, to 40° C., 55° C. and 70° C. By controlled dropwise addition of 405.8 g of 26.4% N-methyl-N-nitroso-p-toluenesulfonamide (MNTSA) solution in DMSO into this KOH solution, diazomethane (DAM) is generated and is aspirated in gaseous form into a glass reactor via a frit by means of vacuum at 500 mbar. The metered addition is effected in such a way that the diazomethane concentration in the gas phase does not exceed a partial pressure of 120 mbar. With a view to determining the DAM quantity and yield, this glass reactor is charged with an acid, for example with a solution of benzoic acid in DMF, so that the DAM aspirated via the frit reacts to completion immediately to form methyl benzoate, and the content thereof is determined analytically and can be utilized as an equivalent for DAM. The following table reproduces the results:
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[CH3:1][N:2]1[C:7](/[CH:8]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=Cc1ccccc1
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Solvent: CCO
Solvent: C1CCNCC1
Product: Cn1c(/C=C/c2ccccc2)c([N+](=O)[O-])c(=O)n(C)c1=O
Yield: 60.3 %

Procedure:
A mixture of 1,3,6-trimethyl-5-nitro-1H-pyrimidine-2,4dione (3.00 g, 15.06 mmol), benzaldehyde (1.58 ml, 15.56 mmol), piperidine (1.41 ml, 15.56 mmol) and a 3 Å molecular sieve (6.00 g) in ethanol (70 ml) was refluxed for 4 hours, filtered and the solid was treated with a mixture of chloroform and methanol. The resulting suspension was filtered again and the filtrates were evaporated. The residue was triturated with diethyl ether and the precipitate collected by filtration and dried under vacuum to yield 1,3-dimethyl-5-nitro-6-((E)styryl)-1H-pyrimidine-2,4-dione (2.61 g, 60%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]([CH3:12])(O)[CH3:10])=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23]#[N:24].S(=O)(=O)(O)[OH:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]([NH:24][C:23](=[O:26])[CH2:22][Cl:21])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Reactant: N#CCCl
Solvent: CC(=O)O
Product: CC(C)(NC(=O)CCl)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-bis(4-chlorophenyl)-2-methyl-2-butanol (Step B, 1.4 g, 4.5 mmol) and chloroacetonitrile (0.57 mL, 9.1 mmol) in acetic acid (0.7 mL) at −10° C. was added concentrated sulfuric acid (0.31 mL, 14 mmol). After stirring at −10° C. for 15 min and room temperature for 2 h, the reaction mixture was poured onto ice (20 g), and the product was extracted with EtOAc (3×20 mL). The combined extracts were washed with brine/saturated aqueous sodium bicarbonate, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][Cl:27]>C1(C)C=CC=CC=1>[Cl-:27].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COCOc1ccccc1CCl
Solvent: Cc1ccccc1
Product: COCOc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 59 %

Procedure:
32 g of triphenylphosphine were added to a solution of 15.0 g of 2-methoxymethoxybenzyl chloride [prepared as described in step (a) above] in 150 ml of toluene, and the resulting mixture was heated under reflux for 14 hours. At the end of this time, the reaction mixture was cooled, and the resulting precipitates were collected by filtration, washed with toluene and dried in vacuo, to give 21.3 g (yield 59%) of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1.[ClH:26]>ClCCl.O1CCOCC1>[ClH:26].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1.[ClH:26]
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 4-(4-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate D4 (0.072 mmol, 25 mg) was dissolved in dichloromethane (5 ml) and was treated with HCl (3 ml of a 4M solution in 1,4-dioxane) at room temperature; the mixture was stirred at room temperature for two hours. Solvent was evaporated to afford the title compound, mono hydrochloride salt, M++H=250.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>CCCCCCC.C(O)C.CC(O)C>[CH3:21][CH:22]([CH3:32])[CH2:23][C@H:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CC(N)c1cccnn1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine (Example 321 a) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol as eluent. The (−)-enantiomer was isolated. MS (EI): m/e=432.5 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH3:25])[CH2:23][OH:24])[CH:17]=[C:16]([C:26]([O:28]CC)=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[N:36]=2)[CH:7]=1)[CH3:2].[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH3:25])[CH2:23][OH:24])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[N:36]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H](C)CO)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@@H](C)CO)cn1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxypropan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 97, 200 mg, 0.34 mmol, 1 equiv.) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.339 mL). The mixture was stirred in the microwave at 100° C. for 15 min The reaction mixture was cooled to room temperature and diluted with water. 1 N HCl was added until pH 3-4 was reached. The reaction mixture was partitioned between ethyl acetate (5 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL), and the organics were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification via reverse phase HPLC (C18 column, acetonitrile/water 0-95% gradient) and concentrated under reduced pressure to provide (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxypropan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (92 mg, 48%).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].CC[O:9][C:10]([CH:12]([C:21](OCC)=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=O>C(O)C>[NH2:5][C:4]1[N:6]=[C:10]([OH:9])[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[C:21]([OH:22])[N:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)cc1Cl
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(O)c(-c2ccc(Cl)cc2Cl)c(O)n1

Procedure:
Sodium (4.52 g, 0.196M) was added in portions to ethanol (150 ml). After all the sodium had dissolved guanidine hydrochloride (12.44 g, 0.13M) was added followed by diethyl 2,4-dichlorophenyl malonate(20 g, 0.0655M). The mixture was refluxed for 6 hours, EtOH was removed under reduced pressure and the residue partitioned between 2N NaOH (400 ml) and EtOAc (400 ml). The aqueous layer was acidified with concentrated hydrochloric acid with cooling and the precipitated solid was filtered and dried (11 g, 62%).
Reaction SMILES: [CH:1]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]1[CH:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8]1)=[CH2:2].C[N+]1([O-])CC[O:26]CC1.CC(O)(C)C.[O-]S(S([O-])=O)=O.[Na+].[Na+].CC(C)=O.[OH2:47]>O=[Os](=O)(=O)=O.O>[OH:47][CH:1]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]1[CH:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8]1)[CH2:2][OH:26]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC(CCCC1NC(=O)CC1C)NC(=O)OC(C)(C)C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: CC1CC(=O)NC1CCCC(NC(=O)OC(C)(C)C)C(O)CO
Reaction time: 18 h

Procedure:
To a stirring solution of the compound from EXAMPLE 259 (3.3 mmol) in 80 mL of acetone:H2O (3:1) is added N-methylmorpholine N-oxide (0.64 g, 4.8 mmol) and 2.5% OsO4 in t-BuOH (3.4 mL, 3.4 mmol). After 18 h, 120 mL of H2O, 8 g of celite, and 1.6 g Na2S2O4 is added to the reaction. The reaction is filtered through a pad of wet celite. To the filtrate is added 200 mL of 1M KHSO4. The filtrate is extracted with 3×200 mL EtOAc. The combined organic layers are dried, filtered, and stripped. The residue is purified by chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].ClC(N(C)C)=C(C)C.[NH:19]1[C:27]2[C:22](=[C:23]([C:28]3[CH:29]=[C:30]([NH2:37])[C:31]4[CH:32]=[N:33][NH:34][C:35]=4[CH:36]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH:37][C:30]1[CH:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][NH:19]3)[CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2)=[O:8]
Reactant: Cn1ncc(Cl)c1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(Cl)c1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A solution of 4-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (available from Fluorochem) (50 mg) in dry DCM (10 ml) was treated with 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.041 ml) (available from Acros) and allowed to stir at 20° C. for 10 min when a solution of 6-(1H-indol-4-yl)-1H-indazol-4-amine (77 mg) and triethylamine (0.043 ml) in DCM (5 ml) was added and the mixture stirred at 20° C. for 18 h. The mixture was poured onto an aminopropyl SPE cartridge (1 g) and allowed to stand for 2 h, then the mixture was eluted with methanol (5 ml) and blown to dryness under a stream of nitrogen. The crude product was purified by mass directed preparative HPLC (Method A) to give the title compound as a white solid (15 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:51])[CH:46]([OH:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58])[CH2:5][C:4]1=[O:66])[CH3:2].[N+:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[S:76](Cl)(=[O:78])=[O:77])([O-:69])=[O:68]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:51])[CH:46]([O:52][S:76]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=3[N+:67]([O-:69])=[O:68])(=[O:77])=[O:78])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:63]([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(O)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC

Procedure:
The reaction of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(3"-hydroxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone with o-nitrobenzenesulfonyl chloride as in Example 34 yields 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(3"-o-nitrobenzenesulfonyloxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.83) (3.6 g, 10.29 mmol) and commercially available 3-nitrophenylboronic acid (2.062 g, 12.35 mmol) according to the general procedure VI. Obtained as a light brown solid (2.1 g, 46%). MS (ISP) 437.2 [(M+H)+].
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:9]2[CH2:10][CH2:11][CH:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8]2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCC3)CC2)cc1

Procedure:
The compound was prepared from 4-pyrrolidin-1-yl-piperidine (Aldrich) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 276.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: BrCc1ccccc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCc4ccccc4)cc3)cc21

Procedure:
Analogously to Example 308a, 0.103 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.0533 g of benzyl bromide are reacted. The title compound is obtained as a colourless oil. Rf=0.23 (1:1 EtOAc-heptane); Rt=5.95.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C([Li])CCC.C1(O[C:36]#[N:37])C=CC=CC=1.[OH-].[Na+]>O1CCCC1.CCCCCC>[CH2:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:36]#[N:37])=[CH:5][CH:6]=2)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Reactant: N#COc1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C#CC#N)cc2)CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A solution of 1.55 g of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene in 35 ml of absolute tetrahydrofuran was placed at about -45° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 8.8 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at the same temperature for a further 90 minutes, then cooled to -78° C. and treated with 0.79 ml of phenyl cyanate. The mixture was subsequently stirred at -78° C. for a further 3 hours, then poured into 50 ml of 1N sodium hydroxide and extracted three times with 50 ml of diethyl ether/petroleum ether (1:1) each time. The organic phases were washed with 50 ml of 1N sodium hydroxide and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (1.17 g) on silica gel with hexane followed by 3% ethyl acetate/petroleum ether gave 740 mg (69%) of p-[2-(trans-4-pentylcyclohexyl)ethyl]phenylpropiolonitrile as colourless crystals (purity 97.3%) which were recrystallized further from methanol; m.p. (C-N) 36.7° C., cl.p. (N-I) 105.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[Br-].[CH:17]1([Zn+])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1COCC1>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>[CH:17]1([C:2]2[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [Zn+]C1CCCCC1
Reactant: Cc1nc(C#Cc2cnc(Cl)nc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2cnc(C3CCCCC3)nc2)cs1
Temperature: 150 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine, 50 mg (0.043mmol, 0.05 eq) tetrakis(triphenylphosphine)palladium(0), and 2 mL of 0.5 M cyclohexylzinc bromide in THF (1 mmol, 1.1 eq) were combined. The reaction mixture was heated at 150° C. in the microwave for 5 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 40% EtOAc/Hexanes) gave 2-cyclohexyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine (L-001152744). LC-MS calculated for C16H17N3S 283, observed m/e 284.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC[O:25][C:26]1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl.[C]=[O:41].O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:26]([OH:25])=[O:41])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C]=O
Reactant: COC(=O)c1ccc(Br)cc1-c1ccccc1
Reactant: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cc1-c1ccccc1

Procedure:
A solution of 4-bromo-2-phenylbenzoic acid methyl ester (1.0 equivalent), Pd(OAc)2 (0.05 equivalent) and DPPE (1.0 equivalent) is heated in DMF to 65° C. under 4 atm. of carbon monoxide until TLC analysis indicates that the reaction is complete. The reaction mixture is poured into water and extracted with ethyl acetate which is dried and evaporated. The product is purified by chromatography on silica gel.